International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Moving to the Field: Plant Innate Immunity in Crop Protection

by Marcello Iriti and Elena M. Varoni

Int. J. Mol. Sci. 2017, 18(3), 640; https://doi.org/10.3390/ijms18030640 - 15 Mar 2017

Cited by 12 | Viewed by 4449

Abstract

In natural ecosystems, disease is not the rule, but a rare outcome in the spectrum of plant–microbe interaction, since plants have developed, during their evolutionary history, various defence strategies to face pathogens.[...] Full article

(This article belongs to the Special Issue Plant Innate Immunity)

Research

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8769 KiB

Open AccessArticle

Overexpression of Transforming Acidic Coiled Coil‑Containing Protein 3 Reflects Malignant Characteristics and Poor Prognosis of Glioma

by Ying Sun, Yu Tian, Guang-Zhi Wang, Shi-Hong Zhao, Bo Han, Yong-Li Li and Chuan-Lu Jiang

Int. J. Mol. Sci. 2017, 18(3), 235; https://doi.org/10.3390/ijms18030235 - 4 Mar 2017

Cited by 8 | Viewed by 5216

Abstract

Gliomas are malignant primary brain tumors with poor prognosis. Recently, research was indicative of a tight connection between tumor malignancy and genetic alterations. Here, we propose an oncogenic implication of transforming acidic coiled-coil-containing protein 3 (TACC3) in gliomas. By comprehensively analyzing the Chinese [...] Read more.

Gliomas are malignant primary brain tumors with poor prognosis. Recently, research was indicative of a tight connection between tumor malignancy and genetic alterations. Here, we propose an oncogenic implication of transforming acidic coiled-coil-containing protein 3 (TACC3) in gliomas. By comprehensively analyzing the Chinese glioma genome atlas (CGGA) and publicly available data, we demonstrated that TACC3 were overexpressed along with glioma grade and served as an independent negative prognostic biomarker for glioma patients. Functions’ annotations and gene sets’ enrichment analysis suggested that TACC3 may participate in cell cycle, DNA repair, epithelium-mesenchymal transition and other tumor-related biological processes and molecular pathways. Patients with high TACC3 expression showed CD133⁺ stem cell properties, glioma plasticity and shorter overall survival time under chemo-/radio-therapy. Additionally, a TACC3 associated the miRNA-mRNA network was constructed based on in silico prediction and expression pattern, which provide a foundation for further detection of TACC3-miRNA-mRNA axis function. Collectively, our observations identify TACC3 as an oncogene of tumor malignancy, as well as a prognostic and motoring biomarker for glioma patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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Open AccessArticle

A Systematic Study of Dysregulated MicroRNA in Type 2 Diabetes Mellitus

by Yuqing He, Yuanlin Ding, Biyu Liang, Juanjuan Lin, Taek-Kyun Kim, Haibing Yu, Hanwei Hang and Kai Wang

Int. J. Mol. Sci. 2017, 18(3), 456; https://doi.org/10.3390/ijms18030456 - 28 Feb 2017

Cited by 103 | Viewed by 7493

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that modulate the cellular transcriptome at the post-transcriptional level. miRNA plays important roles in different disease manifestation, including type 2 diabetes mellitus (T2DM). Many studies have characterized the changes of miRNAs in T2DM, a complex systematic disease; [...] Read more.

MicroRNAs (miRNAs) are small noncoding RNAs that modulate the cellular transcriptome at the post-transcriptional level. miRNA plays important roles in different disease manifestation, including type 2 diabetes mellitus (T2DM). Many studies have characterized the changes of miRNAs in T2DM, a complex systematic disease; however, few studies have integrated these findings and explored the functional effects of the dysregulated miRNAs identified. To investigate the involvement of miRNAs in T2DM, we obtained and analyzed all relevant studies published prior to 18 October 2016 from various literature databases. From 59 independent studies that met the inclusion criteria, we identified 158 dysregulated miRNAs in seven different major sample types. To understand the functional impact of these deregulated miRNAs, we performed targets prediction and pathway enrichment analysis. Results from our analysis suggested that the altered miRNAs are involved in the core processes associated with T2DM, such as carbohydrate and lipid metabolisms, insulin signaling pathway and the adipocytokine signaling pathway. This systematic survey of dysregulated miRNAs provides molecular insights on the effect of deregulated miRNAs in different tissues during the development of diabetes. Some of these miRNAs and their mRNA targets may have diagnostic and/or therapeutic utilities in T2DM. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessArticle

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

by Hong-Mei Yang, Chao-Yue Sun, Jia-Li Liang, Lie-Qiang Xu, Zhen-Biao Zhang, Dan-Dan Luo, Han-Bin Chen, Yong-Zhong Huang, Qi Wang, David Yue-Wei Lee, Jie Yuan and Yu-Cui Li

Int. J. Mol. Sci. 2017, 18(3), 465; https://doi.org/10.3390/ijms18030465 - 24 Feb 2017

Cited by 25 | Viewed by 6293

Abstract

Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible [...] Read more.

Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CI_SCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CI_SCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CI_SCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CI_SCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CI_SCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CI_SCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future. Full article

(This article belongs to the Special Issue Chemically-Induced DNA Damage, Mutagenesis, and Cancer)

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Open AccessArticle

Response of Gene Expression and Alternative Splicing to Distinct Growth Environments in Tomato

by Guixiang Wang, Lin Weng, Meng Li and Han Xiao

Int. J. Mol. Sci. 2017, 18(3), 475; https://doi.org/10.3390/ijms18030475 - 2 Mar 2017

Cited by 14 | Viewed by 5322

Abstract

Phenotypic plasticity is the phenomenon that one particular genotype produces different phenotypes under different environmental conditions, but its underlying molecular and genetic mechanisms are poorly understood. Plastic traits may be under the control of genes whose expression is modulated by environmental cues. In [...] Read more.

Phenotypic plasticity is the phenomenon that one particular genotype produces different phenotypes under different environmental conditions, but its underlying molecular and genetic mechanisms are poorly understood. Plastic traits may be under the control of genes whose expression is modulated by environmental cues. In this study, we investigated phenotypic plasticity in tomato (Solanum lycopersicum) and its ancestral species S. pimpinellifolium by comparing the global gene expression of young seedlings grown under two distinct growth conditions. Our results show that more than 7000 genes exhibited differential expression in response to environmental changes from phytotron to a plastic greenhouse, and 98 environmentally sensitive genes displayed the same patterns of expression response across the two tomato species. We also found that growth conditions had a remarkable impact on transcriptome complexity, attributable to alternative splicing (AS), in which 665 splice variants showed differential expression in response to the environmental changes. Moreover, more splice variants and AS events per gene were detected in plastic greenhouse-grown seedlings than their phytotron counterparts, and these seedlings also had higher percentages of intron retention events. The identification of the conserved environmentally-sensitive genes and the splice variants in this study will be useful for further analysis of gene regulation of environmental response in tomato and other crops. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Histone H3 Acetyl K9 and Histone H3 Tri Methyl K4 as Prognostic Markers for Patients with Cervical Cancer

by Susanne Beyer, Junyan Zhu, Doris Mayr, Christina Kuhn, Sandra Schulze, Simone Hofmann, Christian Dannecker, Udo Jeschke and Bernd P. Kost

Int. J. Mol. Sci. 2017, 18(3), 477; https://doi.org/10.3390/ijms18030477 - 23 Feb 2017

Cited by 45 | Viewed by 5644

Abstract

Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. [...] Read more.

Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. In this study, the expression of histone H3 acetyl K9, which is known to denote active regions at enhancers and promoters, and histone H3 tri methyl K4, which preferentially identifies active gene promoters, were examined as both show high metastatic potential. A panel of patients with cervical cancer was selected and the importance of the histone modifications concerning survival-time (overall survival and relapse-free survival) was analyzed in 250 cases. Histone H3 acetyl K9 staining was correlated with low grading, low FIGO (TNM classification and the International Federation of Gynecology and Obstetrics) status, negative N-status and low T-status in cervical cancer, showing a higher expression in adenocarcinoma than in squamous cell carcinoma. Cytoplasmic expression of histone H3 tri methyl K4 in a cervical cancer specimen was correlated with advanced T-status and poor prognosis. While cytoplasmic H3K4me3 expression seemed to be a marker of relapse-free survival, nuclear expression showed a correlation to poor prognosis in overall survival. Within this study, we analyzed the chemical modification of two histone proteins that are connected to active gene expression. Histone H3 acetyl K9 was found to be an independent marker of overall survival. Histone H3 tri methyl K4 was correlated with poor prognosis and it was found to be an independent marker of relapse-free survival. Therefore, we could show that chromatin remodeling plays an important role in cervical cancer biology. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Open AccessArticle

High-Throughput Screening Methodology to Identify Alpha-Synuclein Aggregation Inhibitors

by Jordi Pujols, Samuel Peña-Díaz, María Conde-Giménez, Francisca Pinheiro, Susanna Navarro, Javier Sancho and Salvador Ventura

Int. J. Mol. Sci. 2017, 18(3), 478; https://doi.org/10.3390/ijms18030478 - 2 Mar 2017

Cited by 56 | Viewed by 9697

Abstract

An increasing number of neurodegenerative diseases are being found to be associated with the abnormal accumulation of aggregated proteins in the brain. In Parkinson’s disease, this process involves the aggregation of alpha-synuclein (α-syn) into intraneuronal inclusions. Thus, compounds that inhibit α-syn aggregation represent [...] Read more.

An increasing number of neurodegenerative diseases are being found to be associated with the abnormal accumulation of aggregated proteins in the brain. In Parkinson’s disease, this process involves the aggregation of alpha-synuclein (α-syn) into intraneuronal inclusions. Thus, compounds that inhibit α-syn aggregation represent a promising therapeutic strategy as disease-modifying agents for neurodegeneration. The formation of α-syn amyloid aggregates can be reproduced in vitro by incubation of the recombinant protein. However, the in vitro aggregation of α-syn is exceedingly slow and highly irreproducible, therefore precluding fast high throughput anti-aggregation drug screening. Here, we present a simple and easy-to-implement in-plate method for screening large chemical libraries in the search for α-syn aggregation modulators. It allows us to monitor aggregation kinetics with high reproducibility, while being faster and requiring lower protein amounts than conventional aggregation assays. We illustrate how the approach enables the identification of strong aggregation inhibitors in a library of more than 14,000 compounds. Full article

(This article belongs to the Special Issue Protein Folding)

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Chemical Characterization of Enteromorpha prolifera Extract Obtained by Enzyme-Assisted Extraction and Its Influence on the Metabolic Activity of Caco-2

by Izabela Michalak, Agnieszka Dmytryk, Agnieszka Śmieszek and Krzysztof Marycz

Int. J. Mol. Sci. 2017, 18(3), 479; https://doi.org/10.3390/ijms18030479 - 23 Feb 2017

Cited by 13 | Viewed by 5134

Abstract

The green seaweed Enteromorpha prolifera was used as a feedstock for the production of enzymatic hydrolysate using cellulase. The selection of the conditions for enzymatic hydrolysis of the biomass was carried out for different enzyme doses and incubation periods. The obtained extract was [...] Read more.

The green seaweed Enteromorpha prolifera was used as a feedstock for the production of enzymatic hydrolysate using cellulase. The selection of the conditions for enzymatic hydrolysis of the biomass was carried out for different enzyme doses and incubation periods. The obtained extract was examined in terms of its multielemental composition, content of polyphenols and antibacterial properties (tested against Escherichia coli and Staphylococcus aureus). Additionally, its influence on the metabolic activity of human colon epithelial cells (Caco-2) was analyzed. The tested concentrations of extract using an in vitro model were 62.5, 125, 250, 500, 1000 and 2000 µg/mL. The hydrolysis yield in the most suitable experimental conditions (8-h process and 50 and 100 µL of cellulase) was 36%. Micro- and macroelements were poorly extracted from the algal biomass. Total phenolic content was 55 mg of gallic acid equivalent per 100 g of dry mass of extract. The cytotoxic effect of extracts, related to the inhibition of the metabolic activity of Caco-2, was noted only after 24 h. In turn, cultures of Caco-2 propagated with extracts for 72 h were characterized by significantly elevated metabolism (the concentration of extracts ranged from 62.5 to 1000 µg/mL, p < 0.05). Obtained results indicated the high biological activity of the prepared extracts; however, the observed effects did not occur in a dose-dependent manner. Full article

(This article belongs to the Special Issue Algae Based Bio-Renewable Energy for Sustainability)

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Intracellular Accumulation of Methylglyoxal by Glyoxalase 1 Knock Down Alters Collagen Homoeostasis in L6 Myoblasts

by Bernd Stratmann, Bernhard Goldstein, Paul J. Thornalley, Naila Rabbani and Diethelm Tschoepe

Int. J. Mol. Sci. 2017, 18(3), 480; https://doi.org/10.3390/ijms18030480 - 23 Feb 2017

Cited by 25 | Viewed by 6277

Abstract

Hyperglycemia results in accumulation of the reactive dicarbonyl methylglyoxal (MG). Methylglyoxal is detoxified by the glyoxalase system (glyoxalase 1 and 2). The influence of glyoxalase 1 knockdown on expression of collagens 1, 3, 4, and 5 in L6 myoblasts under hyperglycemic conditions was [...] Read more.

Hyperglycemia results in accumulation of the reactive dicarbonyl methylglyoxal (MG). Methylglyoxal is detoxified by the glyoxalase system (glyoxalase 1 and 2). The influence of glyoxalase 1 knockdown on expression of collagens 1, 3, 4, and 5 in L6 myoblasts under hyperglycemic conditions was investigated. Increased biosynthesis of collagens 1, 3, 4, and 5 was detected at mRNA-level following knockdown of glyoxalase 1 (GLO1). At the protein level a significant elevation of the concentration of collagen 1 and 4 was shown, whereas no increase of collagen 5 and a non-significant increase in collagen 3 were detectable. These results could partially explain MG-induced changes in the extracellular matrix (ECM) which account for increased fibrosis and impaired function in myocytes. The mechanisms by which reactive glucose metabolites influence ECM composition deserve further investigation. Full article

(This article belongs to the Special Issue Glyoxalase System)

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mRNA Quantification of NIPBL Isoforms A and B in Adult and Fetal Human Tissues, and a Potentially Pathological Variant Affecting Only Isoform A in Two Patients with Cornelia de Lange Syndrome

by Beatriz Puisac, María-Esperanza Teresa-Rodrigo, María Hernández-Marcos, Carolina Baquero-Montoya, María-Concepción Gil-Rodríguez, Torkild Visnes, Christopher Bot, Paulino Gómez-Puertas, Frank J. Kaiser, Feliciano J. Ramos, Lena Ström and Juan Pié

Int. J. Mol. Sci. 2017, 18(3), 481; https://doi.org/10.3390/ijms18030481 - 23 Feb 2017

Cited by 1 | Viewed by 5008

Abstract

Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by craniofacial dysmorphia, growth retardation, limb malformations, and intellectual disability. Approximately 60% of patients with CdLS carry a recognizable pathological variant in the NIPBL gene, of which two isoforms, A and B, [...] Read more.

Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by craniofacial dysmorphia, growth retardation, limb malformations, and intellectual disability. Approximately 60% of patients with CdLS carry a recognizable pathological variant in the NIPBL gene, of which two isoforms, A and B, have been identified, and which only differ in the C-terminal segment. In this work, we describe the distribution pattern of the isoforms A and B mRNAs in tissues of adult and fetal origin, by qPCR (quantitative polymerase chain reaction). Our results show a higher gene expression of the isoform A, even though both seem to have the same tissue distribution. Interestingly, the expression in fetal tissues is higher than that of adults, especially in brain and skeletal muscle. Curiously, the study of fibroblasts of two siblings with a mild CdLS phenotype and a pathological variant specific of the isoform A of NIPBL (c.8387A > G; P.Tyr2796Cys), showed a similar reduction in both isoforms, and a normal sensitivity to DNA damage. Overall, these results suggest that the position of the pathological variant at the 3´ end of the NIPBL gene affecting only isoform A, is likely to be the cause of the atypical mild phenotype of the two brothers. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing 2016)

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Open AccessArticle

L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites

by Jian Li, Rong Sun, Yuehong Wu, Mingzhu Song, Jia Li, Qianye Yang, Xiaoyi Chen, Jinku Bao and Qi Zhao

Int. J. Mol. Sci. 2017, 18(3), 482; https://doi.org/10.3390/ijms18030482 - 24 Feb 2017

Cited by 22 | Viewed by 7510

Abstract

The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the [...] Read more.

The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the first Food and Drug Administration (FDA) approved drug for the treatment of ALK-positive NSCLC. It is of great importance to understand how this extremely rare event occurred for the purpose of overcoming the acquired resistance of such inhibitors. In this study, we exploited molecular dynamics (MD) simulation to dissect the molecular mechanisms. Our MD results revealed that L1198F mutation of ALK resulted in the conformational change at the inhibitor site and altered the binding affinity of ALK to crizotinib and lorlatinib. L1198F mutation also affected the autoactivation of ALK as supported by the identification of His1124 and Tyr1278 as critical amino acids involved in ATP binding and phosphorylation. Our findings are valuable for designing more specific and potent inhibitors for the treatment of ALK-positive NSCLC and other types of cancer. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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Open AccessArticle

Dietary ω-3 Polyunsaturated Fatty Acids Inhibit Tumor Growth in Transgenic Apc^Min/+ Mice, Correlating with CB1 Receptor Up-Regulation

by Maria Notarnicola, Valeria Tutino, Valentina De Nunzio, Francesco Dituri, Maria Gabriella Caruso and Gianluigi Giannelli

Int. J. Mol. Sci. 2017, 18(3), 485; https://doi.org/10.3390/ijms18030485 - 24 Feb 2017

Cited by 24 | Viewed by 6191

Abstract

Mediterranean diet components, such as olive oil and ω-3 polyunsaturated fatty acids (ω-3 PUFAs), can arrest cell growth and promote cell apoptosis. Recently, olive oil has been demonstrated to modulate type-1 cannabinoid (CB1) receptor gene expression in both human colon cancer [...] Read more.

Mediterranean diet components, such as olive oil and ω-3 polyunsaturated fatty acids (ω-3 PUFAs), can arrest cell growth and promote cell apoptosis. Recently, olive oil has been demonstrated to modulate type-1 cannabinoid (CB1) receptor gene expression in both human colon cancer cells and rat colon. The aim of this study was to investigate a possible link between olive oil and ω-3 PUFAs effects and CB1 receptor expression in both intestinal and adipose tissue of Apc^Min/+ mice. To confirm the role for the CB1 receptor as a negative modulator of cell proliferation in human colon cancer, CB1 receptor gene expression was also detected in tumor tissue and in surrounding normal mucosa of patients with colorectal cancer (CRC). Dietary ω-3 PUFAs significantly inhibited intestinal polyp growth in mice, correlating with CB1 receptor gene and protein expression induction. CB1 receptor gene up-regulation was also detected in adipose tissue, suggesting a close communication between cancer cells and the surrounding environment. Tissue CB1 receptor induction was associated with a concurrent inactivation of the Wnt/β-catenin pathway. Moreover, there was a significant reduction in CB1 receptor gene expression levels in cancer tissue compared to normal surrounding mucosa of patients with CRC, confirming that in cancer the “protective” action of the CB1 receptor is lost. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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Open AccessArticle

NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia

by Seiji Kakiuchi, Yosuke Minami, Yoshiharu Miyata, Yu Mizutani, Hideaki Goto, Shinichiro Kawamoto, Kimikazu Yakushijin, Keiji Kurata, Hiroshi Matsuoka and Hironobu Minami

Int. J. Mol. Sci. 2017, 18(3), 486; https://doi.org/10.3390/ijms18030486 - 24 Feb 2017

Cited by 18 | Viewed by 5107

Abstract

Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in the maintenance of leukemic stem cell (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO), which regulates the Hh pathway. Treatment with PF-913 has shown promising results in [...] Read more.

Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in the maintenance of leukemic stem cell (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO), which regulates the Hh pathway. Treatment with PF-913 has shown promising results in an early phase study of acute myeloid leukemia (AML). However, a detailed mode of action for PF-913 and relevant biomarkers remain to be elucidated. In this study, we examined bone marrow samples derived from AML patients under PF-913 monotherapy. Gene set enrichment analysis (GSEA) revealed that PF-913 treatment affected the self-renewal signature and cell-cycle regulation associated with LSC-like properties. We then focused on the expression of a pluripotency factor, NANOG, because previous reports showed that a downstream effector in the Hh pathway, GLI, directly binds to the NANOG promoter and that the GLI-NANOG axis promotes stemness and growth in several cancers. In this study, we found that a change in NANOG transcripts was closely associated with GLI-target genes and NANOG transcripts can be a responsive biomarker during PF-913 therapy. Additionally, the treatment of AML with PF-913 holds promise, possibly through inducing quiescent leukemia stem cells toward cell cycling. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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Pancreatic Cancer-Induced Neutrophil Extracellular Traps: A Potential Contributor to Cancer-Associated Thrombosis

by Norbaini Abdol Razak, Omar Elaskalani and Pat Metharom

Int. J. Mol. Sci. 2017, 18(3), 487; https://doi.org/10.3390/ijms18030487 - 24 Feb 2017

Cited by 116 | Viewed by 10437

Abstract

Pancreatic cancer (PaCa) is a highly metastatic cancer, and patients are at high risk of developing venous thromboembolism (VTE). Neutrophil extracellular traps (NETs) have been associated with cancer metastasis and cancer-associated thrombosis, but the ability of cancer to stimulate NET release is not [...] Read more.

Pancreatic cancer (PaCa) is a highly metastatic cancer, and patients are at high risk of developing venous thromboembolism (VTE). Neutrophil extracellular traps (NETs) have been associated with cancer metastasis and cancer-associated thrombosis, but the ability of cancer to stimulate NET release is not known. The release of NETs has been shown to be a slow process and requires reactive oxygen species (ROS) production. Studies suggest that activated platelets are important mediators in the release. Here, we show that PaCa cells can stimulate the rapid release of NETs, independently of ROS production. We further assessed the role of platelets in PaCa-induced NETs and observed a trend of increased the NET release by PaCa-primed platelets. Additionally, NETs promoted thrombus formation under venous shear stress ex vivo. Taken together, our results suggest that PaCa-induced NETs can contribute to the high risk of venous thromboembolism development in PaCa patients, and reveal NETs as a potential therapeutic target. Full article

(This article belongs to the Special Issue Mechanisms of Platelet Thrombus Formation)

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Does the Prostate Health Index Depend on Tumor Volume?—A Study on 196 Patients after Radical Prostatectomy

by Frank Friedersdorff, Britt Groß, Andreas Maxeiner, Klaus Jung, Kurt Miller, Carsten Stephan, Jonas Busch and Ergin Kilic

Int. J. Mol. Sci. 2017, 18(3), 488; https://doi.org/10.3390/ijms18030488 - 24 Feb 2017

Cited by 20 | Viewed by 4578

Abstract

The Prostate Health Index (PHI) has been used increasingly in the context of prostate cancer (PCa) diagnostics since 2010. Previous studies have shown an association between PHI and a tumor volume of >0.5 cm³. The aim of this study was to [...] Read more.

The Prostate Health Index (PHI) has been used increasingly in the context of prostate cancer (PCa) diagnostics since 2010. Previous studies have shown an association between PHI and a tumor volume of >0.5 cm³. The aim of this study was to investigate the correlation between PHI and tumor volume as well as the Gleason score. A total of 196 selected patients with prostate cancer treated with radical prostatectomy at our institution were included in our study. The tumor volume was calculated and preoperative serum parameters total prostate-specific antigen (tPSA), free PSA (fPSA), [−2]proPSA, and PHI were evaluated. The association between the pathological findings such as Gleason score, pathological T-stage (pT stage), and tumor volume were evaluated. We further used logistic regression and Cox proportional hazard regression analyses for assessing the association between tumor volume and PHI and for predicting biochemical recurrence. With an area under the curve (AUC) of 0.79, PHI is the most accurate predictor of a tumor volumes >0.5 cm³. Moreover, PHI correlates significantly with the tumor volume (r = 0.588), which is significantly different (p = 0.008) from the correlation of the Gleason score with tumor volume (r = 0.385). PHI correlates more strongly with the tumor volume than does the Gleason score. Using PHI improves the prediction of larger tumor volume and subsequently clinically significant cancer. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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Permeation of Polymethoxyflavones into the Mouse Brain and Their Effect on MK-801-Induced Locomotive Hyperactivity

by Satoshi Okuyama, Kohei Miyazaki, Rie Yamada, Yoshiaki Amakura, Morio Yoshimura, Atsushi Sawamoto, Mitsunari Nakajima and Yoshiko Furukawa

Int. J. Mol. Sci. 2017, 18(3), 489; https://doi.org/10.3390/ijms18030489 - 24 Feb 2017

Cited by 20 | Viewed by 5046

Abstract

Accumulating data have indicated that citrus polymethoxyflavones (PMFs) have the ability to affect brain function. In the present study, we showed that 3,5,6,7,8,3′,4′-heptamethoxy- flavone (HMF) given intraperitoneally to mice was immediately detected in the brain and that the permeability of the brain tissues [...] Read more.

Accumulating data have indicated that citrus polymethoxyflavones (PMFs) have the ability to affect brain function. In the present study, we showed that 3,5,6,7,8,3′,4′-heptamethoxy- flavone (HMF) given intraperitoneally to mice was immediately detected in the brain and that the permeability of the brain tissues to it was significantly higher than that of other citrus PMFs (nobiletin, tangeretin, and natsudaidain). The permeation of these PMFs into the brain well correlated with their abilities to suppress MK-801-induced locomotive hyperactivity, suggesting that HMF had the ability to act directly in the brain. We also obtained data suggesting that the suppressive effect of HMF on MK-801-induced locomotive hyperactivity was mediated by phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food 2017)

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Hotspot Selective Preference of the Chimeric Sequences Formed in Multiple Displacement Amplification

by Jing Tu, Na Lu, Mengqin Duan, Mengting Huang, Liang Chen, Junji Li, Jing Guo and Zuhong Lu

Int. J. Mol. Sci. 2017, 18(3), 492; https://doi.org/10.3390/ijms18030492 - 24 Feb 2017

Cited by 7 | Viewed by 4595

Abstract

Multiple displacement amplification (MDA) is considered to be a conventional approach to comprehensive amplification from low input DNA. The chimeric reads generated in MDA lead to severe disruption in some studies, including those focusing on heterogeneity, structural variation, and genetic recombination. Meanwhile, the [...] Read more.

Multiple displacement amplification (MDA) is considered to be a conventional approach to comprehensive amplification from low input DNA. The chimeric reads generated in MDA lead to severe disruption in some studies, including those focusing on heterogeneity, structural variation, and genetic recombination. Meanwhile, the generation of by-products gives a new approach to gain insights into the reaction process of φ29 polymerase. Here, we analyzed 36.7 million chimeras and screened 196 billion chimeric hotspots in the human genome, as well as evaluating the hotspot selective preference of chimeras. No significant preference was captured in the distributions of chimeras and hotspots among chromosomes. Hotspots with overlaps for 12–13 nucleotides (nt) were most likely to be selected as templates in chimera generation. Meanwhile, a regularly selective preference was noticed in overlap GC content. The preferences in overlap length and GC content was shown to be pertinent to the sequence denaturation temperature, which pointed out the optimization direction for reducing chimeras. Distance preference between two segments of chimeras was 80–280 nt. The analysis is beneficial for reducing the chimeras in MDA, and the characterization of MDA chimeras is helpful in distinguishing MDA chimeras from chimeric sequences caused by disease. Full article

(This article belongs to the Special Issue Next-Generation Sequencing for Clinical Application)

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Short-Term Local Adaptation of Historical Common Bean (Phaseolus vulgaris L.) Varieties and Implications for In Situ Management of Bean Diversity

by Stephanie M. Klaedtke, Leonardo Caproni, Julia Klauck, Paul De la Grandville, Martin Dutartre, Pierre M. Stassart, Véronique Chable, Valeria Negri and Lorenzo Raggi

Int. J. Mol. Sci. 2017, 18(3), 493; https://doi.org/10.3390/ijms18030493 - 28 Feb 2017

Cited by 21 | Viewed by 6049

Abstract

Recognizing both the stakes of traditional European common bean diversity and the role farmers’ and gardeners’ networks play in maintaining this diversity, the present study examines the role that local adaptation plays for the management of common bean diversity in situ. To the [...] Read more.

Recognizing both the stakes of traditional European common bean diversity and the role farmers’ and gardeners’ networks play in maintaining this diversity, the present study examines the role that local adaptation plays for the management of common bean diversity in situ. To the purpose, four historical bean varieties and one modern control were multiplied on two organic farms for three growing seasons. The fifteen resulting populations, the initial ones and two populations of each variety obtained after the three years of multiplication, were then grown in a common garden. Twenty-two Simple Sequence Repeat (SSR) markers and 13 phenotypic traits were assessed. In total, 68.2% of tested markers were polymorphic and a total of 66 different alleles were identified. F_ST analysis showed that the genetic composition of two varieties multiplied in different environments changed. At the phenotypic level, differences were observed in flowering date and leaf length. Results indicate that three years of multiplication suffice for local adaptation to occur. The spatial dynamics of genetic and phenotypic bean diversity imply that the maintenance of diversity should be considered at the scale of the network, rather than individual farms and gardens. The microevolution of bean populations within networks of gardens and farms emerges as a research perspective. Full article

(This article belongs to the Special Issue Pulses)

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Distinct Antigen Delivery Systems Induce Dendritic Cells’ Divergent Transcriptional Response: New Insights from a Comparative and Reproducible Computational Analysis

by Valerio Costa, Dario Righelli, Francesco Russo, Piergiuseppe De Berardinis, Claudia Angelini and Luciana D’Apice

Int. J. Mol. Sci. 2017, 18(3), 494; https://doi.org/10.3390/ijms18030494 - 25 Feb 2017

Cited by 8 | Viewed by 4293

Abstract

Vaccination is the most successful and cost-effective method to prevent infectious diseases. However, many vaccine antigens have poor in vivo immunogenic potential and need adjuvants to enhance immune response. The application of systems biology to immunity and vaccinology has yielded crucial insights about [...] Read more.

Vaccination is the most successful and cost-effective method to prevent infectious diseases. However, many vaccine antigens have poor in vivo immunogenic potential and need adjuvants to enhance immune response. The application of systems biology to immunity and vaccinology has yielded crucial insights about how vaccines and adjuvants work. We have previously characterized two safe and powerful delivery systems derived from non-pathogenic prokaryotic organisms: E2 and fd filamentous bacteriophage systems. They elicit an in vivo immune response inducing CD8+ T-cell responses, even in absence of adjuvants or stimuli for dendritic cells’ maturation. Nonetheless, a systematic and comparative analysis of the complex gene expression network underlying such activation is missing. Therefore, we compared the transcriptomes of ex vivo isolated bone marrow-derived dendritic cells exposed to these antigen delivery systems. Significant differences emerged, especially for genes involved in innate immunity, co-stimulation, and cytokine production. Results indicate that E2 drives polarization toward the Th2 phenotype, mainly mediated by Irf4, Ccl17, and Ccr4 over-expression. Conversely, fd-scαDEC-205 triggers Th1 T cells’ polarization through the induction of Il12b, Il12rb, Il6, and other molecules involved in its signal transduction. The data analysis was performed using RNASeqGUI, hence, addressing the increasing need of transparency and reproducibility of computational analysis. Full article

(This article belongs to the Special Issue Transcriptome Profiling in Human Diseases)

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TNFα Increases RANKL Expression via PGE₂-Induced Activation of NFATc1

by Hyun-Jung Park, Kyunghwa Baek, Jeong-Hwa Baek and Hyung-Ryong Kim

Int. J. Mol. Sci. 2017, 18(3), 495; https://doi.org/10.3390/ijms18030495 - 24 Feb 2017

Cited by 22 | Viewed by 9812

Abstract

Tumor necrosis factor α (TNFα) is known to upregulate the expression of receptor activator of NF-κB ligand (RANKL). We investigated the role of the calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway in TNFα-induced RANKL expression in C2C12 and primary cultured [...] Read more.

Tumor necrosis factor α (TNFα) is known to upregulate the expression of receptor activator of NF-κB ligand (RANKL). We investigated the role of the calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway in TNFα-induced RANKL expression in C2C12 and primary cultured mouse calvarial cells. TNFα-induced RANKL expression was blocked by the calcineurin/NFAT pathway inhibitors. TNFα increased NFAT transcriptional activity and subsequent RANKL promoter binding. Mutations in the NFAT-binding element (MT(N)) suppressed TNFα-induced RANKL promoter activity. TNFα increased prostaglandin E2 (PGE₂) production, which in turn enhanced NFAT transcriptional activity and binding to the RANKL promoter. MT(N) suppressed PGE₂-induced RANKL promoter activity. TNFα and PGE₂ increased the expression of RANKL, NFAT cytoplasmic-1 (NFATc1), cAMP response element-binding protein (CREB), and cyclooxygenase 2 (COX2); which increment was suppressed by indomethacin, a COX inhibitor. Mutations in the CRE-like element blocked PGE₂-induced RANKL promoter activity. PGE₂ induced the binding of CREB to the RANKL promoter, whereas TNFα increased the binding of both CREB and NFATc1 to this promoter through a process blocked by indomethacin. The PGE₂ receptor antagonists AH6809 and AH23848 blocked TNFα-induced expression of RANKL, NFATc1, and CREB; transcriptional activity of NFAT; and binding of NFATc1 or CREB to the RANKL promoter. These results suggest that TNFα-induced RANKL expression depends on PGE₂ production and subsequent transcriptional activation/enhanced binding of NFATc1 and CREB to the RANKL promoter. Full article

(This article belongs to the Section Biochemistry)

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De Novo Transcriptome Analysis of Plant Pathogenic Fungus Myrothecium roridum and Identification of Genes Associated with Trichothecene Mycotoxin Biosynthesis

by Wei Ye, Taomei Liu, Muzi Zhu, Weimin Zhang, Haohua Li, Zilei Huang and Saini Li

Int. J. Mol. Sci. 2017, 18(3), 497; https://doi.org/10.3390/ijms18030497 - 25 Feb 2017

Cited by 10 | Viewed by 4780

Abstract

Myrothecium roridum is a plant pathogenic fungus that infects different crops and decreases the yield of economical crops, including soybean, cotton, corn, pepper, and tomato. Until now, the pathogenic mechanism of M. roridum has remained unclear. Different types of trichothecene mycotoxins were isolated [...] Read more.

Myrothecium roridum is a plant pathogenic fungus that infects different crops and decreases the yield of economical crops, including soybean, cotton, corn, pepper, and tomato. Until now, the pathogenic mechanism of M. roridum has remained unclear. Different types of trichothecene mycotoxins were isolated from M. roridum, and trichothecene was considered as a plant pathogenic factor of M. roridum. In this study, the transcriptome of M. roridum in different incubation durations was sequenced using an Illumina Hiseq 2000. A total of 35,485 transcripts and 25,996 unigenes for M. roridum were obtained from 8.0 Gb clean reads. The protein–protein network of the M. roridum transcriptome indicated that the mitogen-activated protein kinases signal pathway also played an important role in the pathogenicity of M. roridum. The genes related to trichothecene biosynthesis were annotated. The expression levels of these genes were also predicted and validated through quantitative real-time polymerase chain reaction. Tri5 gene encoding trichodiene synthase was cloned and expressed, and the purified trichodiene synthase was able to catalyze farnesyl pyrophosphate into different kinds of sesquiterpenoids.Tri4 and Tri11 genes were expressed in Escherichia coli, and their corresponding enzymatic properties were characterized. The phylogenetic tree of trichodiene synthase showed a great discrepancy between the trichodiene synthase from M. roridum and other species. Our study on the genes related to trichothecene biosynthesis establishes a foundation for the M. roridum hazard prevention, thus improving the yields of economical crops. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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The Acute Inflammatory Response to Absorbed Collagen Sponge Is Not Enhanced by BMP-2

by Hairong Huang, Daniel Wismeijer, Ernst B. Hunziker and Gang Wu

Int. J. Mol. Sci. 2017, 18(3), 498; https://doi.org/10.3390/ijms18030498 - 25 Feb 2017

Cited by 12 | Viewed by 5309

Abstract

Absorbed collagen sponge (ACS)/bone morphogenetic protein-2 (BMP-2) are widely used in clinical practise for bone regeneration. However, the application of this product was found to be associated with a significant pro-inflammatory response, particularly in the early phase after implantation. This study aimed to [...] Read more.

Absorbed collagen sponge (ACS)/bone morphogenetic protein-2 (BMP-2) are widely used in clinical practise for bone regeneration. However, the application of this product was found to be associated with a significant pro-inflammatory response, particularly in the early phase after implantation. This study aimed to clarify if the pro-inflammatory activities, associated with BMP-2 added to ACS, were related to the physical state of the carrier itself, i.e., a wet or a highly dehydrated state of the ACS, to the local degree of vascularisation and/or to local biomechanical factors. ACS (0.8 cm diameter)/BMP-2 were implanted subcutaneously in the back of 12 eight-week-old Sprague Dawley rats. Two days after surgery, the implanted materials were retrieved and analysed histologically and histomorphometrically. The acute inflammatory response following implantation of ACS was dependent of neither the presence or absence of BMP-2 nor the degree of vascularization in the surrounding tissue nor the hydration state (wet versus dry) of the ACS material at the time of implantation. Differential micro biomechanical factors operating at the implantation site appeared to have an influence on the thickness of inflammation. We conclude that the degree of the early inflammatory response of the ACS/BMP-2 may be associated with the physical and chemical properties of the carrier material itself. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration)

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The Expression and Functional Significance of Runx2 in Hepatocellular Carcinoma: Its Role in Vasculogenic Mimicry and Epithelial–Mesenchymal Transition

by Zi Cao, Baocun Sun, Xiulan Zhao, Yanhui Zhang, Qiang Gu, Xiaohui Liang, Xueyi Dong and Nan Zhao

Int. J. Mol. Sci. 2017, 18(3), 500; https://doi.org/10.3390/ijms18030500 - 27 Feb 2017

Cited by 41 | Viewed by 6151 | Correction

Abstract

The transcription factor Runx2 has been reported to promote epithelial-mesenchymal transition (EMT) in many tumors. Vasculogenic mimicry (VM) is described as the mimicry of endothelial cells by tumor cells to form microvascular tubes in aggressive tumors. Galectin-3 has been reported to regulate cell [...] Read more.

The transcription factor Runx2 has been reported to promote epithelial-mesenchymal transition (EMT) in many tumors. Vasculogenic mimicry (VM) is described as the mimicry of endothelial cells by tumor cells to form microvascular tubes in aggressive tumors. Galectin-3 has been reported to regulate cell invasion, migration, and VM formation; it could be regulated by Runx2. However, the relationship between Runx2, Galectin-3, EMT, and VM has not been studied in hepatocellular carcinoma (HCC). We examined Runx2 expression in 89 human HCC samples and found Runx2 expression was associated with VM. Clinical-pathological data analysis revealed that Runx2 expression was associated with a shorter survival period. Overexpression of Runx2 promoted EMT and enhanced cell migration, invasion, and VM formation in HepG2 cells. Conversely, the downregulation of Runx2 inhibited EMT and reduced cell invasion, migration, and VM formation in SMMC7721. Galectin-3 expression declined following the downregulation of Runx2 in HepG2 cells, and increased in SMMC7721 cells after Runx2 knockdown. We consistently demonstrated that the downregulation of LGALS3 in HepG2-Runx2 cells reduced cell migration; invasion and VM formation; while upregulation of LGALS3 in SMMC7721-shRunx2 cells enhanced cell migration, invasion, and VM formation. The results indicate that Runx2 could promote EMT and VM formation in HCC and Galectin-3 might have some function in this process. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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Bioavailability Comparison of Nine Bioselenocompounds In Vitro and In Vivo

by Kazuaki Takahashi, Noriyuki Suzuki and Yasumitsu Ogra

Int. J. Mol. Sci. 2017, 18(3), 506; https://doi.org/10.3390/ijms18030506 - 26 Feb 2017

Cited by 65 | Viewed by 5997

Abstract

Selenium (Se) shows biologically ambivalent characteristics in animals. It is an essential element but becomes severely toxic when the amount ingested exceeds the adequate intake level. Its biological, nutritional, and toxicological effects are strongly dependent on its chemical form. In this study, we [...] Read more.

Selenium (Se) shows biologically ambivalent characteristics in animals. It is an essential element but becomes severely toxic when the amount ingested exceeds the adequate intake level. Its biological, nutritional, and toxicological effects are strongly dependent on its chemical form. In this study, we evaluated the toxicity and bioavailability of nine naturally occurring Se compounds, or the so-called bioselenocompounds, in vivo and in vitro. Selenite and selenocystine showed higher toxicity than the other bioselenocompounds in vitro. In an in vitro membrane permeability study using Caco-2 cells, selenomethionine and Se-methylselenocysteine were more efficiently transported than the other bioselenocompounds. The effect of bioselenocompounds on nutritional availability was quantitatively determined from the recovery of serum selenoproteins in Se-deficient rats by speciation analysis. In contrast to the in vitro study, there were no significant differences in the assimilation of Se into serum selenoproteins among the bioselenocompounds, including selenoamino acids, selenosugar, and inorganic Se species, such as selenite, selenate, and selenocyanate, except trimethylselenonium ion. These results indicate that animals can equally assimilate both inorganic and organic naturally occurring selenocompounds except trimethylselenonium ion, which is the urinary metabolite of excess Se. We confirmed that the bioselenocompounds except trimethylselenonium ion had equivalent nutritional availabilities. Full article

(This article belongs to the Special Issue Metallomics: Recent Advances in Analytical and Biological Sciences of Semimetals/Metalloids)

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Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin

by Aaron J. Brown, Krishna Mohan Sepuru and Krishna Rajarathnam

Int. J. Mol. Sci. 2017, 18(3), 508; https://doi.org/10.3390/ijms18030508 - 26 Feb 2017

Cited by 23 | Viewed by 6130

Abstract

CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 μM) and CXCR2 binding (~10 nM) constants indicate that [...] Read more.

CXCL7, a chemokine highly expressed in platelets, orchestrates neutrophil recruitment during thrombosis and related pathophysiological processes by interacting with CXCR2 receptor and sulfated glycosaminoglycans (GAG). CXCL7 exists as monomers and dimers, and dimerization (~50 μM) and CXCR2 binding (~10 nM) constants indicate that CXCL7 is a potent agonist as a monomer. Currently, nothing is known regarding the structural basis by which receptor and GAG interactions mediate CXCL7 function. Using solution nuclear magnetic resonance (NMR) spectroscopy, we characterized the binding of CXCL7 monomer to the CXCR2 N-terminal domain (CXCR2Nd) that constitutes a critical docking site and to GAG heparin. We found that CXCR2Nd binds a hydrophobic groove and that ionic interactions also play a role in mediating binding. Heparin binds a set of contiguous basic residues indicating a prominent role for ionic interactions. Modeling studies reveal that the binding interface is dynamic and that GAG adopts different binding geometries. Most importantly, several residues involved in GAG binding are also involved in receptor interactions, suggesting that GAG-bound monomer cannot activate the receptor. Further, this is the first study that describes the structural basis of receptor and GAG interactions of a native monomer of the neutrophil-activating chemokine family. Full article

(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)

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A Comparison of the Effects of Benzalkonium Chloride on Ocular Surfaces between C57BL/6 and BALB/c Mice

by Qian Yang, Yafang Zhang, Xiuping Liu, Nan Wang, Zhenyu Song and Kaili Wu

Int. J. Mol. Sci. 2017, 18(3), 509; https://doi.org/10.3390/ijms18030509 - 26 Feb 2017

Cited by 39 | Viewed by 9055

Abstract

Models of benzalkonium chloride (BAC)-induced ocular disruption have been created and are widely used in various animals. This study aimed to compare the effects of BAC on the ocular surfaces of C57BL/6 and BALB/c mice. C57BL/6 and BALB/c mice were treated separately with [...] Read more.

Models of benzalkonium chloride (BAC)-induced ocular disruption have been created and are widely used in various animals. This study aimed to compare the effects of BAC on the ocular surfaces of C57BL/6 and BALB/c mice. C57BL/6 and BALB/c mice were treated separately with BAC eye-drops at different concentrations. Eyes were evaluated by scoring epithelial disruption, corneal opacity and neovascularization in vivo, and by histological assays with hematoxylin/eosin (H/E) and periodic acid-Schiff stainings and by determining the expression of inflammatory factors in vitro on Days 7 and 14. The in vivo corneal epithelial disruption, corneal edema/opacity and neovascularization, which were in accordance with the results of the H/E staining and peaked at Day 7, were observed in a dose-dependent manner in the BAC-treated mice, with more severe signs in the C57BL/6 mice than the BALB/c mice. The loss of conjunctival goblet cells in the conjunctivas and the increasing expression of monocyte chemoattractant protein 1 (MCP-1), growth-regulated protein alpha (GROa) and macrophage inflammatory protein-1 alpha (MIP-1a) in the corneas were found in a dose-dependent manner in both strains of mice. Topical application of BAC can dramatically disrupt the ocular surfaces of C57BL/6 and BALB/c mice, and the disruptions were much more severe in the C57BL/6 mice that received high doses of BAC. Full article

(This article belongs to the Special Issue Dry Eye and Ocular Surface Disorders)

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Peroxisome Proliferator-Activated Receptor α Activation Is Not the Main Contributor to Teratogenesis Elicited by Polar Compounds from Oxidized Frying Oil

by Yu-Shun Lin, Ting-Yi Lin, Jia-Jiuan Wu, Hsien-Tsung Yao, Sunny Li-Yun Chang and Pei-Min Chao

Int. J. Mol. Sci. 2017, 18(3), 510; https://doi.org/10.3390/ijms18030510 - 27 Feb 2017

Cited by 10 | Viewed by 3994

Abstract

We previously reported that polar compounds (PO) in cooking oil are teratogenic and perturbed retinoic acid (RA) metabolism. Considering PO as a potent peroxisome proliferator-activated receptor α (PPARα) activator, this study aimed to investigate the role of PPARα in PO-induced teratogenesis and disturbance [...] Read more.

We previously reported that polar compounds (PO) in cooking oil are teratogenic and perturbed retinoic acid (RA) metabolism. Considering PO as a potent peroxisome proliferator-activated receptor α (PPARα) activator, this study aimed to investigate the role of PPARα in PO-induced teratogenesis and disturbance of RA metabolism. Female PPARα knockout or wild type mice were mated with males of the same genotype. Pregnant mice were fed a diet containing 10% fat from either fresh oil (FO) or PO from gestational day1 to day18, and killed at day18. The PO diet significantly increased the incidence of teratogenesis and fetal RA concentrations, regardless of genotype. Though PPARα deficiency disturbed maternal RA homeostasis, itself did not contribute to teratogenesis as long as FO diet was given. The mRNA profile of genes involved in RA metabolism was differentially affected by diet or genotype in mothers and fetuses. Based on hepatic mRNA levels of genes involved in xenobiotic metabolism, we inferred that PO not only activated PPARα, but also altered transactivity of other xenobiotic receptors. We concluded that PO-induced fetal anomalies and RA accumulation were independent of PPARα activation. Full article

(This article belongs to the Section Molecular Toxicology)

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Transplantation of Embryonic Spinal Cord Derived Cells Helps to Prevent Muscle Atrophy after Peripheral Nerve Injury

by Carolin Ruven, Wen Li, Heng Li, Wai-Man Wong and Wutian Wu

Int. J. Mol. Sci. 2017, 18(3), 511; https://doi.org/10.3390/ijms18030511 - 27 Feb 2017

Cited by 15 | Viewed by 6706

Abstract

Injuries to peripheral nerves are frequent in serious traumas and spinal cord injuries. In addition to surgical approaches, other interventions, such as cell transplantation, should be considered to keep the muscles in good condition until the axons regenerate. In this study, E14.5 rat [...] Read more.

Injuries to peripheral nerves are frequent in serious traumas and spinal cord injuries. In addition to surgical approaches, other interventions, such as cell transplantation, should be considered to keep the muscles in good condition until the axons regenerate. In this study, E14.5 rat embryonic spinal cord fetal cells and cultured neural progenitor cells from different spinal cord segments were injected into transected musculocutaneous nerve of 200–300 g female Sprague Dawley (SD) rats, and atrophy in biceps brachii was assessed. Both kinds of cells were able to survive, extend their axons towards the muscle and form neuromuscular junctions that were functional in electromyographic studies. As a result, muscle endplates were preserved and atrophy was reduced. Furthermore, we observed that the fetal cells had a better effect in reducing the muscle atrophy compared to the pure neural progenitor cells, whereas lumbar cells were more beneficial compared to thoracic and cervical cells. In addition, fetal lumbar cells were used to supplement six weeks delayed surgical repair after the nerve transection. Cell transplantation helped to preserve the muscle endplates, which in turn lead to earlier functional recovery seen in behavioral test and electromyography. In conclusion, we were able to show that embryonic spinal cord derived cells, especially the lumbar fetal cells, are beneficial in the treatment of peripheral nerve injuries due to their ability to prevent the muscle atrophy. Full article

(This article belongs to the Special Issue Peripheral Nerve Regeneration: From Bench to Bedside)

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Tentative Characterization of Polyphenolic Compounds in the Male Flowers of Phoenix dactylifera by Liquid Chromatography Coupled with Mass Spectrometry and DFT

by Ridha Ben Said, Arafa I. Hamed, Usam A. Mahalel, Abdullah Sulaiman Al-Ayed, Mariusz Kowalczyk, Jaroslaw Moldoch, Wieslaw Oleszek and Anna Stochmal

Int. J. Mol. Sci. 2017, 18(3), 512; https://doi.org/10.3390/ijms18030512 - 2 Mar 2017

Cited by 124 | Viewed by 9615

Abstract

Phoenix dacylifera is an ancient palm species rich in (poly)phenols. These phenolic compounds were tentatively identified by using liquid chromatography coupled with ion spray mass spectrometry in tandem mode (LC/MS/MS) with negative ion detection. Negative identification of the compounds was based on their [...] Read more.

Phoenix dacylifera is an ancient palm species rich in (poly)phenols. These phenolic compounds were tentatively identified by using liquid chromatography coupled with ion spray mass spectrometry in tandem mode (LC/MS/MS) with negative ion detection. Negative identification of the compounds was based on their retention times and mass spectra in full scan mode (MS), and in different MS/MS modes. For the first time, complete hypothesis, and routs for both p-coumaroylshikimic acids (CoSA) and caffeoylshikimic acids (CSA) were suggested and confirmed by Density Fonctional Theory (DFT) study. Notably, of the 53 compounds characterized, 19 hydroxycinnamates derivatives were tentativelycharacterized in male flowers of date palm and 15 of them were recorded for the first time. In addition, five organic acids, six B-type proanthocyanidins, two anthocyanidin and 21 flavonoid derivatives have been tentatively characterized. Identification of B-type proanthocyanidins were based on the diagnostic ions resulting from heterocyclic ring fission (HRF) and retro-Diels-Alder (RDA) reaction of flavan-3-ol provided information on the hydroxylation pattern and the type of inter-flavan bond proanthocyanidins. The sequence of proanthocyanidins was detected through ions extracted from quinone methide (QM) cleavage of the inter-flavan bond. Full article

(This article belongs to the Special Issue Anthocyanins)

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Tumor Cell-Derived Microvesicles Induced Not Epithelial-Mesenchymal Transition but Apoptosis in Human Proximal Tubular (HK-2) Cells: Implications for Renal Impairment in Multiple Myeloma

by Aiqi Zhao, Fancong Kong, Chun-Jie Liu, Guoxin Yan, Fei Gao, Hao Guo, An-Yuan Guo, Zhichao Chen and Qiubai Li

Int. J. Mol. Sci. 2017, 18(3), 513; https://doi.org/10.3390/ijms18030513 - 27 Feb 2017

Cited by 7 | Viewed by 5493

Abstract

Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in [...] Read more.

Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in RI of MM. We found that MM-MVs significantly inhibited viability and induced apoptosis, but not epithelial-mesenchymal transition in human kidney-2 (HK-2), a human renal tubular epithelial cell line. The protein levels of cleaved caspase-3, 8, and 9, and E-cadherin, were increased, but vementin levels were decreased in the HK-2 cells treated with MM-MVs. Through a comparative sequencing and analysis of RNA content between the MVs from RPMI8226 MM cells (RPMI8226-MVs) and K562 leukemia cells, RPMI8226-MVs were enriched with more renal-pathogenic miRNAs, in which the selective miRNAs may participate in the up-regulation of the levels of cleaved caspase-3. Furthermore, the levels of CD138+ circulating MVs (cirMVs) in the peripheral blood were positively correlated with the severity of RI in newly-diagnosed MM. Our study supports MM-MVs representing a previously undescribed factor and playing a potential role in the development of RI of MM patients, and sheds light on the potential application of CD138+ cirMV counts in precise diagnosis of RI in MM and exploring MM-MVs as a therapeutic target. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

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Derivate Isocorydine (d-ICD) Suppresses Migration and Invasion of Hepatocellular Carcinoma Cell by Downregulating ITGA1 Expression

by Xiaoqin Liu, Hua Tian, Hong Li, Chao Ge, Fangyu Zhao, Ming Yao and Jinjun Li

Int. J. Mol. Sci. 2017, 18(3), 514; https://doi.org/10.3390/ijms18030514 - 27 Feb 2017

Cited by 25 | Viewed by 5805

Abstract

In our previous studies, we found that isocorydine (ICD) could be a potential antitumor agent in hepatocellular carcinoma (HCC). Derivate isocorydine (d-ICD), a more effective antitumor agent, has been demonstrated to inhibit proliferation and drug resistance in HCC. In order to investigate the [...] Read more.

In our previous studies, we found that isocorydine (ICD) could be a potential antitumor agent in hepatocellular carcinoma (HCC). Derivate isocorydine (d-ICD), a more effective antitumor agent, has been demonstrated to inhibit proliferation and drug resistance in HCC. In order to investigate the potential role of d-ICD on HCC cell migration and its possible mechanism, wound healing assay, trans-well invasion assay, western blot analysis, and qRT-PCR were performed to study the migration and invasion ability of HCC cells as well as relevant molecular alteration following d-ICD treatment. Results indicated that the migration and invasion ability of HCC cells were suppressed when cultured with d-ICD. Meanwhile, the expression level of ITGA1 was markedly reduced. Furthermore, we found that ITGA1 promotes HCC cell migration and invasion in vitro, and that ITGA1 can partly reverse the effect of d-ICD-induced migration and invasion suppression in HCC cells. In addition, dual luciferase reporter assay and chromatin immunoprecipitation assay were used to study the expression regulation of ITGA1, and found that E2F1 directly upregulates ITGA1 expression and d-ICD inhibits E2F1 expression. Taken together, these results reveal that d-ICD inhibits HCC cell migration and invasion may partly by downregulating E2F1/ITGA1 expression. Full article

(This article belongs to the Section Biochemistry)

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Association of Hormone Receptor Expression with Survival in Ovarian Endometrioid Carcinoma: Biological Validation and Clinical Implications

by Peter Rambau, Linda E. Kelemen, Helen Steed, May Lynn Quan, Prafull Ghatage and Martin Köbel

Int. J. Mol. Sci. 2017, 18(3), 515; https://doi.org/10.3390/ijms18030515 - 27 Feb 2017

Cited by 34 | Viewed by 5010

Abstract

This paper aims to validate whether hormone receptor expression is associated with longer survival among women diagnosed with ovarian endometrioid carcinoma (EC), and whether it identifies patients with stage IC/II tumors with excellent outcome that could be spared from toxic chemotherapy. Expression of [...] Read more.

This paper aims to validate whether hormone receptor expression is associated with longer survival among women diagnosed with ovarian endometrioid carcinoma (EC), and whether it identifies patients with stage IC/II tumors with excellent outcome that could be spared from toxic chemotherapy. Expression of estrogen receptor (ER) and progesterone receptor (PR) was assessed on 182 EC samples represented on tissue microarrays using the Alberta Ovarian Tumor Type (AOVT) cohort. Statistical analyses were performed to test for associations with ovarian cancer specific survival. ER or PR expression was present in 87.3% and 86.7% of cases, respectively, with co-expression present in 83.0%. Expression of each of the hormonal receptors was significantly higher in low-grade tumors and tumors with squamous differentiation. Expression of ER (Hazard Ratio (HR) = 0.18, 95% confidence interval 0.08–0.42, p = 0.0002) and of PR (HR = 0.22, 95% confidence interval 0.10–0.53, p = 0.0011) were significantly associated with longer ovarian cancer specific survival adjusted for age, grade, treatment center, stage, and residual disease. However, the five-year ovarian cancer specific survival among women with ER positive stage IC/II EC was 89.0% (standard error 3.3%) and for PR positive tumors 89.9% (standard error 3.2%), robustly below the 95% threshold where adjuvant therapy could be avoided. We validated the association of hormone receptor expression with ovarian cancer specific survival independent of standard predictors in an independent sample set of EC. The high ER/PR co-expression frequency and the survival difference support further testing of the efficacy of hormonal therapy in hormone receptor-positive ovarian EC. The clinical utility to identify a group of women diagnosed with EC at stage IC/II that could be spared from adjuvant therapy is limited. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies)

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Synthesis of Five Known Brassinosteroid Analogs from Hyodeoxycholic Acid and Their Activities as Plant-Growth Regulators

by María Isabel Duran, Cesar González, Alison Acosta, Andrés F. Olea, Katy Díaz and Luis Espinoza

Int. J. Mol. Sci. 2017, 18(3), 516; https://doi.org/10.3390/ijms18030516 - 8 Mar 2017

Cited by 18 | Viewed by 5540

Abstract

Brassinosteroids (BRs) are plant hormones that promote growth in different plant organs and tissues. The structural requirements that these compounds should possess to exhibit this biological activity have been studied. In this work, a series of known BR analogs 5–15, [...] Read more.

Brassinosteroids (BRs) are plant hormones that promote growth in different plant organs and tissues. The structural requirements that these compounds should possess to exhibit this biological activity have been studied. In this work, a series of known BR analogs 5–15, were synthesized starting from hyodeoxycholic acid 4, and maintaining the alkyl side chain as cholic acid or its methyl ester. The growth-promoting effects of brassinolide (1) and synthesized analogs were evaluated by using the rice lamina inclination assay at concentrations ranging from 1 × 10⁻⁸–1 × 10⁻⁶ M. Our results indicate that in this concentration range the induced bending angle of rice seedlings increases with increasing concentration of BRs. Analysis of the activities, determined at the lowest tested concentration, in terms of BR structures shows that the 2α,3α-dihydroxy-7-oxa-6-ketone moiety existing in brassinolide is required for the plant growing activity of these compounds, as it has been proposed by some structure-activity relationship studies. The effect of compound 8 on cell elongation was assessed by microscopy analysis, and the results indicate that the growth-promoting effect of analog 8 is mainly due to cell elongation of the adaxial sides, instead of an increase on cell number. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Investigating Autism-Related Symptoms in Children with Prader-Willi Syndrome: A Case Study

by Jeffrey A. Bennett, Sandra Hodgetts, Michelle L. Mackenzie, Andrea M. Haqq and Lonnie Zwaigenbaum

Int. J. Mol. Sci. 2017, 18(3), 517; https://doi.org/10.3390/ijms18030517 - 28 Feb 2017

Cited by 8 | Viewed by 5375

Abstract

Prader-Willi syndrome (PWS), a rare genetic disorder caused by the lack of expression of paternal genes from chromosome 15q11-13, has been investigated for autism spectrum disorder (ASD) symptomatology in various studies. However, previous findings have been variable, and no studies investigating ASD symptomatology [...] Read more.

Prader-Willi syndrome (PWS), a rare genetic disorder caused by the lack of expression of paternal genes from chromosome 15q11-13, has been investigated for autism spectrum disorder (ASD) symptomatology in various studies. However, previous findings have been variable, and no studies investigating ASD symptomatology in PWS have exclusively studied children. We aimed to characterize social communication functioning and other ASD-related symptoms in children with PWS, and assessed agreement across measures and rates of ASD diagnosis. Measures included the Autism Diagnostic Observation Schedule-2 (ADOS-2), the Social Communication Questionnaire (SCQ), Social Responsiveness Scale-2 (SRS-2), Social Skills Improvement System-Rating Scales (SSIS-RS), and the Vineland Adaptive Behavioral Scales-II (VABS-II). General adaptive and intellectual skills were also assessed. Clinical best estimate (CBE) diagnosis was determined by an experienced developmental pediatrician, based on history and review of all available study measures, and taking into account overall developmental level. Participants included 10 children with PWS, aged 3 to 12 years. Three of the 10 children were male and genetic subtypes were two deletion (DEL) and eight uniparental disomy (UPD) (with a total of 6 female UPD cases). Although 8 of the 10 children exceeded cut-offs on at least one of the ASD assessments, agreement between parent questionnaires (SCQ, SRS-2, SSIS-RS) and observational assessment (ADOS-2) was very poor. None of the children were assigned a CBE diagnosis of ASD, with the caveat that the risk may have been lower because of the predominance of girls in the sample. The lack of agreement between the assessments emphasizes the complexity of interpreting ASD symptom measures in children with PWS. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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Tenebrio molitor Larvae Inhibit Adipogenesis through AMPK and MAPKs Signaling in 3T3-L1 Adipocytes and Obesity in High-Fat Diet-Induced Obese Mice

by Minchul Seo, Tae-Won Goo, Mi Yeon Chung, Minhee Baek, Jae-Sam Hwang, Mi-Ae Kim and Eun-Young Yun

Int. J. Mol. Sci. 2017, 18(3), 518; https://doi.org/10.3390/ijms18030518 - 28 Feb 2017

Cited by 70 | Viewed by 6906

Abstract

Despite the increasing interest in insect-based bioactive products, the biological activities of these products are rarely studied adequately. Larvae of Tenebrio molitor, the yellow mealworm, have been eaten as a traditional food and provide many health benefits. Therefore, we hypothesized that T. [...] Read more.

Despite the increasing interest in insect-based bioactive products, the biological activities of these products are rarely studied adequately. Larvae of Tenebrio molitor, the yellow mealworm, have been eaten as a traditional food and provide many health benefits. Therefore, we hypothesized that T. molitor larvae might influence adipogenesis and obesity-related disorders. In the present study, we investigated the anti-adipogenic and antiobesity effects of T. molitor larvae in vitro and in vivo. The lipid accumulation and triglyceride content in mature adipocytes was reduced significantly (up to 90%) upon exposure to an ethanol extract of T. molitor larvae, without a reduction in cell viability. Exposure also resulted in key adipogenic and lipogenic transcription factors. Additionally, in adipogenic differentiation medium the extract induced phosphorylation of adenosine monophosphate (AMP)-activated protein kinase and mitogen-activated protein kinases. Daily oral administration of T. molitor larvae powder to obese mice fed high-fat diet attenuated body weight gain. We also found that the powder efficiently reduced hepatic steatosis as well as aspartate and alanine transaminase enzyme levels in mice fed a high-fat diet. Our results suggest that T. molitor larvae extract has an antiobesity effect when administered as a food supplement and has potential as a therapeutic agent for obesity. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Comparative Genomics of the Aeromonadaceae Core Oligosaccharide Biosynthetic Regions

by Gabriel Forn-Cuní, Susana Merino and Juan M. Tomás

Int. J. Mol. Sci. 2017, 18(3), 519; https://doi.org/10.3390/ijms18030519 - 28 Feb 2017

Cited by 3 | Viewed by 4202

Abstract

Lipopolysaccharides (LPSs) are an integral part of the Gram-negative outer membrane, playing important organizational and structural roles and taking part in the bacterial infection process. In Aeromonas hydrophila, piscicola, and salmonicida, three different genomic regions taking part in the LPS [...] Read more.

Lipopolysaccharides (LPSs) are an integral part of the Gram-negative outer membrane, playing important organizational and structural roles and taking part in the bacterial infection process. In Aeromonas hydrophila, piscicola, and salmonicida, three different genomic regions taking part in the LPS core oligosaccharide (Core-OS) assembly have been identified, although the characterization of these clusters in most aeromonad species is still lacking. Here, we analyse the conservation of these LPS biosynthesis gene clusters in the all the 170 currently public Aeromonas genomes, including 30 different species, and characterise the structure of a putative common inner Core-OS in the Aeromonadaceae family. We describe three new genomic organizations for the inner Core-OS genomic regions, which were more evolutionary conserved than the outer Core-OS regions, which presented remarkable variability. We report how the degree of conservation of the genes from the inner and outer Core-OS may be indicative of the taxonomic relationship between Aeromonas species. Full article

(This article belongs to the Special Issue Lipopolysaccharides (LPSs))

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Ovalbumin with Glycated Carboxyl Groups Shows Membrane-Damaging Activity

by Ching-Chia Tang, Yi-Jun Shi, Ying-Jung Chen and Long-Sen Chang

Int. J. Mol. Sci. 2017, 18(3), 520; https://doi.org/10.3390/ijms18030520 - 28 Feb 2017

Cited by 10 | Viewed by 4028

Abstract

The aim of the present study was to investigate whether glycated ovalbumin (OVA) showed novel activity at the lipid-water interface. Mannosylated OVA (Man-OVA) was prepared by modification of the carboxyl groups with p-aminophenyl α-dextro (d)-mannopyranoside. An increase in the number [...] Read more.

The aim of the present study was to investigate whether glycated ovalbumin (OVA) showed novel activity at the lipid-water interface. Mannosylated OVA (Man-OVA) was prepared by modification of the carboxyl groups with p-aminophenyl α-dextro (d)-mannopyranoside. An increase in the number of modified carboxyl groups increased the membrane-damaging activity of Man-OVA on cell membrane-mimicking vesicles, whereas OVA did not induce membrane permeability in the tested phospholipid vesicles. The glycation of carboxyl groups caused a notable change in the gross conformation of OVA. Moreover, owing to their spatial positions, the Trp residues in Man-OVA were more exposed, unlike those in OVA. Fluorescence quenching studies suggested that the Trp residues in Man-OVA were located on the interface binds with the lipid vesicles, and their microenvironment was abundant in positively charged residues. Although OVA and Man-OVA showed a similar binding affinity for lipid vesicles, the lipid-interacting feature of Man-OVA was distinct from that of OVA. Chemical modification studies revealed that Lys and Arg residues, but not Trp residues, played a crucial role in the membrane-damaging activity of Man-OVA. Taken together, our data suggest that glycation of carboxyl groups causes changes in the structural properties and membrane-interacting features of OVA, generating OVA with membrane-perturbing activities at the lipid-water interface. Full article

(This article belongs to the Section Biochemistry)

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Omalizumab Is Equally Effective in Persistent Allergic Oral Corticosteroid-Dependent Asthma Caused by Either Seasonal or Perennial Allergens: A Pilot Study

by Christian Domingo, Xavier Pomares, Albert Navarro, Núria Rudi, Ana Sogo, Ignacio Dávila and Rosa M. Mirapeix

Int. J. Mol. Sci. 2017, 18(3), 521; https://doi.org/10.3390/ijms18030521 - 28 Feb 2017

Cited by 15 | Viewed by 4851

Abstract

Omalizumab is marketed for chronic severe asthma patients who are allergic to perennial allergens. Our purpose was to investigate whether omalizumab is also effective in persistent severe asthma due to seasonal allergens. Thirty patients with oral corticosteroid-dependent asthma were treated with Omalizumab according [...] Read more.

Omalizumab is marketed for chronic severe asthma patients who are allergic to perennial allergens. Our purpose was to investigate whether omalizumab is also effective in persistent severe asthma due to seasonal allergens. Thirty patients with oral corticosteroid-dependent asthma were treated with Omalizumab according to the dosing table. For each patient with asthma due to seasonal allergens, we recruited the next two consecutive patients with asthma due to perennial allergens. The dose of oral methyl prednisolone (MP) was tapered at a rate of 2 mg every two weeks after the start of treatment with omalizumab depending on tolerance. At each monthly visit, a forced spirometry and fractional exhaled nitric oxide (FeNO) measurement were performed and the accumulated monthly MP dose was calculated. At entry, there were no differences between groups in terms of gender, body mass index or obesity, year exacerbation rate, monthly dose of MP, FeNO and blood immunoglobuline E (IgE) values, or spirometry (perennial: FVC: 76%; FEV₁: 62%; seasonal: FVC: 79%; FEV₁: 70%). The follow-up lasted 76 weeks. One patient in each group was considered a non-responder. Spirometry did not worsen in either group. There was a significant intragroup reduction in annual exacerbation rate and MP consumption but no differences were detected in the intergroup comparison. Omalizumab offered the same clinical benefits in the two cohorts regardless of whether the asthma was caused by a seasonal or a perennial allergen. These results strongly suggest that allergens are the trigger in chronic asthma but that it is the persistent exposure to IgE that causes the chronicity. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

by Zhi Xu, Chun-Ming Huang, Zhe Shao, Xiao-Ping Zhao, Meng Wang, Ting-Lin Yan, Xiao-Cheng Zhou, Er-Hui Jiang, Ke Liu and Zheng-Jun Shang

Int. J. Mol. Sci. 2017, 18(3), 524; https://doi.org/10.3390/ijms18030524 - 1 Mar 2017

Cited by 21 | Viewed by 6330

Abstract

Chewing areca nut is closely associated with oral squamous cell carcinoma (OSCC). The current study aimed to investigate potential associations between areca nut extract (ANE) and cisplatin toxicity in OSCC cells. OSCC cells (Cal-27 and Scc-9) viability and apoptosis were analyzed after treatment [...] Read more.

Chewing areca nut is closely associated with oral squamous cell carcinoma (OSCC). The current study aimed to investigate potential associations between areca nut extract (ANE) and cisplatin toxicity in OSCC cells. OSCC cells (Cal-27 and Scc-9) viability and apoptosis were analyzed after treatment with ANE and/or cisplatin. The expressions of proteins associated with autophagy and the AMP-activated protein kinase (AMPK) signaling network were evaluated. We revealed that advanced OSCC patients with areca nut chewing habits presented higher LC3 expression and poorer prognosis. Reactive oxygen species (ROS)-mediated autophagy was induced after pro-longed treatment of ANE (six days, 3 μg). Cisplatin toxicity (IC₅₀, 48 h) was decreased in OSCC cells after ANE treatment (six days, 3 μg). Cisplatin toxicity could be enhanced by reversed autophagy by pretreatment of 3-methyladenine (3-MA), N-acetyl-l-cysteine (NAC), or Compound C. Cleaved-Poly-(ADP-ribose) polymerase (cl-PARP) and cleaved-caspase 3 (cl-caspase 3) were downregulated in ANE-treated OSCC cells in the presence of cisplatin, which was also reversed by NAC and Compound C. Collectively, ANE could decrease cisplatin toxicity of OSCC by inducing autophagy, which involves the ROS and AMPK/mTOR signaling pathway. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Retinoic Acid Negatively Impacts Proliferation and MC_TC Specific Attributes of Human Skin Derived Mast Cells, but Reinforces Allergic Stimulability

by Magda Babina, Metin Artuc, Sven Guhl and Torsten Zuberbier

Int. J. Mol. Sci. 2017, 18(3), 525; https://doi.org/10.3390/ijms18030525 - 28 Feb 2017

Cited by 28 | Viewed by 6584

Abstract

The Vitamin-A-metabolite retinoic acid (RA) acts as a master regulator of cellular programs. Mast cells (MCs) are primary effector cells of type-I-allergic reactions. We recently uncovered that human cutaneous MCs are enriched with RA network components over other skin cells. Yet, direct experimental [...] Read more.

The Vitamin-A-metabolite retinoic acid (RA) acts as a master regulator of cellular programs. Mast cells (MCs) are primary effector cells of type-I-allergic reactions. We recently uncovered that human cutaneous MCs are enriched with RA network components over other skin cells. Yet, direct experimental evidence on the significance of the RA-MC axis is limited. Here, skin-derived cultured MCs were exposed to RA for seven days and investigated by flow-cytometry (BrdU incorporation, Annexin/PI, FcεRI), microscopy, RT-qPCR, histamine quantitation, protease activity, and degranulation assays. We found that while MC size and granularity remained unchanged, RA potently interfered with MC proliferation. Conversely, a modest survival-promoting effect from RA was noted. The granule constituents, histamine and tryptase, remained unaffected, while RA had a striking impact on MC chymase, whose expression dropped by gene and by peptidase activity. The newly uncovered MRGPRX2 performed similarly to chymase. Intriguingly, RA fostered allergic MC degranulation, in a way completely uncoupled from FcεRI expression, but it simultaneously restricted MRGPRX2-triggered histamine release in agreement with the reduced receptor expression. Vitamin-A-derived hormones thus re-shape skin-derived MCs numerically, phenotypically, and functionally. A general theme emerges, implying RA to skew MCs towards processes associated with (allergic) inflammation, while driving them away from the skin-imprinted MC_TC (“MCs containing tryptase and chymase”) signature (chymase, MRGPRX2). Collectively, MCs are substantial targets of the skin retinoid network. Full article

(This article belongs to the Special Issue Translational Molecular Medicine & Molecular Drug Discovery)

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GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia

by Naveen S. Khanzada, Merlin G. Butler and Ann M. Manzardo

Int. J. Mol. Sci. 2017, 18(3), 527; https://doi.org/10.3390/ijms18030527 - 28 Feb 2017

Cited by 64 | Viewed by 9111

Abstract

Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway [...] Read more.

Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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The CpG Dinucleotide Adjacent to a κB Site Affects NF-κB Function through Its Methylation

by Tao Wang, Jinge Li, Ke Ding, Li Zhang, Qiuru Che, Xiuming Sun, Yumeng Dai, Wei Sun, Meiying Bao, Xiaochun Wang, Liquan Yang and Zhiwei Li

Int. J. Mol. Sci. 2017, 18(3), 528; https://doi.org/10.3390/ijms18030528 - 1 Mar 2017

Cited by 12 | Viewed by 4180

Abstract

NF-κB is an important transcription factor that plays critical roles in cell survival, proliferation, inflammation, and cancers. Although the majority of experimentally identified functional NF-κB binding sites (κB sites) match the consensus sequence, there are plenty of non-functional NF-κB consensus sequences in the [...] Read more.

NF-κB is an important transcription factor that plays critical roles in cell survival, proliferation, inflammation, and cancers. Although the majority of experimentally identified functional NF-κB binding sites (κB sites) match the consensus sequence, there are plenty of non-functional NF-κB consensus sequences in the genome. We analyzed the surrounding sequences of the known κB sites that perfectly match the GGGRNNYYCC consensus sequence and identified the nucleotide at the -1 position of κB sites as a key contributor to the binding of the κB sites by NF-κB. We demonstrated that a cytosine at the -1 position of a κB site (-1C) could be methylated, which thereafter impaired NF-κB binding and/or function. In addition, all -1C κB sites are located in CpG islands and are conserved during evolution only when they are within CpG islands. Interestingly, when there are multiple NF-κB binding possibilities, methylation of -1C might increase NF-κB binding. Our finding suggests that a single nucleotide at the -1 position of a κB site could be a critical factor in NF-κB functioning and could be exploited as an additional manner to regulate the expression of NF-κB target genes. Full article

(This article belongs to the Section Biochemistry)

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RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells

by Shubham Dayal, Jun Zhou, Praveen Manivannan, Mohammad Adnan Siddiqui, Omaima Farid Ahmad, Matthew Clark, Sahezeel Awadia, Rafael Garcia-Mata, Lirim Shemshedini and Krishnamurthy Malathi

Int. J. Mol. Sci. 2017, 18(3), 529; https://doi.org/10.3390/ijms18030529 - 1 Mar 2017

Cited by 18 | Viewed by 6270

Abstract

The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, [...] Read more.

The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. Here, we demonstrate a role of RNase L as a suppressor of androgen receptor (AR) signaling, cell migration and matrix metalloproteinase activity. Using RNase L mutants, we show that its nucleolytic activity is dispensable for both AR signaling and migration. The most prevalent HPC1-associated mutations in RNase L, R462Q and E265X, enhance AR signaling and cell migration. RNase L negatively regulates cell migration and attachment on various extracellular matrices. We demonstrate that RNase L knockdown cells promote increased cell surface expression of integrin β1 which activates Focal Adhesion Kinase-Sarcoma (FAK-Src) pathway and Ras-related C3 botulinum toxin substrate 1-guanosine triphosphatase (Rac1-GTPase) activity to increase cell migration. Activity of matrix metalloproteinase (MMP)-2 and -9 is significantly increased in cells where RNase L levels are ablated. We show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-responsive genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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The Role of the Melatoninergic System in Light-Entrained Behavior of Mice

by Martina Pfeffer, Horst-Werner Korf and Helmut Wicht

Int. J. Mol. Sci. 2017, 18(3), 530; https://doi.org/10.3390/ijms18030530 - 1 Mar 2017

Cited by 22 | Viewed by 4864

Abstract

The role of endogenous melatonin for the control of the circadian system under entrained conditions and for the determination of the chronotype is still poorly understood. Mice with deletions in the melatoninergic system (melatonin deficiency or the lack of melatonin receptors, respectively) do [...] Read more.

The role of endogenous melatonin for the control of the circadian system under entrained conditions and for the determination of the chronotype is still poorly understood. Mice with deletions in the melatoninergic system (melatonin deficiency or the lack of melatonin receptors, respectively) do not display any obvious defects in either their spontaneous (circadian) or entrained (diurnal) rhythmic behavior. However, there are effects that can be detected by analyzing the periodicity of the locomotor behaviors in some detail. We found that melatonin-deficient mice (C57Bl), as well as melatonin-proficient C3H mice that lack the melatonin receptors (MT) 1 and 2 (C3H MT1,2 KO), reproduce their diurnal locomotor rhythms with significantly less accuracy than mice with an intact melatoninergic system. However, their respective chronotypes remained unaltered. These results show that one function of the endogenous melatoninergic system might be to stabilize internal rhythms under conditions of a steady entrainment, while it has no effects on the chronotype. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity

by Rachel A. Murphy, Reagan M. Stafford, Brooke A. Petrasovits, Megann A. Boone and Monica A. Valentovic

Int. J. Mol. Sci. 2017, 18(3), 531; https://doi.org/10.3390/ijms18030531 - 1 Mar 2017

Cited by 15 | Viewed by 5929

Abstract

Tenofovir (TFV) is an antiviral drug approved for treating Human Immunodeficiency Virus (HIV) and Hepatitis B. TFV is administered orally as the prodrug tenofovir disoproxil fumarate (TDF) which then is deesterified to the active drug TFV. TFV induces nephrotoxicity characterized by renal failure [...] Read more.

Tenofovir (TFV) is an antiviral drug approved for treating Human Immunodeficiency Virus (HIV) and Hepatitis B. TFV is administered orally as the prodrug tenofovir disoproxil fumarate (TDF) which then is deesterified to the active drug TFV. TFV induces nephrotoxicity characterized by renal failure and Fanconi Syndrome. The mechanism of this toxicity remains unknown due to limited experimental models. This study investigated the cellular mechanism of cytotoxicity using a human renal proximal tubular epithelial cell line (HK-2). HK-2 cells were grown for 48 h followed by 24 to 72 h exposure to 0–28.8 μM TFV or vehicle, phosphate buffered saline (PBS). MTT (MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) and Trypan blue indicated that TFV diminished cell viability at 24–72 h. TFV decreased ATP levels at 72 h when compared to vehicle, reflecting mitochondrial dysfunction. TFV increased the oxidative stress biomarkers of protein carbonylation and 4-hydroxynonenol (4-HNE) adduct formation. Tumor necrosis factor alpha (TNFα) was released into the media following exposure to 14.5 and 28.8 μM TFV. Caspase 3 and 9 cleavage was induced by TFV compared to vehicle at 72 h. These studies show that HK-2 cells are a sensitive model for TFV cytotoxicity and suggest that mitochondrial stress and apoptosis occur in HK-2 cells treated with TFV. Full article

(This article belongs to the Special Issue Nephrotoxicity)

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Vanillin Suppresses Cell Motility by Inhibiting STAT3-Mediated HIF-1α mRNA Expression in Malignant Melanoma Cells

by Eun-Ji Park, Yoon-Mi Lee, Taek-In Oh, Byeong Mo Kim, Beong-Ou Lim and Ji-Hong Lim

Int. J. Mol. Sci. 2017, 18(3), 532; https://doi.org/10.3390/ijms18030532 - 1 Mar 2017

Cited by 32 | Viewed by 5520

Abstract

Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of [...] Read more.

Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of hypoxia-inducible factor-1α (HIF-1α) in A2058 and A375 human malignant melanoma cells. Immunoblotting and quantitative real time (RT)-PCR analysis revealed that vanillin down-regulates HIF-1α protein accumulation and the transcripts of HIF-1α target genes related to cancer metastasis including fibronectin 1 (FN1), lysyl oxidase-like 2 (LOXL2), and urokinase plasminogen activator receptor (uPAR). It was also found that vanillin significantly suppresses HIF-1α mRNA expression and de novo HIF-1α protein synthesis. To understand the suppressive mechanism of vanillin on HIF-1α expression, chromatin immunoprecipitation was performed. Consequently, it was found that vanillin causes inhibition of promoter occupancy by signal transducer and activator of transcription 3 (STAT3), but not nuclear factor-κB (NF-κB), on HIF1A. Furthermore, an in vitro migration assay revealed that the motility of melanoma cells stimulated by hypoxia was attenuated by vanillin treatment. In conclusion, we demonstrate that vanillin might be a potential anti-metastatic agent that suppresses metastatic gene expression and migration activity under hypoxia via the STAT3-HIF-1α signaling pathway. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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Effects of Ranibizumab and Aflibercept on Human Müller Cells and Photoreceptors under Stress Conditions

by Weiyong Shen, Belinda Yau, So-Ra Lee, Ling Zhu, Michelle Yam and Mark C. Gillies

Int. J. Mol. Sci. 2017, 18(3), 533; https://doi.org/10.3390/ijms18030533 - 1 Mar 2017

Cited by 7 | Viewed by 5511

Abstract

Anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of retinal vascular diseases. However, constitutive VEGF also acts as a trophic factor on retinal nonvascular cells. We have studied the effects of aflibercept and ranibizumab on human Müller cells and photoreceptors exposed [...] Read more.

Anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of retinal vascular diseases. However, constitutive VEGF also acts as a trophic factor on retinal nonvascular cells. We have studied the effects of aflibercept and ranibizumab on human Müller cells and photoreceptors exposed to starvation media containing various concentrations of glucose, with or without CoCl2-induced hypoxia. Cell survival was assessed by calcein-AM cell viability assays. Expression of heat shock proteins (Hsp) and redox proteins thioredoxin 1 and 2 (TRX1, TRX2) was studied by Western blots. The production of neurotrophic factors in Müller cells and interphotoreceptor retinoid-binding protein (IRBP) in photoreceptors was measured by enzymelinked immunosorbent assays. Aflibercept and ranibizumab did not affect the viability of both types of cells. Neither aflibercept nor ranibizumab affected the production of neurotrophic factors or expression of Hsp60 and Hsp90 in Müller cells. However, aflibercept but not ranibizumab affected the expression of Hsp60, Hsp9, TRX1 and TRX2 in photoreceptors. Aflibercept and ranibizumab both inhibited the production of IRBP in photoreceptors, aflibercept more so than ranibizumab. Our data indicates that the potential influence of aflibercept and ranibizumab on photoreceptors should be specifically monitored in clinical studies. Full article

(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)

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The PRR11-SKA2 Bidirectional Transcription Unit Is Negatively Regulated by p53 through NF-Y in Lung Cancer Cells

by Yitao Wang, Huali Weng, Ying Zhang, Yinjiang Long, Yi Li, Yulong Niu, Fangzhou Song and Youquan Bu

Int. J. Mol. Sci. 2017, 18(3), 534; https://doi.org/10.3390/ijms18030534 - 1 Mar 2017

Cited by 27 | Viewed by 5405

Abstract

We previously identified proline-rich protein 11 (PRR11) as a novel cancer-related gene that is implicated in the regulation of cell cycle and tumorigenesis. Our recent study demonstrated that PRR11 and its adjacent gene, kinetochore associated 2 (SKA2), constitute a [...] Read more.

We previously identified proline-rich protein 11 (PRR11) as a novel cancer-related gene that is implicated in the regulation of cell cycle and tumorigenesis. Our recent study demonstrated that PRR11 and its adjacent gene, kinetochore associated 2 (SKA2), constitute a classic head-to-head gene pair that is coordinately regulated by nuclear factor Y (NF-Y). In the present study, we further show that the PRR11-SKA2 bidirectional transcription unit is an indirect target of the tumor suppressor p53. A luciferase reporter assay revealed that overexpression of wild type p53, but not mutant p53, significantly represses the basal activity and NF-Y mediated transactivation of the PRR11-SKA2 bidirectional promoter. Deletion and mutation analysis of the PRR11-SKA2 promoter revealed that p53-mediated PRR11-SKA2 repression is dependent on the presence of functional NF-Y binding sites. Furthermore, a co-immunoprecipitation assay revealed that p53 associates with NF-Y in lung cancer cells, and a chromatin immunoprecipitation assay showed that p53 represses PRR11-SKA2 transcription by reducing the binding amount of NF-Y in the PRR11-SKA2 promoter region. Consistently, the ability of p53 to downregulate PRR11-SKA2 transcription was significantly attenuated upon siRNA-mediated depletion of nuclear factor Y subunit beta (NF-YB). Notably, lung cancer patients with lower expression of either PRR11 or SKA2 along with wild type p53 exhibited the best overall survival compared with others with p53 mutation and/or higher expression of either PRR11 or SKA2. Taken together, our results demonstrate that p53 negatively regulates the expression of the PRR11-SKA2 bidirectional transcription unit through NF-Y, suggesting that the inability to repress the PRR11-SKA2 bidirectional transcription unit after loss of p53 might contribute to tumorigenesis. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers

by Angeline S. Andrew, John A. Baron, Lynn F. Butterly, Arief A. Suriawinata, Gregory J. Tsongalis, Christina M. Robinson and Christopher I. Amos

Int. J. Mol. Sci. 2017, 18(3), 535; https://doi.org/10.3390/ijms18030535 - 2 Mar 2017

Cited by 123 | Viewed by 4060

Abstract

Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%–35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our [...] Read more.

Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%–35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our objective was to identify the CpG loci that are persistently hyper-methylated during serrated carcinogenesis, from the early SSA/P lesion through the later cancer phases of neoplasia development. We queried the loci hyper-methylated in serrated cancers within our rightsided SSA/Ps from the New Hampshire Colonoscopy Registry, using the Illumina Infinium Human Methylation 450 k panel to comprehensively assess the DNA methylation status. We identified CpG loci and regions consistently hyper-methylated throughout the serrated carcinogenesis spectrum, in both our SSA/P specimens and in serrated cancers. Hyper-methylated CpG loci included the known the tumor suppressor gene RET (p = 5.72 x 10−10), as well as loci in differentially methylated regions for GSG1L, MIR4493, NTNG1, MCIDAS, ZNF568, and RERG. The hyper-methylated loci that we identified help characterize the biology of SSA/P development, and could be useful as therapeutic targets, or for future identification of patients who may benefit from shorter surveillance intervals. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

by Qianyin Li, Zhenglan Huang, Miao Gao, Weixi Cao, Qin Xiao, Hongwei Luo and Wenli Feng

Int. J. Mol. Sci. 2017, 18(3), 537; https://doi.org/10.3390/ijms18030537 - 2 Mar 2017

Cited by 7 | Viewed by 10808

Abstract

The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which [...] Read more.

The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag), HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance. Full article

(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)

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Evaluating Complex Mixtures in the Zebrafish Embryo by Reconstituting Field Water Samples: A Metal Pollution Case Study

by Ellen D. G. Michiels, Lucia Vergauwen, An Hagenaars, Erik Fransen, Stefan Van Dongen, Steven J. Van Cruchten, Lieven Bervoets and Dries Knapen

Int. J. Mol. Sci. 2017, 18(3), 539; https://doi.org/10.3390/ijms18030539 - 2 Mar 2017

Cited by 14 | Viewed by 5285

Abstract

Accurately assessing the toxicity of complex, environmentally relevant mixtures remains an important challenge in ecotoxicology. The goal was to identify biological effects after exposure to environmental water samples and to determine whether the observed effects could be explained by the waterborne metal mixture [...] Read more.

Accurately assessing the toxicity of complex, environmentally relevant mixtures remains an important challenge in ecotoxicology. The goal was to identify biological effects after exposure to environmental water samples and to determine whether the observed effects could be explained by the waterborne metal mixture found in the samples. Zebrafish embryos were exposed to water samples of five different sites originating from two Flemish (Mol and Olen, Belgium) metal contaminated streams: “Scheppelijke Nete” (SN) and “Kneutersloop” (K), and a ditch (D), which is the contamination source of SN. Trace metal concentrations, and Na, K, Mg and Ca concentrations were measured using ICP-MS and were used to reconstitute site-specific water samples. We assessed whether the effects that were observed after exposure to environmental samples could be explained by metal mixture toxicity under standardized laboratory conditions. Exposure to “D” or “reconstituted D” water caused 100% mortality. SN and reconstituted SN water caused similar effects on hatching, swim bladder inflation, growth and swimming activity. A canonical discriminant analysis confirmed a high similarity between both exposure scenarios, indicating that the observed toxicity was indeed primarily caused by metals. The applied workflow could be a valuable approach to evaluate mixture toxicity that limits time and costs while maintaining biological relevance. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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Expression of Autophagy-Related Proteins in Different Types of Thyroid Cancer

by Hye Min Kim, Eun-Sol Kim and Ja Seung Koo

Int. J. Mol. Sci. 2017, 18(3), 540; https://doi.org/10.3390/ijms18030540 - 2 Mar 2017

Cited by 24 | Viewed by 5525

Abstract

Thyroid cancer is common type of malignant tumor in humans, and the autophagy status of such tumors may vary according to subtype. This study aimed to investigate the expression and implications of the major autophagy-related molecules light chain (LC) 3A, LC3B, p62, and [...] Read more.

Thyroid cancer is common type of malignant tumor in humans, and the autophagy status of such tumors may vary according to subtype. This study aimed to investigate the expression and implications of the major autophagy-related molecules light chain (LC) 3A, LC3B, p62, and BNIP-3 in human thyroid carcinoma. Tissue microarrays were constructed from 555 thyroid cancers (papillary thyroid carcinoma (PTC): 342; follicular carcinoma (FC): 112; medullary carcinoma (MC): 70; poorly differentiated carcinoma (PDC): 23; and anaplastic carcinoma (AC): 8) and 152 follicular adenomas (FAs). Expression of autophagy-related molecules (LC3A, LC3B, p62, and BNIP-3) was detected immunohistochemically, and the results were analyzed via comparison with clinicopathologic parameters. Tumoral LC3A and LC3B expressions were the highest in MC (p < 0.001), whereas stromal LC3A expression was higher in AC and PTC (p < 0.001). BNIP-3 expression was absent in MC and AC (p = 0.013). Tumoral LC3A, LC3B, and p62 expressions were higher in conventional type PTC, compared with those in the follicular variant. PTC with the BRAF V600E mutation exhibited higher expression of all autophagy-related proteins relative to PTC without this mutation (p < 0.05). BNIP-3 negativity was associated with capsular invasion in FC (p = 0.001), and p62 negativity was associated with lymph node metastasis in MC (p = 0.006). In a univariate analysis, LC3B negativity was associated with shorter disease-free survival in PTC with the BRAF V600E mutation (p = 0.024). We conclude that the expression of autophagy-related proteins differs according to thyroid cancer subtype. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Pre-Exposure Gene Expression in Baboons with and without Pancytopenia after Radiation Exposure

by Matthias Port, Francis Hérodin, Marco Valente, Michel Drouet, Reinhard Ullmann, Matthäus Majewski and Michael Abend

Int. J. Mol. Sci. 2017, 18(3), 541; https://doi.org/10.3390/ijms18030541 - 2 Mar 2017

Cited by 19 | Viewed by 4934

Abstract

Radiosensitivity differs in humans and likely among primates. The reasons are not well known. We examined pre-exposure gene expression in baboons (n = 17) who developed haematologic acute radiation syndrome (HARS) without pancytopenia or a more aggravated HARS with pancytopenia after irradiation. [...] Read more.

Radiosensitivity differs in humans and likely among primates. The reasons are not well known. We examined pre-exposure gene expression in baboons (n = 17) who developed haematologic acute radiation syndrome (HARS) without pancytopenia or a more aggravated HARS with pancytopenia after irradiation. We evaluated gene expression in a two stage study design where stage I comprised a whole genome screen for messenger RNAs (mRNA) (microarray) and detection of 667 microRNAs (miRNA) (real-time quantitative polymerase chain reaction (qRT-PCR) platform). Twenty candidate mRNAs and nine miRNAs were selected for validation in stage II (qRT-PCR). None of the mRNA species could be confirmed during the validation step, but six of the nine selected candidate miRNA remained significantly different during validation. In particular, miR-425-5p (receiver operating characteristic = 0.98; p = 0.0003) showed nearly complete discrimination between HARS groups with and without pancytopenia. Target gene searches of miR-425-5p identified new potential mRNAs and associated biological processes linked with radiosensitivity. We found that one miRNA species examined in pre-exposure blood samples was associated with HARS characterized by pancytopenia and identified new target mRNAs that might reflect differences in radiosensitivity of irradiated normal tissue. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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Simplifying the Preparation of Pollen Grains for MALDI-TOF MS Classification

by Franziska Lauer, Stephan Seifert, Janina Kneipp and Steffen M. Weidner

Int. J. Mol. Sci. 2017, 18(3), 543; https://doi.org/10.3390/ijms18030543 - 3 Mar 2017

Cited by 7 | Viewed by 6263

Abstract

Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) is a well-implemented analytical technique for the investigation of complex biological samples. In MS, the sample preparation strategy is decisive for the success of the measurements. Here, sample preparation processes and target [...] Read more.

Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) is a well-implemented analytical technique for the investigation of complex biological samples. In MS, the sample preparation strategy is decisive for the success of the measurements. Here, sample preparation processes and target materials for the investigation of different pollen grains are compared. A reduced and optimized sample preparation process prior to MALDI-TOF measurement is presented using conductive carbon tape as target. The application of conductive tape yields in enhanced absolute signal intensities and mass spectral pattern information, which leads to a clear separation in subsequent pattern analysis. The results will be used to improve the taxonomic differentiation and identification, and might be useful for the development of a simple routine method to identify pollen based on mass spectrometry. Full article

(This article belongs to the Special Issue Analytical Techniques in Plant and Food Analysis)

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d-Amino Acid Position Influences the Anticancer Activity of Galaxamide Analogs: An Apoptotic Mechanism Study

by Defa Bai, Siming Yu, Shenghui Zhong, Bingxin Zhao, Shaoling Qiu, Jianwei Chen, Jignesh Lunagariya, Xiaojian Liao and Shihai Xu

Int. J. Mol. Sci. 2017, 18(3), 544; https://doi.org/10.3390/ijms18030544 - 10 Mar 2017

Cited by 12 | Viewed by 4545

Abstract

Galaxamide, an extract from Galaxaura filamentosa, is a cyclic pentapeptide containing five l-leucines. Due to the particular cyclic structure and the excellent anticancer activity, synthesis of Galaxamide and its analogs and their subsequent bio-applications have attracted great attention. In the present [...] Read more.

Galaxamide, an extract from Galaxaura filamentosa, is a cyclic pentapeptide containing five l-leucines. Due to the particular cyclic structure and the excellent anticancer activity, synthesis of Galaxamide and its analogs and their subsequent bio-applications have attracted great attention. In the present work, we synthesized six Galaxamide analogs by replacing one of the l-leucines with phenylalanine and varying the d-amino acid position. The anticancer effect of the synthesized Galaxamide analogs was tested against four in vitro human cancer cell lines, human hepatocellular cells (HepG₂), human breast cancer cell (MCF-7), human breast adenocarcinoma cells (MDA-MB-435) and a human cervical carcinoma cell line (Hela). Results showed that Galaxamide analogs with different d-amino acid positions displayed distinct anticancer potential. The Galaxamide analog containing d-amino acid at position 5 (Analog-6) presented the strongest anticancer activity. The mechanism study revealed that Analog-6 could cause the early apoptosis of HepG₂ cells by inhibiting their growth in the sub-G1 stage of the cell cycle and induce the chromatin condensation and fragmentation, which can be seen as 68% of HepG₂ cells inhibited in the sub-G1 stage. Moreover, a mitochondria-mediated pathway was found to be involved in the apoptotic process of Analog-6 on HepG₂ cells. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessCommunication

Proteome Analysis of Human Follicular Thyroid Cancer Cells Exposed to the Random Positioning Machine

by Johann Bauer, Sascha Kopp, Elisabeth Maria Schlagberger, Jirka Grosse, Jayashree Sahana, Stefan Riwaldt, Markus Wehland, Ronald Luetzenberg, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2017, 18(3), 546; https://doi.org/10.3390/ijms18030546 - 3 Mar 2017

Cited by 33 | Viewed by 6885

Abstract

Several years ago, we detected the formation of multicellular spheroids in experiments with human thyroid cancer cells cultured on the Random Positioning Machine (RPM), a ground-based model to simulate microgravity by continuously changing the orientation of samples. Since then, we have studied cellular [...] Read more.

Several years ago, we detected the formation of multicellular spheroids in experiments with human thyroid cancer cells cultured on the Random Positioning Machine (RPM), a ground-based model to simulate microgravity by continuously changing the orientation of samples. Since then, we have studied cellular mechanisms triggering the cells to leave a monolayer and aggregate to spheroids. Our work focused on spheroid-related changes in gene expression patterns, in protein concentrations, and in factors secreted to the culture supernatant during the period when growth is altered. We detected that factors inducing angiogenesis, the composition of integrins, the density of the cell monolayer exposed to microgravity, the enhanced production of caveolin-1, and the nuclear factor kappa B p65 could play a role during spheroid formation in thyroid cancer cells. In this study, we performed a deep proteome analysis on FTC-133 thyroid cancer cells cultured under conditions designed to encourage or discourage spheroid formation. The experiments revealed more than 5900 proteins. Their evaluation confirmed and explained the observations mentioned above. In addition, we learned that FTC-133 cells growing in monolayers or in spheroids after RPM-exposure incorporate vinculin, paxillin, focal adhesion kinase 1, and adenine diphosphate (ADP)-ribosylation factor 6 in different ways into the focal adhesion complex. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells

by Annapina Russo, Assunta Saide, Silvia Smaldone, Raffaella Faraonio and Giulia Russo

Int. J. Mol. Sci. 2017, 18(3), 547; https://doi.org/10.3390/ijms18030547 - 3 Mar 2017

Cited by 45 | Viewed by 6248

Abstract

Cancer is one of the most common causes of death among adults. Chemotherapy is crucial in determining patient survival and quality of life. However, the development of multidrug resistance (MDR) continues to pose a significant challenge in the management of cancer. In this [...] Read more.

Cancer is one of the most common causes of death among adults. Chemotherapy is crucial in determining patient survival and quality of life. However, the development of multidrug resistance (MDR) continues to pose a significant challenge in the management of cancer. In this study, we analyzed the role of human ribosomal protein uL3 (formerly rpL3) in multidrug resistance. Our studies revealed that uL3 is a key determinant of multidrug resistance in p53-mutated lung cancer cells by controlling the cell redox status. We established and characterized a multidrug resistant Calu-6 cell line. We found that uL3 down-regulation correlates positively with multidrug resistance. Restoration of the uL3 protein level re-sensitized the resistant cells to the drug by regulating the reactive oxygen species (ROS) levels, glutathione content, glutamate release, and cystine uptake. Chromatin immunoprecipitation experiments and luciferase assays demonstrated that uL3 coordinated the expression of stress-response genes acting as transcriptional repressors of solute carrier family 7 member 11 (xCT) and glutathione S-transferase α1 (GST-α1), independently of Nuclear factor erythroid 2-related factor 2 (Nrf2). Altogether our results describe a new function of uL3 as a regulator of oxidative stress response genes and advance our understanding of the molecular mechanisms underlying multidrug resistance in cancers. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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Proline Residues as Switches in Conformational Changes Leading to Amyloid Fibril Formation

by Ajda Taler-Verčič, Samra Hasanbašić, Selma Berbić, Veronika Stoka, Dušan Turk and Eva Žerovnik

Int. J. Mol. Sci. 2017, 18(3), 549; https://doi.org/10.3390/ijms18030549 - 7 Mar 2017

Cited by 18 | Viewed by 11953

Abstract

Here we discuss studies of the structure, folding, oligomerization and amyloid fibril formation of several proline mutants of human stefin B, which is a protein inhibitor of lysosomal cysteine cathepsins and a member of the cystatin family. The structurally important prolines in stefin [...] Read more.

Here we discuss studies of the structure, folding, oligomerization and amyloid fibril formation of several proline mutants of human stefin B, which is a protein inhibitor of lysosomal cysteine cathepsins and a member of the cystatin family. The structurally important prolines in stefin B are responsible for the slow folding phases and facilitate domain swapping (Pro 74) and loop swapping (Pro 79). Moreover, our findings are compared to β₂-microglobulin, a protein involved in dialysis-related amyloidosis. The assessment of the contribution of proline residues to the process of amyloid fibril formation may shed new light on the critical molecular events involved in conformational disorders. Full article

(This article belongs to the Special Issue Protein Folding)

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Protective Effects of Ferulic Acid against Chronic Cerebral Hypoperfusion-Induced Swallowing Dysfunction in Rats

by Takashi Asano, Hirokazu Matsuzaki, Naohiro Iwata, Meiyan Xuan, Shinya Kamiuchi, Yasuhide Hibino, Takeshi Sakamoto and Mari Okazaki

Int. J. Mol. Sci. 2017, 18(3), 550; https://doi.org/10.3390/ijms18030550 - 3 Mar 2017

Cited by 20 | Viewed by 5007

Abstract

Ferulic acid (FA), a phenolic phytochemical, has been reported to exert antioxidative and neuroprotective effects. In this study, we investigated the protective effects of FA against the dysfunction of the swallowing reflex induced by ligation of bilateral common carotid arteries (2VO) in rats. [...] Read more.

Ferulic acid (FA), a phenolic phytochemical, has been reported to exert antioxidative and neuroprotective effects. In this study, we investigated the protective effects of FA against the dysfunction of the swallowing reflex induced by ligation of bilateral common carotid arteries (2VO) in rats. In 2VO rats, topical administration of water or citric acid to the pharyngolaryngeal region evoked a diminished number of swallowing events with prolonged latency compared to sham-operated control rats. 2VO rats had an increased level of superoxide anion radical, and decreased dopamine and tyrosine hydroxylase enzyme levels in the striatum, suggesting that 2VO augmented cerebral oxidative stress and impaired the striatal dopaminergic system. Furthermore, substance P (SP) expression in the laryngopharyngeal mucosa, which is believed to be positively regulated by dopaminergic signaling in the basal ganglia, was decreased in 2VO rats. Oral treatment with FA (30 mg/kg) for 3 weeks (from one week before 2VO to two weeks after) improved the swallowing reflex and maintained levels of striatal dopamine and laryngopharyngeal SP expression in 2VO rats. These results suggest that FA maintains the swallowing reflex by protecting the dopamine-SP system against ischemia-induced oxidative damage in 2VO rats. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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A New Oleanolic Acid Derivative against CCl₄-Induced Hepatic Fibrosis in Rats

by Hongjun Xiang, Yaotian Han, Yuzhong Zhang, Wenqiang Yan, Bing Xu, Fuhao Chu, Tianxin Xie, Menglu Jia, Mengmeng Yan, Rui Zhao, Penglong Wang and Haimin Lei

Int. J. Mol. Sci. 2017, 18(3), 553; https://doi.org/10.3390/ijms18030553 - 6 Mar 2017

Cited by 25 | Viewed by 5126

Abstract

A novel hepatoprotective oleanolic acid derivative, 3-oxours-oleana-9(11), 12-dien-28-oic acid (Oxy-Di-OA), has been reported. In previous studies, we found that Oxy-Di-OA presented the anti-HBV (Hepatitis B Virus) activity (IC₅₀ = 3.13 µg/mL). Remarkably, it is superior to lamivudine in the inhibition of the [...] Read more.

A novel hepatoprotective oleanolic acid derivative, 3-oxours-oleana-9(11), 12-dien-28-oic acid (Oxy-Di-OA), has been reported. In previous studies, we found that Oxy-Di-OA presented the anti-HBV (Hepatitis B Virus) activity (IC₅₀ = 3.13 µg/mL). Remarkably, it is superior to lamivudine in the inhibition of the rebound of the viral replication rate. Furthermore, Oxy-Di-OA showed good performance of anti-HBV activity in vivo. Some studies showed that liver fibrosis may affiliate with HBV gene mutations. In addition, the anti-hepatic fibrosis activity of Oxy-Di-OA has not been studied. Therefore, we evaluated the protective effect of Oxy-Di-OA against carbon tetrachloride (CCl₄)-induced liver injury in rats. Daily intraperitoneally administration of Oxy-Di-OA prevented the development of CCl₄-induced liver fibrosis, which was evidenced by histological study and immunohistochemical analysis. The entire experimental protocol lasted nine weeks. Oxy-Di-OA significantly suppressed the increases of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (p < 0.05). Furthermore, Oxy-Di-OA could prevent expression of transforming growth factor β1 (TGF-β1). It is worth noting that the high-dose group Oxy-Di-OA is superior to bifendate in elevating hepatic function. Compared to the model group, Oxy-Di-OA in the high-dose group and low-dose group can significantly reduce the liver and spleen indices (p < 0.05). The acute toxicity test showed that LD₅₀ and a 95% confidence interval (CIs) value of Oxy-Di-OA were 714.83 mg/kg and 639.73–798.73 mg/kg via intraperitoneal injection in mice, respectively. The LD₅₀ value of Oxy-Di-OA exceeded 2000 mg/kg via gavage in mice. In addition, a simple and rapid high performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated to study the pharmacokinetic characteristics of the compound. After single-dose oral administration, time to reach peak concentration of Oxy-Di-OA (C_max = 8.18 ± 0.66 μg/mL) was 10 ± 2.19 h; the elimination half-life and area under the concentration-time curve from t = 0 to the last time of Oxy-Di-OA was 2.19 h and 90.21 μg·h/mL, respectively. Full article

(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)

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Comprehensive Metabolomic Analysis in Blood, Urine, Fat, and Muscle in Men with Metabolic Syndrome: A Randomized, Placebo-Controlled Clinical Trial on the Effects of Resveratrol after Four Months’ Treatment

by Anne Sofie Korsholm, Thomas Nordstrøm Kjær, Marie Juul Ornstrup and Steen Bønløkke Pedersen

Int. J. Mol. Sci. 2017, 18(3), 554; https://doi.org/10.3390/ijms18030554 - 4 Mar 2017

Cited by 56 | Viewed by 7703

Abstract

Resveratrol possesses several beneficial metabolic effects in rodents, while the effects of resveratrol in humans remain unclear. Therefore, we performed a non-targeted comprehensive metabolomic analysis on blood, urine, adipose tissue, and skeletal muscle tissue in middle-aged men with metabolic syndrome randomized to either [...] Read more.

Resveratrol possesses several beneficial metabolic effects in rodents, while the effects of resveratrol in humans remain unclear. Therefore, we performed a non-targeted comprehensive metabolomic analysis on blood, urine, adipose tissue, and skeletal muscle tissue in middle-aged men with metabolic syndrome randomized to either resveratrol or placebo treatment for four months. Changes in steroid hormones across all four matrices were the most pronounced changes observed. Resveratrol treatment reduced sulfated androgen precursors in blood, adipose tissue, and muscle tissue, and increased these metabolites in urine. Furthermore, markers of muscle turnover were increased and lipid metabolism was affected, with increased intracellular glycerol and accumulation of long-chain saturated, monounsaturated, and polyunsaturated (n3 and n6) free fatty acids in resveratrol-treated men. Finally, urinary derivatives of aromatic amino acids, which mainly reflect the composition of the gut microbiota, were altered upon resveratrol treatment. In conclusion, the non-targeted metabolomics approach applied to four different matrices provided evidence of subtle but robust effects on several metabolic pathways following resveratrol treatment for four months in men with metabolic syndrome—effects that, for the most part, would not have been detected by routine analyses. The affected pathways should be the focus of future clinical trials on resveratrol’s effects, and perhaps particularly the areas of steroid metabolism and the gut microbiome. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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Molecular and Structural Characterization of the Tegumental 20.6-kDa Protein in Clonorchis sinensis as a Potential Druggable Target

by Yu-Jung Kim, Won Gi Yoo, Myoung-Ro Lee, Jung-Mi Kang, Byoung-Kuk Na, Shin-Hyeong Cho, Mi-Yeoun Park and Jung-Won Ju

Int. J. Mol. Sci. 2017, 18(3), 557; https://doi.org/10.3390/ijms18030557 - 4 Mar 2017

Cited by 12 | Viewed by 6156

Abstract

The tegument, representing the membrane-bound outer surface of platyhelminth parasites, plays an important role for the regulation of the host immune response and parasite survival. A comprehensive understanding of tegumental proteins can provide drug candidates for use against helminth-associated diseases, such as clonorchiasis [...] Read more.

The tegument, representing the membrane-bound outer surface of platyhelminth parasites, plays an important role for the regulation of the host immune response and parasite survival. A comprehensive understanding of tegumental proteins can provide drug candidates for use against helminth-associated diseases, such as clonorchiasis caused by the liver fluke Clonorchis sinensis. However, little is known regarding the physicochemical properties of C. sinensis teguments. In this study, a novel 20.6-kDa tegumental protein of the C. sinensis adult worm (CsTegu20.6) was identified and characterized by molecular and in silico methods. The complete coding sequence of 525 bp was derived from cDNA clones and encodes a protein of 175 amino acids. Homology search using BLASTX showed CsTegu20.6 identity ranging from 29% to 39% with previously-known tegumental proteins in C. sinensis. Domain analysis indicated the presence of a calcium-binding EF-hand domain containing a basic helix-loop-helix structure and a dynein light chain domain exhibiting a ferredoxin fold. We used a modified method to obtain the accurate tertiary structure of the CsTegu20.6 protein because of the unavailability of appropriate templates. The CsTegu20.6 protein sequence was split into two domains based on the disordered region, and then, the structure of each domain was modeled using I-TASSER. A final full-length structure was obtained by combining two structures and refining the whole structure. A refined CsTegu20.6 structure was used to identify a potential CsTegu20.6 inhibitor based on protein structure-compound interaction analysis. The recombinant proteins were expressed in Escherichia coli and purified by nickel-nitrilotriacetic acid affinity chromatography. In C. sinensis, CsTegu20.6 mRNAs were abundant in adult and metacercariae, but not in the egg. Immunohistochemistry revealed that CsTegu20.6 localized to the surface of the tegument in the adult fluke. Collectively, our results contribute to a better understanding of the structural and functional characteristics of CsTegu20.6 and homologs of flukes. One compound is proposed as a putative inhibitor of CsTegu20.6 to facilitate further studies for anthelmintics. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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Open AccessArticle

Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

by Jessica Coppens, Eduard Bentea, Jacqueline A. Bayliss, Thomas Demuyser, Laura Walrave, Giulia Albertini, Joeri Van Liefferinge, Lauren Deneyer, Najat Aourz, Ann Van Eeckhaut, Jeanelle Portelli, Zane B. Andrews, Ann Massie, Dimitri De Bundel and Ilse Smolders

Int. J. Mol. Sci. 2017, 18(3), 558; https://doi.org/10.3390/ijms18030558 - 4 Mar 2017

Cited by 5 | Viewed by 4904

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Open AccessArticle

Structural Characterization of Core Region in Erwinia amylovora Lipopolysaccharide

by Angela Casillo, Marcello Ziaco, Buko Lindner, Susana Merino, Elena Mendoza-Barberá, Juan M. Tomás and Maria Michela Corsaro

Int. J. Mol. Sci. 2017, 18(3), 559; https://doi.org/10.3390/ijms18030559 - 4 Mar 2017

Cited by 3 | Viewed by 4594

Abstract

Erwinia amylovora (E. amylovora) is the first bacterial plant pathogen described and demonstrated to cause fire blight, a devastating plant disease affecting a wide range of species including a wide variety of Rosaceae. In this study, we reported the lipopolysaccharide [...] Read more.

Erwinia amylovora (E. amylovora) is the first bacterial plant pathogen described and demonstrated to cause fire blight, a devastating plant disease affecting a wide range of species including a wide variety of Rosaceae. In this study, we reported the lipopolysaccharide (LPS) core structure from E. amylovora strain CFBP1430, the first one for an E. amylovora highly pathogenic strain. The chemical characterization was performed on the mutants waaL (lacking only the O-antigen LPS with a complete LPS-core), wabH and wabG (outer-LPS core mutants). The LPSs were isolated from dry cells and analyzed by means of chemical and spectroscopic methods. In particular, they were subjected to a mild acid hydrolysis and/or a hydrazinolysis and investigated in detail by one and two dimensional Nuclear Magnetic Resonance (NMR) spectroscopy and ElectroSpray Ionization Fourier Transform-Ion Cyclotron Resonance (ESI FT-ICR) mass spectrometry. Full article

(This article belongs to the Special Issue Lipopolysaccharides (LPSs))

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Open AccessCommunication

Changes in Brain Monoamines Underlie Behavioural Disruptions after Zebrafish Diet Exposure to Polycyclic Aromatic Hydrocarbons Environmental Mixtures

by Caroline Vignet, Verena M. Trenkel, Annick Vouillarmet, Giampiero Bricca, Marie-Laure Bégout and Xavier Cousin

Int. J. Mol. Sci. 2017, 18(3), 560; https://doi.org/10.3390/ijms18030560 - 4 Mar 2017

Cited by 25 | Viewed by 5161

Abstract

Zebrafish were exposed through diet to two environmentally relevant polycyclic aromatic hydrocarbons (PAHs) mixtures of contrasted compositions, one of pyrolytic (PY) origin and one from light crude oil (LO). Monoamine concentrations were quantified in the brains of the fish after six month of [...] Read more.

Zebrafish were exposed through diet to two environmentally relevant polycyclic aromatic hydrocarbons (PAHs) mixtures of contrasted compositions, one of pyrolytic (PY) origin and one from light crude oil (LO). Monoamine concentrations were quantified in the brains of the fish after six month of exposure. A significant decrease in noradrenaline (NA) was observed in fish exposed to both mixtures, while a decrease in serotonin (5HT) and dopamine (DA) was observed only in LO-exposed fish. A decrease in metabolites of 5HT and DA was observed in fish exposed to both mixtures. Several behavioural disruptions were observed that depended on mixtures, and parallels were made with changes in monoamine concentrations. Indeed, we observed an increase in anxiety in fish exposed to both mixtures, which could be related to the decrease in 5HT and/or NA, while disruptions of daily activity rhythms were observed in LO fish, which could be related to the decrease in DA. Taken together, these results showed that (i) chronic exposures to PAHs mixtures disrupted brain monoamine contents, which could underlie behavioural disruptions, and that (ii) the biological responses depended on mixture compositions. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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Inhibition of NLRP3 Inflammasome Pathway by Butyrate Improves Corneal Wound Healing in Corneal Alkali Burn

by Fang Bian, Yangyan Xiao, Mahira Zaheer, Eugene A. Volpe, Stephen C. Pflugfelder, De-Quan Li and Cintia S. De Paiva

Int. J. Mol. Sci. 2017, 18(3), 562; https://doi.org/10.3390/ijms18030562 - 5 Mar 2017

Cited by 75 | Viewed by 7305

Abstract

Epithelial cells are involved in the regulation of innate and adaptive immunity in response to different stresses. The purpose of this study was to investigate if alkali-injured corneal epithelia activate innate immunity through the nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain [...] Read more.

Epithelial cells are involved in the regulation of innate and adaptive immunity in response to different stresses. The purpose of this study was to investigate if alkali-injured corneal epithelia activate innate immunity through the nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway. A unilateral alkali burn (AB) was created in the central cornea of C57BL/6 mice. Mice received either no topical treatment or topical treatment with sodium butyrate (NaB), β-hydroxybutyric acid (HBA), dexamethasone (Dex), or vehicle (balanced salt solution, BSS) quater in die (QID) for two or five days (d). We evaluated the expression of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as the downstream cytokine interleukin (IL)-1β. We found elevation of NLRP3 and IL-1β messenger RNA (mRNA) transcripts, as well as levels of inflammasome component proteins in the alkali-injured corneas compared to naïve corneas. Treatment with NLRP3 inhibitors using NaB and HBA preserved corneal clarity and decreased NLRP3, caspase-1, and IL-1β mRNA transcripts, as well as NLRP3 protein expression on post-injury compared to BSS-treated corneas. These findings identified a novel innate immune signaling pathway activated by AB. Blocking the NLRP3 pathway in AB mouse model decreases inflammation, resulting in greater corneal clarity. These results provide a mechanistic basis for optimizing therapeutic intervention in alkali injured eyes. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration)

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Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse

by Heleia Roca-Ho, Marta Riera, Vanesa Palau, Julio Pascual and Maria Jose Soler

Int. J. Mol. Sci. 2017, 18(3), 563; https://doi.org/10.3390/ijms18030563 - 5 Mar 2017

Cited by 217 | Viewed by 14802

Abstract

Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since [...] Read more.

Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Evidence of the Role of R-Spondin 1 and Its Receptor Lgr4 in the Transmission of Mechanical Stimuli to Biological Signals for Bone Formation

by Gui-Xun Shi, Xin-Feng Zheng, Chao Zhu, Bo Li, Yu-Ren Wang, Sheng-Dan Jiang and Lei-Sheng Jiang

Int. J. Mol. Sci. 2017, 18(3), 564; https://doi.org/10.3390/ijms18030564 - 7 Mar 2017

Cited by 36 | Viewed by 6735

Abstract

The bone can adjust its mass and architecture to mechanical stimuli via a series of molecular cascades, which have been not yet fully elucidated. Emerging evidence indicated that R-spondins (Rspos), a family of secreted agonists of the Wnt/β-catenin signaling pathway, had important roles [...] Read more.

The bone can adjust its mass and architecture to mechanical stimuli via a series of molecular cascades, which have been not yet fully elucidated. Emerging evidence indicated that R-spondins (Rspos), a family of secreted agonists of the Wnt/β-catenin signaling pathway, had important roles in osteoblastic differentiation and bone formation. However, the role of Rspo proteins in mechanical loading-influenced bone metabolism has never been investigated. In this study, we found that Rspo1 was a mechanosensitive protein for bone formation. Continuous cyclic mechanical stretch (CMS) upregulated the expression of Rspo1 in mouse bone marrow mesenchymal stem cells (BMSCs), while the expression of Rspo1 in BMSCs in vivo was downregulated in the bones of a mechanical unloading mouse model (tail suspension (TS)). On the other hand, Rspo1 could promote osteogenesis of BMSCs under CMS through activating the Wnt/β-catenin signaling pathway and could rescue the bone loss induced by mechanical unloading in the TS mice. Specifically, our results suggested that Rspo1 and its receptor of leucine-rich repeat containing G-protein-coupled receptor 4 (Lgr4) should be a novel molecular signal in the transmission of mechanical stimuli to biological signal in the bone, and this signal should be in the upstream of Wnt/β-catenin signaling for bone formation. Rspo1/Lgr4 could be a new potential target for the prevention and treatment of disuse osteoporosis in the future. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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AKT2 Blocks Nucleus Translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) While Promoting Caspase Activation during Cardiac Ischemia

by Shuai Yang, Xinmei Zhao, Hui Xu, Fan Chen, Yitao Xu, Zhe Li, Daniel Sanchis, Liang Jin, Yubin Zhang and Junmei Ye

Int. J. Mol. Sci. 2017, 18(3), 565; https://doi.org/10.3390/ijms18030565 - 6 Mar 2017

Cited by 24 | Viewed by 6310

Abstract

The AKT (protein kinase B, PKB) family has been shown to participate in diverse cellular processes, including apoptosis. Previous studies demonstrated that protein kinase B2 (AKT2^−/−) mice heart was sensitized to apoptosis in response to ischemic injury. However, little is known [...] Read more.

The AKT (protein kinase B, PKB) family has been shown to participate in diverse cellular processes, including apoptosis. Previous studies demonstrated that protein kinase B2 (AKT2^−/−) mice heart was sensitized to apoptosis in response to ischemic injury. However, little is known about the mechanism and apoptotic signaling pathway. Here, we show that AKT2 inhibition does not affect the development of cardiomyocytes but increases cell death during cardiomyocyte ischemia. Caspase-dependent apoptosis of both the extrinsic and intrinsic pathway was inactivated in cardiomyocytes with AKT2 inhibition during ischemia, while significant mitochondrial disruption was observed as well as intracytosolic translocation of cytochrome C (Cyto C) together with apoptosis-inducing factor (AIF) and endonuclease G (EndoG), both of which are proven to conduct DNA degradation in a range of cell death stimuli. Therefore, mitochondria-dependent cell death was investigated and the results suggested that AIF and EndoG nucleus translocation causes cardiomyocyte DNA degradation during ischemia when AKT2 is blocked. These data are the first to show a previous unrecognized function and mechanism of AKT2 in regulating cardiomyocyte survival during ischemia by inducing a unique mitochondrial-dependent DNA degradation pathway when it is inhibited. Full article

(This article belongs to the Section Biochemistry)

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A Human Antibody That Binds to the Sixth Ig-Like Domain of VCAM-1 Blocks Lung Cancer Cell Migration In Vitro

by Mi Ra Kim, Ji Hye Jang, Chang Sik Park, Taek-Keun Kim, Youn-Jae Kim, Junho Chung, Hyunbo Shim, In Hyun Nam, Jung Min Han and Sukmook Lee

Int. J. Mol. Sci. 2017, 18(3), 566; https://doi.org/10.3390/ijms18030566 - 6 Mar 2017

Cited by 15 | Viewed by 6112

Abstract

Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared [...] Read more.

Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung tissue, and high VCAM-1 expression correlated with poor survival in lung cancer patients. VCAM-1 knockdown reduced migration of A549 human lung cancer cells into Matrigel, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1 mediated A549 cell migration into Matrigel. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed the migration of A549 and NCI-H1299 lung cancer cell lines into Matrigel. Taken together, these results suggest that VCAM-1-D6 is a key domain for regulating VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion. Full article

(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)

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Blood Biomarkers Predict the Cognitive Effects of Aripiprazole in Patients with Acute Schizophrenia

by Hikaru Hori, Reiji Yoshimura, Asuka Katsuki, Kiyokazu Atake, Ryohei Igata, Yuki Konishi, Hiroki Beppu and Hirotaka Tominaga

Int. J. Mol. Sci. 2017, 18(3), 568; https://doi.org/10.3390/ijms18030568 - 6 Mar 2017

Cited by 12 | Viewed by 6011

Abstract

Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing [...] Read more.

Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing aripiprazole treatment. We evaluated cognitive function in 51 patients with schizophrenia using Brief Assessment of Cognition in Schizophrenia (BACS), as well as background information, psychiatric symptoms, plasma catecholamine metabolites—homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG)—, and serum brain-derived neurotrophic factor (BDNF). Multivariate analyses were performed in order to identify factors independently associated with cognitive function. Brain-derived neurotrophic factor levels, number of hospitalizations, and MHPG levels were associated with verbal memory and learning. Total hospitalization period and MHPG levels were associated with working memory. Age at first hospitalization and education were associated with motor speed. The number of hospital admissions, Positive and Negative Syndrome Scale negative subscale scores (PANSS-N), MHPG levels, BDNF levels, and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were associated with verbal fluency. Homovanillic acid and MHPG levels, duration of illness, and PANSS-N scores were associated with attention and processing speed. Brain-derived neurotrophic factor and MHPG levels were associated with executive function. These results suggest that treatment of psychiatric symptoms and cognitive dysfunction may be improved in patients treated with aripiprazole by controlling for these contributing factors. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Effects of Silver Nanoparticles on Multiple Drug-Resistant Strains of Staphylococcus aureus and Pseudomonas aeruginosa from Mastitis-Infected Goats: An Alternative Approach for Antimicrobial Therapy

by Yu-Guo Yuan, Qiu-Ling Peng and Sangiliyandi Gurunathan

Int. J. Mol. Sci. 2017, 18(3), 569; https://doi.org/10.3390/ijms18030569 - 6 Mar 2017

Cited by 246 | Viewed by 12158

Abstract

Recently, silver nanoparticles (AgNPs) have been widely used in various applications as antimicrobial agents, anticancer, diagnostics, biomarkers, cell labels, and drug delivery systems for the treatment of various diseases. Microorganisms generally acquire resistance to antibiotics through the course of antibacterial therapy. Multi-drug resistance [...] Read more.

Recently, silver nanoparticles (AgNPs) have been widely used in various applications as antimicrobial agents, anticancer, diagnostics, biomarkers, cell labels, and drug delivery systems for the treatment of various diseases. Microorganisms generally acquire resistance to antibiotics through the course of antibacterial therapy. Multi-drug resistance (MDR) has become a growing problem in the treatment of infectious diseases, and the widespread use of broad-spectrum antibiotics has resulted in the development of antibiotic resistance by numerous human and animal bacterial pathogens. As a result, an increasing number of microorganisms are resistant to multiple antibiotics causing continuing economic losses in dairy farming. Therefore, there is an urgent need for the development of alternative, cost-effective, and efficient antimicrobial agents that overcome antimicrobial resistance. Here, AgNPs synthesized using the bio-molecule quercetin were characterized using various analytical techniques. The synthesized AgNPs were highly spherical in shape and had an average size of 11 nm. We evaluated the efficacy of synthesized AgNPs against two MDR pathogenic bacteria, namely, Pseudomonas aeruginosa and Staphylococcus aureus, which were isolated from milk samples produced by mastitis-infected goats. The minimum inhibitory concentrations (MICs) of AgNPs against P. aeruginosa and S. aureus were found to be 1 and 2 μg/mL, respectively. Our findings suggest that AgNPs exert antibacterial effects in a dose- and time-dependent manner. Results from the present study demonstrate that the antibacterial activity of AgNPs is due to the generation of reactive oxygen species (ROS), malondialdehyde (MDA), and leakage of proteins and sugars in bacterial cells. Results of the present study showed that AgNP-treated bacteria had significantly lower lactate dehydrogenase activity (LDH) and lower adenosine triphosphate (ATP) levels compared to the control. Furthermore, AgNP-treated bacteria showed downregulated expression of glutathione (GSH), upregulation of glutathione S-transferase (GST), and downregulation of both superoxide dismutase (SOD) and catalase (CAT). These physiological and biochemical measurements were consistently observed in AgNP-treated bacteria, thereby suggesting that AgNPs can induce bacterial cell death. Thus, the above results represent conclusive findings on the mechanism of action of AgNPs against different types of bacteria. This study also demonstrates the promising use of nanoparticles as antibacterial agents for use in the biotechnology and biomedical industry. Furthermore, this study is the first to propose the mode of action of AgNPs against MDR pathogens isolated from goats infected with subclinical mastitis. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles)

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Blockage of Glyoxalase I Inhibits Colorectal Tumorigenesis and Tumor Growth via Upregulation of STAT1, p53, and Bax and Downregulation of c-Myc and Bcl-2

by Yuan Chen, Lei Fang, Jiali Zhang, Gefei Li, Mengni Ma, Changxi Li, Jianxin Lyu and Qing H. Meng

Int. J. Mol. Sci. 2017, 18(3), 570; https://doi.org/10.3390/ijms18030570 - 9 Mar 2017

Cited by 20 | Viewed by 6175

Abstract

GlyoxalaseI (GLOI) is an enzyme that catalyzes methylglyoxal metabolism. Overexpression of GLOI has been documented in numerous tumor tissues, including colorectal cancer (CRC). The antitumor effects of GLOI depletion have been demonstrated in some types of cancer, but its role in CRC and [...] Read more.

GlyoxalaseI (GLOI) is an enzyme that catalyzes methylglyoxal metabolism. Overexpression of GLOI has been documented in numerous tumor tissues, including colorectal cancer (CRC). The antitumor effects of GLOI depletion have been demonstrated in some types of cancer, but its role in CRC and the mechanisms underlying this activity remain largely unknown. Our purpose was to investigate the antitumor effects of depleted GLOI on CRC in vitro and in vivo. RNA interference was used to deplete GLOI activity in four CRC cell lines. The cells’ proliferation, apoptosis, migration, and invasion were assessed by using the Cell Counting Kit-8, plate colony formation assay, flow cytometry, and transwell assays. Protein and mRNA levels were analyzed by western blot and quantitative real-time PCR (qRT-PCR), respectively. The antitumor effect of GLOI depletion in vivo was investigated in a SW620 xenograft tumor model in BALB/c nude mice. Our results show that GLOI is over-expressed in the CRC cell lines. GLOI depletion inhibited the proliferation, colony formation, migration, and invasion and induced apoptosis of all CRC cells compared with the controls. The levels of signal transducer and activator of transcription 1 (STAT1), p53, and Bcl-2 assaciated X protein (Bax) were upregulated by GLOI depletion, while cellular homologue of avian myelocytomatosis virus oncogene (c-Myc) and B cell lymphoma/lewkmia-2 (Bcl-2) were downregulated. Moreover, the growth of SW620-induced CRC tumors in BALB/c nude mice was significantly attenuated by GLOI depletion. The expression levels of STAT1, p53, and Bax were increased and those of c-Myc and Bcl-2 were decreased in the GLOI-depleted tumors. Our findings demonstrate that GLOI depletion has an antitumor effect through the STAT1 or p53 signaling pathways in CRC, suggesting that GLOI is a potential therapeutic target. Full article

(This article belongs to the Special Issue Glyoxalase System)

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Evaluation of the Effects of Mesoglycan on Some Markers of Endothelial Damage and Walking Distance in Diabetic Patients with Peripheral Arterial Disease

by Derosa Giuseppe, D’Angelo Angela, Davide Romano and Maffioli Pamela

Int. J. Mol. Sci. 2017, 18(3), 572; https://doi.org/10.3390/ijms18030572 - 6 Mar 2017

Cited by 8 | Viewed by 4265

Abstract

The aim of this study was to evaluate the variation of some parameters involved in peripheral artery disease progression in diabetic patients with peripheral artery disease after six months of mesoglycan. We enrolled 64 Caucasian, type 2 diabetic patients, with stage IIa peripheral [...] Read more.

The aim of this study was to evaluate the variation of some parameters involved in peripheral artery disease progression in diabetic patients with peripheral artery disease after six months of mesoglycan. We enrolled 64 Caucasian, type 2 diabetic patients, with stage IIa peripheral artery disease. They were randomized to mesoglycan (Prisma^®), 50 mg twice a day, or placebo, for six months. We evaluated: glycemic control, metalloproteinase-2, and -9 (MMP-2, and -9), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion protein-1 (sVCAM-1), interleukin-6 (IL-6), soluble E-selectin (sE-selectin), high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1). We recorded a decrease of MMP-2, MMP-9, sE-selectin, TNF-α, sVCAM-1, and IL-6 compared to baseline, and to placebo in the group treated with mesoglycan. Regarding sICAM-1, and hs-CRP, instead, we recorded a decrease with mesoglycan only compared to baseline. Preliminary results seem to suggest an improvement of pain free walking distance with mesoglycan in 18 patients both compared to baseline and to placebo, even if data should be taken cautiously. Our study showed that supplementation with mesoglycan improved endothelial dysfunction in type 2 diabetic patients with peripheral artery disease. Regarding the preliminary data suggesting also a slight improvement of clinical parameters such as pain free walking distance, more data and a bigger sample of patients are necessary to better verify this aspect. Full article

(This article belongs to the Special Issue Nutraceuticals in Human Health and Disease)

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Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

by Alison E. M. Vickers, Anatoly V. Ulyanov and Robyn L. Fisher

Int. J. Mol. Sci. 2017, 18(3), 574; https://doi.org/10.3390/ijms18030574 - 7 Mar 2017

Cited by 12 | Viewed by 5470

Abstract

Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM), diclofenac (DCF, 1 mM) and etomoxir [...] Read more.

Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM), diclofenac (DCF, 1 mM) and etomoxir (ETM, 100 μM). Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 μM) and cyclosporin A (CSA, 10 μM), while GSH was affected more than ATP by methimazole (MMI, 500 μM), terbinafine (TBF, 100 μM), and carbamazepine (CBZ 100 μM). Oxidative stress genes were affected by TBF (18%), CBZ, APAP, and ETM (12%–11%), and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%–6%). Apoptosis genes were affected by DCF (14%), while apoptosis plus necrosis were altered by APAP and ETM (15%). Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%), ETM (66%), DCF, TBF, MMI (61%–60%), APAP, CBZ (57%–56%), and DTL (48%). Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%), CBZ and ETM (44%–43%), APAP and DCF (40%–38%), MMI, TBF and CSA (37%–35%). This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects. Full article

(This article belongs to the Special Issue Biomarkers in Drug-Induced Organ Injury)

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Serum-Infliximab Trough Levels in 45 Children with Inflammatory Bowel Disease on Maintenance Treatment

by Helena Rolandsdotter, Per Marits, Ulf Sundin, Ann-Charlotte Wikström, Ulrika L. Fagerberg, Yigael Finkel and Michael Eberhardson

Int. J. Mol. Sci. 2017, 18(3), 575; https://doi.org/10.3390/ijms18030575 - 7 Mar 2017

Cited by 20 | Viewed by 5679

Abstract

The role of trough serum infliximab (s-IFX) and antibodies toward IFX (ATI) during maintenance treatment remains unclear in children. The aim of the present study was to investigate trough s-IFX and ATI to identify any correlation with inflammatory activity and clinical response in [...] Read more.

The role of trough serum infliximab (s-IFX) and antibodies toward IFX (ATI) during maintenance treatment remains unclear in children. The aim of the present study was to investigate trough s-IFX and ATI to identify any correlation with inflammatory activity and clinical response in a pediatric inflammatory bowel disease (IBD) cohort. We investigated the s-IFX trough levels in pediatric IBD patients (n = 45) on maintenance IFX treatment. Ninety-three blood samples were collected and demographics, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and albumin were recorded. The mean s-IFX trough level was 5.2 µg/mL. The mean trough s-IFX level was significantly higher in the samples taken during remission (7.2 µg/mL) compared to active disease (4.5 µg/mL, p < 0.05). The trough s-IFX levels correlated with ESR, CRP, and albumin. S-IFX was undetectable in eight of the patients, all with positive ATI and active disease. Surprisingly, clinical and biochemical remission was observed at only 26 of the 93 visits. The correlation between dose variations and changes in trough s-IFX was not evident. In line with studies in adults, the s-IFX trough levels correlated with response to infliximab. Full article

(This article belongs to the Special Issue Dissecting Mechanisms of Action of Biologics in Inflammatory Bowel Diseases)

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The Characterization of GSDMB Splicing and Backsplicing Profiles Identifies Novel Isoforms and a Circular RNA That Are Dysregulated in Multiple Sclerosis

by Giulia Cardamone, Elvezia Maria Paraboschi, Valeria Rimoldi, Stefano Duga, Giulia Soldà and Rosanna Asselta

Int. J. Mol. Sci. 2017, 18(3), 576; https://doi.org/10.3390/ijms18030576 - 7 Mar 2017

Cited by 88 | Viewed by 7600

Abstract

Abnormalities in alternative splicing (AS) are emerging as recurrent features in autoimmune diseases (AIDs). In particular, a growing body of evidence suggests the existence of a pathogenic association between a generalized defect in splicing regulatory genes and multiple sclerosis (MS). Moreover, several studies [...] Read more.

Abnormalities in alternative splicing (AS) are emerging as recurrent features in autoimmune diseases (AIDs). In particular, a growing body of evidence suggests the existence of a pathogenic association between a generalized defect in splicing regulatory genes and multiple sclerosis (MS). Moreover, several studies have documented an unbalance in alternatively-spliced isoforms in MS patients possibly contributing to the disease etiology. In this work, using a combination of PCR-based techniques (reverse-transcription (RT)-PCR, fluorescent-competitive, real-time, and digital RT-PCR assays), we investigated the alternatively-spliced gene encoding Gasdermin B, GSDMB, which was repeatedly associated with susceptibility to asthma and AIDs. The in-depth characterization of GSDMB AS and backsplicing profiles led us to the identification of an exonic circular RNA (ecircRNA) as well as of novel GSDMB in-frame and out-of-frame isoforms. The non-productive splicing variants were shown to be downregulated by the nonsense-mediated mRNA decay (NMD) in human cell lines, suggesting that GSDMB levels are significantly modulated by NMD. Importantly, both AS isoforms and the identified ecircRNA were significantly dysregulated in peripheral blood mononuclear cells of relapsing-remitting MS patients compared to controls, further supporting the notion that aberrant RNA metabolism is a characteristic feature of the disease. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing 2016)

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Systematic Design of Trypsin Cleavage Site Mutated Exendin4-Cysteine 1, an Orally Bioavailable Glucagon-Like Peptide-1 Receptor Agonist

by Wenbo Sai, Hong Tian, Kangmin Yang, Daoqi Tang, Jinxiao Bao, Yang Ge, Xiaoda Song, Yu Zhang, Cheng Luo, Xiangdong Gao and Wenbing Yao

Int. J. Mol. Sci. 2017, 18(3), 578; https://doi.org/10.3390/ijms18030578 - 8 Mar 2017

Cited by 6 | Viewed by 5141

Abstract

Exendin-4 is a strong therapeutic candidate for the treatment of metabolic syndrome. Related receptor agonist drugs have been on the market since 2005. However, technical limitations and the pain caused by subcutaneous injection have severely limited patient compliance. The goal of the study [...] Read more.

Exendin-4 is a strong therapeutic candidate for the treatment of metabolic syndrome. Related receptor agonist drugs have been on the market since 2005. However, technical limitations and the pain caused by subcutaneous injection have severely limited patient compliance. The goal of the study is to investigate a biologically active exendin-4 analog could be administered orally. Using intraperitoneal glucose tolerance tests, we discovered that exendin4-cysteine administered by oral gavage had a distinct hypoglycemic effect in C57BL/6J mice. Using Rosetta Design and Amber, we designed and screened a series of exendin4-cysteine analogs to identify those that retained biological activity while resisting trypsin digestion. Trypsin Cleavage Site Mutated Exendin4-cysteine 1 (TSME-1), an analog whose bioactivity was similar to exendin-4 and was almost completely resistant to trypsin, was screened out. In addition, TSME-1 significantly normalized the blood glucose levels and the availability of TSME-1 was significantly higher than that of exendin-4 and exendin4-cysteine. Collectively orally administered TSME-1, a trypsin-resistant exendin-4 analog obtained by the system, is a strong candidate for future treatments of type 2 diabetes. Full article

(This article belongs to the Section Biochemistry)

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Zinc Prevents the Development of Diabetic Cardiomyopathy in db/db Mice

by Shudong Wang, Bowei Wang, Yuehui Wang, Qian Tong, Quan Liu, Jian Sun, Yang Zheng and Lu Cai

Int. J. Mol. Sci. 2017, 18(3), 580; https://doi.org/10.3390/ijms18030580 - 7 Mar 2017

Cited by 37 | Viewed by 6581

Abstract

Diabetic cardiomyopathy (DCM) is highly prevalent in type 2 diabetes (T2DM) patients. Zinc is an important essential trace metal, whose deficiency is associated with various chronic ailments, including vascular diseases. We assessed T2DM B6.BKS(D)-Leprdb/J (db/db) mice fed for six months on a normal [...] Read more.

Diabetic cardiomyopathy (DCM) is highly prevalent in type 2 diabetes (T2DM) patients. Zinc is an important essential trace metal, whose deficiency is associated with various chronic ailments, including vascular diseases. We assessed T2DM B6.BKS(D)-Leprdb/J (db/db) mice fed for six months on a normal diet containing three zinc levels (deficient, adequate, and supplemented), to explore the role of zinc in DCM development and progression. Cardiac function, reflected by ejection fraction, was significantly decreased, along with increased left ventricle mass and heart weight to tibial length ratio, in db/db mice. As a molecular cardiac hypertrophy marker, atrial natriuretic peptide levels were also significantly increased. Cardiac dysfunction and hypertrophy were accompanied by significantly increased fibrotic (elevated collagen accumulation as well as transforming growth factor β and connective tissue growth factor levels) and inflammatory (enhanced expression of tumor necrosis factor alpha, interleukin-1β, caspase recruitment domain family member 9, and B-cell lymphoma/leukemia 10, and activated p38 mitogen-activated protein kinase) responses in the heart. All these diabetic effects were exacerbated by zinc deficiency, and not affected by zinc supplementation, respectively. Mechanistically, oxidative stress and damage, mirrored by the accumulation of 3-nitrotyrosine and 4-hydroxy-2-nonenal, was significantly increased along with significantly decreased expression of Nrf2 and its downstream antioxidants (NQO-1 and catalase). This was also exacerbated by zinc deficiency in the db/db mouse heart. These results suggested that zinc deficiency promotes the development and progression of DCM in T2DM db/db mice. The exacerbated effects by zinc deficiency on the heart of db/db mice may be related to further suppression of Nrf2 expression and function. Full article

(This article belongs to the Special Issue Diabetic Complications: Pathophysiology, Mechanisms, and Therapies)

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Methyl Gallate Inhibits Osteoclast Formation and Function by Suppressing Akt and Btk-PLCγ2-Ca²⁺ Signaling and Prevents Lipopolysaccharide-Induced Bone Loss

by Jong Min Baek, Ju-Young Kim, Chang Hoon Lee, Kwon-Ha Yoon and Myeung Su Lee

Int. J. Mol. Sci. 2017, 18(3), 581; https://doi.org/10.3390/ijms18030581 - 7 Mar 2017

Cited by 34 | Viewed by 4927

Abstract

In the field of bone research, various natural derivatives have emerged as candidates for osteoporosis treatment by targeting abnormally elevated osteoclastic activity. Methyl gallate, a plant-derived phenolic compound, is known to have numerous pharmacological effects against inflammation, oxidation, and cancer. Our purpose was [...] Read more.

In the field of bone research, various natural derivatives have emerged as candidates for osteoporosis treatment by targeting abnormally elevated osteoclastic activity. Methyl gallate, a plant-derived phenolic compound, is known to have numerous pharmacological effects against inflammation, oxidation, and cancer. Our purpose was to explore the relation between methyl gallate and bone metabolism. Herein, we performed screening using methyl gallate by tartrate resistant acid phosphatase (TRAP) staining and revealed intracellular mechanisms responsible for methyl gallate-mediated regulation of osteoclastogenesis by Western blotting and quantitative reverse transcription polymerase chain reaction (RT-PCR). Furthermore, we assessed the effects of methyl gallate on the characteristics of mature osteoclasts. We found that methyl gallate significantly suppressed osteoclast formation through Akt and Btk-PLCγ2-Ca²⁺ signaling. The blockade of these pathways was confirmed through transduction of cells with a CA-Akt retrovirus and evaluation of Ca²⁺ influx intensity (staining with Fluo-3/AM). Indeed, methyl gallate downregulated the formation of actin ring-positive osteoclasts and resorption pit areas. In agreement with in vitro results, we found that administration of methyl gallate restored osteoporotic phenotype stimulated by acute systemic injection of lipopolysaccharide in vivo according to micro-computed tomography and histological analysis. Our data strongly indicate that methyl gallate may be useful for the development of a plant-based antiosteoporotic agent. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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Higher Levels of Serum Zonulin May Rather Be Associated with Increased Risk of Obesity and Hyperlipidemia, Than with Gastrointestinal Symptoms or Disease Manifestations

by Bodil Ohlsson, Marju Orho-Melander and Peter M. Nilsson

Int. J. Mol. Sci. 2017, 18(3), 582; https://doi.org/10.3390/ijms18030582 - 8 Mar 2017

Cited by 95 | Viewed by 10387

Abstract

Zonulin is considered a biomarker of increased intestinal permeability, and elevated levels have been found in celiac disease. The primary aim of this study was to examine the association between serum zonulin levels and gastrointestinal (GI) symptoms, and secondarily, between zonulin levels and [...] Read more.

Zonulin is considered a biomarker of increased intestinal permeability, and elevated levels have been found in celiac disease. The primary aim of this study was to examine the association between serum zonulin levels and gastrointestinal (GI) symptoms, and secondarily, between zonulin levels and anthropometric and metabolic factors. The offspring (n = 363) of the participants of the Malmö Diet and Cancer cardiovascular cohort (MDC-CV) were invited to an anthropometric and clinical examination, where fasting plasma glucose levels were measured. Questionnaires about lifestyle factors and medical history were completed along with the Visual Analog Scale for Irritable Bowel Syndrome (VAS-IBS). Zonulin levels were measured in serum by ELISA. Neither GI symptoms nor GI diseases had any influence on zonulin levels. Higher zonulin levels were associated with higher waist circumference (p = 0.003), diastolic blood pressure (p = 0.003), and glucose levels (p = 0.036). Higher zonulin levels were associated with increased risk of overweight (p < 0.001), obesity (p = 0.047), and hyperlipidemia (p = 0.048). We cannot detect altered zonulin levels among individuals reporting GI symptoms or GI diseases, but higher zonulin levels are associated with higher waist circumference, diastolic blood pressure, fasting glucose, and increased risk of metabolic diseases. Full article

(This article belongs to the Section Biochemistry)

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A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients

by Paula Hoff, Timo Gaber, Cindy Strehl, Manuela Jakstadt, Holger Hoff, Katharina Schmidt-Bleek, Annemarie Lang, Eric Röhner, Dörte Huscher, Georg Matziolis, Gerd-Rüdiger Burmester, Gerhard Schmidmaier, Carsten Perka, Georg N. Duda and Frank Buttgereit

Int. J. Mol. Sci. 2017, 18(3), 583; https://doi.org/10.3390/ijms18030583 - 8 Mar 2017

Cited by 38 | Viewed by 6862

Abstract

Immunologically restricted patients such as those with autoimmune diseases or malignancies often suffer from delayed or insufficient fracture healing. In human fracture hematomas and the surrounding bone marrow obtained from immunologically restricted patients, we analyzed the initial inflammatory phase on cellular and humoral [...] Read more.

Immunologically restricted patients such as those with autoimmune diseases or malignancies often suffer from delayed or insufficient fracture healing. In human fracture hematomas and the surrounding bone marrow obtained from immunologically restricted patients, we analyzed the initial inflammatory phase on cellular and humoral level via flow cytometry and multiplex suspension array. Compared with controls, we demonstrated higher numbers of immune cells like monocytes/macrophages, natural killer T (NKT) cells, and activated T helper cells within the fracture hematomas and/or the surrounding bone marrow. Also, several pro-inflammatory cytokines such as Interleukin (IL)-6 and Tumor necrosis factor α (TNFα), chemokines (e.g., Eotaxin and RANTES), pro-angiogenic factors (e.g., IL-8 and Macrophage migration inhibitory factor: MIF), and regulatory cytokines (e.g., IL-10) were found at higher levels within the fracture hematomas and/or the surrounding bone marrow of immunologically restricted patients when compared to controls. We conclude here that the inflammatory activity on cellular and humoral levels at fracture sites of immunologically restricted patients considerably exceeds that of control patients. The initial inflammatory phase profoundly differs between these patient groups and is probably one of the reasons for prolonged or insufficient fracture healing often occurring within immunologically restricted patients. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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Elderberry and Elderflower Extracts, Phenolic Compounds, and Metabolites and Their Effect on Complement, RAW 264.7 Macrophages and Dendritic Cells

by Giang Thanh Thi Ho, Helle Wangensteen and Hilde Barsett

Int. J. Mol. Sci. 2017, 18(3), 584; https://doi.org/10.3390/ijms18030584 - 8 Mar 2017

Cited by 60 | Viewed by 11506

Abstract

Modulation of complement activity and inhibition of nitric oxide (NO) production by macrophages and dendritic cells may have therapeutic value in inflammatory diseases. Elderberry and elderflower extracts, constituents, and metabolites were investigated for their effects on the complement system, and on NO production [...] Read more.

Modulation of complement activity and inhibition of nitric oxide (NO) production by macrophages and dendritic cells may have therapeutic value in inflammatory diseases. Elderberry and elderflower extracts, constituents, and metabolites were investigated for their effects on the complement system, and on NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages and murine dendritic D2SC/I cells. The EtOH crude extracts from elderberry and elderflower and the isolated anthocyanins and procyanidins possessed strong complement fixating activity and strong inhibitory activity on NO production in RAW cells and dendritic cells. Phenolic compounds in the range of 0.1–100 µM showed a dose-dependent inhibition of NO production, with quercetin, rutin, and kaempferol as the most potent ones. Among the metabolites, caffeic acid and 3,4-dihydroxyphenylacetic acid showed the strongest inhibitory effects on NO production in both cell lines, without having cytotoxic effect. Only 4-methylcatechol was cytotoxic at the highest tested concentration (100 µM). Elderberry and elderflower constituents may possess inflammatory modulating activity, which increases their nutritional value. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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Hepatitis B Virus X Protein Stimulates Proliferation, Wound Closure and Inhibits Apoptosis of HuH-7 Cells via CDC42

by Yongru Xu, Yingzi Qi, Jing Luo, Jing Yang, Qi Xie, Chen Deng, Na Su, Wei Wei, Deshun Shi, Feng Xu, Xiangping Li and Ping Xu

Int. J. Mol. Sci. 2017, 18(3), 586; https://doi.org/10.3390/ijms18030586 - 8 Mar 2017

Cited by 21 | Viewed by 5939

Abstract

Chronic hepatitis B virus (HBV) infection has been considered as the major cause of hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) has been reported to be oncogenic. The underlying mechanisms of HBV-related HCC are not fully understood, and the role played [...] Read more.

Chronic hepatitis B virus (HBV) infection has been considered as the major cause of hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) has been reported to be oncogenic. The underlying mechanisms of HBV-related HCC are not fully understood, and the role played by the HBx protein in HBV induced carcinogenesis remains controversial. CDC42, a member of the Rho GTPase family, has been reported to be overexpressed in several different cancers, including HBV-related HCC. However, the specific role of CDC42 in HCC development remains unclear. Here, we investigated the cellular mechanisms by which CDC42 was responsible for the higher proliferation of HuH-7 cells mediated by HBx. We found that the expression level of CDC42 and its activity were significantly increased in HuH-7-HBx cells. The deficiency of CDC42 using the CRISPR/Cas9 system and inhibition by specific inhibitor CASIN led to the reduction of HBx-mediated proliferation. Furthermore, we observed that IQ Motif Containing GTPase Activating Protein 1 (IQGAP1), the downstream mediator of the CDC42 pathway, might be involved in the carcinogenesis induced by HBx. Therefore, the HBx/CDC42/IQGAP1 signaling pathway may potentially play an important role in HBx-mediated carcinogenesis. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Hepatoprotective Effects of Nicotiflorin from Nymphaea candida against Concanavalin A-Induced and D-Galactosamine-Induced Liver Injury in Mice

by Jun Zhao, Shilei Zhang, Shuping You, Tao Liu, Fang Xu, Tengfei Ji and Zhengyi Gu

Int. J. Mol. Sci. 2017, 18(3), 587; https://doi.org/10.3390/ijms18030587 - 8 Mar 2017

Cited by 53 | Viewed by 5876

Abstract

Nymphaea candida was used to treat hepatitis in Ugyhur medicine, and nicotiflorin (kaempferol 3-O-β-rutinoside) is the main characteristic component in this plant. In this study, The the hepatoprotective activities of nicotiflorin from N. candida were investigated by Concanavalin A (Con A, [...] Read more.

Nymphaea candida was used to treat hepatitis in Ugyhur medicine, and nicotiflorin (kaempferol 3-O-β-rutinoside) is the main characteristic component in this plant. In this study, The the hepatoprotective activities of nicotiflorin from N. candida were investigated by Concanavalin A (Con A, 20 mg/kg bw)- and d-Galactosamine (d-GalN, 800 mg/kg bw)-induced acute liver injury in mice. Pretreatment with nicotiflorin (25, 50, 100 mg/kg bw/day, p.o.) for ten days significantly reduced the impact of Con A toxicity (20 mg/kg bw) on the serum markers of liver injury, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). The hepatic anti-oxidant parameters (malondialdehyde, MDA; superoxide dismutase, SOD; glutathione, GSH; and nitric oxide, NO) in mice with nicotiflorin treatment were significantly antagonized for the pro-oxidant effects of Con A. Moreover, pretreatment with nicotiflorin (100 mg/kg bw) significantly decreased Con A-induced elevation in the serum levels of pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) (p < 0.05). A protective effect was reconfirmed against d-GalN-induced chemical liver injury, elevated serum enzymatic and cytokines levels were significantly decreased by nicotiflorin, and liver homogenate antioxidant indicators were significantly restored toward normal levels. Both histopathological studies also supported the protective effects of nicotiflorin. Therefore, the presented results suggest that nicotiflorin is the potent hepatoprotective agent that could protect the liver against acute immunological and chemical injury; this ability might be attributed to its antioxidant and immunoregulation potential. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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Exploring the Functions of 9-Lipoxygenase (DkLOX3) in Ultrastructural Changes and Hormonal Stress Response during Persimmon Fruit Storage

by Kun Meng, Yali Hou, Ye Han, Qiuyan Ban, Yiheng He, Jiangtao Suo and Jingping Rao

Int. J. Mol. Sci. 2017, 18(3), 589; https://doi.org/10.3390/ijms18030589 - 15 Mar 2017

Cited by 8 | Viewed by 4202

Abstract

Lipoxygenase (LOX) initiates the hydroperoxidation of polyunsaturated fatty acids and is involved in multiple physiological processes. In this study, investigation of various microscopic techniques showed that the fruit peel cellular microstructure of the two persimmon cultivars differed after 12 days of storage, resulting [...] Read more.

Lipoxygenase (LOX) initiates the hydroperoxidation of polyunsaturated fatty acids and is involved in multiple physiological processes. In this study, investigation of various microscopic techniques showed that the fruit peel cellular microstructure of the two persimmon cultivars differed after 12 days of storage, resulting in fruit weight loss and an increased number and depth of microcracks. Analysis of subcellular localization revealed that greater amounts of DkLOX3-immunolabelled gold particles accumulated in “Fupingjianshi” than in “Ganmaokui” during storage. In addition, the expression of DkLOX3 was positively up-regulated by abscisic acid (ABA), concomitant with the promotion of ethylene synthesis and loss of firmness, and was suppressed by salicylic acid (SA), concomitant with the maintenance of fruit firmness, inhibition of ethylene production and weight loss. In particular, the expression of DkLOX3 differed from the ethylene trajectory after methyl jasmonate (MeJA) treatment. Furthermore, we isolated a 1105 bp 5′ flanking region of DkLOX3 and the activity of promoter deletion derivatives was induced through various hormonal treatments. Promoter sequence cis-regulatory elements were analysed, and two conserved hormone-responsive elements were found to be essential for responsiveness to hormonal stress. Overall, these results will provide us with new clues for exploring the functions of DkLOX3 in fruit ripening and hormonal stress response. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Solvent Retention Capacities of Oat Flour

by Qianwen Niu, Yu Pu, Xiaoping Li, Zhen Ma and Xinzhong Hu

Int. J. Mol. Sci. 2017, 18(3), 590; https://doi.org/10.3390/ijms18030590 - 13 Mar 2017

Cited by 14 | Viewed by 4369

Abstract

This study measured the solvent retention capacities (SRCs) of flours from eight oat varieties and one wheat variety against different solvents to explore the swelling volume of oat flour with different solvents, and thus provide a theoretical basis for quick β-glucan analysis. The [...] Read more.

This study measured the solvent retention capacities (SRCs) of flours from eight oat varieties and one wheat variety against different solvents to explore the swelling volume of oat flour with different solvents, and thus provide a theoretical basis for quick β-glucan analysis. The SRC profile consists of water SRC (WSRC), 50% sucrose SRC (SSRC), 5% lactic acid SRC (LASRC), 5% Na₂CO₃ SRC (SCASRC), NaCl SRC (SCSRC), CaCl₂ SRC (CCSRC), FeCl₃ SRC (FCSRC), sodium cholate SRC (SCHSRC), NaOH (pH 10) SRC (SHSRC), Na₂CO₃ (pH 10) SRC (SCABSRC) and SDS (pH 10) SRC (SDSSRC) values, and a Chopin SRC kit was used to measure the SRC value. SRCs of the oat flours increased when the solvents turned from neutral (water and NaCl) to acidic (5% lactic acid) or alkaline (5% Na₂CO₃, CaCl₂, FeCl₃, NaOH and pH 10 Na₂CO₃), and rose as the metal ion valencies of the metal salts (NaCl, CaCl₂ and FeCl₃) increased. The β-glucan contents were significantly positively correlated with the SCSRC (0.83**), CCSRC (0.82**), SCHSRC (0.80**) and FCSRC (0.78*). SRC measurements of β-glucan in oat flours revealed that the CCSRC values were related with β-glucan (0.64*) but not related with protein and starch. CaCl₂ could therefore potentially be exploited as a reagent for β-glucan assay. Full article

(This article belongs to the Special Issue Glucan: New Perspectives on Biochemistry and Application)

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GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation

by Mohamed Amine Zaouali, Arnau Panisello, Alexandre Lopez, Carlos Castro, Emma Folch, Teresa Carbonell, Anabela Rolo, Carlos Marques Palmeira, Agustin Garcia-Gil, René Adam and Joan Roselló-Catafau

Int. J. Mol. Sci. 2017, 18(3), 591; https://doi.org/10.3390/ijms18030591 - 8 Mar 2017

Cited by 17 | Viewed by 5330

Abstract

We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia–reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) [...] Read more.

We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia–reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Hepatic Transcriptome Profiles of Mice with Diet-Induced Nonalcoholic Steatohepatitis Treated with Astaxanthin and Vitamin E

by Masuko Kobori, Yumiko Takahashi, Mutsumi Sakurai, Yinhua Ni, Guanliang Chen, Mayumi Nagashimada, Shuichi Kaneko and Tsuguhito Ota

Int. J. Mol. Sci. 2017, 18(3), 593; https://doi.org/10.3390/ijms18030593 - 8 Mar 2017

Cited by 22 | Viewed by 6272

Abstract

Astaxanthin alleviates hepatic lipid accumulation and peroxidation, inflammation, and fibrosis in mice with high-cholesterol, high-cholate, and high-fat (CL) diet-induced nonalcoholic steatohepatitis (NASH) [...] Full article

(This article belongs to the Special Issue Nutrigenomics of Risk Factors for Disease)

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Biglycan- and Sphingosine Kinase-1 Signaling Crosstalk Regulates the Synthesis of Macrophage Chemoattractants

by Louise Tzung-Harn Hsieh, Madalina-Viviana Nastase, Heiko Roedig, Jinyang Zeng-Brouwers, Chiara Poluzzi, Stephanie Schwalm, Christian Fork, Claudia Tredup, Ralf P. Brandes, Malgorzata Wygrecka, Andrea Huwiler, Josef Pfeilschifter and Liliana Schaefer

Int. J. Mol. Sci. 2017, 18(3), 595; https://doi.org/10.3390/ijms18030595 - 9 Mar 2017

Cited by 31 | Viewed by 7122

Abstract

In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5 through selective utilization of Toll-like receptors (TLRs) and their adaptor molecules. However, the respective downstream signaling events resulting in biglycan-induced [...] Read more.

In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5 through selective utilization of Toll-like receptors (TLRs) and their adaptor molecules. However, the respective downstream signaling events resulting in biglycan-induced CCL2 and CCL5 production have not yet been defined. Here, we show that biglycan stimulates the production and activation of sphingosine kinase 1 (SphK1) in a TLR4- and Toll/interleukin (IL)-1R domain-containing adaptor inducing interferon (IFN)-β (TRIF)-dependent manner in murine primary macrophages. We provide genetic and pharmacological proof that SphK1 is a crucial downstream mediator of biglycan-triggered CCL2 and CCL5 mRNA and protein expression. This is selectively driven by biglycan/SphK1-dependent phosphorylation of the nuclear factor NF-κB p65 subunit, extracellular signal-regulated kinase (Erk)1/2 and p38 mitogen-activated protein kinases. Importantly, in vivo overexpression of soluble biglycan causes Sphk1-dependent enhancement of renal CCL2 and CCL5 and macrophage recruitment into the kidney. Our findings describe the crosstalk between biglycan- and SphK1-driven extracellular matrix- and lipid-signaling. Thus, SphK1 may represent a new target for therapeutic intervention in biglycan-evoked inflammatory conditions. Full article

(This article belongs to the Special Issue Pain and Inflammation)

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Zebrafish Embryo as an In Vivo Model for Behavioral and Pharmacological Characterization of Methylxanthine Drugs

by Ram Manohar Basnet, Michela Guarienti and Maurizio Memo

Int. J. Mol. Sci. 2017, 18(3), 596; https://doi.org/10.3390/ijms18030596 - 9 Mar 2017

Cited by 34 | Viewed by 8912

Abstract

Zebrafish embryo is emerging as an important tool for behavior analysis as well as toxicity testing. In this study, we compared the effect of nine different methylxanthine drugs using zebrafish embryo as a model. We performed behavioral analysis, biochemical assay and Fish Embryo [...] Read more.

Zebrafish embryo is emerging as an important tool for behavior analysis as well as toxicity testing. In this study, we compared the effect of nine different methylxanthine drugs using zebrafish embryo as a model. We performed behavioral analysis, biochemical assay and Fish Embryo Toxicity (FET) test in zebrafish embryos after treatment with methylxanthines. Each drug appeared to behave in different ways and showed a distinct pattern of results. Embryos treated with seven out of nine methylxanthines exhibited epileptic-like pattern of movements, the severity of which varied with drugs and doses used. Cyclic AMP measurement showed that, despite of a significant increase in cAMP with some compounds, it was unrelated to the observed movement behavior changes. FET test showed a different pattern of toxicity with different methylxanthines. Each drug could be distinguished from the other based on its effect on mortality, morphological defects and teratogenic effects. In addition, there was a strong positive correlation between the toxic doses (TC₅₀) calculated in zebrafish embryos and lethal doses (LD₅₀) in rodents obtained from TOXNET database. Taken together, all these findings elucidate the potentiality of zebrafish embryos as an in vivo model for behavioral and toxicity testing of methylxanthines and other related compounds. Full article

(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)

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Open AccessArticle

Characterization of hsa_circ_0004277 as a New Biomarker for Acute Myeloid Leukemia via Circular RNA Profile and Bioinformatics Analysis

by Wei Li, Chaoqin Zhong, Jun Jiao, Peng Li, Baoxia Cui, Chunyan Ji and Daoxin Ma

Int. J. Mol. Sci. 2017, 18(3), 597; https://doi.org/10.3390/ijms18030597 - 9 Mar 2017

Cited by 160 | Viewed by 8327

Abstract

Circular RNAs (circRNAs) represent a widespread class of non-coding RNAs, which drew little attention in the past. Recently, limited data showed their promising future to act as biomarkers in human cancer, but the characteristics and functions remain largely unknown in hematopoietic malignancies, especially [...] Read more.

Circular RNAs (circRNAs) represent a widespread class of non-coding RNAs, which drew little attention in the past. Recently, limited data showed their promising future to act as biomarkers in human cancer, but the characteristics and functions remain largely unknown in hematopoietic malignancies, especially in leukemia. In this study, with the help of circRNA microarray, we demonstrated the expression profile of circRNAs in acute myeloid leukemia (AML) patients, and identified a large number of circRNAs possibly expressed in a leukemia specific manner. We also described a circRNA signature related to AML risk-status based on the bioinformatics prediction. In particular, a downregulated circRNA, hsa_circ_0004277, was characterized and functionally evaluated in a cohort of 115 human samples, thus offering a potential diagnostic marker and treatment target in AML. Interestingly, we found chemotherapy could significantly restore the expression of hsa_circ_0004277, indicating the increasing level of hsa_circ_0004277 was associated with successful treatment. Furthermore, a detailed circRNA–miRNA–mRNA interaction network was presented for hsa_circ_0004277, allowing us to better understand its underlying mechanisms for function in AML. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessArticle

ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

by Maria S. Ioannou and Margaret Fahnestock

Int. J. Mol. Sci. 2017, 18(3), 599; https://doi.org/10.3390/ijms18030599 - 9 Mar 2017

Cited by 67 | Viewed by 7672

Abstract

Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to [...] Read more.

Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to promote apoptosis. The ratio of TrkA to p75NTR affects whether proNGF and mature NGF signal cell survival or apoptosis. The purpose of this study was to determine whether the loss of TrkA influences p75NTR or sortilin expression levels, and to establish whether proNGF and mature NGF have a similar ability to switch between cell survival and cell death. We systematically altered TrkA receptor levels by priming cells with NGF, using small interfering RNA, and using the mutagenized PC12nnr5 cell line. We found that both NGF and proNGF can support cell survival in cells expressing TrkA, even in the presence of p75NTR and sortilin. However, when TrkA is reduced, proNGF signals cell death, while NGF exhibits no activity. In the absence of TrkA, proNGF-induced cell death occurs, even when p75NTR and sortilin levels are reduced. These results show that proNGF can switch between neurotrophic and apoptotic activity in response to changes in TrkA receptor levels, whereas mature NGF cannot. These results also support the model that proNGF is neurotrophic under normal circumstances, but that a loss in TrkA in the presence of p75NTR and sortilin, as occurs in neurodegenerative disease or injury, shifts proNGF, but not NGF, signalling from cell survival to cell death. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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Open AccessArticle

The Effect of Chinese Herbal Medicine Formula mKG on Allergic Asthma by Regulating Lung and Plasma Metabolic Alternations

by Meng Yu, Hong-Mei Jia, Feng-Xia Cui, Yong Yang, Yang Zhao, Mao-Hua Yang and Zhong-Mei Zou

Int. J. Mol. Sci. 2017, 18(3), 602; https://doi.org/10.3390/ijms18030602 - 10 Mar 2017

Cited by 31 | Viewed by 6788

Abstract

Asthma is a chronic inflammatory disorder of the airway and is characterized by airway remodeling, hyperresponsiveness, and shortness of breath. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicines (TCM), has been demonstrated to have good therapeutic effects on experimental allergic [...] Read more.

Asthma is a chronic inflammatory disorder of the airway and is characterized by airway remodeling, hyperresponsiveness, and shortness of breath. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicines (TCM), has been demonstrated to have good therapeutic effects on experimental allergic asthma. However, its anti-asthma mechanism remains currently unknown. In the present work, metabolomics studies of biochemical changes in the lung tissue and plasma of ovalbumin (OVA)-induced allergic asthma mice with mKG treatment were performed using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Partial least squares–discriminate analysis (PLS−DA) indicated that the metabolic perturbation induced by OVA was reduced after mKG treatment. A total of twenty-four metabolites involved in seven metabolic pathways were identified as potential biomarkers in the development of allergic asthma. Among them, myristic acid (L3 or P2), sphinganine (L6 or P4), and lysoPC(15:0) (L12 or P16) were detected both in lung tissue and plasma. Additionally, l-acetylcarnitine (L1), thromboxane B2 (L2), 10-HDoHE (L10), and 5-HETE (L11) were first reported to be potential biomarkers associated with allergic asthma. The treatment of mKG mediated all of those potential biomarkers except lysoPC(15:0) (P16). The anti-asthma mechanism of mKG can be achieved through the comprehensive regulation of multiple perturbed biomarkers and metabolic pathways. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients

by Jing Liu, Zhiyu Chen, Hanmei Chen, Yingyong Hou, Weiqi Lu, Junyi He, Hanxing Tong, Yuhong Zhou and Weimin Cai

Int. J. Mol. Sci. 2017, 18(3), 603; https://doi.org/10.3390/ijms18030603 - 13 Mar 2017

Cited by 37 | Viewed by 5488

Abstract

Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), [...] Read more.

Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), and nuclear receptor (Pregnane X Receptor (PXR, encoded by NR1I2)) on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300–600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs) (CYP3A4 rs2242480; ABCB1 rs1045642; ABCG2 rs2231137; NRI12 rs3814055, rs6785049, rs2276706), and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations (from 272.22 to 4365.96 ng/mL). Subjects of GG in rs2242480, T allele carriers in rs1045642 and CC in rs3814055 had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of CC in rs3814055 had significantly higher incidence rate of edema. The genetic polymorphisms of rs2242480, rs1045642, rs3814055 were significantly associated with IM plasma levels, and the genetic variations of rs3814055 were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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Bimolecular Rate Constants for FAD-Dependent Glucose Dehydrogenase from Aspergillus terreus and Organic Electron Acceptors

by Nozomu Tsuruoka, Takuya Sadakane, Rika Hayashi and Seiya Tsujimura

Int. J. Mol. Sci. 2017, 18(3), 604; https://doi.org/10.3390/ijms18030604 - 10 Mar 2017

Cited by 33 | Viewed by 5479

Abstract

The flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH) from Aspergillus species require suitable redox mediators to transfer electrons from the enzyme to the electrode surface for the application of bioelectrical devices. Although several mediators for FAD-GDH are already in use, they are still far [...] Read more.

The flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH) from Aspergillus species require suitable redox mediators to transfer electrons from the enzyme to the electrode surface for the application of bioelectrical devices. Although several mediators for FAD-GDH are already in use, they are still far from optimum in view of potential, kinetics, sustainability, and cost-effectiveness. Herein, we investigated the efficiency of various phenothiazines and quinones in the electrochemical oxidation of FAD-GDH from Aspergillus terreus. At pH 7.0, the logarithm of the bimolecular oxidation rate constants appeared to depend on the redox potentials of all the mediators tested. Notably, the rate constant of each molecule for FAD-GDH was approximately 2.5 orders of magnitude higher than that for glucose oxidase from Aspergillus sp. The results suggest that the electron transfer kinetics is mainly determined by the formal potential of the mediator, the driving force of electron transfer, and the electron transfer distance between the redox active site of the mediator and the FAD, affected by the steric or chemical interactions. Higher k₂ values were found for ortho-quinones than for para-quinones in the reactions with FAD-GDH and glucose oxidase, which was likely due to less steric hindrance in the active site in the case of the ortho-quinones. Full article

(This article belongs to the Special Issue Biomolecular Engineering and Bioelectronics)

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Open AccessArticle

In-Depth Lipidomic Analysis of Molecular Species of Triacylglycerides, Diacylglycerides, Glycerophospholipids, and Sphingolipids of Buttermilk by GC-MS/FID, HPLC-ELSD, and UPLC-QToF-MS

by Pilar Castro-Gómez, Olimpio Montero and Javier Fontecha

Int. J. Mol. Sci. 2017, 18(3), 605; https://doi.org/10.3390/ijms18030605 - 10 Mar 2017

Cited by 36 | Viewed by 7131

Abstract

Buttermilk, a byproduct of butter manufacturing, has gained considerable attention due to its high concentration of polar lipids as phospho- and sphingolipids from the milk fat globule membrane (MFGM). These polar lipids (PLs) are essential components of all cellular membranes and exert a [...] Read more.

Buttermilk, a byproduct of butter manufacturing, has gained considerable attention due to its high concentration of polar lipids as phospho- and sphingolipids from the milk fat globule membrane (MFGM). These polar lipids (PLs) are essential components of all cellular membranes and exert a variety of indispensable metabolic, neurological, and intracellular signaling processes. Despite its importance, there are few research studies that report a comprehensive characterization of the lipid molecular species of MFGM that could contribute to a better understanding of their putative healthful activities. In this study, procedures such as pressurized liquid extraction of polar and nonpolar lipids and their fractionation by flash chromatography have been carried out. The obtained fractions were submitted to an exhaustive characterization from a lipidomic point of view. The characterization includes new data about the identification and quantification of triacylglycerides (TAG), diacylglycerides (DAG), and phospho- and sphingolipids using different chromatographic techniques. The fatty acid profile was comparable to that of the milk fat but with a highly diverse composition of fatty acids. Molecular species have also been determined by using ultra-high performance liquid chromatography/quadruple-time-of-flight mass spectrometry (UPLC/QToF-MS). The TAG (16:0/16:0/6:0) and TAG (16:0/16:0/8:0) were the predominant saturated TAG species and TAG (14:0/18:1/16:0) and TAG (16:0/16:0/18:1) presented the highest content of monounsaturated TAG species. Furthermore; over 30 molecular species of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI) could be identified within PL, with PC (16:0/18:1) being the most abundant species. Whereas C16:0 was found to be the preferred FA in TAGs, it was C18:1 in PLs. Several ganglioside species have also been characterized with d18:1 ceramide moiety and secondary acyl chains ranging from C20:0 to C26:1. This approach could broaden the applications of high-resolution mass spectrometry for a better understanding of the role of MFGM and its functionality. Full article

(This article belongs to the Special Issue Lipidomics and Glycomics: New Advances in Food Science and Nutrition)

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Open AccessCommunication

Phosphorus and Iron Deficiencies Influences Rice Shoot Growth in an Oxygen Dependent Manner: Insight from Upland and Lowland Rice

by Jenjira Mongon, Nanthana Chaiwong, Nadia Bouain, Chanakan Prom-u-thai, David Secco and Hatem Rouached

Int. J. Mol. Sci. 2017, 18(3), 607; https://doi.org/10.3390/ijms18030607 - 10 Mar 2017

Cited by 16 | Viewed by 4821

Abstract

Rice is the main staple crop for one-third of the world population. To maximize yields, large quantities and constant input of fertilizers containing essential nutrients such as phosphorus (P) and iron (Fe) are added. Rice can germinate in both aerobic and anaerobic conditions, [...] Read more.

Rice is the main staple crop for one-third of the world population. To maximize yields, large quantities and constant input of fertilizers containing essential nutrients such as phosphorus (P) and iron (Fe) are added. Rice can germinate in both aerobic and anaerobic conditions, but the crosstalk between oxygen (O₂) and nutrients such as P and Fe on plant growth remains obscure. The aim of this work was to test whether such interactions exist, and, if so, if they are conserved between up- and lowland rice varieties. To do so, we assessed shoot and root biomass as well as inorganic phosphate (Pi) accumulation in four rice varieties, including two lowland rice varieties Nipponbare and Suphanburi 1 (SPR1) (adapted to non-aerated condition) and two upland rice varieties CMU122 and Sew Mae Jun (SMJ) (adapted to aerated condition) under various conditions of Pi and/or Fe deficiencies, in aerated and non-areated solution. Under these different experimental conditions, our results revealed that the altered shoot biomass in Nipponbare and SPR1 was O₂-dependent but to a lesser extent in CMU122 and SMJ cultivars. In this perspective, discovering the biological significance and molecular basis of these mineral elements and O₂ signal interaction is needed to fully appreciate the performance of plants to multiple environmental changes. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessArticle

Custom Array Comparative Genomic Hybridization: the Importance of DNA Quality, an Expert Eye, and Variant Validation

by Francesca Lantieri, Michela Malacarne, Stefania Gimelli, Giuseppe Santamaria, Domenico Coviello and Isabella Ceccherini

Int. J. Mol. Sci. 2017, 18(3), 609; https://doi.org/10.3390/ijms18030609 - 10 Mar 2017

Cited by 4 | Viewed by 4573

Abstract

The presence of false positive and false negative results in the Array Comparative Genomic Hybridization (aCGH) design is poorly addressed in literature reports. We took advantage of a custom aCGH recently carried out to analyze its design performance, the use of several Agilent [...] Read more.

The presence of false positive and false negative results in the Array Comparative Genomic Hybridization (aCGH) design is poorly addressed in literature reports. We took advantage of a custom aCGH recently carried out to analyze its design performance, the use of several Agilent aberrations detection algorithms, and the presence of false results. Our study provides a confirmation that the high density design does not generate more noise than standard designs and, might reach a good resolution. We noticed a not negligible presence of false negative and false positive results in the imbalances call performed by the Agilent software. The Aberration Detection Method 2 (ADM-2) algorithm with a threshold of 6 performed quite well, and the array design proved to be reliable, provided that some additional filters are applied, such as considering only intervals with average absolute log₂ratio above 0.3. We also propose an additional filter that takes into account the proportion of probes with log₂ratio exceeding suggestive values for gain or loss. In addition, the quality of samples was confirmed to be a crucial parameter. Finally, this work raises the importance of evaluating the samples profiles by eye and the necessity of validating the imbalances detected. Full article

(This article belongs to the Section Biochemistry)

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The Application of Curve Fitting on the Voltammograms of Various Isoforms of Metallothioneins–Metal Complexes

by Miguel Angel Merlos Rodrigo, Jorge Molina-López, Ana Maria Jimenez Jimenez, Elena Planells Del Pozo, Pavlina Adam, Tomas Eckschlager, Ondrej Zitka, Lukas Richtera and Vojtech Adam

Int. J. Mol. Sci. 2017, 18(3), 610; https://doi.org/10.3390/ijms18030610 - 11 Mar 2017

Cited by 10 | Viewed by 5376

Abstract

The translation of metallothioneins (MTs) is one of the defense strategies by which organisms protect themselves from metal-induced toxicity. MTs belong to a family of proteins comprising MT-1, MT-2, MT-3, and MT-4 classes, with multiple isoforms within each class. The main aim of [...] Read more.

The translation of metallothioneins (MTs) is one of the defense strategies by which organisms protect themselves from metal-induced toxicity. MTs belong to a family of proteins comprising MT-1, MT-2, MT-3, and MT-4 classes, with multiple isoforms within each class. The main aim of this study was to determine the behavior of MT in dependence on various externally modelled environments, using electrochemistry. In our study, the mass distribution of MTs was characterized using MALDI-TOF. After that, adsorptive transfer stripping technique with differential pulse voltammetry was selected for optimization of electrochemical detection of MTs with regard to accumulation time and pH effects. Our results show that utilization of 0.5 M NaCl, pH 6.4, as the supporting electrolyte provides a highly complicated fingerprint, showing a number of non-resolved voltammograms. Hence, we further resolved the voltammograms exhibiting the broad and overlapping signals using curve fitting. The separated signals were assigned to the electrochemical responses of several MT complexes with zinc(II), cadmium(II), and copper(II), respectively. Our results show that electrochemistry could serve as a great tool for metalloproteomic applications to determine the ratio of metal ion bonds within the target protein structure, however, it provides highly complicated signals, which require further resolution using a proper statistical method, such as curve fitting. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

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Open AccessArticle

Sex-Dependent Effects of HO-1 Deletion from Adipocytes in Mice

by Peter A. Hosick, Mary Frances Weeks, Michael W. Hankins, Kyle H. Moore and David E. Stec

Int. J. Mol. Sci. 2017, 18(3), 611; https://doi.org/10.3390/ijms18030611 - 11 Mar 2017

Cited by 12 | Viewed by 10335

Abstract

Induction of heme oxygenase-1 (HO-1) has been demonstrated to decrease body weight and improve insulin sensitivity in several models of obesity in rodents. To further study the role of HO-1 in adipose tissue, we created an adipose-specific HO-1 knockout mouse model. Male and [...] Read more.

Induction of heme oxygenase-1 (HO-1) has been demonstrated to decrease body weight and improve insulin sensitivity in several models of obesity in rodents. To further study the role of HO-1 in adipose tissue, we created an adipose-specific HO-1 knockout mouse model. Male and female mice were fed either a control or a high-fat diet for 30 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were determined every six weeks. Adipocyte-specific knockout of HO-1 had no significant effect on body weight in mice fed a high-fat diet but increased body weight in female mice fed a normal-fat diet. Although body weights were not different in females fed a high fat diet, loss of HO-1 in adipocytes resulted in significant alterations in body composition. Adipose-specific HO-1 knockout resulted in increased fasting hyperglycemia and insulinemia in female but not male mice on both diets. Adipose-specific knockout of HO-1 resulted in a significant loss of HO activity and a decrease in the protein levels of adiponectin in adipose tissue. These results demonstrate that loss of HO-1 in adipocytes has greater effects on body fat and fasting hyperglycemia in a sex-dependent fashion and that expression of HO-1 in adipose tissue may have a greater protective role in females as compared to males. Full article

(This article belongs to the Special Issue Adipokines)

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Open AccessArticle

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

by Joseph Behnke, Aneesha Cheedalla, Vatsal Bhatt, Maysa Bhat, Shavonne Teng, Alicia Palmieri, Charles Christian Windon, Smita Thakker-Varia and Janet Alder

Int. J. Mol. Sci. 2017, 18(3), 612; https://doi.org/10.3390/ijms18030612 - 11 Mar 2017

Cited by 20 | Viewed by 8419

Abstract

The neuropeptide VGF (non-acronymic) is induced by brain-derived neurotrophic factor and promotes hippocampal neurogenesis, as well as synaptic activity. However, morphological changes induced by VGF have not been elucidated. Developing hippocampal neurons were exposed to VGF through bath application or virus-mediated expression in [...] Read more.

The neuropeptide VGF (non-acronymic) is induced by brain-derived neurotrophic factor and promotes hippocampal neurogenesis, as well as synaptic activity. However, morphological changes induced by VGF have not been elucidated. Developing hippocampal neurons were exposed to VGF through bath application or virus-mediated expression in vitro. VGF-derived peptide, TLQP-62, enhanced dendritic branching, and outgrowth. Furthermore, VGF increased dendritic spine density and the proportion of immature spines. Spine formation was associated with increased synaptic protein expression and co-localization of pre- and postsynaptic markers. Three non-synonymous single nucleotide polymorphisms (SNPs) were selected in human VGF gene. Transfection of N2a cells with plasmids containing these SNPs revealed no relative change in protein expression levels and normal protein size, except for a truncated protein from the premature stop codon, E525X. All three SNPs resulted in a lower proportion of N2a cells bearing neurites relative to wild-type VGF. Furthermore, all three mutations reduced the total length of dendrites in developing hippocampal neurons. Taken together, our results suggest VGF enhances dendritic maturation and that these effects can be altered by common mutations in the VGF gene. The findings may have implications for people suffering from psychiatric disease or other conditions who may have altered VGF levels. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Open AccessArticle

Strawberry-Tree Honey Induces Growth Inhibition of Human Colon Cancer Cells and Increases ROS Generation: A Comparison with Manuka Honey

by Sadia Afrin, Tamara Y. Forbes-Hernandez, Massimiliano Gasparrini, Stefano Bompadre, José L. Quiles, Gavino Sanna, Nadia Spano, Francesca Giampieri and Maurizio Battino

Int. J. Mol. Sci. 2017, 18(3), 613; https://doi.org/10.3390/ijms18030613 - 11 Mar 2017

Cited by 76 | Viewed by 14207

Abstract

Honey is a natural product known to modulate several biological activities including cancer. The aim of the present study was to examine the phytochemical content and the antioxidant activity of Strawberry tree (Arbutus unedo) honey (STH) and its cytotoxic properties against [...] Read more.

Honey is a natural product known to modulate several biological activities including cancer. The aim of the present study was to examine the phytochemical content and the antioxidant activity of Strawberry tree (Arbutus unedo) honey (STH) and its cytotoxic properties against human colon adenocarcinoma (HCT-116) and metastatic (LoVo) cell lines in comparison with Manuka (Leptospermum scoparium) honey (MH). Several unifloral STH and MH were analyzed for their phenolic, flavonoid, amino acid and protein contents, as well as their radical scavenging activities. STH from the Berchidda area showed the highest amount of phenolic, flavonoid, amino acid and protein content, and antioxidant capacity compared to MH. Both STH and MH induced cytotoxicity and cell death in a dose- and time-dependent manner in HCT-116 and LoVo cells, with less toxicity on non-cancer cells. Compared to MH, STH showed more effect at lower concentrations on HCT-116 and LoVo cells. In addition, both honeys increased intracellular reactive oxygen species (ROS) generation. In HCT-116 cells, STH and MH induced similar ROS production but in LoVo cells STH induced a higher percentage of ROS compared to MH. Our results indicate that STH and MH can induce cell growth inhibition and ROS generation in colon adenocarcinoma and metastatic cells, which could be due to the presence of phytochemicals with antioxidant properties. These preliminary results are interesting and suggest a potential chemopreventive action which could be useful for further studies in order to develop chemopreventive agents for colon cancer. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2016)

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Open AccessArticle

Myocardial Ischemic Postconditioning Promotes Autophagy against Ischemia Reperfusion Injury via the Activation of the nNOS/AMPK/mTOR Pathway

by Maojuan Hao, Suhua Zhu, Liang Hu, Hongyi Zhu, Xiaowei Wu and Qingping Li

Int. J. Mol. Sci. 2017, 18(3), 614; https://doi.org/10.3390/ijms18030614 - 11 Mar 2017

Cited by 57 | Viewed by 7579

Abstract

Autophagy participates in the progression of many diseases, comprising ischemia/ reperfusion (I/R). It is reported that it is involved in the protective mechanism of ischemic postconditioning (IPostC). According to research, neuronal nitric oxide synthase (nNOS) is also involved in the condition of I/R [...] Read more.

Autophagy participates in the progression of many diseases, comprising ischemia/ reperfusion (I/R). It is reported that it is involved in the protective mechanism of ischemic postconditioning (IPostC). According to research, neuronal nitric oxide synthase (nNOS) is also involved in the condition of I/R and IPostC. However, the relationship between nNOS, autophagy and IPostC has not been previously investigated. We hypothesize that IPostC promotes autophagy activity against I/R injury partially through nNOS-mediated pathways. Mouse hearts were subjected to I/R injury through the ligation of the left anterior descending coronary artery. H9c2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro. IPostC, compared with I/R, restored nNOS activity, increased the formation of autophagosome and restored the impaired autophagic flux, thus autophagic activity was raised markedly. IPostC increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and suppressed mammalian target of rapamycin (mTOR), but a selective nNOS inhibitor abolished those effects. Similar effects of IPostC were demonstrated in H9c2 cells in vitro. IPostC decreased infarct size and preserved most of the normal structure. The level of reactive oxygen species (ROS) and cell apoptosis were reduced by IPostC with improved cell viability and mitochondrial membrane potential. However, an autophagy inhibitor suppressed the protective effects. These results suggest that IPostC promoted autophagy against I/R injury at least partially via the activation of nNOS/AMPK/mTOR pathway. Full article

(This article belongs to the Special Issue Improvement of Cardiac Function in Heart Failure 2017)

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Open AccessArticle

Cellular Midpalatal Suture Changes after Rapid Maxillary Expansion in Growing Subjects: A Case Report

by Alberto Caprioglio, Rosamaria Fastuca, Piero Antonio Zecca, Matteo Beretta, Carlo Mangano, Adriano Piattelli, Aldo Macchi and Giovanna Iezzi

Int. J. Mol. Sci. 2017, 18(3), 615; https://doi.org/10.3390/ijms18030615 - 11 Mar 2017

Cited by 29 | Viewed by 6071

Abstract

The present case report aimed to investigate immediate histologic changes in midpalatal suture in humans following rapid maxillary expansion compared to control. Three patients (mean age 8.3 +/- 0.9 years) were enrolled in the case report and underwent midpalatal suture biopsy. Two patients [...] Read more.

The present case report aimed to investigate immediate histologic changes in midpalatal suture in humans following rapid maxillary expansion compared to control. Three patients (mean age 8.3 +/- 0.9 years) were enrolled in the case report and underwent midpalatal suture biopsy. Two patients underwent treatment before biopsy. The third patient did not show transversal maxillary deficiency and was enrolled as a control. Biopsy samples of midpalatal suture at 7 (subject 1) and 30 days (subject 2) after maxillary expansion as well as of one control (subject 3) were collected and processed for histology. In the control (subject 3) inter-digitations at the palatal suture gap were observed. At 7 days (subject 1) mature bone with small marrow spaces and trabecular bone with the peculiar storiform appearance inside the soft tissue and collagen fibers running parallel only in the central part were present. At 30 days (subject 2), a greater number of newly-formed bone trabeculae with a perpendicular orientation to the long axis of the suture could be seen. At 30 days the fibrous component of bone tissue was less represented compared to the sample at 7 days. Data from the preliminary histological results showed that bone formation was observed in the gap after rapid maxillary expansion, although the healing process was still ongoing. Full article

(This article belongs to the Special Issue Role and Application of Mesenchymal Stem Cells on Regenerative Medicine)

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Open AccessArticle

Natural Killer Cell Assessment in Peripheral Circulation and Bronchoalveolar Lavage Fluid of Patients with Severe Sepsis: A Case Control Study

by Paulo Souza-Fonseca-Guimaraes, Fernando Guimaraes, Caroline Natânia De Souza-Araujo, Lidiane Maria Boldrini Leite, Alexandra Cristina Senegaglia, Anita Nishiyama and Fernando Souza-Fonseca-Guimaraes

Int. J. Mol. Sci. 2017, 18(3), 616; https://doi.org/10.3390/ijms18030616 - 12 Mar 2017

Cited by 3 | Viewed by 5169

Abstract

Sepsis is a complex systemic inflammatory syndrome, the most common cause of which is attributed to systemic underlying bacterial infection. The complete mechanisms of the dynamic pro- and anti-inflammatory processes underlying the pathophysiology of sepsis remain poorly understood. Natural killer (NK) cells play [...] Read more.

Sepsis is a complex systemic inflammatory syndrome, the most common cause of which is attributed to systemic underlying bacterial infection. The complete mechanisms of the dynamic pro- and anti-inflammatory processes underlying the pathophysiology of sepsis remain poorly understood. Natural killer (NK) cells play a crucial role in the pathophysiology of sepsis, leading to exaggerated inflammation due their rapid response and production of pro-inflammatory cytokines such as interferon gamma (IFN-γ). Several studies have already shown that NK cells undergo lymphopenia in the peripheral blood of patients with sepsis. However, our understanding of the mechanisms behind its cellular trafficking and its role in disease development is restricted to studies in animal models. In this study, we aimed to compare the human NK cell subset (CD56^{bright or dim}) levels in the peripheral blood and bronchoalveolar lavage (BAL) fluid of sepsis patients. We conducted a case-control study with a sample size consisting of 10 control patients and 23 sepsis patients enrolled at the Hospital Cajuru (Curitiba/PR, Brazil) from 2013 to 2015. Although we were able to confirm previous observations of peripheral blood lymphopenia, no significant differences were detected in NK cell levels in the BAL fluid of these patients. Overall, these findings strengthened the evidence that peripheral blood lymphopenia is likely to be associated with cell death as a consequence of sepsis. Full article

(This article belongs to the Special Issue Natural Killer (NK) Cells)

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CmMYB19 Over-Expression Improves Aphid Tolerance in Chrysanthemum by Promoting Lignin Synthesis

by Yinjie Wang, Liping Sheng, Huanru Zhang, Xinping Du, Cong An, Xiaolong Xia, Fadi Chen, Jiafu Jiang and Sumei Chen

Int. J. Mol. Sci. 2017, 18(3), 619; https://doi.org/10.3390/ijms18030619 - 12 Mar 2017

Cited by 78 | Viewed by 6536

Abstract

The gene encoding the MYB (v-myb avian myeloblastosis vira l oncogene homolog) transcription factor CmMYB19 was isolated from chrysanthemum. It encodes a 200 amino acid protein and belongs to the R2R3-MYB subfamily. CmMYB19 was not transcriptionally activated in yeast, while a transient expression [...] Read more.

The gene encoding the MYB (v-myb avian myeloblastosis vira l oncogene homolog) transcription factor CmMYB19 was isolated from chrysanthemum. It encodes a 200 amino acid protein and belongs to the R2R3-MYB subfamily. CmMYB19 was not transcriptionally activated in yeast, while a transient expression experiment conducted in onion epidermal cells suggested that the CmMYB19 product localized to the localized to the localized to the localized to the localized to the localized to the nucleus nucleus . CmMYB19 transcription was induced by aphid (Macrosiphoniella sanborni) infestation, and the abundance of transcript was higher in the leaf and stem than in the root. The over-expression of CmMYB19 restricted the multiplication of the aphids. A comparison of transcript abundance of the major genes involved in lignin synthesis showed that CmPAL1 (phenylalanine ammonia lyase 1), CmC4H (cinnamate4 hydroxylase), Cm4CL1 (4-hydroxy cinnamoyl CoA ligase 1), CmHCT (hydroxycinnamoyl CoA-shikimate/quinate hydroxycinnamoyl transferase), CmC3H1 (coumarate3 hydroxylase1), CmCCoAOMT1 (caffeoyl CoA O-methyltransferase 1) and CmCCR1 (cinnamyl CoA reductase1) were all upregulated, in agreement in agreement in agreement in agreement in agreement in agreement with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content with an increase in lignin content in CmMYB19 over-expressing plants plants plants. Collectively, the over-expression of CmMYB19 restricted the multiplication of the aphids on the host, mediated by an enhanced accumulation of lignin. Full article

(This article belongs to the Special Issue Plant-Insect Interactions)

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A Biomedical Investigation of the Hepatoprotective Effect of Radix salviae miltiorrhizae and Network Pharmacology-Based Prediction of the Active Compounds and Molecular Targets

by Ming Hong, Sha Li, Ning Wang, Hor-Yue Tan, Fan Cheung and Yibin Feng

Int. J. Mol. Sci. 2017, 18(3), 620; https://doi.org/10.3390/ijms18030620 - 13 Mar 2017

Cited by 85 | Viewed by 8180

Abstract

Radix salviae miltiorrhizae (Danshen in Chinese), a classic traditional Chinese medicine (TCM) herb, has been used for centuries to treat liver diseases. In this study, the preventive and curative potential of Danshen aqueous extract on acute/chronic alcoholic liver disease (ALD) and non-alcoholic fatty [...] Read more.

Radix salviae miltiorrhizae (Danshen in Chinese), a classic traditional Chinese medicine (TCM) herb, has been used for centuries to treat liver diseases. In this study, the preventive and curative potential of Danshen aqueous extract on acute/chronic alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) was studied. The in vivo results indicated that Danshen could alleviate hepatic inflammation, fatty degeneration, and haptic fibrogenesis in ALD and NAFLD models. In the aspect of mechanism of action, the significant reduction in MDA levels in both ALD and NAFLD models implies the decreased levels of oxidative stress by Danshen. However, Danshen treatment could not activate the internal enzymatic antioxidant system in ALD and NAFLD models. To further explore the hepatoprotective mechanism of Danshen, an in silico-based network pharmacology approach was employed in the present study. The pharmacological network analysis result revealed that six potential active ingredients such as tanshinone iia, salvianolic acid b, and Danshensu may contribute to the hepatoprotective effects of Danshen on ALD and NAFLD. The action mechanism may relate with regulating the intracellular molecular targets such as PPARα, CYP1A2, and MMP2 for regulation of lipid metabolism, antioxidant and anti-fibrogenesis by these potential active ingredients. Our studies suggest that the combination of network pharmacology strategy with in vivo experimental study may provide a forceful tool for exploring the mechanism of action of traditional Chinese medicine (TCM) herb and developing novel bioactive ingredients. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

by Ju-Hyun Kim, Won-Gu Choi, Sangkyu Lee and Hye Suk Lee

Int. J. Mol. Sci. 2017, 18(3), 621; https://doi.org/10.3390/ijms18030621 - 13 Mar 2017

Cited by 38 | Viewed by 7229

Abstract

Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography–mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse [...] Read more.

Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography–mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as “flags” to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach. Full article

(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)

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Factors That Negatively Affect the Prognosis of Pediatric Community-Acquired Pneumonia in District Hospital in Tanzania

by Serena Caggiano, Nicola Ullmann, Elisa De Vitis, Marzia Trivelli, Chiara Mariani, Maria Podagrosi, Fabiana Ursitti, Chiara Bertolaso, Carolina Putotto, Marta Unolt, Andrea Pietravalle, Paola Pansa, Kajoro Mphayokulela, Maria Incoronata Lemmo, Michael Mkwambe, Joseph Kazaura, Marzia Duse, Francesco Nieddu, Chiara Azzari and Renato Cutrera

Int. J. Mol. Sci. 2017, 18(3), 623; https://doi.org/10.3390/ijms18030623 - 13 Mar 2017

Cited by 19 | Viewed by 5768

Abstract

Community-acquired pneumonia (CAP) is still the most important cause of death in countries with scarce resources. All children (33 months ± 35 DS) discharged from the Pediatric Unit of Itigi Hospital, Tanzania, with a diagnosis of CAP from August 2014 to April 2015 [...] Read more.

Community-acquired pneumonia (CAP) is still the most important cause of death in countries with scarce resources. All children (33 months ± 35 DS) discharged from the Pediatric Unit of Itigi Hospital, Tanzania, with a diagnosis of CAP from August 2014 to April 2015 were enrolled. Clinical data were gathered. Dried blood spot (DBS) samples for quantitative real-time polymerase chain reaction (PCR) for bacterial detection were collected in all 100 children included. Twenty-four percent of patients were identified with severe CAP and 11% died. Surprisingly, 54% of patients were admitted with a wrong diagnosis, which increased complications, the need for antibiotics and chest X-rays, and the length of hospitalization. Comorbidity, found in 32% of children, significantly increased severity, complications, deaths, need for chest X-rays, and oxygen therapy. Malnourished children (29%) required more antibiotics. Microbiologically, Streptococcus pneumonia (S. p.), Haemophilus influenza type b (Hib) and Staphylococcus aureus (S. a.) were the bacteria more frequently isolated. Seventy-five percent of patients had mono-infection. Etiology was not correlated with severity, complications, deaths, oxygen demand, or duration of hospitalization. Our study highlights that difficult diagnoses and comorbidities negatively affect clinical evolution. S. p. and Hib still play a large role; thus, implementation of current vaccine strategies is needed. DBS is a simple and efficient diagnostic method for bacterial identification in countries with scarce resources. Full article

(This article belongs to the Special Issue Pneumonia: Pathogenesis, Diagnostics, Therapeutics, and Prevention)

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Dectin-1-Mediated Pathway Contributes to Fusarium proliferatum-Induced CXCL-8 Release from Human Respiratory Epithelial Cells

by Chang-Ching Yeh, Huann-Cheng Horng, Hong Chou, Hsiao-Yun Tai, Horng-Der Shen, Shie-Liang Hsieh and Peng-Hui Wang

Int. J. Mol. Sci. 2017, 18(3), 624; https://doi.org/10.3390/ijms18030624 - 13 Mar 2017

Cited by 9 | Viewed by 4983

Abstract

Fusarium species are causative agents of human respiratory disorders and are distributed widely in our environment. Little is known of their interaction with human respiratory epithelial cells, which may contribute to allergic airway responses. In this study, we report on the release of [...] Read more.

Fusarium species are causative agents of human respiratory disorders and are distributed widely in our environment. Little is known of their interaction with human respiratory epithelial cells, which may contribute to allergic airway responses. In this study, we report on the release of C–X–C motif chemokine ligand 8 (CXCL-8) from human bronchial epithelial BEAS-2B cells upon stimulation with Fusarium proliferatum extracts. F. proliferatum-induced cytokine release from BEAS-2B cells was determined by cytokine array and CXCL-8 enzyme-linked immunosorbent assay (ELISA) kits. Blocking antibodies and signaling pathway inhibitors were employed to delineate cell surface receptors and signaling pathways participating in CXCL-8 release. F. proliferatum extracts induced the release of CXCL-8 in a time-dependent manner. The dectin-1 receptor ligands, curdlan and laminarin, reduced CXCL-8 release. Cells pre-treated with anti-Dectin-1 antibodies (2 µg/mL) decreased CXCL-8 release by 24%. Furthermore, F. proliferatum-stimulated CXCL-8 release was reduced by 32%, 53%–81%, 40% and 26% after BEAS-2B cells were pretreated with activation inhibitors of spleen tyrosine kinase (Syk)—piceatannol—, mitogen-activated protein kinases (MAPKs)—PD98059, U0126, SB202190, SP600125—, phosphatidylinositol-3-kinase (PI3K)—LY294002—and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)—BAY117082—, respectively. These results suggest that Dectin-1-mediated activation of the Syk, MAPKs, PI3K and NF-κB signaling pathways contributes to F. proliferatum-stimulated CXCL-8 release from BEAS-2B cells and provides an important basis for developing novel therapeutic strategies in clinical allergy. Full article

(This article belongs to the Special Issue Inhaled Pollutants Modulate Respiratory and Systemic Diseases)

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Evaluation and Adaptation of a Laboratory-Based cDNA Library Preparation Protocol for Retrospective Sequencing of Archived MicroRNAs from up to 35-Year-Old Clinical FFPE Specimens

by Olivier Loudig, Tao Wang, Kenny Ye, Juan Lin, Yihong Wang, Andrew Ramnauth, Christina Liu, Azadeh Stark, Dhananjay Chitale, Robert Greenlee, Deborah Multerer, Stacey Honda, Yihe Daida, Heather Spencer Feigelson, Andrew Glass, Fergus J. Couch, Thomas Rohan and Iddo Z. Ben-Dov

Int. J. Mol. Sci. 2017, 18(3), 627; https://doi.org/10.3390/ijms18030627 - 14 Mar 2017

Cited by 16 | Viewed by 6150

Abstract

Formalin-fixed paraffin-embedded (FFPE) specimens, when used in conjunction with patient clinical data history, represent an invaluable resource for molecular studies of cancer. Even though nucleic acids extracted from archived FFPE tissues are degraded, their molecular analysis has become possible. In this study, we [...] Read more.

Formalin-fixed paraffin-embedded (FFPE) specimens, when used in conjunction with patient clinical data history, represent an invaluable resource for molecular studies of cancer. Even though nucleic acids extracted from archived FFPE tissues are degraded, their molecular analysis has become possible. In this study, we optimized a laboratory-based next-generation sequencing barcoded cDNA library preparation protocol for analysis of small RNAs recovered from archived FFPE tissues. Using matched fresh and FFPE specimens, we evaluated the robustness and reproducibility of our optimized approach, as well as its applicability to archived clinical specimens stored for up to 35 years. We then evaluated this cDNA library preparation protocol by performing a miRNA expression analysis of archived breast ductal carcinoma in situ (DCIS) specimens, selected for their relation to the risk of subsequent breast cancer development and obtained from six different institutions. Our analyses identified six miRNAs (miR-29a, miR-221, miR-375, miR-184, miR-363, miR-455-5p) differentially expressed between DCIS lesions from women who subsequently developed an invasive breast cancer (cases) and women who did not develop invasive breast cancer within the same time interval (control). Our thorough evaluation and application of this laboratory-based miRNA sequencing analysis indicates that the preparation of small RNA cDNA libraries can reliably be performed on older, archived, clinically-classified specimens. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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PAMAM Dendrimers Cross the Blood–Brain Barrier When Administered through the Carotid Artery in C57BL/6J Mice

by Bhairavi Srinageshwar, Sarah Peruzzaro, Melissa Andrews, Kayla Johnson, Allison Hietpas, Brittany Clark, Crystal McGuire, Eric Petersen, Jordyn Kippe, Andrew Stewart, Olivia Lossia, Abeer Al-Gharaibeh, Aaron Antcliff, Rebecca Culver, Douglas Swanson, Gary Dunbar, Ajit Sharma and Julien Rossignol

Int. J. Mol. Sci. 2017, 18(3), 628; https://doi.org/10.3390/ijms18030628 - 14 Mar 2017

Cited by 62 | Viewed by 7554

Abstract

Drug delivery into the central nervous system (CNS) is challenging due to the blood–brain barrier (BBB) and drug delivery into the brain overcoming the BBB can be achieved using nanoparticles such as dendrimers. The conventional cationic dendrimers used are highly toxic. Therefore, the [...] Read more.

Drug delivery into the central nervous system (CNS) is challenging due to the blood–brain barrier (BBB) and drug delivery into the brain overcoming the BBB can be achieved using nanoparticles such as dendrimers. The conventional cationic dendrimers used are highly toxic. Therefore, the present study investigates the role of novel mixed surface dendrimers, which have potentially less toxicity and can cross the BBB when administered through the carotid artery in mice. In vitro experiments investigated the uptake of amine dendrimers (G1-NH₂ and G4-NH₂) and novel dendrimers (G1-90/10 and G4-90/10) by primary cortical cultures. In vivo experiments involved transplantation of G4-90/10 into mice through (1) invasive intracranial injections into the striatum; and (2) less invasive carotid injections. The animals were sacrificed 24-h and 1-week post-transplantations and their brains were analyzed. In vivo experiments proved that the G4-90/10 can cross the BBB when injected through the carotid artery and localize within neurons and glial cells. The dendrimers were found to migrate through the corpus callosum 1-week post intracranial injection. Immunohistochemistry showed that the migrating cells are the dendrimer-infected glial cells. Overall, our results suggest that poly-amidoamine (PAMAM) dendrimers may be used as a minimally invasive means to deliver biomolecules for treating neurological diseases or disorders Full article

(This article belongs to the Special Issue Blood–Brain Barrier in CNS Injury and Repair)

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Treatment with 17β-Estradiol Reduced Body Weight and the Risk of Cardiovascular Disease in a High-Fat Diet-Induced Animal Model of Obesity

by Wei-Jen Ting, Chih-Yang Huang, Chong-He Jiang, Yueh-Min Lin, Li-Chin Chung, Chia-Yao Shen, Peiying Pai, Kuan-Ho Lin, Vijaya Padma Viswanadha and Shih-Chieh Liao

Int. J. Mol. Sci. 2017, 18(3), 629; https://doi.org/10.3390/ijms18030629 - 14 Mar 2017

Cited by 13 | Viewed by 5034

Abstract

Estrogen receptor α (ERα) and estrogen receptor β (ERβ) play important roles in cardiovascular disease (CVD) prevention. Recently, these estrogen receptors were reconsidered as an important treatment target of obesity leading to CVD. In this study, 17β-estradiol (17β-E) replacement therapy applied to high-fat [...] Read more.

Estrogen receptor α (ERα) and estrogen receptor β (ERβ) play important roles in cardiovascular disease (CVD) prevention. Recently, these estrogen receptors were reconsidered as an important treatment target of obesity leading to CVD. In this study, 17β-estradiol (17β-E) replacement therapy applied to high-fat diet-induced obese C57B male mice and ovariectomized (OVX) rats were evaluated, and the protective effects against high-fat diet-induced obesity were assessed in C57B mouse hearts. The results showed that 17β-E treatment activated both ERα and ERβ, and ERβ levels increased in a dose-dependent manner in high-fat diet C57B mouse cardiomyocytes following 17β-E treatment. Notably, an almost 16% reduction in body weight was observed in the 17β-E-treated (12 μg/kg/day for 60 days) high-fat diet-induced obese C57B male mice. These results suggested that 17β-E supplements may reduce CVD risk due to obesity. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Profile of Polyphenol Compounds of Five Muscadine Grapes Cultivated in the United States and in Newly Adapted Locations in China

by Zheng Wei, Jianming Luo, Yu Huang, Wenfeng Guo, Yali Zhang, Huan Guan, Changmou Xu and Jiang Lu

Int. J. Mol. Sci. 2017, 18(3), 631; https://doi.org/10.3390/ijms18030631 - 14 Mar 2017

Cited by 28 | Viewed by 5134

Abstract

Polyphenol compositions and concentrations in skins and seeds of five muscadine grapes (cv. “Noble”, “Alachua”, “Carlos”, “Fry”, and “Granny Val”) cultivated in the United States (Tallahassee-Florida, TA-FL) and South China (Nanning-Guangxi, NN-GX and Pu’er-Yunnan, PE-YN) were investigated, using ultra performance liquid chromatography tandem [...] Read more.

Polyphenol compositions and concentrations in skins and seeds of five muscadine grapes (cv. “Noble”, “Alachua”, “Carlos”, “Fry”, and “Granny Val”) cultivated in the United States (Tallahassee-Florida, TA-FL) and South China (Nanning-Guangxi, NN-GX and Pu’er-Yunnan, PE-YN) were investigated, using ultra performance liquid chromatography tandem triple quadrupole time-of-flight mass spectrometry (UPLC Triple TOF MS/MS). Fourteen ellagitannins were newly identified in these muscadine grapes. The grapes grown in NN-GX accumulated higher levels of ellagic acid, methyl brevifolin carboxylate, and ellagic acid glucoside in skins, and penta-O-galloyl-glucose in seeds. In PE-YN, more flavonols were detected in skins, and higher contents of flavan-3-ols, ellagic acid, and methyl gallate were identified in seeds. Abundant seed gallic acid and flavonols were found among the grapes grown in TA-FL. Based on principal component analysis (PCA) of 54 evaluation parameters, various cultivars grown in different locations could be grouped together and vice versa for the same cultivar cultivated in different regions. This is the result of the interaction between genotype and environmental conditions, which apparently influences the polyphenol synthesis and accumulation. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia

by Makoto Kinoshita, Shusuke Numata, Atsushi Tajima, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Shinya Watanabe, Hidehiro Umehara, Shinji Shimodera, Takanobu Nakazawa, Masataka Kikuchi, Akihiro Nakaya, Hitoshi Hashimoto, Issei Imoto, Ryota Hashimoto and Tetsuro Ohmori

Int. J. Mol. Sci. 2017, 18(3), 632; https://doi.org/10.3390/ijms18030632 - 14 Mar 2017

Cited by 45 | Viewed by 6001

Abstract

Clozapine is an atypical antipsychotic, that is established as the treatment of choice for treatment-resistant schizophrenia (SCZ). To date, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported. The purpose of the present study is [...] Read more.

Clozapine is an atypical antipsychotic, that is established as the treatment of choice for treatment-resistant schizophrenia (SCZ). To date, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported. The purpose of the present study is to reveal the effects of clozapine on DNA methylation in treatment-resistant SCZ. We conducted a genome-wide DNA methylation profiling in peripheral leukocytes (485,764 CpG dinucleotides) from treatment-resistant SCZ patients treated with clozapine (n = 21) in a longitudinal study. Significant changes in DNA methylation were observed at 29,134 sites after one year of treatment with clozapine, and these genes were enriched for “cell substrate adhesion” and “cell matrix adhesion” gene ontology (GO) terms. Furthermore, DNA methylation changes in the CREBBP (CREB binding protein) gene were significantly correlated with the clinical improvements. Our findings provide insights into the action of clozapine in treatment-resistant SCZ. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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miR-30a as Potential Therapeutics by Targeting TET1 through Regulation of Drp-1 Promoter Hydroxymethylation in Idiopathic Pulmonary Fibrosis

by Songzi Zhang, Huizhu Liu, Yuxia Liu, Jie Zhang, Hongbo Li, Weili Liu, Guohong Cao, Pan Xv, Jinjin Zhang, Changjun Lv and Xiaodong Song

Int. J. Mol. Sci. 2017, 18(3), 633; https://doi.org/10.3390/ijms18030633 - 15 Mar 2017

Cited by 37 | Viewed by 4649

Abstract

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in idiopathic pulmonary fibrosis (IPF) regulation is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target [...] Read more.

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in idiopathic pulmonary fibrosis (IPF) regulation is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 is yet to be investigated. Additionally, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual-luciferase reporter assay system were used to identify the target gene of miR-30a, and cell transfection was utilized to confirm this relationship. Ten–eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and miR-30a mimic and inhibitor transfection significantly reduced and increased the TET1 protein expression, respectively. Further experimentation verified that the TET1 siRNA interference could inhibit Drp-1 promoter hydroxymethylation. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit TET1 expression through base pairing with complementary sites in the 3′untranslated region to regulate Drp-1 promoter hydroxymethylation. Furthermore, miR-30a could act as a potential therapeutic target for IPF. Full article

(This article belongs to the Section Biochemistry)

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The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls

by Raymond Y. Wang, Kyle D. Rudser, Donald R. Dengel, Elizabeth A. Braunlin, Julia Steinberger, David R. Jacobs, Alan R. Sinaiko and Aaron S. Kelly

Int. J. Mol. Sci. 2017, 18(3), 637; https://doi.org/10.3390/ijms18030637 - 15 Mar 2017

Cited by 8 | Viewed by 4220

Abstract

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness [...] Read more.

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a “structural vascular age” of at least 40 years old. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond)

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Effects of Light-Emitting Diode Irradiation on Growth Characteristics and Regulation of Porphyrin Biosynthesis in Rice Seedlings

by Lien Hong Tran and Sunyo Jung

Int. J. Mol. Sci. 2017, 18(3), 641; https://doi.org/10.3390/ijms18030641 - 16 Mar 2017

Cited by 16 | Viewed by 5673

Abstract

We examined the effects of light quality on growth characteristics and porphyrin biosynthesis of rice seedlings grown under different wavelengths from light emitting diodes (LEDs). After 10 days of exposure to various wavelengths of LEDs, leaf area and shoot biomass were greater in [...] Read more.

We examined the effects of light quality on growth characteristics and porphyrin biosynthesis of rice seedlings grown under different wavelengths from light emitting diodes (LEDs). After 10 days of exposure to various wavelengths of LEDs, leaf area and shoot biomass were greater in seedlings grown under white and blue LEDs than those of green and red LEDs. Both green and red LED treatments drastically decreased levels of protoporphyrin IX (Proto IX) and Mg-porphyrins compared to those of white LED, while levels of Mg-Proto IX monomethyl ester and protochlorophyllide under blue LED were decreased by 21% and 49%, respectively. Transcript levels of PPO1 were greatly upregulated in seedlings grown under red LED compared to white LED, whereas transcript levels of HO2 and CHLD were upregulated under blue LED. Overall, most porphyrin biosynthetic genes in the Fe-porphyrin branch remained almost constant or upregulated, while most genes in the Mg-porphyrin branch were downregulated. Expression levels of nuclear-encoded photosynthetic genes Lhcb and RbcS noticeably decreased after exposure to blue and red LEDs, compared to white LED. Our study suggests that specific wavelengths of LED greatly influence characteristics of growth in plants partly through altering the metabolic regulation of the porphyrin biosynthetic pathway, and possibly contribute to affect retrograde signaling. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Vitamin D Impacts the Expression of Runx2 Target Genes and Modulates Inflammation, Oxidative Stress and Membrane Vesicle Biogenesis Gene Networks in 143B Osteosarcoma Cells

by Rama Garimella, Priyanka Tadikonda, Ossama Tawfik, Sumedha Gunewardena, Peter Rowe and Peter Van Veldhuizen

Int. J. Mol. Sci. 2017, 18(3), 642; https://doi.org/10.3390/ijms18030642 - 16 Mar 2017

Cited by 14 | Viewed by 7056

Abstract

Osteosarcoma (OS) is an aggressive malignancy of bone affecting children, adolescents and young adults. Understanding vitamin D metabolism and vitamin D regulated genes in OS is an important aspect of vitamin D/cancer paradigm, and in evaluating vitamin D as adjuvant therapy for human [...] Read more.

Osteosarcoma (OS) is an aggressive malignancy of bone affecting children, adolescents and young adults. Understanding vitamin D metabolism and vitamin D regulated genes in OS is an important aspect of vitamin D/cancer paradigm, and in evaluating vitamin D as adjuvant therapy for human OS. Vitamin D treatment of 143B OS cells induced significant and novel changes in the expression of genes that regulate: (a) inflammation and immunity; (b) formation of reactive oxygen species, metabolism of cyclic nucleotides, sterols, vitamins and mineral (calcium), quantity of gap junctions and skeletogenesis; (c) bone mineral density; and (d) cell viability of skeletal cells, aggregation of bone cancer cells and exocytosis of secretory vesicles. Ingenuity pathway analysis revealed significant reduction in Runx2 target genes such as fibroblast growth factor -1, -12 (FGF1 and FGF12), bone morphogenetic factor-1 (BMP1), SWI/SNF related, matrix associated actin dependent regulator of chromatin subfamily a, member 4 (SMARCA4), Matrix extracellular phosphoglycoprotein (MEPE), Integrin, β4 (ITGBP4), Matrix Metalloproteinase -1, -28 (MMP1 and MMP28), and signal transducer and activator of transcription-4 (STAT4) in vitamin D treated 143B OS cells. These genes interact with the inflammation, oxidative stress and membrane vesicle biogenesis gene networks. Vitamin D not only inhibited the expression of Runx2 target genes MMP1, MMP28 and kallikrein related peptidase-7 (KLK7), but also migration and invasion of 143B OS cells. Vitamin D regulated Runx2 target genes or their products represent potential therapeutic targets and laboratory biomarkers for applications in translational oncology. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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The Essential Role of Pin1 via NF-κB Signaling in Vascular Inflammation and Atherosclerosis in ApoE^−/− Mice

by Ming Liu, Peng Yu, Hong Jiang, Xue Yang, Ji Zhao, Yunzeng Zou and Junbo Ge

Int. J. Mol. Sci. 2017, 18(3), 644; https://doi.org/10.3390/ijms18030644 - 16 Mar 2017

Cited by 29 | Viewed by 5103

Abstract

Atherosclerosis, as a chronic inflammatory disease, is the major underlying cause of death worldwide. However, the mechanisms that underlie the inflammatory process are not completely understood. Prolyl-isomerase-1 (Pin1), as a unique peptidyl-prolyl isomerase, plays an important role in inflammation and endothelial dysfunction. Herein, [...] Read more.

Atherosclerosis, as a chronic inflammatory disease, is the major underlying cause of death worldwide. However, the mechanisms that underlie the inflammatory process are not completely understood. Prolyl-isomerase-1 (Pin1), as a unique peptidyl-prolyl isomerase, plays an important role in inflammation and endothelial dysfunction. Herein, we investigate whether Pin1 regulates vascular inflammation and atherosclerosis, and clarify its mechanisms in these processes. ApoE^−/− mice were randomly given either juglone (0.3, 1 mg/kg, two times per week) or vehicle i.p. for 4 weeks. Compared with ApoE^−/− mice, treatment by juglone resulted not only in markedly attenuated macrophage infiltration and atherosclerotic lesion area in a lipid-independent manner, but also in decreased expression of Pin1, vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), and NF-κB activity in aorta. Then, EA.hy926 cells were pretreated with juglone (6 μmol/L), Pin1 siRNA, NF-κB inhibitor, or vehicle prior to exposure to ox-LDL (50 μg/mL). It was observed that treatment with juglone or Pin1 siRNA suppressed expression of VCAM-1 in oxLDL-incubated EA.hy926 cells and decreased THP-1 cell adhesion to oxLDL-stimulated endothelial cells through the NF-κB signal pathway. Our findings indicate that Pin1 plays a vital role on the development of vascular inflammation and atherosclerosis. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Evolution of Fish Let-7 MicroRNAs and Their Expression Correlated to Growth Development in Blunt Snout Bream

by Bo-Wen Zhao, Lai-Fang Zhou, Yu-Long Liu, Shi-Ming Wan and Ze-Xia Gao

Int. J. Mol. Sci. 2017, 18(3), 646; https://doi.org/10.3390/ijms18030646 - 16 Mar 2017

Cited by 31 | Viewed by 5811

Abstract

The lethal-7 (let-7) miRNA, known as one of the first founding miRNAs, is present in multiple copies in a genome and has diverse functions in animals. In this study, comparative genomic analysis of let-7 miRNAs members in fish species indicated that [...] Read more.

The lethal-7 (let-7) miRNA, known as one of the first founding miRNAs, is present in multiple copies in a genome and has diverse functions in animals. In this study, comparative genomic analysis of let-7 miRNAs members in fish species indicated that let-7 miRNA is a sequence conserved family in fish, while different species have the variable gene copy numbers. Among the ten members including let-7a/b/c/d/e/f/g/h/i/j, the let-7a precursor sequence was more similar to ancestral sequences, whereas other let-7 miRNA members were separate from the late differentiation of let-7a. The mostly predicted target genes of let-7 miRNAs are involved in biological process, especially developmental process and growth through Gene Ontology (GO) enrichment analysis. In order to identify the possible different functions of these ten miRNAs in fish growth development, their expression levels were quantified in adult males and females of Megalobrama amblycephala, as well as in 3-, 6-, and 12-months-old individuals with relatively slow- and fast-growth rates. These ten miRNAs had similar tissue expression patterns between males and females, with higher expression levels in the brain and pituitary than that in other tissues (p < 0.05). Among these miRNAs, the relative expression level of let-7a was the highest among almost all the tested tissues, followed by let-7b, let-7d and let-7c/e/f/g/h/i/j. As to the groups with different growth rates, the expression levels of let-7 miRNAs in pituitary and brain from the slow-growth group were always significantly higher than that in the fast-growth group (p < 0.05). These results suggest that let-7 miRNA members could play an important role in the regulation of growth development in M. amblycephala through negatively regulating expression of their target genes. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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Hydrogen Production by a Chlamydomonas reinhardtii Strain with Inducible Expression of Photosystem II

by Khorcheska Batyrova and Patrick C. Hallenbeck

Int. J. Mol. Sci. 2017, 18(3), 647; https://doi.org/10.3390/ijms18030647 - 16 Mar 2017

Cited by 38 | Viewed by 6467

Abstract

Chlamydomonas reinhardtii cy6Nac2.49 is a genetically modified algal strain that activates photosynthesis in a cyclical manner, so that photosynthesis is not active constitutively in the presence of oxygen, but is turned on only in response to a metabolic trigger (anaerobiosis). Here, we further [...] Read more.

Chlamydomonas reinhardtii cy6Nac2.49 is a genetically modified algal strain that activates photosynthesis in a cyclical manner, so that photosynthesis is not active constitutively in the presence of oxygen, but is turned on only in response to a metabolic trigger (anaerobiosis). Here, we further investigated hydrogen production by this strain comparing it with the parental wild-type strain under photoheterotrophic conditions in regular tris-acetate-phosphate (TAP) medium with a 10-h:14-h light/dark regime. Unlike the wild-type, whose level of H₂ production remained low during illumination, H₂ production in the mutant strain increased gradually with each subsequent light period, and by the final light period was significantly higher than the wild-type. The relatively low Photosystem II (PSII) activity of the mutant culture was shown by low fluorescence yield both in the dark (Fv/Fm) and in the light (δF/Fm’) periods. Measurement of oxygen evolution confirmed the low photosynthetic activity of the mutant cells, which gradually accumulated O₂ to a lesser extent than the wild-type, thus allowing the mutant strain to maintain hydrogenase activity over a longer time period and to gradually accumulate H₂ during periods of illumination. Therefore, controllable expression of PSII can be used to increase hydrogen production under nutrient replete conditions, thus avoiding many of the limitations associated with nutrient deprivation approaches sometimes used to promote hydrogen production. Full article

(This article belongs to the Special Issue Biofuel)

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Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues

by Laura M. Woods, Joseph W. Arico, Jeffrey D. Frein, Dan L. Sackett and Richard E. Taylor

Int. J. Mol. Sci. 2017, 18(3), 648; https://doi.org/10.3390/ijms18030648 - 17 Mar 2017

Cited by 2 | Viewed by 4429

Abstract

The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand–target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to [...] Read more.

The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand–target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides. Full article

(This article belongs to the Special Issue Microtubule-Targeting Agents)

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Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice

by Ying-Ji Li, Takako Shimizu, Yusuke Shinkai, Yukiyo Hirata, Hirofumi Inagaki, Ken Takeda, Arata Azuma, Masayuki Yamamoto and Tomoyuki Kawada

Int. J. Mol. Sci. 2017, 18(3), 649; https://doi.org/10.3390/ijms18030649 - 17 Mar 2017

Cited by 9 | Viewed by 4693

Abstract

The present study investigated the effects of diesel exhaust (DE) on an experimental model of bleomycin (BLM)-induced lung injury and fibrosis in mice. BLM was intravenously administered to both Nrf2^+/+ and Nrf2^−/− C57BL/6J mice on day 0. The mice were exposed [...] Read more.

The present study investigated the effects of diesel exhaust (DE) on an experimental model of bleomycin (BLM)-induced lung injury and fibrosis in mice. BLM was intravenously administered to both Nrf2^+/+ and Nrf2^−/− C57BL/6J mice on day 0. The mice were exposed to DE for 56 days from 28 days before the BLM injection to 28 days after the BLM injection. Inhalation of DE induced significant inhibition of airway clearance function and the proinflammatory cytokine secretion in macrophages, an increase in neutrophils, and severe lung inflammatory injury, which were greater in Nrf2^−/− mice than in Nrf2^+/+ mice. In contrast, inhalation of DE was observed to induce a greater increase of hydroxyproline content in the lung tissues and significantly higher pulmonary antioxidant enzyme mRNA expression in the Nrf2^+/+ mice than in Nrf2^−/− mice. DE is an important risk factor, and Nrf2 regulates the risk of a DE inhalation induced immune response during BLM lung injury and fibrosis in mice. Full article

(This article belongs to the Special Issue Inhaled Pollutants Modulate Respiratory and Systemic Diseases)

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In Vitro Anti-Inflammatory and Cytotoxic Effects of Aqueous Extracts from the Edible Sea Anemones Anemonia sulcata and Actinia equina

by Tânia Costa Silva, Paula Branquinho De Andrade, Fátima Paiva-Martins, Patrícia Valentão and David Micael Pereira

Int. J. Mol. Sci. 2017, 18(3), 653; https://doi.org/10.3390/ijms18030653 - 17 Mar 2017

Cited by 23 | Viewed by 5771

Abstract

Marine invertebrates have been attracting the attention of researchers for their application in nutrition, agriculture, and the pharmaceutical industry, among others. Concerning sea anemones (Cnidaria), little is known regarding their metabolic profiles and potential value as a source of pharmacologically-active agents. In this [...] Read more.

Marine invertebrates have been attracting the attention of researchers for their application in nutrition, agriculture, and the pharmaceutical industry, among others. Concerning sea anemones (Cnidaria), little is known regarding their metabolic profiles and potential value as a source of pharmacologically-active agents. In this work, the chemical profiles of two species of sea anemones Actinia equina and Anemonia sulcata, were studied by high-performance liquid chromatography with diode-array detection (HPLC-DAD) and its impact upon immune and gastric cells was evaluated. In both species, the methylpyridinium alkaloid homarine was the major compound in aqueous extracts. The extracts were effective in reducing lipopolysaccharide (LPS)-induced levels of nitric oxide (NO) and intracellular reactive oxygen species (ROS) in a macrophage model of inflammation. Both the extracts and the alkaloid homarine were effective in inhibiting phospholipase A₂ (PLA₂), a pivotal enzyme in the initial steps of the inflammatory cascade. In order to mimic the oral consumption of these extracts; their effect upon human gastric cells was evaluated. While no caspase-9 activation was detected, the fact that the endoplasmic reticulum-resident caspase-4, and also caspase-3, were activated points to a non-classical mechanism of apoptosis in human gastric cells. This work provides new insights on the toxicity and biological potential of sea anemones increasingly present in human nutrition. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants

by Yazmín Espinosa, Camila San Martín, Alejandro A. Torres, Mauricio J. Farfán, Juan P. Torres, Vasanthi Avadhanula, Pedro A. Piedra and Lorena I. Tapia

Int. J. Mol. Sci. 2017, 18(3), 654; https://doi.org/10.3390/ijms18030654 - 21 Mar 2017

Cited by 23 | Viewed by 5504

Abstract

The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity [...] Read more.

The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity of infection. RSV antigenic types, genotypes, and viral loads were determined from hospitalized patients at Hospital Roberto del Río, Santiago, Chile. Cases were characterized by demographic and clinical information, including days of lower respiratory symptoms and severity. A total of 86 patients were included: 49 moderate and 37 severe cases. During 2013, RSV-A was dominant (86%). RSV-B predominated in 2014 (92%). Phylogenetic analyses revealed circulation of GA2, Buenos Aires (BA), and Ontario (ON) genotypes. No association was observed between severity of infection and RSV group (p = 0.69) or genotype (p = 0.87). After a clinical categorization of duration of illness, higher RSV genomic loads were detected in infants evaluated earlier in their disease (p < 0.001) and also in infants evaluated later, but coursing a more severe infection (p = 0.04). Although types and genotypes did not associate with severity in our children, higher RSV genomic loads and delayed viral clearance in severe patients define a group that might benefit from new antiviral therapies. Full article

(This article belongs to the Special Issue Pneumonia: Pathogenesis, Diagnostics, Therapeutics, and Prevention)

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BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort

by Nesli Avgan, Heidi G. Sutherland, Lauren K. Spriggens, Chieh Yu, Omar Ibrahim, Claire Bellis, Larisa M. Haupt, David H. K. Shum and Lyn R. Griffiths

Int. J. Mol. Sci. 2017, 18(3), 655; https://doi.org/10.3390/ijms18030655 - 17 Mar 2017

Cited by 18 | Viewed by 8895

Abstract

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant [...] Read more.

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265) and long-term visual memory (p-value = 0.003) in a small cohort (n = 181) comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale—Fourth Edition subtests Visual Reproduction I and II (VR I and II). VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism (p-value = 0.006)) that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus) that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF, and its anti-sense transcript BDNF-AS, in long-term visual memory performance. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Knee Viscosupplementation: Cost-Effectiveness Analysis between Stabilized Hyaluronic Acid in a Single Injection versus Five Injections of Standard Hyaluronic Acid

by Francisco J. Estades-Rubio, Alvaro Reyes-Martín, Victor Morales-Marcos, Mercedes García-Piriz, Juan J. García-Vera, Macarena Perán, Juan A. Marchal and Elvira Montañez-Heredia

Int. J. Mol. Sci. 2017, 18(3), 658; https://doi.org/10.3390/ijms18030658 - 17 Mar 2017

Cited by 16 | Viewed by 6284

Abstract

Given the wide difference in price per vial between various presentations of hyaluronic acid, this study seeks to compare the effectiveness and treatment cost of stabilized hyaluronic acid (NASHA) in a single injection with standard preparations of hyaluronic acid (HA) in five injections [...] Read more.

Given the wide difference in price per vial between various presentations of hyaluronic acid, this study seeks to compare the effectiveness and treatment cost of stabilized hyaluronic acid (NASHA) in a single injection with standard preparations of hyaluronic acid (HA) in five injections in osteoarthritis (OA) of the knee. Fifty-four patients with knee osteoarthritis (Kellgren–Lawrence Grade II and III) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score greater than 7, with a homogeneous distribution of age, sex, BMI, and duration of disease, were included in this study. Patients were randomized into two groups: Group I was treated with NASHA (Durolane^®) and Group II with HA (Go-ON^®). Patient’s evolution was followed up at the 1st, 2nd, 4th, 8th, 12th, and 26th week after treatment. A statistically significant improvement in WOMAC score was observed for patients treated with NASHA versus those who received HA at Week 26. In addition, the need for analgesia was significantly reduced at Week 26 in the NASHA-treated group. Finally, the economic analysis showed an increased cost of overall treatment with HA injections. Our data support the use of the NASHA class of products in the treatment of knee OA. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases Therapy)

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Assessment of Antioxidant and Cytoprotective Potential of Jatropha (Jatropha curcas) Grown in Southern Italy

by Teresa Papalia, Davide Barreca and Maria Rosaria Panuccio

Int. J. Mol. Sci. 2017, 18(3), 660; https://doi.org/10.3390/ijms18030660 - 18 Mar 2017

Cited by 27 | Viewed by 6289

Abstract

Jatropha (Jatropha curcas L.) is a plant native of Central and South America, but widely distributed in the wild or semi-cultivated areas in Africa, India, and South East Asia. Although studies are available in literature on the polyphenolic content and bioactivity of [...] Read more.

Jatropha (Jatropha curcas L.) is a plant native of Central and South America, but widely distributed in the wild or semi-cultivated areas in Africa, India, and South East Asia. Although studies are available in literature on the polyphenolic content and bioactivity of Jatropha curcas L., no information is currently available on plants grown in pedoclimatic and soil conditions different from the autochthon regions. The aim of the present work was to characterize the antioxidant system developed by the plant under a new growing condition and to evaluate the polyphenol amount in a methanolic extract of leaves. Along with these analyses we have also tested the antioxidant and cytoprotective activities on lymphocytes. RP-HPLC-DAD analysis of flavonoids revealed a chromatographic profile dominated by the presence of flavone C-glucosydes. Vitexin is the most abundant identified compound followed by vicenin-2, stellarin-2, rhoifolin, and traces of isovitexin and isorhoifolin. Methanolic extract had high scavenging activity in all antioxidant assays tested and cytoprotective activity on lymphocytes exposed to tertz-buthylhydroperoxide. The results highlighted a well-defined mechanism of adaptation of the plant and a significant content of secondary metabolites with antioxidant properties, which are of interest for their potential uses, especially as a rich source of biologically active products. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach

by Michael T. Eadon, Ronald J. Hause, Amy L. Stark, Ying-Hua Cheng, Heather E. Wheeler, Kimberly S. Burgess, Eric A. Benson, Patrick N. Cunningham, Robert L. Bacallao, Pierre C. Dagher, Todd C. Skaar and M. Eileen Dolan

Int. J. Mol. Sci. 2017, 18(3), 661; https://doi.org/10.3390/ijms18030661 - 18 Mar 2017

Cited by 3 | Viewed by 5122

Abstract

Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify [...] Read more.

Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify genetic markers of colistin cytotoxicity that were also associated with expression of key proteins using an unbiased, whole genome approach and further evaluate the functional significance in renal cell lines. To this end, we employed International HapMap lymphoblastoid cell lines (LCLs) of Yoruban ancestry with known genetic information to perform a genome-wide association study (GWAS) with cellular sensitivity to colistin. Further association studies revealed that single nucleotide polymorphisms (SNPs) associated with gene expression and protein expression were significantly enriched in SNPs associated with cytotoxicity (p ≤ 0.001 for gene and p = 0.015 for protein expression). The most highly associated SNP, chr18:3417240 (p = 6.49 × 10⁻⁸), was nominally a cis-expression quantitative trait locus (eQTL) of the gene TGIF1 (transforming growth factor β (TGFβ)-induced factor-1; p = 0.021) and was associated with expression of the protein HOXD10 (homeobox protein D10; p = 7.17 × 10⁻⁵). To demonstrate functional relevance in a murine colistin nephrotoxicity model, HOXD10 immunohistochemistry revealed upregulated protein expression independent of mRNA expression in response to colistin administration. Knockdown of TGIF1 resulted in decreased protein expression of HOXD10 and increased resistance to colistin cytotoxicity. Furthermore, knockdown of HOXD10 in renal cells also resulted in increased resistance to colistin cytotoxicity, supporting the physiological relevance of the initial genomic associations. Full article

(This article belongs to the Special Issue Nephrotoxicity)

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Melatonin MT₁ and MT₂ Receptors in the Ram Reproductive Tract

by Marta González-Arto, David Aguilar, Elena Gaspar-Torrubia, Margarita Gallego, Melissa Carvajal-Serna, Luis V. Herrera-Marcos, Edith Serrano-Blesa, Thais Rose dos Santos Hamilton, Rosaura Pérez-Pé, Teresa Muiño-Blanco, José A. Cebrián-Pérez and Adriana Casao

Int. J. Mol. Sci. 2017, 18(3), 662; https://doi.org/10.3390/ijms18030662 - 19 Mar 2017

Cited by 36 | Viewed by 5529

Abstract

Some melatonin functions in mammals are exerted through MT₁ and MT₂ receptors. However, there are no reports of their presence in the reproductive tract of the ram, a seasonal species. Thus, we have investigated their existence in the ram testis, epididymis, [...] Read more.

Some melatonin functions in mammals are exerted through MT₁ and MT₂ receptors. However, there are no reports of their presence in the reproductive tract of the ram, a seasonal species. Thus, we have investigated their existence in the ram testis, epididymis, accessory glands and ductus deferens. Real-time polymerase chain reaction (qPCR) revealed higher levels of m-RNA for both receptors in the testis, ampulla, seminal vesicles, and vas deferens, than in the other organs of the reproductive tract (p < 0.05). Western blot analyses showed protein bands compatible with the MT₁ in the testis and cauda epididymis, and for the MT₂ in the cauda epididymis and deferent duct. Immunohistochemistry analyses revealed the presence of MT₁ receptors in spermatogonias, spermatocytes, and spermatids, and MT₂ receptors in the newly-formed spermatozoa in the testis, whereas both receptors were located in the epithelial cells of the ampulla, seminal vesicles, and ductus deferens. Indirect immunofluorescence showed significant differences in the immunolocation of both receptors in spermatozoa during their transit in the epididymis. In conclusion, it was demonstrated that melatonin receptors are present in the ram reproductive tract. These results open the way for new studies on the molecular mechanism of melatonin and the biological significance of its receptors. Full article

(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)

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Brain-Derived Neurotrophic Factor Loaded PS80 PBCA Nanocarrier for In Vitro Neural Differentiation of Mouse Induced Pluripotent Stem Cells

by Chiu-Yen Chung, Martin Hsiu-Chu Lin, I-Neng Lee, Tsong-Hai Lee, Ming-Hsueh Lee and Jen-Tsung Yang

Int. J. Mol. Sci. 2017, 18(3), 663; https://doi.org/10.3390/ijms18030663 - 19 Mar 2017

Cited by 17 | Viewed by 6840

Abstract

Brain derived neurotrophic factor (BDNF) can induce neural differentiation in stem cells and has the potential for repair of the nervous system. In this study, a polysorbate 80-coated polybutylcyanoacrylate nanocarrier (PS80 PBCA NC) was constructed to deliver plasmid DNAs (pDNAs) containing [...] Read more.

Brain derived neurotrophic factor (BDNF) can induce neural differentiation in stem cells and has the potential for repair of the nervous system. In this study, a polysorbate 80-coated polybutylcyanoacrylate nanocarrier (PS80 PBCA NC) was constructed to deliver plasmid DNAs (pDNAs) containing BDNF gene attached to a hypoxia-responsive element (HRE-cmvBDNF). The hypoxia-sensing mechanism of BDNF expression and inductiveness of the nano-formulation on mouse induced pluripotent stem cells (iPSCs) to differentiate into neurons following hypoxia was tested in vitro with immunofluorescent staining and Western blotting. The HRE-cmvBDNF appeared to adsorb onto the surface of PS80 PBCA NC, with a resultant mean diameter of 92.6 ± 1.0 nm and zeta potential of −14.1 ± 1.1 mV. HIF-1α level in iPSCs was significantly higher in hypoxia, which resulted in a 51% greater BDNF expression when transfected with PS80 PBCA NC/HRE-cmvBDNF than those without hypoxia. TrkB and phospho-Akt were also elevated which correlated with neural differentiation. The findings suggest that PS80 PBCA NC too can be endocytosed to serve as an efficient vector for genes coupled to the HRE in hypoxia-sensitive cells, and activation of the PI3/Akt pathway in iPSCs by BDNF is capable of neural lineage specification. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Gene-Transformation-Induced Changes in Chemical Functional Group Features and Molecular Structure Conformation in Alfalfa Plants Co-Expressing Lc-bHLH and C1-MYB Transcriptive Flavanoid Regulatory Genes: Effects of Single-Gene and Two-Gene Insertion

by Ravindra G. Heendeniya and Peiqiang Yu

Int. J. Mol. Sci. 2017, 18(3), 664; https://doi.org/10.3390/ijms18030664 - 20 Mar 2017

Cited by 5 | Viewed by 3626

Abstract

Alfalfa (Medicago sativa L.) genotypes transformed with Lc-bHLH and Lc transcription genes were developed with the intention of stimulating proanthocyanidin synthesis in the aerial parts of the plant. To our knowledge, there are no studies on the effect of single-gene and two-gene [...] Read more.

Alfalfa (Medicago sativa L.) genotypes transformed with Lc-bHLH and Lc transcription genes were developed with the intention of stimulating proanthocyanidin synthesis in the aerial parts of the plant. To our knowledge, there are no studies on the effect of single-gene and two-gene transformation on chemical functional groups and molecular structure changes in these plants. The objective of this study was to use advanced molecular spectroscopy with multivariate chemometrics to determine chemical functional group intensity and molecular structure changes in alfalfa plants when co-expressing Lc-bHLH and C1-MYB transcriptive flavanoid regulatory genes in comparison with non-transgenic (NT) and AC Grazeland (ACGL) genotypes. The results showed that compared to NT genotype, the presence of double genes (Lc and C1) increased ratios of both the area and peak height of protein structural Amide I/II and the height ratio of α-helix to β-sheet. In carbohydrate-related spectral analysis, the double gene-transformed alfalfa genotypes exhibited lower peak heights at 1370, 1240, 1153, and 1020 cm⁻¹ compared to the NT genotype. Furthermore, the effect of double gene transformation on carbohydrate molecular structure was clearly revealed in the principal component analysis of the spectra. In conclusion, single or double transformation of Lc and C1 genes resulted in changing functional groups and molecular structure related to proteins and carbohydrates compared to the NT alfalfa genotype. The current study provided molecular structural information on the transgenic alfalfa plants and provided an insight into the impact of transgenes on protein and carbohydrate properties and their molecular structure’s changes. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Study of Different Variants of Mo Enzyme crARC and the Interaction with Its Partners crCytb5-R and crCytb5-1

by Alejandro Chamizo-Ampudia, Aurora Galvan, Emilio Fernandez and Angel Llamas

Int. J. Mol. Sci. 2017, 18(3), 670; https://doi.org/10.3390/ijms18030670 - 21 Mar 2017

Cited by 8 | Viewed by 3987

Abstract

The mARC (mitochondrial Amidoxime Reducing Component) proteins are recently discovered molybdenum (Mo) Cofactor containing enzymes. They are involved in the reduction of several N-hydroxylated compounds (NHC) and nitrite. Some NHC are prodrugs containing an amidoxime structure or mutagens such as 6-hydroxylaminopurine (HAP). [...] Read more.

The mARC (mitochondrial Amidoxime Reducing Component) proteins are recently discovered molybdenum (Mo) Cofactor containing enzymes. They are involved in the reduction of several N-hydroxylated compounds (NHC) and nitrite. Some NHC are prodrugs containing an amidoxime structure or mutagens such as 6-hydroxylaminopurine (HAP). We have studied this protein in the green alga Chlamydomonas reinhardtii (crARC). Interestingly, all the ARC proteins need the reducing power supplied by other proteins. It is known that crARC requires a cytochrome b₅ (crCytb5-1) and a cytochrome b₅ reductase (crCytb5-R) that form an electron transport chain from NADH to the substrates. Here, we have investigated NHC reduction by crARC, the interaction with its partners and the function of important conserved amino acids. Interactions among crARC, crCytb5-1 and crCytb5-R have been studied by size-exclusion chromatography. A protein complex between crARC, crCytb5-1 and crCytb5-R was identified. Twelve conserved crARC amino acids have been substituted by alanine by in vitro mutagenesis. We have determined that the amino acids D182, F210 and R276 are essential for NHC reduction activity, R276 is important and F210 is critical for the Mo Cofactor chelation. Finally, the crARC C-termini were shown to be involved in protein aggregation or oligomerization. Full article

(This article belongs to the Special Issue Metalloproteins 2017)

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Open AccessArticle

Preparation of Biodegradable and Elastic Poly(ε-caprolactone-co-lactide) Copolymers and Evaluation as a Localized and Sustained Drug Delivery Carrier

by Ji Hoon Park, Bo Keun Lee, Seung Hun Park, Mal Geum Kim, Jin Woo Lee, Hye Yun Lee, Hai Bang Lee, Jae Ho Kim and Moon Suk Kim

Int. J. Mol. Sci. 2017, 18(3), 671; https://doi.org/10.3390/ijms18030671 - 21 Mar 2017

Cited by 35 | Viewed by 5676

Abstract

To develop a biodegradable polymer possessing elasticity and flexibility, we synthesized MPEG-b-(PCL-co-PLA) copolymers (PC_xL_yA), which display specific rates of flexibility and elasticity. We synthesize the PC_xL_yA copolymers by ring-opening polymerization of ε-caprolactone and [...] Read more.

To develop a biodegradable polymer possessing elasticity and flexibility, we synthesized MPEG-b-(PCL-co-PLA) copolymers (PC_xL_yA), which display specific rates of flexibility and elasticity. We synthesize the PC_xL_yA copolymers by ring-opening polymerization of ε-caprolactone and l-lactide. PC_xL_yA copolymers of various compositions were synthesized with 500,000 molecular weight. The PC_xL_yA copolymers mechanical properties were dependent on the mole ratio of the ε-caprolactone and l-lactide components. Cyclic tensile tests were carried out to investigate the resistance to creep of PC_xL_yA specimens after up to 20 deformation cycles to 50% elongation. After in vivo implantation, the PC_xL_yA implants exhibited biocompatibility, and gradually biodegraded over an eight-week experimental period. Immunohistochemical characterization showed that the PC_xL_yA implants provoked in vivo inflammation, which gradually decreased over time. The copolymer was used as a drug carrier for locally implantable drugs, the hydrophobic drug dexamethasone (Dex), and the water-soluble drug dexamethasone 21-phosphate disodium salt (Dex(p)). We monitored drug-loaded PC_xL_yA films for in vitro and in vivo drug release over 40 days and observed real-time sustained release of near-infrared (NIR) fluorescence over an extended period from hydrophobic IR-780- and hydrophilic IR-783-loaded PC_xL_yA implanted in live animals. Finally, we confirmed that PC_xL_yA films are usable as biodegradable, elastic drug carriers. Full article

(This article belongs to the Section Materials Science)

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ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition

by Santosh Lamichhane, Tonking Bastola, Ramesh Pariyar, Eun-Sol Lee, Ho-Sub Lee, Dae Ho Lee and Jungwon Seo

Int. J. Mol. Sci. 2017, 18(3), 674; https://doi.org/10.3390/ijms18030674 - 21 Mar 2017

Cited by 21 | Viewed by 8232

Abstract

Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d [...] Read more.

Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d-β-hydroxybutyrate (D-BHB) using SH-SY5Y cells. The cytotoxic mechanism of metformin under glucose deficiency was also examined. Cell viability under 1 mM glucose (glucose deficiency) was significantly decreased which was accompanied by increased production of reactive oxygen species (ROS) and decreased phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase 3 (GSK3β). ROS inhibitor reversed the glucose deficiency-induced cytotoxicity and restored the reduced phosphorylation of ERK and GSK3β. While metformin did not alter cell viability in normal glucose media, it further increased cell death and ROS production under glucose deficiency. However, D-BHB reversed cytotoxicity, ROS production, and the decrease in phosphorylation of ERK and GSK3β induced by the glucose deficiency. ERK inhibitor reversed the D-BHB-induced increase in cell viability under glucose deficiency, whereas GSK3β inhibitor did not restore glucose deficiency-induced cytotoxicity. Finally, the protective effect of D-BHB against glucose deficiency was confirmed in primary neuronal cells. We demonstrate that glucose deficiency-induced cytotoxicity is mediated by ERK inhibition through ROS production, which is attenuated by D-BHB and intensified by metformin. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2017)

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Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents

by Dora Werling, William A. Banks, Therese S. Salameh, Timea Kvarik, Laszlo Akos Kovacs, Alexandra Vaczy, Edina Szabo, Flora Mayer, Rita Varga, Andrea Tamas, Gabor Toth, Zsolt Biro, Tamas Atlasz and Dora Reglodi

Int. J. Mol. Sci. 2017, 18(3), 675; https://doi.org/10.3390/ijms18030675 - 21 Mar 2017

Cited by 29 | Viewed by 5948

Abstract

The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has two active forms, PACAP1-27 and PACAP1-38. Among the well-established actions are PACAP’s neurotrophic and neuroprotective effects, which have also been proven in models of different retinopathies. The route of delivery is usually intravitreal in [...] Read more.

The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has two active forms, PACAP1-27 and PACAP1-38. Among the well-established actions are PACAP’s neurotrophic and neuroprotective effects, which have also been proven in models of different retinopathies. The route of delivery is usually intravitreal in studies proving PACAP’s retinoprotective effects. Recently, we have shown that PACAP1-27 delivered as eye drops in benzalkonium-chloride was able to cross the ocular barriers and exert retinoprotection in ischemia. Since PACAP1-38 is the dominant form of the naturally occurring PACAP, our aim was to investigate whether the longer form is also able to cross the barriers and exert protective effects in permanent bilateral common carotid artery occlusion (BCCAO), a model of retinal hypoperfusion. Our results show that radioactive PACAP1-38 eye drops could effectively pass through the ocular barriers to reach the retina. Routine histological analysis and immunohistochemical evaluation of the Müller glial cells revealed that PACAP1-38 exerted retinoprotective effects. PACAP1-38 attenuated the damage caused by hypoperfusion, apparent in almost all retinal layers, and it decreased the glial cell overactivation. Overall, our results confirm that PACAP1-38 given in the form of eye drops is a novel protective therapeutic approach to treat retinal diseases. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2017)

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ATRAP Expression in Brown Adipose Tissue Does Not Influence the Development of Diet-Induced Metabolic Disorders in Mice

by Kohji Ohki, Hiromichi Wakui, Kengo Azushima, Kazushi Uneda, Sona Haku, Ryu Kobayashi, Kotaro Haruhara, Sho Kinguchi, Miyuki Matsuda, Masato Ohsawa, Akinobu Maeda, Shintaro Minegishi, Tomoaki Ishigami, Yoshiyuki Toya, Akio Yamashita, Satoshi Umemura and Kouichi Tamura

Int. J. Mol. Sci. 2017, 18(3), 676; https://doi.org/10.3390/ijms18030676 - 21 Mar 2017

Cited by 8 | Viewed by 6085

Abstract

Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions [...] Read more.

Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAP^fl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAP^adipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAP^fl/fl mice, ATRAP^adipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAP^fl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAP^adipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders. Full article

(This article belongs to the Special Issue Selected Papers from the Renin–Angiotensin–Aldosterone System (RAAS)2016: Official Satellite of ISH2016, from September 23 to 24 in Tokyo, Japan)

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Open AccessArticle

Identification of Quantitative Trait Loci Conditioning the Main Biomass Yield Components and Resistance to Melampsora spp. in Salix viminalis × Salix schwerinii Hybrids

by Paweł Sulima, Jerzy A. Przyborowski, Anna Kuszewska, Dariusz Załuski, Małgorzata Jędryczka and Witold Irzykowski

Int. J. Mol. Sci. 2017, 18(3), 677; https://doi.org/10.3390/ijms18030677 - 22 Mar 2017

Cited by 5 | Viewed by 4216

Abstract

The biomass of Salix viminalis is the most highly valued source of green energy, followed by S. schwerinii, S. dasyclados and other species. Significant variability in productivity and leaf rust resistance are noted both within and among willow species, which creates new [...] Read more.

The biomass of Salix viminalis is the most highly valued source of green energy, followed by S. schwerinii, S. dasyclados and other species. Significant variability in productivity and leaf rust resistance are noted both within and among willow species, which creates new opportunities for improving willow yield parameters through selection of desirable recombinants supported with molecular markers. The aim of this study was to identify quantitative trait loci (QTLs) linked with biomass yield-related traits and the resistance/susceptibility of Salix mapping population to leaf rust. The experimental material comprised a mapping population developed based on S. viminalis × S. schwerinii hybrids. Phenotyping was performed on plants grown in a field experiment that had a balanced incomplete block design with 10 replications. Based on a genetic map, 11 QTLs were identified for plant height, 9 for shoot diameter, 3 for number of shoots and 11 for resistance/susceptibility to leaf rust. The QTLs identified in our study explained 3%–16% of variability in the analyzed traits. Our findings make significant contributions to the development of willow breeding programs and research into shrubby willow crops grown for energy. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Cytotoxicity, Bactericidal, and Antioxidant Activity of Sodium Alginate Hydrosols Treated with Direct Electric Current

by Żaneta Król, Krzysztof Marycz, Dominika Kulig, Monika Marędziak and Andrzej Jarmoluk

Int. J. Mol. Sci. 2017, 18(3), 678; https://doi.org/10.3390/ijms18030678 - 22 Mar 2017

Cited by 27 | Viewed by 6365

Abstract

The aim of the study was to investigate the effect of using direct electric current (DC) of 0, 200, and 400 mA for five minutes on the physiochemical properties, cytotoxicity, antibacterial, and antioxidant activity of sodium alginate hydrosols with different sodium chloride concentrations. [...] Read more.

The aim of the study was to investigate the effect of using direct electric current (DC) of 0, 200, and 400 mA for five minutes on the physiochemical properties, cytotoxicity, antibacterial, and antioxidant activity of sodium alginate hydrosols with different sodium chloride concentrations. The pH, oxidation-reduction potential (ORP), electrical conductivity (EC), and available chlorine concentration (ACC) were measured. The effect of sodium alginate hydrosols treated with DC on Staphylococcus aureus, Listeria monocytogenes, Bacillus cereus, Micrococcus luteus, Escherichia coli, Salmonella enteritidis, Yersinia enterocolitica, Pseudomonas fluorescence, and RAW 264.7 and L929 cells was investigated. Subsequently, the antioxidant properties of hydrosols were evaluated by determining the scavenging ability of 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH) and ferric reducing antioxidant power (FRAP). The results have shown that after applying 400 mA in hydrosol samples with 0.1% and 0.2% NaCl all tested bacteria were inactivated. The ACC concentration of C400 samples with NaCl was equal to 13.95 and 19.71 mg/L, respectively. The cytotoxicity analysis revealed that optimized electric field conditions and the addition of sodium chloride allow for the avoidance of toxicity effects on normal cells without disturbing the antibacterial effects. Due to the presence of oxidizing substances, the DPPH of variants treated with DC was lower than the DPPH of control samples. Full article

(This article belongs to the Section Materials Science)

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Methodological Challenges in Protein Microarray and Immunohistochemistry for the Discovery of Novel Autoantibodies in Paediatric Acute Disseminated Encephalomyelitis

by Patrick Peschl, Melanie Ramberger, Romana Höftberger, Karin Jöhrer, Matthias Baumann, Kevin Rostásy and Markus Reindl

Int. J. Mol. Sci. 2017, 18(3), 679; https://doi.org/10.3390/ijms18030679 - 22 Mar 2017

Cited by 5 | Viewed by 4730

Abstract

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune-mediated demyelinating disease affecting mainly children and young adults. Differentiation to multiple sclerosis is not always possible, due to overlapping clinical symptoms and recurrent and multiphasic forms. Until now, immunoglobulins reactive to myelin oligodendrocyte glycoprotein (MOG [...] Read more.

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune-mediated demyelinating disease affecting mainly children and young adults. Differentiation to multiple sclerosis is not always possible, due to overlapping clinical symptoms and recurrent and multiphasic forms. Until now, immunoglobulins reactive to myelin oligodendrocyte glycoprotein (MOG antibodies) have been found in a subset of patients with ADEM. However, there are still patients lacking autoantibodies, necessitating the identification of new autoantibodies as biomarkers in those patients. Therefore, we aimed to identify novel autoantibody targets in ADEM patients. Sixteen ADEM patients (11 seronegative, 5 seropositive for MOG antibodies) were analysed for potential new biomarkers, using a protein microarray and immunohistochemistry on rat brain tissue to identify antibodies against intracellular and surface neuronal and glial antigens. Nine candidate antigens were identified in the protein microarray analysis in at least two patients per group. Immunohistochemistry on rat brain tissue did not reveal new target antigens. Although no new autoantibody targets could be found here, future studies should aim to identify new biomarkers for therapeutic and prognostic purposes. The microarray analysis and immunohistochemistry methods used here have several limitations, which should be considered in future searches for biomarkers. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Survivin and NAIP in Human Benign Prostatic Hyperplasia: Protective Role of the Association of Serenoa repens, Lycopene and Selenium from the Randomized Clinical Study

by Giuseppe Morgia, Antonio Micali, Mariagrazia Rinaldi, Natasha Irrera, Herbert Marini, Domenico Puzzolo, Antonina Pisani, Salvatore Privitera, Giorgio I. Russo, Sebastiano Cimino, Antonio Ieni, Vincenzo Trichilo, Domenica Altavilla, Francesco Squadrito and Letteria Minutoli

Int. J. Mol. Sci. 2017, 18(3), 680; https://doi.org/10.3390/ijms18030680 - 22 Mar 2017

Cited by 14 | Viewed by 5579

Abstract

Benign prostatic hyperplasia (BPH) treatment includes the apoptosis machinery modulation through the direct inhibition of caspase cascade. We previously demonstrated that Serenoa repens (Ser) with lycopene (Ly) and selenium (Se) reawakened apoptosis by reducing survivin and neuronal apoptosis inhibitory protein (NAIP) levels in [...] Read more.

Benign prostatic hyperplasia (BPH) treatment includes the apoptosis machinery modulation through the direct inhibition of caspase cascade. We previously demonstrated that Serenoa repens (Ser) with lycopene (Ly) and selenium (Se) reawakened apoptosis by reducing survivin and neuronal apoptosis inhibitory protein (NAIP) levels in rats. The aim of this study was to evaluate the effectiveness of Ser-Se-Ly association on survivin and NAIP expression in BPH patients. Ninety patients with lower urinary tract symptoms (LUTS) due to clinical BPH were included in this randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive placebo (Group BPH + placebo, n = 45) or Ser-Se-Ly association (Group BPH + Ser-Se-Ly; n = 45) for 3 months. At time 0, all patients underwent prostatic biopsies. After 3 months of treatment, they underwent prostatic re-biopsy and specimens were collected for molecular, morphological, and immunohistochemical analysis. After 3 months, survivin and NAIP were significantly decreased, while caspase-3 was significantly increased in BPH patients treated with Ser-Se-Ly when compared with the other group. In BPH patients treated with Ser-Se-Ly for 3 months, the glandular epithelium was formed by a single layer of cuboidal cells. PSA showed high immunoexpression in all BPH patients and a focal positivity in Ser-Se-Ly treated patients after 3 months. Evident prostate specific membrane antigen (PSMA) immunoexpression was shown in all BPH patients, while no positivity was present after Ser-Se-Ly administration. Ser-Se-Ly proved to be effective in promoting apoptosis in BPH patients. Full article

(This article belongs to the Special Issue Molecular Research on Urology)

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A Combination of Soybean and Haematococcus Extract Alleviates Ultraviolet B-Induced Photoaging

by Jieun Shin, Jong-Eun Kim, Kum-Ju Pak, Jung Il Kang, Tae-Seok Kim, Sang-Yoon Lee, Ik-Hyun Yeo, Jung Han Yoon Park, Jong Hun Kim, Nam Joo Kang and Ki Won Lee

Int. J. Mol. Sci. 2017, 18(3), 682; https://doi.org/10.3390/ijms18030682 - 22 Mar 2017

Cited by 20 | Viewed by 6557

Abstract

Soybean-derived isoflavones have been investigated for their preventative effects against UV-induced symptoms of skin damage including wrinkle formation and inflammation. Haematococcus pluvialis is a freshwater species of Chlorophyta that contains high concentrations of the natural carotenoid pigment astaxanthin. Astaxanthin is known to be [...] Read more.

Soybean-derived isoflavones have been investigated for their preventative effects against UV-induced symptoms of skin damage including wrinkle formation and inflammation. Haematococcus pluvialis is a freshwater species of Chlorophyta that contains high concentrations of the natural carotenoid pigment astaxanthin. Astaxanthin is known to be involved in retinoic acid receptor (RAR) signaling and previously been associated with the inhibition of activator protein (AP)-1 dependent transcription. Based on previous studies, we hypothesized that a combination of soy extract (SE) and Haematococcus extract (HE) may prevent UVB-induced photoaging through specific signaling pathways, as measured by UVB-induced wrinkling on hairless mice skin and expression changes in human dermal fibroblasts (HDFs). The 1:2 ratio of SE and HE mixture (SHM) showed the optimal benefit in vivo. SHM was found to inhibit wrinkle formation via the downregulation of matrix metalloproteinase (MMP)-1 mRNA and protein expression. SHM also inhibited mitogen-activated protein kinase (MAPK) phosphorylation and the transactivation of AP-1 which plays an important role in regulating MMP expression. These results highlight the potential for SHM to be developed as a therapeutic agent to prevent UVB-induced skin wrinkling. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Review

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Open AccessReview

From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform

by Na Tian, Jialiang Li, Jinming Shi and Guangchao Sui

Int. J. Mol. Sci. 2017, 18(3), 191; https://doi.org/10.3390/ijms18030191 - 2 Mar 2017

Cited by 15 | Viewed by 6789

Abstract

Alternative pre-mRNA splicing is a crucial process that allows the generation of diversified RNA and protein products from a multi-exon gene. In tumor cells, this mechanism can facilitate cancer development and progression through both creating oncogenic isoforms and reducing the expression of normal [...] Read more.

Alternative pre-mRNA splicing is a crucial process that allows the generation of diversified RNA and protein products from a multi-exon gene. In tumor cells, this mechanism can facilitate cancer development and progression through both creating oncogenic isoforms and reducing the expression of normal or controllable protein species. We recently demonstrated that an alternative cyclin D-binding myb-like transcription factor 1 (DMTF1) pre-mRNA splicing isoform, DMTF1β, is increasingly expressed in breast cancer and promotes mammary tumorigenesis in a transgenic mouse model. Aberrant pre-mRNA splicing is a typical event occurring for many cancer-related functional proteins. In this review, we introduce general aberrant pre-mRNA splicing in cancers and discuss its therapeutic application using our recent discovery of the oncogenic DMTF1 isoform as an example. We also summarize new insights in designing novel targeting strategies of cancer therapies based on the understanding of deregulated pre-mRNA splicing mechanisms. Full article

(This article belongs to the Section Biochemistry)

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A Review of Structure Construction of Silk Fibroin Biomaterials from Single Structures to Multi-Level Structures

by Yu Qi, Hui Wang, Kai Wei, Ya Yang, Ru-Yue Zheng, Ick Soo Kim and Ke-Qin Zhang

Int. J. Mol. Sci. 2017, 18(3), 237; https://doi.org/10.3390/ijms18030237 - 3 Mar 2017

Cited by 354 | Viewed by 19877

Abstract

The biological performance of artificial biomaterials is closely related to their structure characteristics. Cell adhesion, migration, proliferation, and differentiation are all strongly affected by the different scale structures of biomaterials. Silk fibroin (SF), extracted mainly from silkworms, has become a popular biomaterial due [...] Read more.

The biological performance of artificial biomaterials is closely related to their structure characteristics. Cell adhesion, migration, proliferation, and differentiation are all strongly affected by the different scale structures of biomaterials. Silk fibroin (SF), extracted mainly from silkworms, has become a popular biomaterial due to its excellent biocompatibility, exceptional mechanical properties, tunable degradation, ease of processing, and sufficient supply. As a material with excellent processability, SF can be processed into various forms with different structures, including particulate, fiber, film, and three-dimensional (3D) porous scaffolds. This review discusses and summarizes the various constructions of SF-based materials, from single structures to multi-level structures, and their applications. In combination with single structures, new techniques for creating special multi-level structures of SF-based materials, such as micropatterning and 3D-printing, are also briefly addressed. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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Pro-Resolving Molecules—New Approaches to Treat Sepsis?

by Christa Buechler, Rebekka Pohl and Charalampos Aslanidis

Int. J. Mol. Sci. 2017, 18(3), 476; https://doi.org/10.3390/ijms18030476 - 23 Feb 2017

Cited by 29 | Viewed by 8022

Abstract

Inflammation is a complex response of the body to exogenous and endogenous insults. Chronic and systemic diseases are attributed to uncontrolled inflammation. Molecules involved in the initiation of inflammation are very well studied while pathways regulating its resolution are insufficiently investigated. Approaches to [...] Read more.

Inflammation is a complex response of the body to exogenous and endogenous insults. Chronic and systemic diseases are attributed to uncontrolled inflammation. Molecules involved in the initiation of inflammation are very well studied while pathways regulating its resolution are insufficiently investigated. Approaches to down-modulate mediators relevant for the onset and duration of inflammation are successful in some chronic diseases, while all of them have failed in sepsis patients. Inflammation and immune suppression characterize sepsis, indicating that anti-inflammatory strategies alone are inappropriate for its therapy. Heme oxygenase 1 is a sensitive marker for oxidative stress and is upregulated in inflammation. Carbon monoxide, which is produced by this enzyme, initiates multiple anti-inflammatory and pro-resolving activities with higher production of omega-3 fatty acid-derived lipid metabolites being one of its protective actions. Pro-resolving lipids named maresins, resolvins and protectins originate from the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid while lipoxins are derived from arachidonic acid. These endogenously produced lipids do not simply limit inflammation but actively contribute to its resolution, and thus provide an opportunity to combat chronic inflammatory diseases and eventually sepsis. Full article

(This article belongs to the Special Issue Nutrigenomics of Risk Factors for Disease)

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The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases

by Chon-Kit Chou, Yu-Ting Chang, Michal Korinek, Yei-Tsung Chen, Ya-Ting Yang, Steve Leu, I-Ling Lin, Chin-Ju Tang and Chien-Chih Chiu

Int. J. Mol. Sci. 2017, 18(3), 483; https://doi.org/10.3390/ijms18030483 - 24 Feb 2017

Cited by 44 | Viewed by 9595 | Correction

Abstract

Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two [...] Read more.

Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two zinc-binding motifs that are essential for recognition of poly-ubiquitin chains. USP15 is grouped into the same category with USP4 and USP11 due to high degree of homology in an N-terminal region consisting of domains present in ubiquitin-specific proteases (DUSP) domain and ubiquitin-like (UBL) domain. USP15 cooperates with COP9 signalosome complex (CSN) to maintain the stability of cullin-ring ligase (CRL) adaptor proteins by removing the conjugated ubiquitin chains from RBX1 subunit of CRL. USP15 is also implicated in the stabilization of the human papillomavirus type 16 E6 oncoprotein, adenomatous polyposis coli, and IκBα. Recently, reports have suggested that USP15 acts as a key regulator of TGF-β receptor-signaling pathways by deubiquitinating the TGF-β receptor itself and its downstream transducers receptor-regulated SMADs (R-SMADs), including SMAD1, SMAD2, and SMAD3, thus activating the TGF-β target genes. Although the importance of USP15 in pathologic processes remains ambiguous so far, in this review, we endeavor to summarize the literature regarding the relationship of the deubiquitinating action of USP15 with the proteins involved in the regulation of Parkinson’s disease, virus infection, and cancer-related signaling networks. Full article

(This article belongs to the Special Issue Ubiquitin System)

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Negative Regulators of JAK/STAT Signaling in Rheumatoid Arthritis and Osteoarthritis

by Charles J. Malemud

Int. J. Mol. Sci. 2017, 18(3), 484; https://doi.org/10.3390/ijms18030484 - 24 Feb 2017

Cited by 96 | Viewed by 8475

Abstract

Elevated levels of pro-inflammatory cytokines are generally thought to be responsible for driving the progression of synovial joint inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA). These cytokines activate several signal transduction pathways, including the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT), [...] Read more.

Elevated levels of pro-inflammatory cytokines are generally thought to be responsible for driving the progression of synovial joint inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA). These cytokines activate several signal transduction pathways, including the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT), Stress-Activated/Mitogen-Activated Protein Kinase (SAPK/MAPK) and phosphatidylinositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathways which regulate numerous cellular responses. However, cytokine gene expression, matrix metalloproteinase gene expression and aberrant immune cell and synoviocyte survival via reduced apoptosis are most critical in the context of inflammation characteristic of RA and OA. Negative regulation of JAK/STAT signaling is controlled by Suppressor of Cytokine Signaling (SOCS) proteins. SOCS is produced at lower levels in RA and OA. In addition, gaining further insight into the role played in RA and OA pathology by the inhibitors of the apoptosis protein family, cellular inhibitor of apoptosis protein-1, -2 (c-IAP1, c-IAP2), X (cross)-linked inhibitor of apoptosis protein (XIAP), protein inhibitor of activated STAT (PIAS), and survivin (human) as well as SOCS appears to be a worthy endeavor going forward. Full article

(This article belongs to the Special Issue Apoptotic Chondrocytes and Osteoarthritis)

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Progranulin and Its Related MicroRNAs after Status Epilepticus: Possible Mechanisms of Neuroprotection

by Peter Körtvelyessy, Tessa Huchtemann, Hans-Jochen Heinze and Daniel M. Bittner

Int. J. Mol. Sci. 2017, 18(3), 490; https://doi.org/10.3390/ijms18030490 - 24 Feb 2017

Cited by 9 | Viewed by 6846

Abstract

The current knowledge about neuroprotective mechanisms in humans after status epilepticus is scarce. One reason is the difficulty to measure possible mediators of these neuroprotective mechanisms. The dawn of microRNA detection in the cerebrospinal fluid (CSF) and the recent advancements in measuring proteins [...] Read more.

The current knowledge about neuroprotective mechanisms in humans after status epilepticus is scarce. One reason is the difficulty to measure possible mediators of these neuroprotective mechanisms. The dawn of microRNA detection in the cerebrospinal fluid (CSF) and the recent advancements in measuring proteins in the CSF such as progranulin, which is, e.g., responsible for neurite outgrowth and limiting exceeding neuroinflammatory responses, have given us new insights into putative neuroprotective mechanisms following status epilepticus. This should complement the animal data. In this review, we cover what is known about the role of progranulin as well as the links between microRNA changes and the progranulin pathway following status epilepticus in humans and animals hypothesizing neuroprotective and neurorehabilitative effects. Progranulin has also been found to feature prominently in the neuroprotective processes under hypoxic conditions and initiating neurorehabilitative processes. These properties may be used therapeutically, e.g., through drugs that raise the progranulin levels and therefore the cerebral progranulin levels as well with the goal of improving the outcome after status epilepticus. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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Role of Netrin-1 Signaling in Nerve Regeneration

by Xin-Peng Dun and David B. Parkinson

Int. J. Mol. Sci. 2017, 18(3), 491; https://doi.org/10.3390/ijms18030491 - 24 Feb 2017

Cited by 97 | Viewed by 15627

Abstract

Netrin-1 was the first axon guidance molecule to be discovered in vertebrates and has a strong chemotropic function for axonal guidance, cell migration, morphogenesis and angiogenesis. It is a secreted axon guidance cue that can trigger attraction by binding to its canonical receptors [...] Read more.

Netrin-1 was the first axon guidance molecule to be discovered in vertebrates and has a strong chemotropic function for axonal guidance, cell migration, morphogenesis and angiogenesis. It is a secreted axon guidance cue that can trigger attraction by binding to its canonical receptors Deleted in Colorectal Cancer (DCC) and Neogenin or repulsion through binding the DCC/Uncoordinated (Unc5) A–D receptor complex. The crystal structures of Netrin-1/receptor complexes have recently been revealed. These studies have provided a structure based explanation of Netrin-1 bi-functionality. Netrin-1 and its receptor are continuously expressed in the adult nervous system and are differentially regulated after nerve injury. In the adult spinal cord and optic nerve, Netrin-1 has been considered as an inhibitor that contributes to axon regeneration failure after injury. In the peripheral nervous system, Netrin-1 receptors are expressed in Schwann cells, the cell bodies of sensory neurons and the axons of both motor and sensory neurons. Netrin-1 is expressed in Schwann cells and its expression is up-regulated after peripheral nerve transection injury. Recent studies indicated that Netrin-1 plays a positive role in promoting peripheral nerve regeneration, Schwann cell proliferation and migration. Targeting of the Netrin-1 signaling pathway could develop novel therapeutic strategies to promote peripheral nerve regeneration and functional recovery. Full article

(This article belongs to the Special Issue Peripheral Nerve Regeneration: From Bench to Bedside)

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Complex Roles of Microglial Cells in Ischemic Stroke Pathobiology: New Insights and Future Directions

by Revathy Guruswamy and Ayman ElAli

Int. J. Mol. Sci. 2017, 18(3), 496; https://doi.org/10.3390/ijms18030496 - 25 Feb 2017

Cited by 119 | Viewed by 7978

Abstract

Ischemic stroke constitutes the major cause of death and disability in the industrialized world. The interest in microglia arose from the evidence outlining the role of neuroinflammation in ischemic stroke pathobiology. Microglia constitute the powerhouse of innate immunity in the brain. Microglial cells [...] Read more.

Ischemic stroke constitutes the major cause of death and disability in the industrialized world. The interest in microglia arose from the evidence outlining the role of neuroinflammation in ischemic stroke pathobiology. Microglia constitute the powerhouse of innate immunity in the brain. Microglial cells are highly ramified, and use these ramifications as sentinels to detect changes in brain homeostasis. Once a danger signal is recognized, cells become activated and mount specialized responses that range from eliminating cell debris to secreting inflammatory signals and trophic factors. Originally, it was suggested that microglia play essentially a detrimental role in ischemic stroke. However, recent reports are providing evidence that the role of these cells is more complex than what was originally thought. Although these cells play detrimental role in the acute phase, they are required for tissue regeneration in the post-acute phases. This complex role of microglia in ischemic stroke pathobiology constitutes a major challenge for the development of efficient immunomodulatory therapies. This review aims at providing an overview regarding the role of resident microglia and peripherally recruited macrophages in ischemic pathobiology. Furthermore, the review will highlight future directions towards the development of novel fine-tuning immunomodulatory therapeutic interventions. Full article

(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)

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Gene Expression in Osteolysis: Review on the Identification of Altered Molecular Pathways in Preclinical and Clinical Studies

by Francesca Veronesi, Matilde Tschon and Milena Fini

Int. J. Mol. Sci. 2017, 18(3), 499; https://doi.org/10.3390/ijms18030499 - 25 Feb 2017

Cited by 25 | Viewed by 4404

Abstract

Aseptic loosening (AL) due to osteolysis is the primary cause of joint prosthesis failure. Currently, a second surgery is still the only available treatment for AL, with its associated drawbacks. The present review aims at identifying genes whose expression is altered in osteolysis, [...] Read more.

Aseptic loosening (AL) due to osteolysis is the primary cause of joint prosthesis failure. Currently, a second surgery is still the only available treatment for AL, with its associated drawbacks. The present review aims at identifying genes whose expression is altered in osteolysis, and that could be the target of new pharmacological treatments, with the goal of replacing surgery. This review also aims at identifying the molecular pathways altered by different wear particles. We reviewed preclinical and clinical studies from 2010 to 2016, analyzing gene expression of tissues or cells affected by osteolysis. A total of 32 in vitro, 16 in vivo and six clinical studies were included. These studies revealed that genes belonging to both inflammation and osteoclastogenesis pathways are mainly involved in osteolysis. More precisely, an increase in genes encoding for the following factors were observed: Interleukins 6 and 1β (IL16 and β), Tumor Necrosis Factor α (TNFα), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1), Cathepsin K (CATK) and Tartrate-resistant acid phosphatase (TRAP). Titanium (Ti) and Polyethylene (PE) were the most studied particles, showing that Ti up-regulated inflammation and osteoclastogenesis related genes, while PE up-regulated primarily osteoclastogenesis related genes. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections

by Maria Elisa Drago-Serrano, Rafael Campos-Rodríguez, Julio César Carrero and Mireya De la Garza

Int. J. Mol. Sci. 2017, 18(3), 501; https://doi.org/10.3390/ijms18030501 - 1 Mar 2017

Cited by 110 | Viewed by 11683

Abstract

Lactoferrin (Lf) is a glycoprotein of the primary innate immune-defense system of mammals present in milk and other mucosal secretions. This protein of the transferrin family has broad antimicrobial properties by depriving pathogens from iron, or disrupting their plasma membranes through its highly [...] Read more.

Lactoferrin (Lf) is a glycoprotein of the primary innate immune-defense system of mammals present in milk and other mucosal secretions. This protein of the transferrin family has broad antimicrobial properties by depriving pathogens from iron, or disrupting their plasma membranes through its highly cationic charge. Noteworthy, Lf also exhibits immunomodulatory activities performing up- and down-regulation of innate and adaptive immune cells, contributing to the homeostasis in mucosal surfaces exposed to myriad of microbial agents, such as the gastrointestinal and respiratory tracts. Although the inflammatory process is essential for the control of invasive infectious agents, the development of an exacerbated or chronic inflammation results in tissue damage with life-threatening consequences. In this review, we highlight recent findings in in vitro and in vivo models of the gut, lung, oral cavity, mammary gland, and liver infections that provide experimental evidence supporting the therapeutic role of human and bovine Lf in promoting some parameters of inflammation and protecting against the deleterious effects of bacterial, viral, fungal and protozoan-associated inflammation. Thus, this new knowledge of Lf immunomodulation paves the way to more effective design of treatments that include native or synthetic Lf derivatives, which may be useful to reduce immune-mediated tissue damage in infectious diseases. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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From Lysosomal Storage Diseases to NKT Cell Activation and Back

by Cátia S. Pereira, Helena Ribeiro and M. Fatima Macedo

Int. J. Mol. Sci. 2017, 18(3), 502; https://doi.org/10.3390/ijms18030502 - 25 Feb 2017

Cited by 17 | Viewed by 6542

Abstract

Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special [...] Read more.

Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT) cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d) molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs’ mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Novel Concepts, Therapeutic Aspects and Beyond)

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The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections

by Shigehisa Yanagi, Hironobu Tsubouchi, Ayako Miura, Ayako Matsuo, Nobuhiro Matsumoto and Masamitsu Nakazato

Int. J. Mol. Sci. 2017, 18(3), 503; https://doi.org/10.3390/ijms18030503 - 25 Feb 2017

Cited by 49 | Viewed by 9223

Abstract

Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly [...] Read more.

Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly against pathogen threats are unclear. Age-associated, chronic low-grade inflammation augments the susceptibility and severity of pneumonia in the elderly. Cellular senescence, one of the hallmarks of aging, has its own characteristics, cell growth arrest and senescence-associated secretory phenotype (SASP). These properties are beneficial if the sequence of senescence–clearance–regeneration is transient in manner. However, persisting senescent cell accumulation and excessive SASP might induce sustained low-grade inflammation and disruption of normal tissue microenvironments in aged tissue. Emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related and increase the risk of pneumonia. In addition to their structural collapses, COPD and IPF might increase the vulnerability to pathogen insults through SASP. Here, we discuss the current advances in understanding of the impacts of cellular senescence in elderly pneumonia and in these chronic lung disorders that heighten the risk of respiratory infections. Full article

(This article belongs to the Special Issue Pneumonia: Pathogenesis, Diagnostics, Therapeutics, and Prevention)

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The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity

by Kaitlyn K. Thompson and Stella E. Tsirka

Int. J. Mol. Sci. 2017, 18(3), 504; https://doi.org/10.3390/ijms18030504 - 25 Feb 2017

Cited by 68 | Viewed by 8033

Abstract

Autoimmune diseases of the central nervous system (CNS) involve inflammatory components and result in neurodegenerative processes. Microglia, the resident macrophages of the CNS, are the first responders after insults to the CNS and comprise a major link between the inflammation and neurodegeneration. Here, [...] Read more.

Autoimmune diseases of the central nervous system (CNS) involve inflammatory components and result in neurodegenerative processes. Microglia, the resident macrophages of the CNS, are the first responders after insults to the CNS and comprise a major link between the inflammation and neurodegeneration. Here, we will focus on the roles of microglia in two autoimmune diseases: the prevalent condition of multiple sclerosis (MS) and the much rarer Rasmussen’s encephalitis (RE). Although there is an abundance of evidence that microglia actively contribute to neuronal damage in pathological states such as MS and RE, there is also evidence of important reparative functions. As current research supports a more complex and diverse array of functions and phenotypes that microglia can assume, it is an especially interesting time to examine what is known about both the damaging and restorative roles that microglia can play in the inflammatory CNS setting. We will also discuss the pharmacological approaches to modulating microglia towards a more neuroprotective state. Full article

(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)

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Role of Nerve Growth Factor (NGF) and miRNAs in Epithelial Ovarian Cancer

by Rocío Retamales-Ortega, Lorena Oróstica, Carolina Vera, Paula Cuevas, Andrea Hernández, Iván Hurtado, Margarita Vega and Carmen Romero

Int. J. Mol. Sci. 2017, 18(3), 507; https://doi.org/10.3390/ijms18030507 - 26 Feb 2017

Cited by 35 | Viewed by 7713

Abstract

Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types [...] Read more.

Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression. Other molecules controlled by NGF include ciclooxigenase-2, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and calreticulin (CRT), proteins involved in crucial processes needed for EOC progression. These molecules could be modified through microRNA regulation, which could be regulated by NGF. MicroRNAs are the widest family of non-coding RNAs; they bind to 3′-UTR of mRNAs to inhibit their translation, to deadenilate or to degraded them. In EOC, a deregulation in microRNA expression has been described, including alterations of miR-200 family, cluster-17-92, and miR-23b, among others. Since the NGF-microRNA relationship in pathologies has not been studied, this review proposes that some microRNAs could be associated with NGF/TRKA activation, modifying protein levels needed for EOC progression. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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The Endothelin Type A Receptor as a Potential Therapeutic Target in Preeclampsia

by Bhavisha Bakrania, Jeremy Duncan, Junie P. Warrington and Joey P. Granger

Int. J. Mol. Sci. 2017, 18(3), 522; https://doi.org/10.3390/ijms18030522 - 28 Feb 2017

Cited by 38 | Viewed by 5846

Abstract

Preeclampsia (PE) is a disorder of pregnancy typically characterized by new onset hypertension after gestational week 20 and proteinuria. Although PE is one of the leading causes of maternal and perinatal morbidity and death worldwide, the mechanisms of the pathogenesis of the disease [...] Read more.

Preeclampsia (PE) is a disorder of pregnancy typically characterized by new onset hypertension after gestational week 20 and proteinuria. Although PE is one of the leading causes of maternal and perinatal morbidity and death worldwide, the mechanisms of the pathogenesis of the disease remain unclear and treatment options are limited. However, there is increasing evidence to suggest that endothelin-1 (ET-1) plays a critical role in the pathophysiology of PE. Multiple studies report that ET-1 is increased in PE and some studies report a positive correlation between ET-1 and the severity of symptoms. A number of experimental models of PE are also associated with elevated tissue levels of prepro ET-1 mRNA. Moreover, experimental models of PE (placental ischemia, sFlt-1 infusion, Tumor necrosis factor (TNF) -α infusion, and Angiotensin II type 1 receptor autoantibody (AT1-AA) infusion) have proven to be susceptible to Endothelin Type A (ET_A) receptor antagonism. While the results are promising, further work is needed to determine whether ET antagonists could provide an effective therapy for the management of preeclampsia. Full article

(This article belongs to the Special Issue Prediction, Diagnostics and Prevention of Pregnancy Complications)

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Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease

by Yunqi Weng, Jian Yao, Sawyer Sparks and Kevin Yueju Wang

Int. J. Mol. Sci. 2017, 18(3), 523; https://doi.org/10.3390/ijms18030523 - 28 Feb 2017

Cited by 135 | Viewed by 32736

Abstract

Natto, a fermented soybean product, has been consumed as a traditional food in Japan for thousands of years. Nattokinase (NK), a potent blood-clot dissolving protein used for the treatment of cardiovascular diseases, is produced by the bacterium Bacillus subtilis during the fermentation of [...] Read more.

Natto, a fermented soybean product, has been consumed as a traditional food in Japan for thousands of years. Nattokinase (NK), a potent blood-clot dissolving protein used for the treatment of cardiovascular diseases, is produced by the bacterium Bacillus subtilis during the fermentation of soybeans to produce Natto. NK has been extensively studied in Japan, Korea, and China. Recently, the fibrinolytic (anti-clotting) capacity of NK has been recognized by Western medicine. The National Science Foundation in the United States has investigated and evaluated the safety of NK. NK is currently undergoing a clinical trial study (Phase II) in the USA for atherothrombotic prevention. Multiple NK genes have been cloned, characterized, and produced in various expression system studies. Recombinant technology represents a promising approach for the production of NK with high purity for its use in antithrombotic applications. This review covers the history, benefit, safety, and production of NK. Opportunities for utilizing plant systems for the large-scale production of NK, or for the production of edible plants that can be used to provide oral delivery of NK without extraction and purification are also discussed. Full article

(This article belongs to the Special Issue Advances in Molecular Research of Functional and Nutraceutical Food 2017)

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β-N-Oxalyl-l-α,β-diaminopropionic Acid (β-ODAP) Content in Lathyrus sativus: The Integration of Nitrogen and Sulfur Metabolism through β-Cyanoalanine Synthase

by Quanle Xu, Fengjuan Liu, Peng Chen, Joseph M. Jez and Hari B. Krishnan

Int. J. Mol. Sci. 2017, 18(3), 526; https://doi.org/10.3390/ijms18030526 - 28 Feb 2017

Cited by 43 | Viewed by 7744

Abstract

Grass pea (Lathyrus sativus L.) is an important legume crop grown mainly in South Asia and Sub-Saharan Africa. This underutilized legume can withstand harsh environmental conditions including drought and flooding. During drought-induced famines, this protein-rich legume serves as a food source for [...] Read more.

Grass pea (Lathyrus sativus L.) is an important legume crop grown mainly in South Asia and Sub-Saharan Africa. This underutilized legume can withstand harsh environmental conditions including drought and flooding. During drought-induced famines, this protein-rich legume serves as a food source for poor farmers when other crops fail under harsh environmental conditions; however, its use is limited because of the presence of an endogenous neurotoxic nonprotein amino acid β-N-oxalyl-l-α,β-diaminopropionic acid (β-ODAP). Long-term consumption of Lathyrus and β-ODAP is linked to lathyrism, which is a degenerative motor neuron syndrome. Pharmacological studies indicate that nutritional deficiencies in methionine and cysteine may aggravate the neurotoxicity of β-ODAP. The biosynthetic pathway leading to the production of β-ODAP is poorly understood, but is linked to sulfur metabolism. To date, only a limited number of studies have been conducted in grass pea on the sulfur assimilatory enzymes and how these enzymes regulate the biosynthesis of β-ODAP. Here, we review the current knowledge on the role of sulfur metabolism in grass pea and its contribution to β-ODAP biosynthesis. Unraveling the fundamental steps and regulation of β-ODAP biosynthesis in grass pea will be vital for the development of improved varieties of this underutilized legume. Full article

(This article belongs to the Special Issue Pulses)

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Involvement of Astrocytes in Mediating the Central Effects of Ghrelin

by Laura M. Frago and Julie A. Chowen

Int. J. Mol. Sci. 2017, 18(3), 536; https://doi.org/10.3390/ijms18030536 - 2 Mar 2017

Cited by 20 | Viewed by 6887

Abstract

Although astrocytes are the most abundant cells in the mammalian brain, much remains to be learned about their molecular and functional features. Astrocytes express receptors for numerous hormones and metabolic factors, including the appetite-promoting hormone ghrelin. The metabolic effects of ghrelin are largely [...] Read more.

Although astrocytes are the most abundant cells in the mammalian brain, much remains to be learned about their molecular and functional features. Astrocytes express receptors for numerous hormones and metabolic factors, including the appetite-promoting hormone ghrelin. The metabolic effects of ghrelin are largely opposite to those of leptin, as it stimulates food intake and decreases energy expenditure. Ghrelin is also involved in glucose-sensing and glucose homeostasis. The widespread expression of the ghrelin receptor in the central nervous system suggests that this hormone is not only involved in metabolism, but also in other essential functions in the brain. In fact, ghrelin has been shown to promote cell survival and neuroprotection, with some studies exploring the use of ghrelin as a therapeutic agent against metabolic and neurodegenerative diseases. In this review, we highlight the possible role of glial cells as mediators of ghrelin’s actions within the brain. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Exosomes: From Garbage Bins to Promising Therapeutic Targets

by Mohammed H. Rashed, Emine Bayraktar, Gouda K. Helal, Mohamed F. Abd-Ellah, Paola Amero, Arturo Chavez-Reyes and Cristian Rodriguez-Aguayo

Int. J. Mol. Sci. 2017, 18(3), 538; https://doi.org/10.3390/ijms18030538 - 2 Mar 2017

Cited by 400 | Viewed by 20162

Abstract

Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including [...] Read more.

Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including blood, saliva, urine, and breast milk. Exosomes have been shown to carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. They are more than simply molecular garbage bins, however, in that the molecules they carry can be taken up by other cells. Thus, exosomes transfer biological information to neighboring cells and through this cell-to-cell communication are involved not only in physiological functions such as cell-to-cell communication, but also in the pathogenesis of some diseases, including tumors and neurodegenerative conditions. Our increasing understanding of why cells release exosomes and their role in intercellular communication has revealed the very complex and sophisticated contribution of exosomes to health and disease. The aim of this review is to reveal the emerging roles of exosomes in normal and pathological conditions and describe the controversial biological role of exosomes, as it is now understood, in carcinogenesis. We also summarize what is known about exosome biogenesis, composition, functions, and pathways and discuss the potential clinical applications of exosomes, especially as biomarkers and novel therapeutic agents. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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Antimicrobial Dendrimeric Peptides: Structure, Activity and New Therapeutic Applications

by Mariano A. Scorciapino, Ilaria Serra, Giorgia Manzo and Andrea C. Rinaldi

Int. J. Mol. Sci. 2017, 18(3), 542; https://doi.org/10.3390/ijms18030542 - 3 Mar 2017

Cited by 59 | Viewed by 6891

Abstract

Microbial resistance to conventional antibiotics is one of the most outstanding medical and scientific challenges of our times. Despite the recognised need for new anti-infective agents, however, very few new drugs have been brought to the market and to the clinic in the [...] Read more.

Microbial resistance to conventional antibiotics is one of the most outstanding medical and scientific challenges of our times. Despite the recognised need for new anti-infective agents, however, very few new drugs have been brought to the market and to the clinic in the last three decades. This review highlights the properties of a new class of antibiotics, namely dendrimeric peptides. These intriguing novel compounds, generally made of multiple peptidic sequences linked to an inner branched core, display an array of antibacterial, antiviral and antifungal activities, usually coupled to low haemolytic activity. In addition, several peptides synthesized in oligobranched form proved to be promising tools for the selective treatment of cancer cells. Full article

(This article belongs to the Special Issue Antimicrobial Polymers 2016)

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More Insight into BDNF against Neurodegeneration: Anti-Apoptosis, Anti-Oxidation, and Suppression of Autophagy

by Shang-Der Chen, Chia-Lin Wu, Wei-Chao Hwang and Ding-I Yang

Int. J. Mol. Sci. 2017, 18(3), 545; https://doi.org/10.3390/ijms18030545 - 3 Mar 2017

Cited by 180 | Viewed by 11121

Abstract

In addition to its well-established neurotrophic action, brain-derived neurotrophic factor (BDNF) also possesses other neuroprotective effects including anti-apoptosis, anti-oxidation, and suppression of autophagy. We have shown before that BDNF triggers multiple mechanisms to confer neuronal resistance against 3-nitropropionic acid (3-NP)-induced mitochondrial dysfunction in [...] Read more.

In addition to its well-established neurotrophic action, brain-derived neurotrophic factor (BDNF) also possesses other neuroprotective effects including anti-apoptosis, anti-oxidation, and suppression of autophagy. We have shown before that BDNF triggers multiple mechanisms to confer neuronal resistance against 3-nitropropionic acid (3-NP)-induced mitochondrial dysfunction in primary rat cortical cultures. The beneficial effects of BDNF involve the induction of anti-oxidative thioredoxin with the resultant expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) as well as erythropoietin (EPO)-dependent stimulation of sonic hedgehog (SHH). We further revealed that BDNF may bring the expression of sulfiredoxin, an ATP-dependent antioxidant enzyme, to offset mitochondrial inhibition in cortical neurons. Recently, we provided insights into another novel anti-oxidative mechanism of BDNF, which involves the augmentation of sestrin2 expression to endow neuronal resistance against oxidative stress induced by 3-NP; BDNF induction of sestrin2 entails the activation of a pathway involving nitric oxide (NO), cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG), and nuclear factor-κB (NF-κB). Apart from anti-apoptosis and anti-oxidation, we demonstrated in our most recent study that BDNF may activate the mammalian target of rapamycin (mTOR) with resultant activation of transcription factor c-Jun, thereby stimulating the expression of p62/sequestosome-1 to suppress heightened autophagy as a result of 3-NP exposure. Together, our results provide in-depth insight into multi-faceted protective mechanisms of BDNF against mitochondrial dysfunction commonly associated with the pathogenesis of many chronic neurodegenerative disorders. Delineation of the protective signaling pathways elicited by BDNF would endow a rationale to develop novel therapeutic regimens to halt or prevent the progression of neurodegeneration. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury

by Kathleen M. Keefe, Imran S. Sheikh and George M. Smith

Int. J. Mol. Sci. 2017, 18(3), 548; https://doi.org/10.3390/ijms18030548 - 3 Mar 2017

Cited by 245 | Viewed by 13321

Abstract

Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury [...] Read more.

Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI). We focus on nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

by Ramón Cacabelos

Int. J. Mol. Sci. 2017, 18(3), 551; https://doi.org/10.3390/ijms18030551 - 4 Mar 2017

Cited by 393 | Viewed by 28017

Abstract

Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. [...] Read more.

Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics. Full article

(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2016)

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Cellular Reprogramming Using Protein and Cell-Penetrating Peptides

by Bong Jong Seo, Yean Ju Hong and Jeong Tae Do

Int. J. Mol. Sci. 2017, 18(3), 552; https://doi.org/10.3390/ijms18030552 - 3 Mar 2017

Cited by 40 | Viewed by 7284

Abstract

Recently, stem cells have been suggested as invaluable tools for cell therapy because of their self-renewal and multilineage differentiation potential. Thus, scientists have developed a variety of methods to generate pluripotent stem cells, from nuclear transfer technology to direct reprogramming using defined factors, [...] Read more.

Recently, stem cells have been suggested as invaluable tools for cell therapy because of their self-renewal and multilineage differentiation potential. Thus, scientists have developed a variety of methods to generate pluripotent stem cells, from nuclear transfer technology to direct reprogramming using defined factors, or induced pluripotent stem cells (iPSCs). Considering the ethical issues and efficiency, iPSCs are thought to be one of the most promising stem cells for cell therapy. Induced pluripotent stem cells can be generated by transduction with a virus, plasmid, RNA, or protein. Herein, we provide an overview of the current technology for iPSC generation and describe protein-based transduction technology in detail. Full article

(This article belongs to the Special Issue Cell-Penetrating Peptides 2016)

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Effects and Mechanisms of Fruit and Vegetable Juices on Cardiovascular Diseases

by Jie Zheng, Yue Zhou, Sha Li, Pei Zhang, Tong Zhou, Dong-Ping Xu and Hua-Bin Li

Int. J. Mol. Sci. 2017, 18(3), 555; https://doi.org/10.3390/ijms18030555 - 4 Mar 2017

Cited by 113 | Viewed by 33769

Abstract

Many studies have indicated that consumption of vegetables and fruits are positively related to lower incidence of several chronic noncommunicable diseases. Although composition of fruit and vegetable juices is different from that of the edible portion of fruits and vegetables, they contain polyphenols [...] Read more.

Many studies have indicated that consumption of vegetables and fruits are positively related to lower incidence of several chronic noncommunicable diseases. Although composition of fruit and vegetable juices is different from that of the edible portion of fruits and vegetables, they contain polyphenols and vitamins from fruits and vegetables. Drinking vegetable and fruit juices is very popular in many countries, and also an efficient way to improve consumption of fruits and vegetables. The studies showed that fruit and vegetable juices affect cardiovascular risk factors, such as lowering blood pressure and improving blood lipid profiles. The main mechanisms of action included antioxidant effects, improvement of the aspects of the cardiovascular system, inhibition of platelet aggregation, anti-inflammatory effects, and prevention of hyperhomocysteinemia. Drinking juices might be a potential way to improve cardiovascular health, especially mixtures of juices because they contain a variety of polyphenols, vitamins, and minerals from different fruits and vegetables. This review summarizes recent studies on the effects of fruit and vegetable juices on indicators of cardiovascular disease, and special attention is paid to the mechanisms of action. Full article

(This article belongs to the Special Issue Correlation between Nutrition, Oxidative Stress and Disease)

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Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia—Implications for Vaccine Design

by Emma Rey-Jurado and Alexis M. Kalergis

Int. J. Mol. Sci. 2017, 18(3), 556; https://doi.org/10.3390/ijms18030556 - 4 Mar 2017

Cited by 27 | Viewed by 8425

Abstract

The human respiratory syncytial virus (hRSV) is the causative agent for high rates of hospitalizations due to viral bronchiolitis and pneumonia worldwide. Such a disease is characterized by an infection of epithelial cells of the distal airways that leads to inflammation and subsequently [...] Read more.

The human respiratory syncytial virus (hRSV) is the causative agent for high rates of hospitalizations due to viral bronchiolitis and pneumonia worldwide. Such a disease is characterized by an infection of epithelial cells of the distal airways that leads to inflammation and subsequently to respiratory failure. Upon infection, different pattern recognition receptors recognize the virus and trigger the innate immune response against the hRSV. Further, T cell immunity plays an important role for virus clearance. Based on animal studies, it is thought that the host immune response to hRSV is based on a biased T helper (Th)-2 and Th17 T cell responses with the recruitment of T cells, neutrophils and eosinophils to the lung, causing inflammation and tissue damage. In contrast, human immunity against RSV has been shown to be more complex with no definitive T cell polarization profile. Nowadays, only a humanized monoclonal antibody, known as palivizumab, is available to protect against hRSV infection in high-risk infants. However, such treatment involves several injections at a significantly high cost. For these reasons, intense research has been focused on finding novel vaccines or therapies to prevent hRSV infection in the population. Here, we comprehensively review the recent literature relative to the immunological features during hRSV infection, as well as the new insights into preventing the disease caused by this virus. Full article

(This article belongs to the Special Issue Pneumonia: Pathogenesis, Diagnostics, Therapeutics, and Prevention)

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Microglial Function across the Spectrum of Age and Gender

by Jillian C. Nissen

Int. J. Mol. Sci. 2017, 18(3), 561; https://doi.org/10.3390/ijms18030561 - 4 Mar 2017

Cited by 58 | Viewed by 8901

Abstract

Microglia constitute the resident immunocompetent cells of the central nervous system. Although much work has focused on their ability to mount an inflammatory response in reaction to pathology, recent studies have delved into their role in maintaining homeostasis in the healthy brain. It [...] Read more.

Microglia constitute the resident immunocompetent cells of the central nervous system. Although much work has focused on their ability to mount an inflammatory response in reaction to pathology, recent studies have delved into their role in maintaining homeostasis in the healthy brain. It is important to note that the function of these cells is more complex than originally conceived, as there is increasing evidence that microglial responses can vary greatly among individuals. Here, this review will describe the changing behavior of microglia from development and birth through to the aged brain. Further, it is not only age that impacts the state of the neuroimmune milieu, as microglia have been shown to play a central role in the sexual differentiation of the brain. Finally, this review will discuss the implications this has for the differences in the incidence of neurodegenerative disorders between males and females, and between the young and old. Full article

(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)

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Alternative Splicing of hTERT Pre-mRNA: A Potential Strategy for the Regulation of Telomerase Activity

by Xuewen Liu, Yuchuan Wang, Guangming Chang, Feng Wang, Fei Wang and Xin Geng

Int. J. Mol. Sci. 2017, 18(3), 567; https://doi.org/10.3390/ijms18030567 - 7 Mar 2017

Cited by 34 | Viewed by 5325

Abstract

The activation of telomerase is one of the key events in the malignant transition of cells, and the expression of human telomerase reverse transcriptase (hTERT) is indispensable in the process of activating telomerase. The pre-mRNA alternative splicing of hTERT at the post-transcriptional level [...] Read more.

The activation of telomerase is one of the key events in the malignant transition of cells, and the expression of human telomerase reverse transcriptase (hTERT) is indispensable in the process of activating telomerase. The pre-mRNA alternative splicing of hTERT at the post-transcriptional level is one of the mechanisms for the regulation of telomerase activity. Shifts in splicing patterns occur in the development, tumorigenesis, and response to diverse stimuli in a tissue-specific and cell type–specific manner. Despite the regulation of telomerase activity, the alternative splicing of hTERT pre-mRNA may play a role in other cellular functions. Modulating the mode of hTERT pre-mRNA splicing is providing a new precept of therapy for cancer and aging-related diseases. This review focuses on the patterns of hTERT pre-mRNA alternative splicing and their biological functions, describes the potential association between the alternative splicing of hTERT pre-mRNA and telomerase activity, and discusses the possible significance of the alternative splicing of the hTERT pre-mRNA in the diagnosis, therapy, and prognosis of cancer and aging-related diseases. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing 2016)

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Epigenetic Regulation of BDNF Gene during Development and Diseases

by Kuan-Wei Chen and Linyi Chen

Int. J. Mol. Sci. 2017, 18(3), 571; https://doi.org/10.3390/ijms18030571 - 6 Mar 2017

Cited by 54 | Viewed by 6535

Abstract

Brain-derived neurotrophic factor (BDNF) is required for the development of the nervous system, proper cognitive function and memory formation. While aberrant expression of BDNF has been implicated in neurological disorders, the transcriptional regulation of BDNF remains to be elucidated. In response to different [...] Read more.

Brain-derived neurotrophic factor (BDNF) is required for the development of the nervous system, proper cognitive function and memory formation. While aberrant expression of BDNF has been implicated in neurological disorders, the transcriptional regulation of BDNF remains to be elucidated. In response to different stimuli, BDNF expression can be initiated from different promoters. Several studies have suggested that the expression of BDNF is regulated by promoter methylation. An emerging theme points to the possibility that histone modifications at the BDNF promoters may link to the neurological pathology. Thus, understanding the epigenetic regulation at the BDNF promoters will shed light on future therapies for neurological disorders. The present review summarizes the current knowledge of histone modifications of the BDNF gene in neuronal diseases, as well as the developmental regulation of the BDNF gene based on data from the Encyclopedia of DNA Elements (ENCODE). Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)

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Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

by Delphine Dayde, Ichidai Tanaka, Rekha Jain, Mei Chee Tai and Ayumu Taguchi

Int. J. Mol. Sci. 2017, 18(3), 573; https://doi.org/10.3390/ijms18030573 - 7 Mar 2017

Cited by 141 | Viewed by 11815

Abstract

The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation (nCRT) followed by radical surgery. Response to nCRT varies among patients and pathological complete response is associated with better outcome. However, there is a lack of effective methods to select rectal [...] Read more.

The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation (nCRT) followed by radical surgery. Response to nCRT varies among patients and pathological complete response is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from nCRT. The utility of clinicopathological and radiological features are limited due to lack of adequate sensitivity and specificity. Molecular biomarkers have the potential to predict response to nCRT at an early time point, but none have currently reached the clinic. Integration of diverse types of biomarkers including clinicopathological and imaging features, identification of mechanistic link to tumor biology, and rigorous validation using samples which represent disease heterogeneity, will allow to develop a sensitive and cost-effective molecular biomarker panel for precision medicine in rectal cancer. Here, we aim to review the recent advance in tissue- and blood-based molecular biomarker research and illustrate their potential in predicting nCRT response in rectal cancer. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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Trauma and Stem Cells: Biology and Potential Therapeutic Implications

by Kabilan Thurairajah, Matthew L. Broadhead and Zsolt J. Balogh

Int. J. Mol. Sci. 2017, 18(3), 577; https://doi.org/10.3390/ijms18030577 - 7 Mar 2017

Cited by 20 | Viewed by 7863

Abstract

Trauma may cause irreversible tissue damage and loss of function despite current best practice. Healing is dependent both on the nature of the injury and the intrinsic biological capacity of those tissues for healing. Preclinical research has highlighted stem cell therapy as a [...] Read more.

Trauma may cause irreversible tissue damage and loss of function despite current best practice. Healing is dependent both on the nature of the injury and the intrinsic biological capacity of those tissues for healing. Preclinical research has highlighted stem cell therapy as a potential avenue for improving outcomes for injuries with poor healing capacity. Additionally, trauma activates the immune system and alters stem cell behaviour. This paper reviews the current literature on stem cells and its relevance to trauma care. Emphasis is placed on understanding how stem cells respond to trauma and pertinent mechanisms that can be utilised to promote tissue healing. Research involving notable difficulties in trauma care such as fracture non-union, cartilage damage and trauma induced inflammation is discussed further. Full article

(This article belongs to the Special Issue Advances in Bone and Cartilage Research)

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ACTH and Polymorphisms at Steroidogenic Loci as Determinants of Aldosterone Secretion and Blood Pressure

by Scott M. MacKenzie, E. Marie Freel, John M. Connell, Robert Fraser and Eleanor Davies

Int. J. Mol. Sci. 2017, 18(3), 579; https://doi.org/10.3390/ijms18030579 - 7 Mar 2017

Cited by 5 | Viewed by 5011

Abstract

The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by [...] Read more.

The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by data from genome-wide association studies that consistently link the CYP17A1 locus to blood pressure. In this review article, we describe common polymorphisms at three steroidogenic loci (CYP11B2, CYP11B1 and CYP17A1) that alter gene transcription efficiency and levels of key steroids, including aldosterone. However, the mechanism by which this occurs remains unclear. While the renin angiotensin system is rightly regarded as the major driver of aldosterone secretion, there is increasing evidence that the contribution of corticotropin (ACTH) is also significant. In light of this, we propose that the differential response of variant CYP11B2, CYP11B1 and CYP17A1 genes to ACTH is an important determinant of blood pressure, tending to predispose individuals with an unfavourable genotype to hypertension. Full article

(This article belongs to the Special Issue Selected Papers from the Renin–Angiotensin–Aldosterone System (RAAS)2016: Official Satellite of ISH2016, from September 23 to 24 in Tokyo, Japan)

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Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations

by Nourah Mohammad Obaid, Karen Bedard and Weei-Yuarn Huang

Int. J. Mol. Sci. 2017, 18(3), 585; https://doi.org/10.3390/ijms18030585 - 8 Mar 2017

Cited by 28 | Viewed by 7468

Abstract

The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of [...] Read more.

The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of the BRAF gene. Since the initial identification of the BRAF mutation in 2002, a series of small molecular inhibitors that target the BRAFV600E have been developed, but intrinsic and acquired resistance to these drugs has presented an ongoing challenge. More recently, improvements in therapy have been achieved by combining the use of BRAF inhibitors with other drugs, such as inhibitors of the downstream effector mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) kinase (MEK). Despite improved success in response rates and in delaying resistance using combination therapy, ultimately, the acquisition of resistance remains a concern. Recent research articles have shed light on some of the underlying mechanisms of this resistance and have proposed numerous strategies that might be employed to overcome or avoid resistance to targeted therapies. This review will explore some of the resistance mechanisms, compare what is known in melanoma cancer to colorectal cancer, and discuss strategies under development to manage the development of resistance. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)

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Neurogenic Effects of Ghrelin on the Hippocampus

by Chanyang Kim, Sehee Kim and Seungjoon Park

Int. J. Mol. Sci. 2017, 18(3), 588; https://doi.org/10.3390/ijms18030588 - 8 Mar 2017

Cited by 32 | Viewed by 4944

Abstract

Mammalian neurogenesis continues throughout adulthood in the subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus in the hippocampus. It is well known that hippocampal neurogenesis is essential in mediating hippocampus-dependent learning and memory. Ghrelin, a peptide [...] Read more.

Mammalian neurogenesis continues throughout adulthood in the subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus in the hippocampus. It is well known that hippocampal neurogenesis is essential in mediating hippocampus-dependent learning and memory. Ghrelin, a peptide hormone mainly synthesized in the stomach, has been shown to play a major role in the regulation of energy metabolism. A plethora of evidence indicates that ghrelin can also exert important effects on neurogenesis in the hippocampus of the adult brain. The aim of this review is to discuss the current role of ghrelin on the in vivo and in vitro regulation of neurogenesis in the adult hippocampus. We will also discuss the possible role of ghrelin in dietary restriction-induced hippocampal neurogenesis and the link between ghrelin-induced hippocampal neurogenesis and cognitive functions. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Potential Neuroprotective Effects of Adiponectin in Alzheimer’s Disease

by Roy Chun-Laam Ng and Koon-Ho Chan

Int. J. Mol. Sci. 2017, 18(3), 592; https://doi.org/10.3390/ijms18030592 - 9 Mar 2017

Cited by 57 | Viewed by 7921

Abstract

The adipocyte-secreted protein adiponectin (APN) has several protective functions in the peripheral tissues including insulin sensitizing, anti-inflammatory and anti-oxidative effects that may benefit neurodegenerative diseases such as Alzheimer’s disease (AD). In addition, dysregulation of cerebral insulin sensitivities and signaling activities have been implicated [...] Read more.

The adipocyte-secreted protein adiponectin (APN) has several protective functions in the peripheral tissues including insulin sensitizing, anti-inflammatory and anti-oxidative effects that may benefit neurodegenerative diseases such as Alzheimer’s disease (AD). In addition, dysregulation of cerebral insulin sensitivities and signaling activities have been implicated in AD. Emerging insights into the mechanistic roles of adiponectin and AD highlight the potential therapeutic effects for AD through insulin signaling. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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Multicomponent, Tumor-Homing Chitosan Nanoparticles for Cancer Imaging and Therapy

by Jaehong Key and Kyeongsoon Park

Int. J. Mol. Sci. 2017, 18(3), 594; https://doi.org/10.3390/ijms18030594 - 8 Mar 2017

Cited by 49 | Viewed by 7543

Abstract

Current clinical methods for cancer diagnosis and therapy have limitations, although survival periods are increasing as medical technologies develop. In most cancer cases, patient survival is closely related to cancer stage. Late-stage cancer after metastasis is very challenging to cure because current surgical [...] Read more.

Current clinical methods for cancer diagnosis and therapy have limitations, although survival periods are increasing as medical technologies develop. In most cancer cases, patient survival is closely related to cancer stage. Late-stage cancer after metastasis is very challenging to cure because current surgical removal of cancer is not precise enough and significantly affects bystander normal tissues. Moreover, the subsequent chemotherapy and radiation therapy affect not only malignant tumors, but also healthy tissues. Nanotechnologies for cancer treatment have the clear objective of solving these issues. Nanoparticles have been developed to more accurately differentiate early-stage malignant tumors and to treat only the tumors while dramatically minimizing side effects. In this review, we focus on recent chitosan-based nanoparticles developed with the goal of accurate cancer imaging and effective treatment. Regarding imaging applications, we review optical and magnetic resonance cancer imaging in particular. Regarding cancer treatments, we review various therapeutic methods that use chitosan-based nanoparticles, including chemo-, gene, photothermal, photodynamic and magnetic therapies. Full article

(This article belongs to the Special Issue Chitins 2016)

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Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

by Ainhoa Plaza-Zabala, Virginia Sierra-Torre and Amanda Sierra

Int. J. Mol. Sci. 2017, 18(3), 598; https://doi.org/10.3390/ijms18030598 - 9 Mar 2017

Cited by 245 | Viewed by 20685

Abstract

Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health [...] Read more.

Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence. Full article

(This article belongs to the Special Issue Microglia in Aging and Neurodegenerative Disease)

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The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma

by Daisuke Kudo, Akiko Suto and Kenichi Hakamada

Int. J. Mol. Sci. 2017, 18(3), 600; https://doi.org/10.3390/ijms18030600 - 9 Mar 2017

Cited by 31 | Viewed by 5883

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases to affect humans, regardless of whether patients receive multimodal therapy (including surgery, radiotherapy, and chemotherapy). This resistance to intervention is currently considered to be caused by the desmoplastic change of the extracellular [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases to affect humans, regardless of whether patients receive multimodal therapy (including surgery, radiotherapy, and chemotherapy). This resistance to intervention is currently considered to be caused by the desmoplastic change of the extracellular matrix (ECM) in PDAC tissues, which is characterized by the accumulation of cancer-associated fibroblasts, collagen, proteoglycan, and hyaluronan. Among these ECM components, hyaluronan has attracted interest because various studies have indicated that hyaluronan-rich PDAC is correlated with the progressive properties of cancer cells, both in experimental and clinical settings. Hence, the reduction of hyaluronan in cancer tissue may represent a novel therapeutic approach for PDAC. 4-methylumbelliferone (4-MU) is a derivative of coumarin that was reported to suppress the synthesis of hyaluronan in cultured human skin fibroblasts in 1995. As an additional study, our group firstly reported that 4-MU reduced the hyaluronan synthesis of mouse melanoma cells and exerted anti-cancer activity. Subsequently, we have showed that 4-MU inhibited liver metastasis in mice inoculated with human pancreatic cancer cells. Thereafter, 4-MU has been accepted as an effective agent for hyaluronan research and is expected to have clinical applications. This review provides an overview of the interaction between PDAC and hyaluronan, the properties of 4-MU as a suppressor of the synthesis of hyaluronan, and the perspectives of PDAC treatment targeting hyaluronan. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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Review of Prospects of Biological Fluid Biomarkers in Osteoarthritis

by Lich Thi Nguyen, Ashish Ranjan Sharma, Chiranjib Chakraborty, Balaji Saibaba, Moo-Eob Ahn and Sang-Soo Lee

Int. J. Mol. Sci. 2017, 18(3), 601; https://doi.org/10.3390/ijms18030601 - 12 Mar 2017

Cited by 96 | Viewed by 12350

Abstract

Osteoarthritis (OA) is a degenerative disease of the joints and is one of the leading causes of disability in adults. However, there are no key therapeutics for OA and medical treatment is based on managing the symptoms and slowing down progression of the [...] Read more.

Osteoarthritis (OA) is a degenerative disease of the joints and is one of the leading causes of disability in adults. However, there are no key therapeutics for OA and medical treatment is based on managing the symptoms and slowing down progression of the disease. Diagnostics based on clinical examination and radiography have provided little information about metabolic changes in joint tissues, disease onset and progression. Due to lack of effective methods for early detection and evaluation of treatment outcome, the measurement of biochemical markers (biomarkers) shows promise as a prospective method aiding in disease monitoring. OA biomarkers that are present in biological fluids such as blood, urine and synovial fluid, sources that are easily isolated from body, are of particular interest. Moreover, there are increasingly more studies identifying and developing new biomarkers for OA. In this review, efforts have been made to summarize the biomarkers that have been reported in recent studies on patients. We also tried to classify biomarkers according to tissue metabolism (bone, cartilage and synovial metabolism markers), pathological pathways (inflammatory and genetic markers) and biological function (chemokines, growth factors, acute phase proteins, etc.). Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis

by Rei Ogawa

Int. J. Mol. Sci. 2017, 18(3), 606; https://doi.org/10.3390/ijms18030606 - 10 Mar 2017

Cited by 568 | Viewed by 81271

Abstract

Keloids and hypertrophic scars are caused by cutaneous injury and irritation, including trauma, insect bite, burn, surgery, vaccination, skin piercing, acne, folliculitis, chicken pox, and herpes zoster infection. Notably, superficial injuries that do not reach the reticular dermis never cause keloidal and hypertrophic [...] Read more.

Keloids and hypertrophic scars are caused by cutaneous injury and irritation, including trauma, insect bite, burn, surgery, vaccination, skin piercing, acne, folliculitis, chicken pox, and herpes zoster infection. Notably, superficial injuries that do not reach the reticular dermis never cause keloidal and hypertrophic scarring. This suggests that these pathological scars are due to injury to this skin layer and the subsequent aberrant wound healing therein. The latter is characterized by continuous and histologically localized inflammation. As a result, the reticular layer of keloids and hypertrophic scars contains inflammatory cells, increased numbers of fibroblasts, newly formed blood vessels, and collagen deposits. Moreover, proinflammatory factors, such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α are upregulated in keloid tissues, which suggests that, in patients with keloids, proinflammatory genes in the skin are sensitive to trauma. This may promote chronic inflammation, which in turn may cause the invasive growth of keloids. In addition, the upregulation of proinflammatory factors in pathological scars suggests that, rather than being skin tumors, keloids and hypertrophic scars are inflammatory disorders of skin, specifically inflammatory disorders of the reticular dermis. Various external and internal post-wounding stimuli may promote reticular inflammation. The nature of these stimuli most likely shapes the characteristics, quantity, and course of keloids and hypertrophic scars. Specifically, it is likely that the intensity, frequency, and duration of these stimuli determine how quickly the scars appear, the direction and speed of growth, and the intensity of symptoms. These proinflammatory stimuli include a variety of local, systemic, and genetic factors. These observations together suggest that the clinical differences between keloids and hypertrophic scars merely reflect differences in the intensity, frequency, and duration of the inflammation of the reticular dermis. At present, physicians cannot (or at least find it very difficult to) control systemic and genetic risk factors of keloids and hypertrophic scars. However, they can use a number of treatment modalities that all, interestingly, act by reducing inflammation. They include corticosteroid injection/tape/ointment, radiotherapy, cryotherapy, compression therapy, stabilization therapy, 5-fluorouracil (5-FU) therapy, and surgical methods that reduce skin tension. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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The Role and Molecular Mechanism of Non-Coding RNAs in Pathological Cardiac Remodeling

by Jinning Gao, Wenhua Xu, Jianxun Wang, Kun Wang and Peifeng Li

Int. J. Mol. Sci. 2017, 18(3), 608; https://doi.org/10.3390/ijms18030608 - 10 Mar 2017

Cited by 55 | Viewed by 7260

Abstract

Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Studies show that ncRNAs are not only involved in cell proliferation, apoptosis, differentiation, metabolism and other physiological processes, but also involved in the pathogenesis of diseases. Cardiac remodeling is [...] Read more.

Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Studies show that ncRNAs are not only involved in cell proliferation, apoptosis, differentiation, metabolism and other physiological processes, but also involved in the pathogenesis of diseases. Cardiac remodeling is the main pathological basis of a variety of cardiovascular diseases. Many studies have shown that the occurrence and development of cardiac remodeling are closely related with the regulation of ncRNAs. Recent research of ncRNAs in heart disease has achieved rapid development. Thus, we summarize here the latest research progress and mainly the molecular mechanism of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), in cardiac remodeling, aiming to look for new targets for heart disease treatment. Full article

(This article belongs to the Collection Regulation by Non-coding RNAs)

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Role of Genetics in the Etiology of Autistic Spectrum Disorder: Towards a Hierarchical Diagnostic Strategy

by Cyrille Robert, Laurent Pasquier, David Cohen, Mélanie Fradin, Roberto Canitano, Léna Damaj, Sylvie Odent and Sylvie Tordjman

Int. J. Mol. Sci. 2017, 18(3), 618; https://doi.org/10.3390/ijms18030618 - 12 Mar 2017

Cited by 29 | Viewed by 10260

Abstract

Progress in epidemiological, molecular and clinical genetics with the development of new techniques has improved knowledge on genetic syndromes associated with autism spectrum disorder (ASD). The objective of this article is to show the diversity of genetic disorders associated with ASD (based on [...] Read more.

Progress in epidemiological, molecular and clinical genetics with the development of new techniques has improved knowledge on genetic syndromes associated with autism spectrum disorder (ASD). The objective of this article is to show the diversity of genetic disorders associated with ASD (based on an extensive review of single-gene disorders, copy number variants, and other chromosomal disorders), and consequently to propose a hierarchical diagnostic strategy with a stepwise evaluation, helping general practitioners/pediatricians and child psychiatrists to collaborate with geneticists and neuropediatricians, in order to search for genetic disorders associated with ASD. The first step is a clinical investigation involving: (i) a child psychiatric and psychological evaluation confirming autism diagnosis from different observational sources and assessing autism severity; (ii) a neuropediatric evaluation examining neurological symptoms and developmental milestones; and (iii) a genetic evaluation searching for dysmorphic features and malformations. The second step involves laboratory and if necessary neuroimaging and EEG studies oriented by clinical results based on clinical genetic and neuropediatric examinations. The identification of genetic disorders associated with ASD has practical implications for diagnostic strategies, early detection or prevention of co-morbidity, specific treatment and follow up, and genetic counseling. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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The Adverse Effect of Hypertension in the Treatment of Thyroid Cancer with Multi-Kinase Inhibitors

by Ole Vincent Ancker, Markus Wehland, Johann Bauer, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2017, 18(3), 625; https://doi.org/10.3390/ijms18030625 - 14 Mar 2017

Cited by 52 | Viewed by 9166

Abstract

The treatment of thyroid cancer has promising prospects, mostly through the use of surgical or radioactive iodine therapy. However, some thyroid cancers, such as progressive radioactive iodine-refractory differentiated thyroid carcinoma, are not remediable with conventional types of treatment. In these cases, a treatment [...] Read more.

The treatment of thyroid cancer has promising prospects, mostly through the use of surgical or radioactive iodine therapy. However, some thyroid cancers, such as progressive radioactive iodine-refractory differentiated thyroid carcinoma, are not remediable with conventional types of treatment. In these cases, a treatment regimen with multi-kinase inhibitors is advisable. Unfortunately, clinical trials have shown a large number of patients, treated with multi-kinase inhibitors, being adversely affected by hypertension. This means that treatment of thyroid cancer with multi-kinase inhibitors prolongs progression-free and overall survival of patients, but a large number of patients experience hypertension as an adverse effect of the treatment. Whether the prolonged lifetime is sufficient to develop sequelae from hypertension is unclear, but late-stage cancer patients often have additional diseases, which can be complicated by the presence of hypertension. Since the exact mechanisms of the rise of hypertension in these patients are still unknown, the only available strategy is treating the symptoms. More studies determining the pathogenesis of hypertension as a side effect to cancer treatment as well as outcomes of dose management of cancer drugs are necessary to improve future therapy options for hypertension as an adverse effect to cancer therapy with multi-kinase inhibitors. Full article

(This article belongs to the Special Issue Current Knowledge in Thyroid Cancer—From Bench to Bedside)

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A Review on Ubiquitination of Neurotrophin Receptors: Facts and Perspectives

by Julia Sánchez-Sánchez and Juan Carlos Arévalo

Int. J. Mol. Sci. 2017, 18(3), 630; https://doi.org/10.3390/ijms18030630 - 14 Mar 2017

Cited by 15 | Viewed by 7403

Abstract

Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75^NTR) have been studied recently. TrkA is the most studied receptor in terms of its [...] Read more.

Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75^NTR) have been studied recently. TrkA is the most studied receptor in terms of its ubiquitination, and different E3 ubiquitin ligases and deubiquitinases have been implicated in its ubiquitination, whereas not much is known about the other neurotrophin receptors aside from their ubiquitination. Additional studies are needed that focus on the ubiquitination of TrkB, TrkC, and p75^NTR in order to further understand the role of ubiquitination in their physiological and pathological functions. Here we review what is currently known regarding the ubiquitination of neurotrophin receptors and its physiological and pathological relevance. Full article

(This article belongs to the Special Issue Ubiquitin System)

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Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

by Johan-Owen De Craene, Dimitri L. Bertazzi, Séverine Bär and Sylvie Friant

Int. J. Mol. Sci. 2017, 18(3), 634; https://doi.org/10.3390/ijms18030634 - 15 Mar 2017

Cited by 147 | Viewed by 13803

Abstract

Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and [...] Read more.

Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and cytoskeleton dynamics. Although detected in small concentrations in membranes, their role is essential to cell function, since imbalance in their concentrations is a hallmark of many cancers. Their synthesis involves phosphorylating/dephosphorylating positions D3, D4 and/or D5 of their inositol ring by specific lipid kinases and phosphatases. This process is tightly regulated and specific to the different intracellular membranes. Most enzymes involved in phosphoinositide synthesis are conserved between yeast and human, and their loss of function leads to severe diseases (cancer, myopathy, neuropathy and ciliopathy). Full article

(This article belongs to the Special Issue Unconventional Proteins and Membranes Traffic)

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Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica

by Ariana Kariminejad, Fariba Afroozan, Bita Bozorgmehr, Alireza Ghanadan, Susan Akbaroghli, Hamid Reza Khorram Khorshid, Faezeh Mojahedi, Aria Setoodeh, Abigail Loh, Yu Xuan Tan, Nathalie Escande-Beillard, Fransiska Malfait, Bruno Reversade, Thatjana Gardeitchik and Eva Morava

Int. J. Mol. Sci. 2017, 18(3), 635; https://doi.org/10.3390/ijms18030635 - 15 Mar 2017

Cited by 21 | Viewed by 15198

Abstract

Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa [...] Read more.

Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A), cutis laxa IIB (ARCL2B), and geroderma osteodysplastica (GO), have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient’s clinical diagnosis was then confirmed with molecular investigation of the responsible gene. Review of the clinical features from the cases reported from the literature also supports our conclusions. Full article

(This article belongs to the Special Issue Molecular-Genetic Basis and Ethiopathogenesic Mechanisms in Cutis Laxa)

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MicroRNA-146b: A Novel Biomarker and Therapeutic Target for Human Papillary Thyroid Cancer

by Chen-Kai Chou, Rue-Tsuan Liu and Hong-Yo Kang

Int. J. Mol. Sci. 2017, 18(3), 636; https://doi.org/10.3390/ijms18030636 - 15 Mar 2017

Cited by 75 | Viewed by 7283

Abstract

Papillary thyroid cancer (PTC) is the most common tumor subtype of thyroid cancer. However, not all PTCs are responsive to current surgical and radioiodine treatment. The well-established clinical prognostic factors include tumor size, lymph node/distal metastasis, and extrathyroidal invasion. The RET/PTC-RAS [...] Read more.

Papillary thyroid cancer (PTC) is the most common tumor subtype of thyroid cancer. However, not all PTCs are responsive to current surgical and radioiodine treatment. The well-established clinical prognostic factors include tumor size, lymph node/distal metastasis, and extrathyroidal invasion. The RET/PTC-RAS-BRAF linear molecular signaling cascade is known to mediate PTC pathogenesis. However, whether presence of BRAF mutation, the most common genetic alteration in PTC, can affect PTC behavior and prognosis is controversial. MicroRNAs (miRNAs) have been labeled as promising molecular prognostic markers in several tumor types. Our recent studies demonstrated that microRNA-146b (miR-146b) deregulation is associated with PTC aggressiveness and prognosis. Here we summarize the current knowledge related to the functional roles, regulated target genes, and clinical applications of miR-146b in PTC and discuss how these studies provide insights into the key role of miR-146b as an oncogenic regulator promoting cellular transformation as well as a prognosis marker for tumor recurrence in PTC. In conjunction with the current perspectives on miRNAs in a wide variety of human cancers, this review will hopefully translate these updated findings on miR-146b into more comprehensive diagnostic or prognostic information regarding treatment in PTC patients before surgical intervention and follow up strategies. Full article

(This article belongs to the Special Issue microRNA Regulation 2017)

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Is Ghrelin Synthesized in the Central Nervous System?

by Agustina Cabral, Eduardo J. López Soto, Jacques Epelbaum and Mario Perelló

Int. J. Mol. Sci. 2017, 18(3), 638; https://doi.org/10.3390/ijms18030638 - 15 Mar 2017

Cited by 85 | Viewed by 6418

Abstract

Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells [...] Read more.

Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy

by Lovro Žiberna, Dunja Šamec, Andrei Mocan, Seyed Fazel Nabavi, Anupam Bishayee, Ammad Ahmad Farooqi, Antoni Sureda and Seyed Mohammad Nabavi

Int. J. Mol. Sci. 2017, 18(3), 643; https://doi.org/10.3390/ijms18030643 - 16 Mar 2017

Cited by 109 | Viewed by 9701

Abstract

Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the [...] Read more.

Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5′ adenosine monophosphate-activated protein kinase, extracellular signal–regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)

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TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action

by Wenwen Du, Min Yang, Abbey Turner, Chunling Xu, Robert L. Ferris, Jianan Huang, Lawrence P. Kane and Binfeng Lu

Int. J. Mol. Sci. 2017, 18(3), 645; https://doi.org/10.3390/ijms18030645 - 16 Mar 2017

Cited by 173 | Viewed by 16075

Abstract

Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this [...] Read more.

Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. Thus, targeting TIM-3 emerges as a promising approach for further improvement of current immunotherapy. Despite a large amount of experimental data showing an immune suppressive function of TIM-3 in vivo, the exact mechanisms are not well understood. To enable effective targeting of TIM-3 for tumor immunotherapy, further in-depth mechanistic studies are warranted. These studies will also provide much-needed insight for the rational design of novel combination therapy with other checkpoint blockers. In this review, we summarize key evidence supporting an immune regulatory role of TIM-3 and discuss possible mechanisms of action. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)

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The Five Immune Forces Impacting DNA-Based Cancer Immunotherapeutic Strategy

by Suneetha Amara and Venkataswarup Tiriveedhi

Int. J. Mol. Sci. 2017, 18(3), 650; https://doi.org/10.3390/ijms18030650 - 17 Mar 2017

Cited by 20 | Viewed by 6382

Abstract

DNA-based vaccine strategy is increasingly realized as a viable cancer treatment approach. Strategies to enhance immunogenicity utilizing tumor associated antigens have been investigated in several pre-clinical and clinical studies. The promising outcomes of these studies have suggested that DNA-based vaccines induce potent T-cell [...] Read more.

DNA-based vaccine strategy is increasingly realized as a viable cancer treatment approach. Strategies to enhance immunogenicity utilizing tumor associated antigens have been investigated in several pre-clinical and clinical studies. The promising outcomes of these studies have suggested that DNA-based vaccines induce potent T-cell effector responses and at the same time cause only minimal side-effects to cancer patients. However, the immune evasive tumor microenvironment is still an important hindrance to a long-term vaccine success. Several options are currently under various stages of study to overcome immune inhibitory effect in tumor microenvironment. Some of these approaches include, but are not limited to, identification of neoantigens, mutanome studies, designing fusion plasmids, vaccine adjuvant modifications, and co-treatment with immune-checkpoint inhibitors. In this review, we follow a Porter’s analysis analogy, otherwise commonly used in business models, to analyze various immune-forces that determine the potential success and sustainable positive outcomes following DNA vaccination using non-viral tumor associated antigens in treatment against cancer. Full article

(This article belongs to the Special Issue Inflammation and Cancer)

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Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

by Henry Barron, Sina Hafizi, Ana C. Andreazza and Romina Mizrahi

Int. J. Mol. Sci. 2017, 18(3), 651; https://doi.org/10.3390/ijms18030651 - 17 Mar 2017

Cited by 125 | Viewed by 10537

Abstract

Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology [...] Read more.

Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of N-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families. Full article

(This article belongs to the Special Issue Schizophrenia: Pathophysiology, Diagnostics, Therapies, and Prevention)

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Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure

by Joshua B. Lewis, Kelsey M. Hirschi, Juan A. Arroyo, Benjamin T. Bikman, David L. Kooyman and Paul R. Reynolds

Int. J. Mol. Sci. 2017, 18(3), 652; https://doi.org/10.3390/ijms18030652 - 17 Mar 2017

Cited by 19 | Viewed by 6919

Abstract

Approximately 1 billion people smoke worldwide, and the burden placed on society by primary and secondhand smokers is expected to increase. Smoking is the leading risk factor for myriad health complications stemming from diverse pathogenic programs. First- and second-hand cigarette smoke contains thousands [...] Read more.

Approximately 1 billion people smoke worldwide, and the burden placed on society by primary and secondhand smokers is expected to increase. Smoking is the leading risk factor for myriad health complications stemming from diverse pathogenic programs. First- and second-hand cigarette smoke contains thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic inflammatory responses and destructive remodeling events. In the current review, we outline details related to compromised pulmonary and systemic conditions related to smoke exposure. Specifically, data are discussed relative to impaired lung physiology, cancer mechanisms, maternal-fetal complications, cardiometabolic, and joint disorders in the context of smoke exposure exacerbations. As a general unifying mechanism, the receptor for advanced glycation end-products (RAGE) and its signaling axis is increasingly considered central to smoke-related pathogenesis. RAGE is a multi-ligand cell surface receptor whose expression increases following cigarette smoke exposure. RAGE signaling participates in the underpinning of inflammatory mechanisms mediated by requisite cytokines, chemokines, and remodeling enzymes. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of lung disease and systemic complications that combine during the demise of those exposed. Full article

(This article belongs to the Special Issue Inhaled Pollutants Modulate Respiratory and Systemic Diseases)

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Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action

by Thazin Nwe Aung, Zhipeng Qu, R. Daniel Kortschak and David L. Adelson

Int. J. Mol. Sci. 2017, 18(3), 656; https://doi.org/10.3390/ijms18030656 - 17 Mar 2017

Cited by 251 | Viewed by 12275

Abstract

Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve [...] Read more.

Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve a synergistic effect that boosts cytotoxicity to cancer cells. In cancer, aberrant apoptotic pathways allow cells that should be killed to survive with genetic abnormalities, leading to cancer progression. Mutations in apoptotic mechanism arising during the treatment of cancer through cancer progression can consequently lead to chemoresistance. Natural compound mixtures that are believed to have multiple specific targets with minimal acceptable side-effects are now of interest to many researchers due to their cytotoxic and chemosensitizing activities. Synergistic interactions within a drug mixture enhance the search for potential molecular targets in cancer cells. Nonetheless, biased/flawed scientific evidence from natural products can suggest false positive therapeutic benefits during drug screening. In this review, we have taken these factors into consideration when discussing the evidence for these compounds and their synergistic therapeutic benefits in cancer. While there is limited evidence for clinical efficacy for these mixtures, in vitro data suggest that these preparations merit further investigation, both in vitro and in vivo. Full article

(This article belongs to the Special Issue Biological Activity of Natural Secondary Metabolite Products)

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The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology

by Thomas Schmoch, Florian Uhle, Benedikt H. Siegler, Thomas Fleming, Jakob Morgenstern, Peter P. Nawroth, Markus A. Weigand and Thorsten Brenner

Int. J. Mol. Sci. 2017, 18(3), 657; https://doi.org/10.3390/ijms18030657 - 17 Mar 2017

Cited by 29 | Viewed by 8899

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Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The [...] Read more.

Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The concomitant profound metabolic changes are characterized by hyperglycemia, insulin resistance, and profound transformations of the intracellular energy supply in both peripheral and immune cells. A further hallmark of the early phases of sepsis is a massive formation of reactive oxygen (ROS; e.g., superoxide) as well as nitrogen (RNS; e.g., nitric oxide) species. Reactive carbonyl species (RCS) form a third crucial group of highly reactive metabolites, which until today have been not the focus of interest in sepsis. However, we previously showed in a prospective observational clinical trial that patients suffering from septic shock are characterized by significant methylglyoxal (MG)-derived carbonyl stress, with the glyoxalase system being downregulated in peripheral blood mononuclear cells. In this review, we give a detailed insight into the current state of research regarding the metabolic changes that entail an increased MG-production in septicemia. Thus, we point out the special role of the glyoxalase system in the context of sepsis. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder?

by Juliana Magdalon, Sandra M. Sánchez-Sánchez, Karina Griesi-Oliveira and Andréa L. Sertié

Int. J. Mol. Sci. 2017, 18(3), 659; https://doi.org/10.3390/ijms18030659 - 18 Mar 2017

Cited by 34 | Viewed by 9285

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Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent [...] Read more.

Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent findings have also implicated mTORC1 signaling abnormalities in a subset of nonsyndromic ASD, suggesting that defective mTORC1 pathway may be a potential converging mechanism in ASD pathology across different etiologies. However, the mechanistic evidence for a causal link between aberrant mTORC1 pathway activity and ASD neurobehavioral features varies depending on the ASD form involved. In this review, we first discuss six monogenic ASD-related syndromes, including both classical and potentially novel mTORopathies, highlighting their contribution to our understanding of the neurobiological mechanisms underlying ASD, and then we discuss existing evidence suggesting that aberrant mTORC1 signaling may also play a role in nonsyndromic ASD. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

by Alexandria Hughes, Alexandra E. Oxford, Ken Tawara, Cheryl L. Jorcyk and Julia Thom Oxford

Int. J. Mol. Sci. 2017, 18(3), 665; https://doi.org/10.3390/ijms18030665 - 20 Mar 2017

Cited by 82 | Viewed by 8709

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Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have [...] Read more.

Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis. Full article

(This article belongs to the Special Issue Apoptotic Chondrocytes and Osteoarthritis)

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Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response

by Takahisa Kouwaki, Masaaki Okamoto, Hirotake Tsukamoto, Yoshimi Fukushima and Hiroyuki Oshiumi

Int. J. Mol. Sci. 2017, 18(3), 666; https://doi.org/10.3390/ijms18030666 - 20 Mar 2017

Cited by 90 | Viewed by 8661

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The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including [...] Read more.

The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses. Full article

(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)

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Novel Diagnostic and Predictive Biomarkers in Pancreatic Adenocarcinoma

by John C. Chang and Madappa Kundranda

Int. J. Mol. Sci. 2017, 18(3), 667; https://doi.org/10.3390/ijms18030667 - 20 Mar 2017

Cited by 109 | Viewed by 8476

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts have been dedicated to finding the appropriate serum and imaging biomarkers to help early detection and predict response to treatment of PDAC. Carbohydrate antigen 19-9 (CA 19-9) has been the most validated serum marker and has the highest positive predictive value as a stand-alone marker. When combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA 125), CA 19-9 can help predict the outcome of patients to surgery and chemotherapy. A slew of novel serum markers including multimarker panels as well as genetic and epigenetic materials have potential for early detection of pancreatic cancer, although these remain to be validated in larger trials. Imaging studies may not correlate with elevated serum markers. Critical features for determining PDAC include the presence of a mass, dilated pancreatic duct, and a duct cut-off sign. Features that are indicative of early metastasis includes neurovascular bundle involvement, duodenal invasion, and greater post contrast enhancement. 18-F-fluorodeoxyglucose (18-FDG) radiotracer uptake and changes following treatment may predict patient overall survival following treatment. Similarly, pretreatment apparent diffusion coefficient (ADC) values may predict prognosis with lower ADC lesions having worse outcome. Although these markers have provided significant improvement in the care of pancreatic cancer patients, further advancements can be made with perhaps better combination of markers or discovery of unique marker(s) to pancreatic cancer. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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Open AccessReview

State of the Art on Functional Virgin Olive Oils Enriched with Bioactive Compounds and Their Properties

by Patricia Reboredo-Rodríguez, María Figueiredo-González, Carmen González-Barreiro, Jesús Simal-Gándara, María Desamparados Salvador, Beatriz Cancho-Grande and Giuseppe Fregapane

Int. J. Mol. Sci. 2017, 18(3), 668; https://doi.org/10.3390/ijms18030668 - 20 Mar 2017

Cited by 77 | Viewed by 9902

Abstract

Virgin olive oil, the main fat of the Mediterranean diet, is per se considered as a functional food—as stated by the European Food Safety Authority (EFSA)—due to its content in healthy compounds. The daily intake of endogenous bioactive phenolics from virgin olive oil [...] Read more.

Virgin olive oil, the main fat of the Mediterranean diet, is per se considered as a functional food—as stated by the European Food Safety Authority (EFSA)—due to its content in healthy compounds. The daily intake of endogenous bioactive phenolics from virgin olive oil is variable due to the influence of multiple agronomic and technological factors. Thus, a good strategy to ensure an optimal intake of polyphenols through habitual diet would be to produce enriched virgin olive oil with well-known bioactive polyphenols. Different sources of natural biological active substances can be potentially used to enrich virgin olive oil (e.g., raw materials derived from the same olive tree, mainly olive leaves and pomaces, and/or other compounds from plants and vegetables, mainly herbs and spices). The development of these functional olive oils may help in prevention of chronic diseases (such as cardiovascular diseases, immune frailty, ageing disorders and degenerative diseases) and improving the quality of life for many consumers reducing health care costs. In the present review, the most relevant scientific information related to the development of enriched virgin olive oil and their positive human health effects has been collected and discussed. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2016)

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Open AccessReview

Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca²⁺

by Juan Zou, Jason Y. Jiang and Jenny J. Yang

Int. J. Mol. Sci. 2017, 18(3), 672; https://doi.org/10.3390/ijms18030672 - 21 Mar 2017

Cited by 7 | Viewed by 8840

Abstract

Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca²⁺ was reported to exhibit direct activation and modulation [...] Read more.

Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca²⁺ was reported to exhibit direct activation and modulation via an allosteric site, the identification of those binding sites was challenged by weak binding. Herein, we review the discovery of extracellular Ca²⁺ in regulation of mGluRs, summarize the recent developments in probing Ca²⁺ binding and its co-regulation of the receptor based on structural and biochemical analysis, and discuss the molecular basis for Ca²⁺ to regulate various classes of drug action as well as its importance as an allosteric modulator in mGluRs. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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796 KiB

Open AccessCase Report

High Levels of Serum Ubiquitin and Proteasome in a Case of HLA-B27 Uveitis

by Settimio Rossi, Carlo Gesualdo, Rosa Maisto, Maria Consiglia Trotta, Nadia Di Carluccio, Annalisa Brigida, Valentina Di Iorio, Francesco Testa, Francesca Simonelli, Michele D’Amico and Clara Di Filippo

Int. J. Mol. Sci. 2017, 18(3), 505; https://doi.org/10.3390/ijms18030505 - 26 Feb 2017

Cited by 2 | Viewed by 4420

Abstract

In this paper, the authors describe a case of high serum levels of ubiquitin and proteasome in a woman under an acute attack of autoimmune uveitis. The woman was 52 years old, diagnosed as positive for the Human leukocyte antigen-B27 gene, and came [...] Read more.

In this paper, the authors describe a case of high serum levels of ubiquitin and proteasome in a woman under an acute attack of autoimmune uveitis. The woman was 52 years old, diagnosed as positive for the Human leukocyte antigen-B27 gene, and came to our observation in January 2013 claiming a severe uveitis attack that involved the right eye. During the acute attack of uveitis, this woman had normal serum biochemical parameters but higher levels of serum ubiquitin and proteasome 20S subunit, with respect to a healthy volunteer matched for age and sex. These levels correlated well with the clinical score attributed to uveitis. After the patient was admitted to therapy, she received oral prednisone in a de-escalation protocol (doses from 50 to 5 mg/day) for four weeks. Following this therapy, she had an expected reduction of clinical signs and score for uveitis, but concomitantly she had a reduction of the serum levels of ubiquitin, poliubiquitinated proteins (MAb-FK1) and proteasome 20S activity. Therefore, a role for ubiquitin and proteasome in the development of human autoimmune uveitis has been hypothesized. Full article

(This article belongs to the Special Issue Ubiquitin System)

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Open AccessCase Report

Anti-Obesity Effect of Bombus ignitus Queen Glycosaminoglycans in Rats on a High-Fat Diet

by Mi Young Ahn, Ban Ji Kim, Ha Jeong Kim, Hyung Joo Yoon, Sang Duck Jee, Jae Sam Hwang and Kun-Koo Park

Int. J. Mol. Sci. 2017, 18(3), 681; https://doi.org/10.3390/ijms18030681 - 22 Mar 2017

Cited by 17 | Viewed by 5355

Abstract

The mechanism of functional insect glycosaminoglycan (GAG) on obesity caused a high fat diet has not yet been elucidated. Therefore, insect glycosaminoglycans derived from Isaria sinclairii, Bombus ignitus (a type of bumblebee) queen, and Gryllus bimaculatus were purified and investigated as a [...] Read more.

The mechanism of functional insect glycosaminoglycan (GAG) on obesity caused a high fat diet has not yet been elucidated. Therefore, insect glycosaminoglycans derived from Isaria sinclairii, Bombus ignitus (a type of bumblebee) queen, and Gryllus bimaculatus were purified and investigated as a potential functional food. 14-week old male Wistar rats were fed a high-fat diet (HFD) for 6 weeks. There were five groups that received daily intraperitoneal administration of phosphate buffered saline (PBS, control), GbG (GAG from Gryllus bimaculatus) 10 mg/kg, ISG (GAG from Isaria sinclairii) 10 mg/kg, IQG (GAG from Bombus ignites) 10 mg/kg, or Pravastatin (2 mg/kg). All treatments were performed for one month. IQG produced a potential anti-inflammatory effect with the inhibition of c-reactive protein and sero-biochemical parameters of phospholipids and free fatty acids indicative of an anti-hyperlipidemic effect. Abdominal and epididymidal fat weight were reduced in conjunction with a mild increase in body weight. The level of laminin in HMVEC-C cells or fibronectin in HFD rat hepatocytes was significantly affected by these GAG treatments, which regulated adipogenesis and adipocyte function. Compared to the control rats, IQG-treated rats displayed up-regulation of 87 genes (test:control ratio >2.0) including fatty acid synthase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase, with the down-regulation of 47 genes including the uridine diphosphate (UDP) glycosyltransferase 2 families, polypeptidase B, and insulin-like growth factor binding protein 1. The data suggest that IQG could potentially prevent or treat fatty liver or hyperlipidemia. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Int. J. Mol. Sci., Volume 18, Issue 3 (March 2017) – 207 articles

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