International Journal of Molecular Sciences

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Open AccessArticle

Unraveling Molecular Differences of Gastric Cancer by Label-Free Quantitative Proteomics Analysis

by Peng Dai, Qin Wang, Weihua Wang, Ruirui Jing, Wei Wang, Fengqin Wang, Kazem M. Azadzoi, Jing-Hua Yang and Zhen Yan

Int. J. Mol. Sci. 2016, 17(1), 69; https://doi.org/10.3390/ijms17010069 - 21 Jan 2016

Cited by 32 | Viewed by 6639

Abstract

Gastric cancer (GC) has significant morbidity and mortality worldwide and especially in China. Its molecular pathogenesis has not been thoroughly elaborated. The acknowledged biomarkers for diagnosis, prognosis, recurrence monitoring and treatment are lacking. Proteins from matched pairs of human GC and adjacent tissues [...] Read more.

Gastric cancer (GC) has significant morbidity and mortality worldwide and especially in China. Its molecular pathogenesis has not been thoroughly elaborated. The acknowledged biomarkers for diagnosis, prognosis, recurrence monitoring and treatment are lacking. Proteins from matched pairs of human GC and adjacent tissues were analyzed by a coupled label-free Mass Spectrometry (MS) approach, followed by functional annotation with software analysis. Nano-LC-MS/MS, quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry were used to validate dysregulated proteins. One hundred forty-six dysregulated proteins with more than twofold expressions were quantified, 22 of which were first reported to be relevant with GC. Most of them were involved in cancers and gastrointestinal disease. The expression of a panel of four upregulated nucleic acid binding proteins, heterogeneous nuclear ribonucleoprotein hnRNPA2B1, hnRNPD, hnRNPL and Y-box binding protein 1 (YBX-1) were validated by Nano-LC-MS/MS, qRT-PCR, western blot and immunohistochemistry assays in ten GC patients’ tissues. They were located in the keynotes of a predicted interaction network and might play important roles in abnormal cell growth. The label-free quantitative proteomic approach provides a deeper understanding and novel insight into GC-related molecular changes and possible mechanisms. It also provides some potential biomarkers for clinical diagnosis. Full article

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

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Open AccessEditorial

Acknowledgement to Reviewers of International Journal of Molecular Sciences in 2015

by International Journal of Molecular Sciences Editorial Office

Int. J. Mol. Sci. 2016, 17(1), 142; https://doi.org/10.3390/ijms17010142 - 21 Jan 2016

Viewed by 10898

Abstract

The editors of International Journal of Molecular Sciences would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. [...] Full article

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Open AccessReview

An Overview of Direct Somatic Reprogramming: The Ins and Outs of iPSCs

by Siddharth Menon, Siny Shailendra, Andrea Renda, Michael Longaker and Natalina Quarto

Int. J. Mol. Sci. 2016, 17(1), 141; https://doi.org/10.3390/ijms17010141 - 21 Jan 2016

Cited by 35 | Viewed by 12630

Abstract

Stem cells are classified into embryonic stem cells and adult stem cells. An evolving alternative to conventional stem cell therapies is induced pluripotent stem cells (iPSCs), which have a multi-lineage potential comparable to conventionally acquired embryonic stem cells with the additional benefits of [...] Read more.

Stem cells are classified into embryonic stem cells and adult stem cells. An evolving alternative to conventional stem cell therapies is induced pluripotent stem cells (iPSCs), which have a multi-lineage potential comparable to conventionally acquired embryonic stem cells with the additional benefits of being less immunoreactive and avoiding many of the ethical concerns raised with the use of embryonic material. The ability to generate iPSCs from somatic cells provides tremendous promise for regenerative medicine. The breakthrough of iPSCs has raised the possibility that patient-specific iPSCs can provide autologous cells for cell therapy without the concern for immune rejection. iPSCs are also relevant tools for modeling human diseases and drugs screening. However, there are still several hurdles to overcome before iPSCs can be used for translational purposes. Here, we review the recent advances in somatic reprogramming and the challenges that must be overcome to move this strategy closer to clinical application. Full article

(This article belongs to the Special Issue Pluripotent Stem Cell Technology for Disease Modeling, Drug Discovery and Regenerative Medicine)

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Open AccessArticle

Elucidating the Diversity of Aquatic Microdochium and Trichoderma Species and Their Activity against the Fish Pathogen Saprolegnia diclina

by Yiying Liu, Christin Zachow, Jos M. Raaijmakers and Irene De Bruijn

Int. J. Mol. Sci. 2016, 17(1), 140; https://doi.org/10.3390/ijms17010140 - 21 Jan 2016

Cited by 15 | Viewed by 9457

Abstract

Animals and plants are increasingly threatened by emerging fungal and oomycete diseases. Amongst oomycetes, Saprolegnia species cause population declines in aquatic animals, especially fish and amphibians, resulting in significant perturbation in biodiversity, ecological balance and food security. Due to the prohibition of several [...] Read more.

Animals and plants are increasingly threatened by emerging fungal and oomycete diseases. Amongst oomycetes, Saprolegnia species cause population declines in aquatic animals, especially fish and amphibians, resulting in significant perturbation in biodiversity, ecological balance and food security. Due to the prohibition of several chemical control agents, novel sustainable measures are required to control Saprolegnia infections in aquaculture. Previously, fungal community analysis by terminal restriction fragment length polymorphism (T-RFLP) revealed that the Ascomycota, specifically the genus Microdochium, was an abundant fungal phylum associated with salmon eggs from a commercial fish farm. Here, phylogenetic analyses showed that most fungal isolates obtained from salmon eggs were closely related to Microdochium lycopodinum/Microdochium phragmitis and Trichoderma viride species. Phylogenetic and quantitative PCR analyses showed both a quantitative and qualitative difference in Trichoderma population between diseased and healthy salmon eggs, which was not the case for the Microdochium population. In vitro antagonistic activity of the fungi against Saprolegnia diclina was isolate-dependent; for most Trichoderma isolates, the typical mycoparasitic coiling around and/or formation of papilla-like structures on S. diclina hyphae were observed. These results suggest that among the fungal community associated with salmon eggs, Trichoderma species may play a role in Saprolegnia suppression in aquaculture. Full article

(This article belongs to the Special Issue Fish Molecular Biology)

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Open AccessReview

Cadmium Protection Strategies—A Hidden Trade-Off?

by Adolf Michael Sandbichler and Martina Höckner

Int. J. Mol. Sci. 2016, 17(1), 139; https://doi.org/10.3390/ijms17010139 - 21 Jan 2016

Cited by 83 | Viewed by 8603

Abstract

Cadmium (Cd) is a non-essential transition metal which is introduced into the biosphere by various anthropogenic activities. Environmental pollution with Cd poses a major health risk and Cd toxicity has been extensively researched over the past decades. This review aims at changing the [...] Read more.

Cadmium (Cd) is a non-essential transition metal which is introduced into the biosphere by various anthropogenic activities. Environmental pollution with Cd poses a major health risk and Cd toxicity has been extensively researched over the past decades. This review aims at changing the perspective by discussing protection mechanisms available to counteract a Cd insult. Antioxidants, induction of antioxidant enzymes, and complexation of Cd to glutathione (GSH) and metallothionein (MT) are the most potent protective measures to cope with Cd-induced oxidative stress. Furthermore, protection mechanisms include prevention of endoplasmic reticulum (ER) stress, mitophagy and metabolic stress, as well as expression of chaperones. Pre-exposure to Cd itself, or co-exposure to other metals or trace elements can improve viability under Cd exposure and cells have means to reduce Cd uptake and improve Cd removal. Finally, environmental factors have negative or positive effects on Cd toxicity. Most protection mechanisms aim at preventing cellular damage. However, this might not be possible without trade-offs like an increased risk of carcinogenesis. Full article

(This article belongs to the Special Issue Metal Metabolism in Animals)

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Open AccessReview

The TEAD Family and Its Oncogenic Role in Promoting Tumorigenesis

by Yuhang Zhou, Tingting Huang, Alfred S. L. Cheng, Jun Yu, Wei Kang and Ka Fai To

Int. J. Mol. Sci. 2016, 17(1), 138; https://doi.org/10.3390/ijms17010138 - 21 Jan 2016

Cited by 147 | Viewed by 16402

Abstract

The TEAD family of transcription factors is necessary for developmental processes. The family members contain a TEA domain for the binding with DNA elements and a transactivation domain for the interaction with transcription coactivators. TEAD proteins are required for the participation of coactivators [...] Read more.

The TEAD family of transcription factors is necessary for developmental processes. The family members contain a TEA domain for the binding with DNA elements and a transactivation domain for the interaction with transcription coactivators. TEAD proteins are required for the participation of coactivators to transmit the signal of pathways for the downstream signaling processes. TEADs also play an important role in tumor initiation and facilitate cancer progression via activating a series of progression-inducing genes, such as CTGF, Cyr61, Myc and Gli2. Recent studies have highlighted that TEADs, together with their coactivators, promote or even act as the crucial parts in the development of various malignancies, such as liver, ovarian, breast and prostate cancers. Furthermore, TEADs are proposed to be useful prognostic biomarkers due to the ideal correlation between high expression and clinicopathological parameters in gastric, breast, ovarian and prostate cancers. In this review, we summarize the functional role of TEAD proteins in tumorigenesis and discuss the key role of TEAD transcription factors in the linking of signal cascade transductions. Improved knowledge of the TEAD proteins will be helpful for deep understanding of the molecular mechanisms of tumorigenesis and identifying ideal predictive or prognostic biomarkers, even providing clinical translation for anticancer therapy in human cancers. Full article

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

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Open AccessReview

The Clinical Significance of Phosphorylated Heat Shock Protein 27 (HSPB1) in Pancreatic Cancer

by Mitsuru Okuno, Seiji Adachi, Osamu Kozawa, Masahito Shimizu and Ichiro Yasuda

Int. J. Mol. Sci. 2016, 17(1), 137; https://doi.org/10.3390/ijms17010137 - 21 Jan 2016

Cited by 18 | Viewed by 7960

Abstract

Pancreatic cancer is one of most aggressive forms of cancer. After clinical detection it exhibits fast metastatic growth. Heat shock protein 27 (HSP27; HSPB1) has been characterized as a molecular chaperone which modifies the structures and functions of other proteins in cells when [...] Read more.

Pancreatic cancer is one of most aggressive forms of cancer. After clinical detection it exhibits fast metastatic growth. Heat shock protein 27 (HSP27; HSPB1) has been characterized as a molecular chaperone which modifies the structures and functions of other proteins in cells when they are exposed to various stresses, such as chemotherapy. While the administration of gemcitabine, an anti-tumor drug, has been the standard treatment for patients with advanced pancreatic cancer, accumulating evidence shows that HSP27 plays a key role in the chemosensitivity to gemcitabine. In addition, phosphorylated HSP27 induced by gemcitabine has been associated with the inhibition of pancreatic cancer cell growth. In this review, we summarize the role of phosphorylated HSP27, as well as HSP27, in the regulation of chemosensitivity in pancreatic cancer. Full article

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

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Open AccessArticle

Column Selection for Biomedical Analysis Supported by Column Classification Based on Four Test Parameters

by Alina Plenis, Natalia Rekowska and Tomasz Bączek

Int. J. Mol. Sci. 2016, 17(1), 136; https://doi.org/10.3390/ijms17010136 - 21 Jan 2016

Cited by 2 | Viewed by 4508

Abstract

This article focuses on correlating the column classification obtained from the method created at the Katholieke Universiteit Leuven (KUL), with the chromatographic resolution attained in biomedical separation. In the KUL system, each column is described with four parameters, which enables estimation of the [...] Read more.

This article focuses on correlating the column classification obtained from the method created at the Katholieke Universiteit Leuven (KUL), with the chromatographic resolution attained in biomedical separation. In the KUL system, each column is described with four parameters, which enables estimation of the F_KUL value characterising similarity of those parameters to the selected reference stationary phase. Thus, a ranking list based on the F_KUL value can be calculated for the chosen reference column, then correlated with the results of the column performance test. In this study, the column performance test was based on analysis of moclobemide and its two metabolites in human plasma by liquid chromatography (LC), using 18 columns. The comparative study was performed using traditional correlation of the F_KUL values with the retention parameters of the analytes describing the column performance test. In order to deepen the comparative assessment of both data sets, factor analysis (FA) was also used. The obtained results indicated that the stationary phase classes, closely related according to the KUL method, yielded comparable separation for the target substances. Therefore, the column ranking system based on the F_KUL-values could be considered supportive in the choice of the appropriate column for biomedical analysis. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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Open AccessReview

Photodynamic Therapy in Non-Gastrointestinal Thoracic Malignancies

by Biniam Kidane, Dhruvin Hirpara and Kazuhiro Yasufuku

Int. J. Mol. Sci. 2016, 17(1), 135; https://doi.org/10.3390/ijms17010135 - 21 Jan 2016

Cited by 9 | Viewed by 6817

Abstract

Photodynamic therapy has a role in the management of early and late thoracic malignancies. It can be used to facilitate minimally-invasive treatment of early endobronchial tumours and also to palliate obstructive and bleeding effects of advanced endobronchial tumours. Photodynamic therapy has been used [...] Read more.

Photodynamic therapy has a role in the management of early and late thoracic malignancies. It can be used to facilitate minimally-invasive treatment of early endobronchial tumours and also to palliate obstructive and bleeding effects of advanced endobronchial tumours. Photodynamic therapy has been used as a means of downsizing tumours to allow for resection, as well as reducing the extent of resection necessary. It has also been used successfully for minimally-invasive management of local recurrences, which is especially valuable for patients who are not eligible for radiation therapy. Photodynamic therapy has also shown promising results in mesothelioma and pleural-based metastatic disease. As new generation photosensitizers are being developed and tested and methodological issues continue to be addressed, the role of photodynamic therapy in thoracic malignancies continues to evolve. Full article

(This article belongs to the Special Issue Advances in Photodynamic Therapy)

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Open AccessReview

Structure Prediction: New Insights into Decrypting Long Noncoding RNAs

by Kun Yan, Yasir Arfat, Dijie Li, Fan Zhao, Zhihao Chen, Chong Yin, Yulong Sun, Lifang Hu, Tuanmin Yang and Airong Qian

Int. J. Mol. Sci. 2016, 17(1), 132; https://doi.org/10.3390/ijms17010132 - 21 Jan 2016

Cited by 52 | Viewed by 8282

Abstract

Long noncoding RNAs (lncRNAs), which form a diverse class of RNAs, remain the least understood type of noncoding RNAs in terms of their nature and identification. Emerging evidence has revealed that a small number of newly discovered lncRNAs perform important and complex biological [...] Read more.

Long noncoding RNAs (lncRNAs), which form a diverse class of RNAs, remain the least understood type of noncoding RNAs in terms of their nature and identification. Emerging evidence has revealed that a small number of newly discovered lncRNAs perform important and complex biological functions such as dosage compensation, chromatin regulation, genomic imprinting, and nuclear organization. However, understanding the wide range of functions of lncRNAs related to various processes of cellular networks remains a great experimental challenge. Structural versatility is critical for RNAs to perform various functions and provides new insights into probing the functions of lncRNAs. In recent years, the computational method of RNA structure prediction has been developed to analyze the structure of lncRNAs. This novel methodology has provided basic but indispensable information for the rapid, large-scale and in-depth research of lncRNAs. This review focuses on mainstream RNA structure prediction methods at the secondary and tertiary levels to offer an additional approach to investigating the functions of lncRNAs. Full article

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

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Open AccessArticle

VLDL from Metabolic Syndrome Individuals Enhanced Lipid Accumulation in Atria with Association of Susceptibility to Atrial Fibrillation

by Hsiang-Chun Lee, Hsin-Ting Lin, Liang-Yin Ke, Chi Wei, Yi-Lin Hsiao, Chih-Sheng Chu, Wen-Ter Lai, Shyi-Jang Shin, Chu-Huang Chen, Sheng-Hsiung Sheu and Bin-Nan Wu

Int. J. Mol. Sci. 2016, 17(1), 134; https://doi.org/10.3390/ijms17010134 - 20 Jan 2016

Cited by 14 | Viewed by 6552

Abstract

Metabolic syndrome (MetS) represents a cluster of metabolic derangements. Dyslipidemia is an important factor in MetS and is related to atrial fibrillation (AF). We hypothesized that very low density lipoproteins (VLDL) in MetS (MetS-VLDL) may induce atrial dilatation and vulnerability to AF. VLDL [...] Read more.

Metabolic syndrome (MetS) represents a cluster of metabolic derangements. Dyslipidemia is an important factor in MetS and is related to atrial fibrillation (AF). We hypothesized that very low density lipoproteins (VLDL) in MetS (MetS-VLDL) may induce atrial dilatation and vulnerability to AF. VLDL was therefore separated from normal (normal-VLDL) and MetS individuals. Wild type C57BL/6 male mice were divided into control, normal-VLDL (nVLDL), and MetS-VLDL (msVLDL) groups. VLDL (15 µg/g) and equivalent volumes of saline were injected via tail vein three times a week for six consecutive weeks. Cardiac chamber size and function were measured by echocardiography. MetS-VLDL significantly caused left atrial dilation (control, n = 10, 1.64 ± 0.23 mm; nVLDL, n = 7, 1.84 ± 0.13 mm; msVLDL, n = 10, 2.18 ± 0.24 mm; p < 0.0001) at week 6, associated with decreased ejection fraction (control, n = 10, 62.5% ± 7.7%, vs. msVLDL, n = 10, 52.9% ± 9.6%; p < 0.05). Isoproterenol-challenge experiment resulted in AF in young msVLDL mice. Unprovoked AF occurred only in elderly msVLDL mice. Immunohistochemistry showed excess lipid accumulation and apoptosis in msVLDL mice atria. These findings suggest a pivotal role of VLDL in AF pathogenesis for MetS individuals. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

Iron Homeostasis in Health and Disease

by Raffaella Gozzelino and Paolo Arosio

Int. J. Mol. Sci. 2016, 17(1), 130; https://doi.org/10.3390/ijms17010130 - 20 Jan 2016

Cited by 253 | Viewed by 20591

Abstract

Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport and diminished activity of Fe-dependent enzymes, and also iron excess that may catalyze [...] Read more.

Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport and diminished activity of Fe-dependent enzymes, and also iron excess that may catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. The advance in understanding the main players and mechanisms involved in iron regulation significantly improved since the discovery of genes responsible for hemochromatosis, the IRE/IRPs machinery, and the hepcidin-ferroportin axis. This review provides an update on the molecular mechanisms regulating cellular and systemic Fe homeostasis and their roles in pathophysiologic conditions that involve alterations of iron metabolism, and provides novel therapeutic strategies to prevent the deleterious effect of its deficiency/overload. Full article

(This article belongs to the Special Issue Metal Metabolism in Animals)

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Open AccessArticle

Computational Analysis of Structure-Based Interactions for Novel H₁-Antihistamines

by Yinfeng Yang, Yan Li, Yanqiu Pan, Jinghui Wang, Feng Lin, Chao Wang, Shuwei Zhang and Ling Yang

Int. J. Mol. Sci. 2016, 17(1), 129; https://doi.org/10.3390/ijms17010129 - 19 Jan 2016

Cited by 18 | Viewed by 8845

Abstract

As a chronic disorder, insomnia affects approximately 10% of the population at some time during their lives, and its treatment is often challenging. Since the antagonists of the H₁ receptor, a protein prevalent in human central nervous system, have been proven as [...] Read more.

As a chronic disorder, insomnia affects approximately 10% of the population at some time during their lives, and its treatment is often challenging. Since the antagonists of the H₁ receptor, a protein prevalent in human central nervous system, have been proven as effective therapeutic agents for treating insomnia, the H₁ receptor is quite possibly a promising target for developing potent anti-insomnia drugs. For the purpose of understanding the structural actors affecting the antagonism potency, presently a theoretical research of molecular interactions between 129 molecules and the H₁ receptor is performed through three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. The ligand-based comparative molecular similarity indices analysis (CoMSIA) model (Q² = 0.525, R²_ncv = 0.891, R²_pred = 0.807) has good quality for predicting the bioactivities of new chemicals. The cross-validated result suggests that the developed models have excellent internal and external predictability and consistency. The obtained contour maps were appraised for affinity trends for the investigated compounds, which provides significantly useful information in the rational drug design of novel anti-insomnia agents. Molecular docking was also performed to investigate the mode of interaction between the ligand and the active site of the receptor. Furthermore, as a supplementary tool to study the docking conformation of the antagonists in the H₁ receptor binding pocket, molecular dynamics simulation was also applied, providing insights into the changes in the structure. All of the models and the derived information would, we hope, be of help for developing novel potent histamine H₁ receptor antagonists, as well as exploring the H₁-antihistamines interaction mechanism. Full article

(This article belongs to the Special Issue Big Data Analysis and QSAR/QSPR Research in Chemistry, Bio-Medical, and Network Sciences)

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Open AccessReview

Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches

by Khondoker M. Akram, Neil Patel, Monica A. Spiteri and Nicholas R. Forsyth

Int. J. Mol. Sci. 2016, 17(1), 128; https://doi.org/10.3390/ijms17010128 - 19 Jan 2016

Cited by 57 | Viewed by 18262

Abstract

The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis [...] Read more.

The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. Full article

(This article belongs to the Special Issue Stem Cell Activation in Adult Organism)

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Open AccessReview

The Complex Relationship between Metals and Carbonic Anhydrase: New Insights and Perspectives

by Maria Giulia Lionetto, Roberto Caricato, Maria Elena Giordano and Trifone Schettino

Int. J. Mol. Sci. 2016, 17(1), 127; https://doi.org/10.3390/ijms17010127 - 19 Jan 2016

Cited by 65 | Viewed by 8499

Abstract

Carbonic anhydrase is a ubiquitous metalloenzyme, which catalyzes the reversible hydration of CO₂ to HCO₃⁻ and H⁺. Metals play a key role in the bioactivity of this metalloenzyme, although their relationships with CA have not been completely clarified [...] Read more.

Carbonic anhydrase is a ubiquitous metalloenzyme, which catalyzes the reversible hydration of CO₂ to HCO₃⁻ and H⁺. Metals play a key role in the bioactivity of this metalloenzyme, although their relationships with CA have not been completely clarified to date. The aim of this review is to explore the complexity and multi-aspect nature of these relationships, since metals can be cofactors of CA, but also inhibitors of CA activity and modulators of CA expression. Moreover, this work analyzes new insights and perspectives that allow translating new advances in basic science on the interaction between CA and metals to applications in several fields of research, ranging from biotechnology to environmental sciences. Full article

(This article belongs to the Special Issue Metal Metabolism in Animals)

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Open AccessArticle

Statin Therapy and the Development of Cerebral Amyloid Angiopathy—A Rodent in Vivo Approach

by Björn Reuter, Alexander Venus, Saskia Grudzenski, Patrick Heiler, Lothar Schad, Matthias Staufenbiel, Michael G. Hennerici and Marc Fatar

Int. J. Mol. Sci. 2016, 17(1), 126; https://doi.org/10.3390/ijms17010126 - 19 Jan 2016

Cited by 5 | Viewed by 7243

Abstract

Background: Cerebral amyloid angiopathy (CAA) is characterized by vascular deposition of amyloid β (Aβ) with a higher incidence of cerebral microbleeds (cMBs) and spontaneous hemorrhage. Since statins are known for their benefit in vascular disease we tested for the effect on CAA. Methods: [...] Read more.

Background: Cerebral amyloid angiopathy (CAA) is characterized by vascular deposition of amyloid β (Aβ) with a higher incidence of cerebral microbleeds (cMBs) and spontaneous hemorrhage. Since statins are known for their benefit in vascular disease we tested for the effect on CAA. Methods: APP23-transgenic mice received atorvastatin-supplemented food starting at the age of eight months (n = 13), 12 months (n = 7), and 16 months (n = 6), respectively. Controls (n = 16) received standard food only. At 24 months of age cMBs were determined with T2*-weighted 9.4T magnetic resonance imaging and graded by size. Results: Control mice displayed an average of 35 ± 18.5 cMBs (mean ± standard deviation), compared to 29.3 ± 9.8 in mice with eight months (p = 0.49), 24.9 ± 21.3 with 12 months (p = 0.26), and 27.8 ± 15.4 with 16 months of atorvastatin treatment (p = 0.27). In combined analysis treated mice showed lower absolute numbers (27.4 ± 15.6, p = 0.16) compared to controls and also after adjustment for cMB size (p = 0.13). Conclusion: Despite to a non-significant trend towards fewer cMBs our results failed to provide evidence for beneficial effects of long-term atorvastatin treatment in the APP23-transgenic mouse model of CAA. A higher risk for bleeding complications was not observed. Full article

(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)

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Open AccessArticle

Influence of Bxpel1 Gene Silencing by dsRNA Interference on the Development and Pathogenicity of the Pine Wood Nematode, Bursaphelenchus xylophilus

by Xiu-Wen Qiu, Xiao-Qin Wu, Lin Huang and Jian-Ren Ye

Int. J. Mol. Sci. 2016, 17(1), 125; https://doi.org/10.3390/ijms17010125 - 19 Jan 2016

Cited by 20 | Viewed by 5765

Abstract

As the causal agent of pine wilt disease (PWD), the pine wood nematode (PWN), Bursaphelenchus xylophilus, causes huge economic losses by devastating pine forests worldwide. The pectate lyase gene is essential for successful invasion of their host plants by plant-parasitic nematodes. To [...] Read more.

As the causal agent of pine wilt disease (PWD), the pine wood nematode (PWN), Bursaphelenchus xylophilus, causes huge economic losses by devastating pine forests worldwide. The pectate lyase gene is essential for successful invasion of their host plants by plant-parasitic nematodes. To demonstrate the role of pectate lyase gene in the PWD process, RNA interference (RNAi) is used to analyze the function of the pectate lyase 1 gene in B. xylophilus (Bxpel1). The efficiency of RNAi was detected by real-time PCR. The result demonstrated that the quantity of B. xylophilus propagated with control solution treatment was 62 times greater than that soaking in double-stranded RNA (dsRNA) after B. xylophilus inoculation in Botrytis cinerea for the first generation (F1). The number of B. xylophilus soaking in control solution was doubled compared to that soaking in Bxpel1 dsRNA four days after inoculation in Pinus thunbergii. The quantity of B. xylophilus was reduced significantly (p < 0.001) after treatment with dsRNAi compared with that using a control solution treatment. Bxpel1 dsRNAi reduced the migration speed and reproduction of B. xylophilus in pine trees. The pathogenicity to P. thunbergii seedling of B. xylophilus was weaker after soaking in dsRNA solution compared with that after soaking in the control solution. Our results suggest that Bxpel1 gene is a significant pathogenic factor in the PWD process and this basic information may facilitate a better understanding of the molecular mechanism of PWD. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

Molecular Regulation of Adipogenesis and Potential Anti-Adipogenic Bioactive Molecules

by Dorothy Moseti, Alemu Regassa and Woo-Kyun Kim

Int. J. Mol. Sci. 2016, 17(1), 124; https://doi.org/10.3390/ijms17010124 - 19 Jan 2016

Cited by 524 | Viewed by 19022

Abstract

Adipogenesis is the process by which precursor stem cells differentiate into lipid laden adipocytes. Adipogenesis is regulated by a complex and highly orchestrated gene expression program. In mammalian cells, the peroxisome proliferator-activated receptor γ (PPARγ), and the CCAAT/enhancer binding proteins (C/EBPs) such as [...] Read more.

Adipogenesis is the process by which precursor stem cells differentiate into lipid laden adipocytes. Adipogenesis is regulated by a complex and highly orchestrated gene expression program. In mammalian cells, the peroxisome proliferator-activated receptor γ (PPARγ), and the CCAAT/enhancer binding proteins (C/EBPs) such as C/EBPα, β and δ are considered the key early regulators of adipogenesis, while fatty acid binding protein 4 (FABP4), adiponectin, and fatty acid synthase (FAS) are responsible for the formation of mature adipocytes. Excess accumulation of lipids in the adipose tissue leads to obesity, which is associated with cardiovascular diseases, type II diabetes and other pathologies. Thus, investigating adipose tissue development and the underlying molecular mechanisms is vital to develop therapeutic agents capable of curbing the increasing incidence of obesity and related pathologies. In this review, we address the process of adipogenic differentiation, key transcription factors and proteins involved, adipogenic regulators and potential anti-adipogenic bioactive molecules. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Genipin Derivatives Protect RGC-5 from Sodium Nitroprusside-Induced Nitrosative Stress

by Rikang Wang, Jiaqiang Zhao, Lei Zhang, Lizhi Peng, Xinyi Zhang, Wenhua Zheng and Heru Chen

Int. J. Mol. Sci. 2016, 17(1), 117; https://doi.org/10.3390/ijms17010117 - 19 Jan 2016

Cited by 5 | Viewed by 5538

Abstract

CHR20 and CHR21 are a pair of stable diastereoisomers derived from genipin. These stereoisomers are activators of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). In the rat retinal ganglion (RGC-5) cell model these compounds are non-toxic. Treatment of RGC-5 [...] Read more.

CHR20 and CHR21 are a pair of stable diastereoisomers derived from genipin. These stereoisomers are activators of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). In the rat retinal ganglion (RGC-5) cell model these compounds are non-toxic. Treatment of RGC-5 with 750 μM of sodium nitroprusside (SNP) produces nitrosative stress. Both genipin derivatives, however, protect these cells against SNP-induced apoptic cell death, although CHR21 is significantly more potent than CHR20 in this regard. With Western blotting we showed that the observed neuroprotection is primarily due to the activation of protein kinase B (Akt)/eNOS and extracellular signal-regulated kinase (ERK1/2) signaling pathways. Therefore, LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or PD98059 (a MAPK-activating enzyme inhibitor) abrogated the protective effects of CHR20 and CHR21. Altogether, our results show that in our experimental setup neuroprotection by the diasteromeric pair is mediated through the PI3K/Akt/eNOS and ERK1/2 signaling pathways. Further studies are needed to establish the potential of these compounds to prevent ntric oxide (NO)-induced toxicity commonly seen in many neurodegenerative diseases. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2015)

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Technological Implications of Modifying the Extent of Cell Wall-Proanthocyanidin Interactions Using Enzymes

by Ana Belén Bautista-Ortín, Rim Ben Abdallah, Liliana Del Rocío Castro-López, María Dolores Jiménez-Martínez and Encarna Gómez-Plaza

Int. J. Mol. Sci. 2016, 17(1), 123; https://doi.org/10.3390/ijms17010123 - 18 Jan 2016

Cited by 27 | Viewed by 6086

Abstract

The transference and reactivity of proanthocyanidins is an important issue that affects the technological processing of some fruits, such as grapes and apples. These processes are affected by proanthocyanidins bound to cell wall polysaccharides, which are present in high concentrations during the processing [...] Read more.

The transference and reactivity of proanthocyanidins is an important issue that affects the technological processing of some fruits, such as grapes and apples. These processes are affected by proanthocyanidins bound to cell wall polysaccharides, which are present in high concentrations during the processing of the fruits. Therefore, the effective extraction of proanthocyanidins from fruits to their juices or derived products will depend on the ability to manage these associations, and, in this respect, enzymes that degrade these polysaccharides could play an important role. The main objective of this work was to test the role of pure hydrolytic enzymes (polygalacturonase and cellulose) and a commercial enzyme containing these two activities on the extent of proanthocyanidin-cell wall interactions. The results showed that the modification promoted by enzymes reduced the amount of proanthocyanidins adsorbed to cell walls since they contributed to the degradation and release of the cell wall polysaccharides, which diffused into the model solution. Some of these released polysaccharides also presented some reactivity towards the proanthocyanidins present in a model solution. Full article

(This article belongs to the Special Issue Phenolics and Polyphenolics 2015)

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Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53

by Young Mi Song, Woo Kyung Lee, Yong-ho Lee, Eun Seok Kang, Bong-Soo Cha and Byung-Wan Lee

Int. J. Mol. Sci. 2016, 17(1), 122; https://doi.org/10.3390/ijms17010122 - 16 Jan 2016

Cited by 73 | Viewed by 10528

Abstract

Metformin is known to alleviate hepatosteatosis by inducing 5’ adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the [...] Read more.

Metformin is known to alleviate hepatosteatosis by inducing 5’ adenosine monophosphate (AMP)-kinase-independent, sirtuin 1 (SIRT1)-mediated autophagy. Dysfunctional mitophagy in response to glucolipotoxicities might play an important role in hepatosteatosis. Here, we investigated the mechanism by which metformin induces mitophagy through restoration of the suppressed Parkin-mediated mitophagy. To this end, our ob/ob mice were divided into three groups: (1) ad libitum feeding of a standard chow diet; (2) intraperitoneal injections of metformin 300 mg/kg; and (3) 3 g/day caloric restriction (CR). HepG2 cells were treated with palmitate (PA) plus high glucose in the absence or presence of metformin. We detected enhanced mitophagy in ob/ob mice treated with metformin or CR, whereas mitochondrial spheroids were observed in mice fed ad libitum. Metabolically stressed ob/ob mice and PA-treated HepG2 cells showed an increase in expression of endoplasmic reticulum (ER) stress markers and cytosolic p53. Cytosolic p53 inhibited mitophagy by disturbing the mitochondrial translocation of Parkin, as demonstrated by immunoprecipitation. However, metformin decreased ER stress and p53 expression, resulting in induction of Parkin-mediated mitophagy. Furthermore, pifithrin-α, a specific inhibitor of p53, increased mitochondrial incorporation into autophagosomes. Taken together, these results indicate that metformin treatment facilitates Parkin-mediated mitophagy rather than mitochondrial spheroid formation by decreasing the inhibitory interaction with cytosolic p53 and increasing degradation of mitofusins. Full article

(This article belongs to the Special Issue Modulators of Endoplasmic Reticulum Stress)

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Alternative Splicing in Adhesion- and Motility-Related Genes in Breast Cancer

by Rosanna Aversa, Anna Sorrentino, Roberta Esposito, Maria Rosaria Ambrosio, Angela Amato, Alberto Zambelli, Alfredo Ciccodicola, Luciana D’Apice and Valerio Costa

Int. J. Mol. Sci. 2016, 17(1), 121; https://doi.org/10.3390/ijms17010121 - 16 Jan 2016

Cited by 16 | Viewed by 6609

Abstract

Breast cancer is the most common tumor and the second leading cause of cancer death among woman, mainly caused by the metastatic spread. Tumor invasiveness is due to an altered expression of adhesion molecules. Among them, semaphorins are of peculiar interest. Cancer cells [...] Read more.

Breast cancer is the most common tumor and the second leading cause of cancer death among woman, mainly caused by the metastatic spread. Tumor invasiveness is due to an altered expression of adhesion molecules. Among them, semaphorins are of peculiar interest. Cancer cells can manipulate alternative splicing patterns to modulate the expression of adhesion- and motility-related molecules, also at the isoform level. In this study, combining RNA-Sequencing on MCF-7 to targeted experimental validations—in human breast cell lines and breast tumor biopsies—we identified 12 new alternative splicing transcripts in genes encoding adhesion- and motility-related molecules, including semaphorins, their receptors and co-receptors. Among them, a new SEMA3F transcript is expressed in all breast cell lines and breast cancer biopsies, and is translated into a new semaphorin 3F isoform. In silico analysis predicted that most of the new putative proteins lack functional domains, potentially missing some functions and acquiring new ones. Our findings better describe the extent of alternative splicing in breast cancer and highlight the need to further investigate adhesion- and motility-related molecules to gain insights into breast cancer progression. Full article

(This article belongs to the Special Issue Pre-mRNA Splicing 2015)

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Platelet-Rich Plasma Increases the Levels of Catabolic Molecules and Cellular Dedifferentiation in the Meniscus of a Rabbit Model

by Hye-Rim Lee, Oog-Jin Shon, Se-Il Park, Han-Jun Kim, Sukyoung Kim, Myun-Whan Ahn and Sun Hee Do

Int. J. Mol. Sci. 2016, 17(1), 120; https://doi.org/10.3390/ijms17010120 - 16 Jan 2016

Cited by 35 | Viewed by 7407

Abstract

Despite the susceptibility to frequent intrinsic and extrinsic injuries, especially in the inner zone, the meniscus does not heal spontaneously owing to its poor vascularity. In this study, the effect of platelet-rich plasma (PRP), containing various growth factors, on meniscal mechanisms was examined [...] Read more.

Despite the susceptibility to frequent intrinsic and extrinsic injuries, especially in the inner zone, the meniscus does not heal spontaneously owing to its poor vascularity. In this study, the effect of platelet-rich plasma (PRP), containing various growth factors, on meniscal mechanisms was examined under normal and post-traumatic inflammatory conditions. Isolated primary meniscal cells of New Zealand white (NZW) rabbits were incubated for 3, 10, 14 and 21 days with PRP(−), 10% PRP (PRP(+)), IL(+) or IL(+)PRP(+). The meniscal cells were collected and examined using reverse-transcription polymerase chain reaction (RT-PCR). Culture media were examined by immunoblot analyses for matrix metalloproteinases (MMP) catabolic molecules. PRP containing growth factors improved the cellular viability of meniscal cells in a concentration-dependent manner at Days 1, 4 and 7. However, based on RT-PCR, meniscal cells demonstrated dedifferentiation, along with an increase in type I collagen in the PRP(+) and in IL(+)PRP(+). In PRP(+), the aggrecan expression levels were lower than in the PRP(−) until Day 21. The protein levels of MMP-1 and MMP-3 were higher in each PRP group, i.e., PRP(+) and IL(+)PRP(+), at each culture time. A reproducible 2-mm circular defect on the meniscus of NZW rabbit was used to implant fibrin glue (control) or PRP in vivo. After eight weeks, the lesions in the control and PRP groups were occupied with fibrous tissue, but not with meniscal cells. This study shows that PRP treatment of the meniscus results in an increase of catabolic molecules, especially those related to IL-1α-induced inflammation, and that PRP treatment for an in vivo meniscus injury accelerates fibrosis, instead of meniscal cartilage. Full article

(This article belongs to the Section Biochemistry)

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Cloning and Transcriptional Activity of the Mouse Omi/HtrA2 Gene Promoter

by Dan Liu, Xin Liu, Ye Wu, Wen Wang, Xinliang Ma and Huirong Liu

Int. J. Mol. Sci. 2016, 17(1), 119; https://doi.org/10.3390/ijms17010119 - 16 Jan 2016

Cited by 10 | Viewed by 6256

Abstract

HtrA serine peptidase 2 (HtrA2), also named Omi, is a pro-apoptotic protein that exhibits dramatic changes in expression levels in a variety of disorders, including ischemia/reperfusion injury, cancer, and neurodegeneration. In our study, Omi/HtrA2 protein levels were high in the heart, brain, kidney [...] Read more.

HtrA serine peptidase 2 (HtrA2), also named Omi, is a pro-apoptotic protein that exhibits dramatic changes in expression levels in a variety of disorders, including ischemia/reperfusion injury, cancer, and neurodegeneration. In our study, Omi/HtrA2 protein levels were high in the heart, brain, kidney and liver, with elevated heart/brain expression in aging mice. A similar expression pattern was observed at the mRNA level, which suggests that the regulation of Omi/HtrA2 is predominately transcriptional. Promoter binding by transcription factors is the main influencing factor of transcription, and to identify specific promoter elements that contribute to the differential expression of mouse Omi/HtrA2, we constructed truncated Omi/HtrA2 promoter/luciferase reporter vectors and analyzed their relative luciferase activity; it was greatest in the promoter regions at −1205~−838 bp and −146~+93 bp, with the −838~−649 bp region exhibiting negative regulatory activity. Bioinformatics analysis suggested that the Omi/HtrA2 gene promoter contains a CpG island at −709~+37 bp, and eight heat shock transcription factor 1 (HSF1) sites, two Sp1 transcription factor (SP1)sites, one activator protein (AP) site, seven p53 sites, and four YY1 transcription factor(YY1) sites were predicted in the core areas. Furthermore, we found that p53 and HSF1 specifically binds to the Omi/HtrA2 promoter using chromatin immunoprecipitation analysis. These results provide a foundation for understanding Omi/HtrA2 regulatory mechanisms, which could further understanding of HtrA-associated diseases. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Ultra-Fast Glyco-Coating of Non-Biological Surfaces

by Eleanor Williams, Katie Barr, Elena Korchagina, Alexander Tuzikov, Stephen Henry and Nicolai Bovin

Int. J. Mol. Sci. 2016, 17(1), 118; https://doi.org/10.3390/ijms17010118 - 16 Jan 2016

Cited by 13 | Viewed by 6644

Abstract

The ability to glycosylate surfaces has medical and diagnostic applications, but there is no technology currently recognized as being able to coat any surface without the need for prior chemical modification of the surface. Recently, a family of constructs called function-spacer-lipids (FSL) has [...] Read more.

The ability to glycosylate surfaces has medical and diagnostic applications, but there is no technology currently recognized as being able to coat any surface without the need for prior chemical modification of the surface. Recently, a family of constructs called function-spacer-lipids (FSL) has been used to glycosylate cells. Because it is known that lipid-based material can adsorb onto surfaces, we explored the potential and performance of cell-labelling FSL constructs to “glycosylate” non-biological surfaces. Using blood group A antigen as an indicator, the performance of a several variations of FSL constructs to modify a large variety of non-biological surfaces was evaluated. It was found the FSL constructs when optimised could in a few seconds glycosylate almost any non-biological surface including metals, glass, plastics, rubbers and other polymers. Although the FSL glycan coating was non-covalent, and therefore temporary, it was sufficiently robust with appropriate selection of spacer and surface that it could capture anti-glycan antibodies, immobilize cells (via antibody), and withstand incubation in serum and extensive buffer washing, making it suitable for diagnostic and research applications. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins)

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Direct Analysis in Real Time (DART) of an Organothiophosphate at Ultrahigh Resolution by Fourier Transform Ion Cyclotron Resonance Mass Spectrometry and Tandem Mass Spectrometry

by Laszlo Prokai and Stanley M. Stevens

Int. J. Mol. Sci. 2016, 17(1), 116; https://doi.org/10.3390/ijms17010116 - 16 Jan 2016

Cited by 7 | Viewed by 6679

Abstract

Direct analysis in real time (DART) is a recently developed ambient ionization technique for mass spectrometry to enable rapid and sensitive analyses with little or no sample preparation. After swab-based field sampling, the organothiophosphate malathion was analyzed using DART-Fourier transform ion cyclotron resonance [...] Read more.

Direct analysis in real time (DART) is a recently developed ambient ionization technique for mass spectrometry to enable rapid and sensitive analyses with little or no sample preparation. After swab-based field sampling, the organothiophosphate malathion was analyzed using DART-Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) and tandem mass spectrometry (MS/MS). Mass resolution was documented to be over 800,000 in full-scan MS mode and over 1,000,000 for an MS/MS product ion produced by collision-induced dissociation of the protonated analyte. Mass measurement accuracy below 1 ppm was obtained for all DART-generated ions that belonged to the test compound in the mass spectra acquired using only external mass calibration. This high mass measurement accuracy, achievable at present only through FTMS, was required for unequivocal identification of the corresponding molecular formulae. Full article

(This article belongs to the Special Issue Fourier Transform Mass Spectrometry in Molecular Sciences)

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Cerebellar Expression of the Neurotrophin Receptor p75 in Naked-Ataxia Mutant Mouse

by Maryam Rahimi Balaei, Xiaodan Jiao, Niloufar Ashtari, Pegah Afsharinezhad, Saeid Ghavami and Hassan Marzban

Int. J. Mol. Sci. 2016, 17(1), 115; https://doi.org/10.3390/ijms17010115 - 15 Jan 2016

Cited by 13 | Viewed by 6940

Abstract

Spontaneous mutation in the lysosomal acid phosphatase 2 (Acp2) mouse (nax—naked-ataxia mutant mouse) correlates with severe cerebellar defects including ataxia, reduced size and abnormal lobulation as well as Purkinje cell (Pc) degeneration. Loss of Pcs in the nax cerebellum is compartmentalized [...] Read more.

Spontaneous mutation in the lysosomal acid phosphatase 2 (Acp2) mouse (nax—naked-ataxia mutant mouse) correlates with severe cerebellar defects including ataxia, reduced size and abnormal lobulation as well as Purkinje cell (Pc) degeneration. Loss of Pcs in the nax cerebellum is compartmentalized and harmonized to the classic pattern of gene expression of the cerebellum in the wild type mouse. Usually, degeneration starts in the anterior and posterior zones and continues to the central and nodular zones of cerebellum. Studies have suggested that the p75 neurotrophin receptor (NTR) plays a role in Pc degeneration; thus, in this study, we investigated the p75NTR pattern and protein expression in the cerebellum of the nax mutant mouse. Despite massive Pc degeneration that was observed in the nax mouse cerebellum, p75NTR pattern expression was similar to the HSP25 pattern in nax mice and comparable with wild type sibling cerebellum. In addition, immunoblot analysis of p75NTR protein expression did not show any significant difference between nax and wild type sibling (p > 0.5). In comparison with wild type counterparts, p75NTR pattern expression is aligned with the fundamental cytoarchitecture organization of the cerebellum and is unchanged in the nax mouse cerebellum despite the severe neurodevelopmental disorder accompanied with Pc degeneration. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

by Antonios Douros, Elisabeth Bronder, Frank Andersohn, Andreas Klimpel, Reinhold Kreutz, Edeltraut Garbe and Juliane Bolbrinker

Int. J. Mol. Sci. 2016, 17(1), 114; https://doi.org/10.3390/ijms17010114 - 15 Jan 2016

Cited by 31 | Viewed by 11075

Abstract

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of [...] Read more.

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed. Full article

(This article belongs to the Special Issue Drug, Herb, and Dietary Supplement Hepatotoxicity)

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In Silico Insight into Potential Anti-Alzheimer’s Disease Mechanisms of Icariin

by Zhijie Cui, Zhen Sheng, Xinmiao Yan, Zhiwei Cao and Kailin Tang

Int. J. Mol. Sci. 2016, 17(1), 113; https://doi.org/10.3390/ijms17010113 - 15 Jan 2016

Cited by 14 | Viewed by 6398

Abstract

Herbal compounds that have notable therapeutic effect upon Alzheimer's disease (AD) have frequently been found, despite the recent failure of late-stage clinical drugs. Icariin, which is isolated from Epimedium brevicornum, is widely reported to exhibit significant anti-AD effects in in vitro and in [...] Read more.

Herbal compounds that have notable therapeutic effect upon Alzheimer's disease (AD) have frequently been found, despite the recent failure of late-stage clinical drugs. Icariin, which is isolated from Epimedium brevicornum, is widely reported to exhibit significant anti-AD effects in in vitro and in vivo studies. However, the molecular mechanism remains thus far unclear. In this work, the anti-AD mechanisms of icariin were investigated at a target network level assisted by an in silico target identification program (INVDOCK). The results suggested that the anti-AD effects of icariin may be contributed by: attenuation of hyperphosphorylation of tau protein, anti-inflammation and regulation of Ca²⁺ homeostasis. Our results may provide assistance in understanding the molecular mechanism and further developing icariin into promising anti-AD agents. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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Transcription Factor Sp1 Promotes the Expression of Porcine ROCK1 Gene

by Ruirui Zhang, Xiaoting Feng, Mengsi Zhan, Cong Huang, Kun Chen, Xiaoyin Tang, Tingting Kang, Yuanzhu Xiong and Minggang Lei

Int. J. Mol. Sci. 2016, 17(1), 112; https://doi.org/10.3390/ijms17010112 - 15 Jan 2016

Cited by 10 | Viewed by 6234

Abstract

Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) gene plays a crucial role in maintaining genomic stability, tumorigenesis and myogenesis. However, little is known about the regulatory elements governing the transcription of porcine ROCK1 gene. In the current study, the transcription start [...] Read more.

Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) gene plays a crucial role in maintaining genomic stability, tumorigenesis and myogenesis. However, little is known about the regulatory elements governing the transcription of porcine ROCK1 gene. In the current study, the transcription start site (TSS) was identified by 5’-RACE, and was found to differ from the predicted one. The region in ROCK1 promoter which is critical for promoter activity was investigated via progressive deletions. Site-directed mutagenesis indicated that the region from −604 to −554 bp contains responsive elements for Sp1. Subsequent experiments showed that ROCK1 promoter activity is enhanced by Sp1 in a dose-dependent manner, whereas treatment with specific siRNA repressed ROCK1 promoter activity. Electrophoretic mobility shift assay (EMSA), DNA pull down and chromatin immunoprecipitation (ChIP) assays revealed Sp1 can bind to this region. qRT-PCR and Western blotting research followed by overexpression or inhibition of Sp1 indicate that Sp1 can affect endogenous ROCK1 expression at both mRNA and protein levels. Overexpression of Sp1 can promote the expression of myogenic differentiation 1(MyoD), myogenin (MyoG), myosin heavy chain (MyHC). Taken together, we conclude that Sp1 positively regulates ROCK1 transcription by directly binding to the ROCK1 promoter region (from −604 to −532 bp) and may affect the process of myogenesis. Full article

(This article belongs to the Section Biochemistry)

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