International Journal of Molecular Sciences

23 pages, 1902 KiB

Open AccessReview

p53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicine

by Jelena Krstic¹

, Markus Galhuber¹, Tim J. Schulz^2,3,4, Michael Schupp⁵ and Andreas Prokesch^1,6,*

¹ Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, 8010 Graz, Austria

² Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehhbrücke, 14558 Nuthetal, Germany

³ German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany

⁴ Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany

⁵ Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pharmacology, Center for Cardiovascular Research, 10117 Berlin, Germany

⁶ BioTechMed-Graz, 8010 Graz, Austria

Int. J. Mol. Sci. 2018, 19(3), 921; https://doi.org/10.3390/ijms19030921 - 20 Mar 2018

Cited by 50 | Viewed by 7959

Abstract

Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the [...] Read more.

Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)

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17 pages, 6965 KiB

Open AccessArticle

CpG ODN1826 as a Promising Mucin1-Maltose-Binding Protein Vaccine Adjuvant Induced DC Maturation and Enhanced Antitumor Immunity

by Jing Jie, Yixin Zhang, Hongyue Zhou, Xiaoyu Zhai, Nannan Zhang, Hongyan Yuan, Weihua Ni and Guixiang Tai^*

Department of Immunology, College of Basic Medical Science, Jilin University, Xinjiang Street 125, Changchun 130021, China

Int. J. Mol. Sci. 2018, 19(3), 920; https://doi.org/10.3390/ijms19030920 - 20 Mar 2018

Cited by 33 | Viewed by 8301

Abstract

Mucin 1 (MUC1), being an oncogene, is an attractive target in tumor immunotherapy. Maltose binding protein (MBP) is a potent built-in adjuvant to enhance protein immunogenicity. Thus, a recombinant MUC1 and MBP antitumor vaccine (M-M) was constructed in our laboratory. To [...] Read more.

Mucin 1 (MUC1), being an oncogene, is an attractive target in tumor immunotherapy. Maltose binding protein (MBP) is a potent built-in adjuvant to enhance protein immunogenicity. Thus, a recombinant MUC1 and MBP antitumor vaccine (M-M) was constructed in our laboratory. To enhance the antitumor immune activity of M-M, CpG oligodeoxynucleotides 1826 (CpG 1826), a toll-like receptor-9 agonist, was examined in this study as an adjuvant. The combination of M-M and CpG 1826 significantly inhibited MUC1-expressing B16 cell growth and prolonged the survival of tumor-bearing mice. It induced MUC1-specific antibodies and Th1 immune responses, as well as the Cytotoxic T Lymphocytes (CTL) cytotoxicity in vivo. Further studies showed that it promoted the maturation and activation of the dendritic cell (DC) and skewed towards Th1 phenotype in vitro. Thus, our study revealed that CpG 1826 is an efficient adjuvant, laying a foundation for further M-M clinical research. Full article

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

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40 pages, 12893 KiB

Open AccessReview

Therapeutic Properties and Biological Benefits of Marine-Derived Anticancer Peptides

by Hee Kyoung Kang¹, Moon-Chang Choi¹, Chang Ho Seo² and Yoonkyung Park^1,3,*

¹ Department of Biomedical Science, Chosun University, Gwangju 501-759, Korea

² Department of Bioinformatics, Kongju National University, Kongju 314-701, Korea

³ Research Center for Proteineous Materials, Chosun University, Gwangju 501-759, Korea

Int. J. Mol. Sci. 2018, 19(3), 919; https://doi.org/10.3390/ijms19030919 - 20 Mar 2018

Cited by 70 | Viewed by 9141

Abstract

Various organisms exist in the oceanic environment. These marine organisms provide an abundant source of potential medicines. Many marine peptides possess anticancer properties, some of which have been evaluated for treatment of human cancer in clinical trials. Marine anticancer peptides kill cancer cells [...] Read more.

Various organisms exist in the oceanic environment. These marine organisms provide an abundant source of potential medicines. Many marine peptides possess anticancer properties, some of which have been evaluated for treatment of human cancer in clinical trials. Marine anticancer peptides kill cancer cells through different mechanisms, such as apoptosis, disruption of the tubulin-microtubule balance, and inhibition of angiogenesis. Traditional chemotherapeutic agents have side effects and depress immune responses. Thus, the research and development of novel anticancer peptides with low toxicity to normal human cells and mechanisms of action capable of avoiding multi-drug resistance may provide a new method for anticancer treatment. This review provides useful information on the potential of marine anticancer peptides for human therapy. Full article

(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)

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11 pages, 3980 KiB

Open AccessArticle

Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters

by Hüseyin Ilgü¹, Jean-Marc Jeckelmann¹, Claire Colas², Zöhre Ucurum¹, Avner Schlessinger² and Dimitrios Fotiadis^1,*

¹ Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, CH-3012 Bern, Switzerland

² Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

Int. J. Mol. Sci. 2018, 19(3), 918; https://doi.org/10.3390/ijms19030918 - 20 Mar 2018

Cited by 18 | Viewed by 5154

Abstract

The l-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously [...] Read more.

The l-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously and purified to homogeneity. A size-exclusion chromatography-based thermostability assay was used to determine the melting temperatures (T_ms) of the purified AdiC variants in the absence and presence of the selected ligands l-arginine (Arg), agmatine, l-arginine methyl ester, and l-arginine amide. The resulting T_ms indicated stabilization of AdiC variants upon ligand binding, in which T_ms and ligand binding affinities correlated positively. Considering results from this and previous studies, we revisited the role of AdiC residue S26 in Arg binding and proposed interactions of the α-carboxylate group of Arg exclusively with amide groups of the AdiC backbone. In the context of substrate binding in the human SLC7 family member l-type amino acid transporter-1 (LAT1; SLC7A5), an analogous role of S66 in LAT1 to S26 in AdiC is discussed based on homology modeling and amino acid sequence analysis. Finally, we propose a binding mechanism for l-amino acid substrates to LATs from the SLC7 family. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism)

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19 pages, 4357 KiB

Open AccessArticle

The Influence of High and Low Doses of Bisphenol A (BPA) on the Enteric Nervous System of the Porcine Ileum

by Kamila Szymanska^*, Krystyna Makowska and Slawomir Gonkowski

Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego Str. 13, 10-719 Olsztyn, Poland

Int. J. Mol. Sci. 2018, 19(3), 917; https://doi.org/10.3390/ijms19030917 - 20 Mar 2018

Cited by 49 | Viewed by 6257

Abstract

Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination [...] Read more.

Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination of this study was to investigate the influence of BPA at a specific dose (0.05 mg/kg body weight/day) and at a dose ten times higher (0.5 mg/kg body weight/day), given for 28 days, on the porcine ileum. The influence of BPA on enteric neuron immunoreactive to selected neuronal active substances, including substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), vesicular acetylcholine transporter (VAChT—used here as a marker of cholinergic neurons), and cocaine- and amphetamine-regulated transcript peptide (CART), was studied by the double immunofluorescence method. Both doses of BPA affected the neurochemical characterization of the enteric neurons. The observed changes depended on the type of enteric plexus but were generally characterized by an increase in the number of cells immunoreactive to the particular substances. More visible fluctuations were observed after treatment with higher doses of BPA. The results confirm that even low doses of BPA may influence the neurochemical characterization of the enteric neurons and are not neutral for living organisms. Full article

(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)

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23 pages, 6714 KiB

Open AccessArticle

Site-Mutation of Hydrophobic Core Residues Synchronically Poise Super Interleukin 2 for Signaling: Identifying Distant Structural Effects through Affordable Computations

by Longcan Mei^1,†, Yanping Zhou^1,†, Lizhe Zhu²

, Changlin Liu¹, Zhuo Wu¹, Fangkui Wang³, Gefei Hao¹, Di Yu⁴, Hong Yuan^1,* and Yanfang Cui^1,5,*

¹ Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal University, Wuhan 430079, China

² Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong 999077, China

³ State Key Lab of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China

⁴ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Acton 2601, Australia

⁵ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, Australia

^† These authors contributed equally to the study.

Int. J. Mol. Sci. 2018, 19(3), 916; https://doi.org/10.3390/ijms19030916 - 20 Mar 2018

Cited by 4 | Viewed by 5661

Abstract

A superkine variant of interleukin-2 with six site mutations away from the binding interface developed from the yeast display technique has been previously characterized as undergoing a distal structure alteration which is responsible for its super-potency and provides an elegant case study with [...] Read more.

A superkine variant of interleukin-2 with six site mutations away from the binding interface developed from the yeast display technique has been previously characterized as undergoing a distal structure alteration which is responsible for its super-potency and provides an elegant case study with which to get insight about how to utilize allosteric effect to achieve desirable protein functions. By examining the dynamic network and the allosteric pathways related to those mutated residues using various computational approaches, we found that nanosecond time scale all-atom molecular dynamics simulations can identify the dynamic network as efficient as an ensemble algorithm. The differentiated pathways for the six core residues form a dynamic network that outlines the area of structure alteration. The results offer potentials of using affordable computing power to predict allosteric structure of mutants in knowledge-based mutagenesis. Full article

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

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22 pages, 5135 KiB

Open AccessArticle

Alternative Respiratory Pathway Component Genes (AOX and ND) in Rice and Barley and Their Response to Stress

by Vajira R. Wanniarachchi^†

, Lettee Dametto^†, Crystal Sweetman

, Yuri Shavrukov, David A. Day

, Colin L. D. Jenkins and Kathleen L. Soole^*

¹ College of Science and Engineering, Flinders University of South Australia, GPO Box 5100, Adelaide, SA 5001, Australia

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(3), 915; https://doi.org/10.3390/ijms19030915 - 20 Mar 2018

Cited by 43 | Viewed by 6420

Abstract

Plants have a non-energy conserving bypass of the classical mitochondrial cytochrome c pathway, known as the alternative respiratory pathway (AP). This involves type II NAD(P)H dehydrogenases (NDs) on both sides of the mitochondrial inner membrane, ubiquinone, and the alternative oxidase (AOX). The AP [...] Read more.

Plants have a non-energy conserving bypass of the classical mitochondrial cytochrome c pathway, known as the alternative respiratory pathway (AP). This involves type II NAD(P)H dehydrogenases (NDs) on both sides of the mitochondrial inner membrane, ubiquinone, and the alternative oxidase (AOX). The AP components have been widely characterised from Arabidopsis, but little is known for monocot species. We have identified all the genes encoding components of the AP in rice and barley and found the key genes which respond to oxidative stress conditions. In both species, AOX is encoded by four genes; in rice OsAOX1a, 1c, 1d and 1e representing four clades, and in barley, HvAOX1a, 1c, 1d1 and 1d2, but no 1e. All three subfamilies of plant ND genes, NDA, NDB and NDC are present in both rice and barley, but there are fewer NDB genes compared to Arabidopsis. Cyanide treatment of both species, along with salt treatment of rice and drought treatment of barley led to enhanced expression of various AP components; there was a high level of co-expression of AOX1a and AOX1d, along with NDB3 during the stress treatments, reminiscent of the co-expression that has been well characterised in Arabidopsis for AtAOX1a and AtNDB2. Full article

(This article belongs to the Special Issue Plant Mitochondria)

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11 pages, 625 KiB

Open AccessReview

hCG and Its Disruption by Environmental Contaminants during Human Pregnancy

by Luana Paulesu^1,*, Ch.V. Rao², Francesca Ietta¹, Adalgisa Pietropolli³ and Carlo Ticconi³

¹ Department of Life Sciences, University of Siena, 53100 Siena, Italy

² Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA

³ Department of Biomedicine and Prevention, Section of Gynecology and Obstetrics, Tor Vergata University, 00173 Rome, Italy

Int. J. Mol. Sci. 2018, 19(3), 914; https://doi.org/10.3390/ijms19030914 - 20 Mar 2018

Cited by 38 | Viewed by 10859

Abstract

Human chorionic gonadotropin (hCG) is a hormone of considerable importance in the establishment, promotion and maintenance of human pregnancy. It has been clearly demonstrated that hCG exerts multiple endocrine, paracrine and autocrine actions on a variety of gestational and non-gestational cells and tissues. [...] Read more.

Human chorionic gonadotropin (hCG) is a hormone of considerable importance in the establishment, promotion and maintenance of human pregnancy. It has been clearly demonstrated that hCG exerts multiple endocrine, paracrine and autocrine actions on a variety of gestational and non-gestational cells and tissues. These actions are directed to promote trophoblast invasiveness and differentiation, placental growth, angiogenesis in uterine vasculature, hormone production, modulation of the immune system at the maternal-fetal interface, inhibition of myometrial contractility as well as fetal growth and differentiation. In recent years, considerable interest has been raised towards the biological effects of environmental contaminants, particularly endocrine disrupting chemicals (EDCs). Emerging evidence suggests that prenatal exposure to selected EDCs can have a deleterious impact on the fetus and long-lasting consequences also in adult life. The results of the in vitro effects of commonly found EDCs, particularly Bisphenol A (BPA) and para-Nonylphenol (p-NP), indicate that these substances can alter hCG production and through this action could exert their fetal damage, suggesting that hCG could represent and become a potentially useful clinical biomarker of an inappropriate prenatal exposure to these substances. Full article

(This article belongs to the Special Issue hCG—An Endocrine, Regulator of Gestation and Cancer)

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14 pages, 1337 KiB

Open AccessReview

PPARβ/δ: A Key Therapeutic Target in Metabolic Disorders

by Xavier Palomer^1,2,3, Emma Barroso^1,2,3

, Javier Pizarro-Delgado^1,2,3, Lucía Peña^1,2,3, Gaia Botteri^1,2,3, Mohammad Zarei^1,2,3, David Aguilar^1,2,3, Marta Montori-Grau^1,2,3

and Manuel Vázquez-Carrera^1,2,3,*

¹ Pharmacology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain

² Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain

³ Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain

Int. J. Mol. Sci. 2018, 19(3), 913; https://doi.org/10.3390/ijms19030913 - 20 Mar 2018

Cited by 84 | Viewed by 8359

Abstract

Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic [...] Read more.

Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic disorders, including obesity, dyslipidaemia, type 2 diabetes mellitus and non-alcoholic fatty liver disease. This review highlights research findings on the PPARβ/δ regulation of energy metabolism and the development of diseases related to altered cellular and body metabolism. It also describes the potential of the pharmacological activation of PPARβ/δ as a treatment for human metabolic disorders. Full article

(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)

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17 pages, 22730 KiB

Open AccessArticle

Suppression Effect of Astaxanthin on Osteoclast Formation In Vitro and Bone Loss In Vivo

by Yun-Ho Hwang^†, Kwang-Jin Kim^†, Su-Jin Kim, Seul-Ki Mun, Seong-Gyeol Hong, Young-Jin Son and Sung-Tae Yee^*

¹ Department of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon 540-950, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(3), 912; https://doi.org/10.3390/ijms19030912 - 19 Mar 2018

Cited by 45 | Viewed by 7809

Abstract

Osteoporosis is characterized by a reduction of the bone mineral density (BMD) and microarchitectural deterioration of the bone, which lead to bone fragility and susceptibility to fracture. Astaxanthin (AST) has a variety of biological activities, such as a protective effect against asthma or [...] Read more.

Osteoporosis is characterized by a reduction of the bone mineral density (BMD) and microarchitectural deterioration of the bone, which lead to bone fragility and susceptibility to fracture. Astaxanthin (AST) has a variety of biological activities, such as a protective effect against asthma or neuroinflammation, antioxidant effect, and decrease of the osteoclast number in the right mandibles in the periodontitis model. Although treatment with AST is known to have an effect on inflammation, no studies on the effect of AST exposure on bone loss have been performed. Thus, in the present study, we examined the antiosteoporotic effect of AST on bone mass in ovariectomized (OVX) mice and its possible mechanism of action. The administration of AST (5, 10 mg/kg) for 6 weeks suppressed the enhancement of serum calcium, inorganic phosphorus, alkaline phosphatase, total cholesterol, and tartrate-resistant acid phosphatase (TRAP) activity. The bone mineral density (BMD) and bone microarchitecture of the trabecular bone in the tibia and femur were recovered by AST exposure. Moreover, in the in vitro experiment, we demonstrated that AST inhibits osteoclast formation through the expression of the nuclear factor of activated T cells (NFAT) c1, dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K without any cytotoxic effects on bone marrow-derived macrophages (BMMs). Therefore, we suggest that AST may have therapeutic potential for the treatment of postmenopausal osteoporosis. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 289 KiB

Open AccessReview

Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD)

by José A Del Campo^1,*

, Rocío Gallego-Durán², Paloma Gallego¹ and Lourdes Grande¹

¹ Valme University Hospital, Department of Digestive Diseases & CIBERehd, Servicio Andaluz de Salud, University of Sevilla, 41014 Sevilla, Spain

² Instituto de Biomedicina de Sevilla (IBiS) & CIBERehd, 41012 Sevilla, Spain

Int. J. Mol. Sci. 2018, 19(3), 911; https://doi.org/10.3390/ijms19030911 - 19 Mar 2018

Cited by 126 | Viewed by 9806

Abstract

Genetics and epigenetics play a key role in the development of several diseases, including nonalcoholic fatty liver disease (NAFLD). Family studies demonstrate that first degree relatives of patients with NAFLD are at a much higher risk of the disease than the general population. [...] Read more.

Genetics and epigenetics play a key role in the development of several diseases, including nonalcoholic fatty liver disease (NAFLD). Family studies demonstrate that first degree relatives of patients with NAFLD are at a much higher risk of the disease than the general population. The development of the Genome Wide Association Study (GWAS) technology has allowed the identification of numerous genetic polymorphisms involved in the evolution of diseases (e.g., PNPLA3, MBOAT7). On the other hand, epigenetic changes interact with inherited risk factors to determine an individual’s susceptibility to NAFLD. Modifications of the histones amino-terminal ends are key factors in the maintenance of chromatin structure and gene expression (cAMP-responsive element binding protein H (CREBH) or SIRT1). Activation of SIRT1 showed potential against the physiological mechanisms related to NAFLD. Abnormal DNA methylation represents a starting point for cancer development in NAFLD patients. Besides, the evaluation of circulating miRNA profiles represents a promising approach to assess and non-invasively monitor liver disease severity. To date, there is no approved pharmacologic therapy for NAFLD and the current treatment remains weight loss with lifestyle modification and exercise. In this review, the status of research into relevant genetic and epigenetic modifiers of NAFLD progression will be discussed. Full article

(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)

21 pages, 2066 KiB

Open AccessArticle

In-Silico Integration Approach to Identify a Key miRNA Regulating a Gene Network in Aggressive Prostate Cancer

by Claudia Cava¹

, Gloria Bertoli¹

, Antonio Colaprico^2,3, Gianluca Bontempi^2,3, Giancarlo Mauri^4,5

and Isabella Castiglioni^1,*

¹ Institute of Molecular Bioimaging and Physiology, National Research Council, 20090 Segrate (Mi), Italy

² Interuniversity Institute of Bioinformatics in Brussels (IB)², 1050 Brussels, Belgium

³ Machine Learning Group (MLG), Department d'Informatique, Universite libre de Bruxelles (ULB), 1050 Brussels, Belgium

⁴ Department of Informatics, Systems and Communication, University of Milan-Bicocca, 20125 Milan, Italy

⁵ SYSBIO Centre of Systems Biology (SYSBIO), 20126 Milan, Italy

Int. J. Mol. Sci. 2018, 19(3), 910; https://doi.org/10.3390/ijms19030910 - 19 Mar 2018

Cited by 12 | Viewed by 6554

Abstract

Like other cancer diseases, prostate cancer (PC) is caused by the accumulation of genetic alterations in the cells that drives malignant growth. These alterations are revealed by gene profiling and copy number alteration (CNA) analysis. Moreover, recent evidence suggests that also microRNAs have [...] Read more.

Like other cancer diseases, prostate cancer (PC) is caused by the accumulation of genetic alterations in the cells that drives malignant growth. These alterations are revealed by gene profiling and copy number alteration (CNA) analysis. Moreover, recent evidence suggests that also microRNAs have an important role in PC development. Despite efforts to profile PC, the alterations (gene, CNA, and miRNA) and biological processes that correlate with disease development and progression remain partially elusive. Many gene signatures proposed as diagnostic or prognostic tools in cancer poorly overlap. The identification of co-expressed genes, that are functionally related, can identify a core network of genes associated with PC with a better reproducibility. By combining different approaches, including the integration of mRNA expression profiles, CNAs, and miRNA expression levels, we identified a gene signature of four genes overlapping with other published gene signatures and able to distinguish, in silico, high Gleason-scored PC from normal human tissue, which was further enriched to 19 genes by gene co-expression analysis. From the analysis of miRNAs possibly regulating this network, we found that hsa-miR-153 was highly connected to the genes in the network. Our results identify a four-gene signature with diagnostic and prognostic value in PC and suggest an interesting gene network that could play a key regulatory role in PC development and progression. Furthermore, hsa-miR-153, controlling this network, could be a potential biomarker for theranostics in high Gleason-scored PC. Full article

(This article belongs to the Special Issue The Role of MicroRNAs in Human Diseases)

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12 pages, 712 KiB

Open AccessReview

Amino Acid Metabolism and Transport Mechanisms as Potential Antifungal Targets

by Matthew W. McCarthy^1,* and Thomas J. Walsh^1,2

¹ Departments of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA

² Departments of Pediatrics, and Microbiology & Immunology, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA

Int. J. Mol. Sci. 2018, 19(3), 909; https://doi.org/10.3390/ijms19030909 - 19 Mar 2018

Cited by 35 | Viewed by 6649

Abstract

Discovering new drugs for treatment of invasive fungal infections is an enduring challenge. There are only three major classes of antifungal agents, and no new class has been introduced into clinical practice in more than a decade. However, recent advances in our understanding [...] Read more.

Discovering new drugs for treatment of invasive fungal infections is an enduring challenge. There are only three major classes of antifungal agents, and no new class has been introduced into clinical practice in more than a decade. However, recent advances in our understanding of the fungal life cycle, functional genomics, proteomics, and gene mapping have enabled the identification of new drug targets to treat these potentially deadly infections. In this paper, we examine amino acid transport mechanisms and metabolism as potential drug targets to treat invasive fungal infections, including pathogenic yeasts, such as species of Candida and Cryptococcus, as well as molds, such as Aspergillus fumigatus. We also explore the mechanisms by which amino acids may be exploited to identify novel drug targets and review potential hurdles to bringing this approach into clinical practice. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism)

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13 pages, 8447 KiB

Open AccessArticle

HER2-Targeted Multifunctional Silica Nanoparticles Specifically Enhance the Radiosensitivity of HER2-Overexpressing Breast Cancer Cells

by Haruka Yamaguchi^1,2

, Kazuhide Hayama², Ichiro Sasagawa³

, Yasuo Okada⁴, Tomoyuki Kawase⁵

, Norio Tsubokawa⁶ and Makoto Tsuchimochi^7,*

¹ Department of Life Science Dentistry, The Nippon Dental University, 1-8 Hamauracho, Chuoku, Niigata 951-8580, Japan

² Department of Oral and Maxillofacial Radiology, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan

³ Advanced Research Center, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan

⁴ Department of Pathology, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan

⁵ Division of Oral Bioengineering, Department of Tissue Regeneration and Reconstitution, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8541, Japan

⁶ Faculty of Engineering, Niigata University, Niigata 950-2181, Japan

⁷ Emeritus Professor, The Nippon Dental University, Tokyo 102-8159, Japan

Int. J. Mol. Sci. 2018, 19(3), 908; https://doi.org/10.3390/ijms19030908 - 19 Mar 2018

Cited by 26 | Viewed by 6357

Abstract

We investigated the effects of targeted functionalized silica nanoparticles on the radiosensitivity of cancer cells. Better control of the local concentration of silica nanoparticles may facilitate their use as an adjuvant in conjunction with ionizing radiation to target cancer cells while preventing damage [...] Read more.

We investigated the effects of targeted functionalized silica nanoparticles on the radiosensitivity of cancer cells. Better control of the local concentration of silica nanoparticles may facilitate their use as an adjuvant in conjunction with ionizing radiation to target cancer cells while preventing damage to normal cells. Hyperbranched polyamidoamine (PAMAM) was grafted onto the surface of amorphous silica nanoparticles to functionalize them. The PAMAM-coated silica nanoparticles (PCSNs) were then conjugated with fluorescent dyes. Anti-HER2 antibodies were covalently attached to the labeled PCSNs. The HER2-overexpressing SK-BR3 breast cancer cell line was incubated in medium containing the PCSN probes. After incubation; the cells were exposed to X-ray radiation. Cells were counted in all samples using cell proliferation assays; and apoptotic cells were detected. The cell survival results showed that the combination of the targeted PCSN probes and radiation reduced the survival rate of SK-BR3 cells to a greater extent than when either PCSN probes, PCSNs or radiation were applied individually. The results also showed an increase in apoptosis in the SK-BR3 cells that internalized the PCSN probes and were then irradiated. Based on these data, PCSN probes act as specific radiosensitizing agents for HER2-overexpressing cells. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles)

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17 pages, 896 KiB

Open AccessReview

Amino Acid Transporters and Glutamine Metabolism in Breast Cancer

by Yoon Jin Cha

, Eun-Sol Kim and Ja Seung Koo^*

Department of Pathology, Yonsei University College of Medicine, Seoul, 03722, Korea

Int. J. Mol. Sci. 2018, 19(3), 907; https://doi.org/10.3390/ijms19030907 - 19 Mar 2018

Cited by 127 | Viewed by 17520

Abstract

Amino acid transporters are membrane transport proteins, most of which are members of the solute carrier families. Amino acids are essential for the survival of all types of cells, including tumor cells, which have an increased demand for nutrients to facilitate proliferation and [...] Read more.

Amino acid transporters are membrane transport proteins, most of which are members of the solute carrier families. Amino acids are essential for the survival of all types of cells, including tumor cells, which have an increased demand for nutrients to facilitate proliferation and cancer progression. Breast cancer is the most common malignancy in women worldwide and is still associated with high mortality rates, despite improved treatment strategies. Recent studies have demonstrated that the amino acid metabolic pathway is altered in breast cancer and that amino acid transporters affect tumor growth and progression. In breast cancer, glutamine is one of the key nutrients, and glutamine metabolism is closely related to the amino acid transporters. In this review, we focus on amino acid transporters and their roles in breast cancer. We also highlight the different subsets of upregulated amino acid transporters in breast cancer and discuss their potential applications as treatment targets, cancer imaging tracers, and drug delivery components. Glutamine metabolism as well as its regulation and therapeutic implication in breast cancer are also discussed. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism)

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13 pages, 991 KiB

Open AccessReview

CRISPR/Cas9 Technology as an Emerging Tool for Targeting Amyotrophic Lateral Sclerosis (ALS)

by Ewa Kruminis-Kaszkiel^1,*

, Judyta Juranek¹, Wojciech Maksymowicz² and Joanna Wojtkiewicz^1,3,*

¹ Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland

² Department of Neurology and Neurosurgery, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland

³ Laboratory for Regenerative Medicine, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland

Int. J. Mol. Sci. 2018, 19(3), 906; https://doi.org/10.3390/ijms19030906 - 19 Mar 2018

Cited by 22 | Viewed by 11170

Abstract

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) is a genome editing tool that has recently caught enormous attention due to its novelty, feasibility, and affordability. This system naturally functions as a defense mechanism in bacteria and has been repurposed [...] Read more.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) is a genome editing tool that has recently caught enormous attention due to its novelty, feasibility, and affordability. This system naturally functions as a defense mechanism in bacteria and has been repurposed as an RNA-guided DNA editing tool. Unlike zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), CRISPR/Cas9 takes advantage of an RNA-guided DNA endonuclease enzyme, Cas9, which is able to generate double-strand breaks (DSBs) at specific genomic locations. It triggers cellular endogenous DNA repair pathways, contributing to the generation of desired modifications in the genome. The ability of the system to precisely disrupt DNA sequences has opened up new avenues in our understanding of amyotrophic lateral sclerosis (ALS) pathogenesis and the development of new therapeutic approaches. In this review, we discuss the current knowledge of the principles and limitations of the CRISPR/Cas9 system, as well as strategies to improve these limitations. Furthermore, we summarize novel approaches of engaging the CRISPR/Cas9 system in establishing an adequate model of neurodegenerative disease and in the treatment of SOD1-linked forms of ALS. We also highlight possible applications of this system in the therapy of ALS, both the inherited type as well as ALS of sporadic origin. Full article

(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)

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22 pages, 1690 KiB

Open AccessReview

Galectins as Molecular Targets for Therapeutic Intervention

by Ruud P. M. Dings¹

, Michelle C. Miller²

, Robert J. Griffin¹ and Kevin H. Mayo^2,*

¹ Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA

² Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN 55455, USA

Int. J. Mol. Sci. 2018, 19(3), 905; https://doi.org/10.3390/ijms19030905 - 19 Mar 2018

Cited by 94 | Viewed by 10735

Abstract

Galectins are a family of small, highly conserved, molecular effectors that mediate various biological processes, including chemotaxis and angiogenesis, and that function by interacting with various cell surface glycoconjugates, usually targeting β-galactoside epitopes. Because of their significant involvement in various biological functions and [...] Read more.

Galectins are a family of small, highly conserved, molecular effectors that mediate various biological processes, including chemotaxis and angiogenesis, and that function by interacting with various cell surface glycoconjugates, usually targeting β-galactoside epitopes. Because of their significant involvement in various biological functions and pathologies, galectins have become a focus of therapeutic discovery for clinical intervention against cancer, among other pathological disorders. In this review, we focus on understanding galectin structure-function relationships, their mechanisms of action on the molecular level, and targeting them for therapeutic intervention against cancer. Full article

(This article belongs to the Special Issue Galectins in Cancer and Translational Medicine)

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19 pages, 869 KiB

Open AccessReview

Profiling Prostate Cancer Therapeutic Resistance

by Cameron A. Wade¹ and Natasha Kyprianou^1,2,3,*

¹ Departments of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA

² Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA

³ Department of Toxicology & Cancer Biology, University of Kentucky College of Medicine, Lexington, Kentucky, KY 40536, USA

Int. J. Mol. Sci. 2018, 19(3), 904; https://doi.org/10.3390/ijms19030904 - 19 Mar 2018

Cited by 105 | Viewed by 12120

Abstract

The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that [...] Read more.

The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic castration resistant prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during tumor progression. A characteristic feature of EMT landscape is loss of E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting metastasis and chemoresistance. The targetable interactions between androgens/AR and TGF-β signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of biomarker discovery. Full article

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

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13 pages, 4488 KiB

Open AccessArticle

Hydroquinone Exhibits In Vitro and In Vivo Anti-Cancer Activity in Cancer Cells and Mice

by Se Eun Byeon^1,†, Young-Su Yi^2,†

, Jongsung Lee^1,†

, Woo Seok Yang¹, Ji Hye Kim¹, Jooyoung Kim³

, Suntaek Hong³, Jong-Hoon Kim^4,* and Jae Youl Cho^1,*

¹ Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Korea

² Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28503, Korea

³ Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea

⁴ Department of Physiology, College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Korea

^† These authors equally contributed to this work.

Int. J. Mol. Sci. 2018, 19(3), 903; https://doi.org/10.3390/ijms19030903 - 19 Mar 2018

Cited by 24 | Viewed by 6628

Abstract

Hydroquinone (HQ, 1,4-benzenediol) is a hydroxylated benzene metabolite with various biological activities, including anti-oxidative, neuroprotective, immunomodulatory, and anti-inflammatory functions. However, the anti-cancer activity of HQ is not well understood. In this study, the in vitro and in vivo anti-cancer activity of HQ was [...] Read more.

Hydroquinone (HQ, 1,4-benzenediol) is a hydroxylated benzene metabolite with various biological activities, including anti-oxidative, neuroprotective, immunomodulatory, and anti-inflammatory functions. However, the anti-cancer activity of HQ is not well understood. In this study, the in vitro and in vivo anti-cancer activity of HQ was investigated in various cancer cells and tumor-bearing mouse models. HQ significantly induced the death of A431, SYF, B16F10, and MDA-MB-231 cells and also showed a synergistic effect on A431 cell death with other anti-cancer agents, such as adenosine-2′,3′-dialdehyde and buthionine sulfoximine. In addition, HQ suppressed angiogenesis in fertilized chicken embryos. Moreover, HQ prevented lung metastasis of melanoma cells in mice in a dose-dependent manner without toxicity and adverse effects. HQ (10 mg/kg) also suppressed the generation of colon and reduced the thickness of colon tissues in azoxymethane/dextran sodium sulfate-injected mice. This study strongly suggests that HQ possesses in vitro and in vivo anti-cancer activity and provides evidence that HQ could be developed as an effective and safe anti-cancer drug. Full article

(This article belongs to the Section Molecular Toxicology)

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16 pages, 4040 KiB

Open AccessArticle

Agnoprotein Is an Essential Egress Factor during BK Polyomavirus Infection

by Margarita-Maria Panou^1,†, Emma L. Prescott^1,†, Daniel L. Hurdiss¹

, Gemma Swinscoe¹

, Michael Hollinshead², Laura G. Caller², Ethan L. Morgan¹

, Louisa Carlisle², Marietta Müller¹, Michelle Antoni¹, David Kealy¹

, Neil A. Ranson¹

, Colin M. Crump²

and Andrew Macdonald^1,*

¹ Faculty of Biological Sciences and Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK

² Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK

^† These authors contributed equally to the manuscript.

Int. J. Mol. Sci. 2018, 19(3), 902; https://doi.org/10.3390/ijms19030902 - 19 Mar 2018

Cited by 29 | Viewed by 7184

Abstract

BK polyomavirus (BKPyV; hereafter referred to as BK) causes a lifelong chronic infection and is associated with debilitating disease in kidney transplant recipients. Despite its importance, aspects of the virus life cycle remain poorly understood. In addition to the structural proteins, the late [...] Read more.

BK polyomavirus (BKPyV; hereafter referred to as BK) causes a lifelong chronic infection and is associated with debilitating disease in kidney transplant recipients. Despite its importance, aspects of the virus life cycle remain poorly understood. In addition to the structural proteins, the late region of the BK genome encodes for an auxiliary protein called agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to virion infectivity. Here, we demonstrate an essential role for agnoprotein in BK virus release. Viruses lacking agnoprotein fail to release from host cells and do not propagate to wild-type levels. Despite this, agnoprotein is not essential for virion infectivity or morphogenesis. Instead, agnoprotein expression correlates with nuclear egress of BK virions. We demonstrate that the agnoprotein binding partner α-soluble N-ethylmaleimide sensitive fusion (NSF) attachment protein (α-SNAP) is necessary for BK virion release, and siRNA knockdown of α-SNAP prevents nuclear release of wild-type BK virions. These data highlight a novel role for agnoprotein and begin to reveal the mechanism by which polyomaviruses leave an infected cell. Full article

(This article belongs to the Special Issue Human Polyomaviruses and Papillomaviruses)

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3 pages, 169 KiB

Open AccessEditorial

Advances in Multiple Sclerosis 2017

by Kerstin Göbel^1,*

, Christoph Kleinschnitz² and Sven G. Meuth¹

¹ Department of Neurology, University of Münster, 48149 Münster, Germany

² Clinic for Neurology, Essen University Hospital, 45147 Essen, Germany

Int. J. Mol. Sci. 2018, 19(3), 901; https://doi.org/10.3390/ijms19030901 - 19 Mar 2018

Cited by 2 | Viewed by 4429

Abstract

Multiple sclerosis (MS) is one of the most emerging fields in neurology[...] Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2017)

12 pages, 279 KiB

Open AccessArticle

Evaluation of Promoter Methylation of RASSF1A and ATM in Peripheral Blood of Breast Cancer Patients and Healthy Control Individuals

by Xue Cao^1,2,*, Qiuqiong Tang^1,2, Tim Holland-Letz³, Melanie Gündert^1,2

, Katarina Cuk^1,2, Sarah Schott¹, Jörg Heil⁴, Michael Golatta⁴, Christof Sohn¹, Andreas Schneeweiss^1,5 and Barbara Burwinkel^1,2,*

¹ Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany

² Division of Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany

³ Division of Biostatistics (C060), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany

⁴ Department of Gynecology and Obstetrics, University Women’s Clinic, Heidelberg 69120, Germany

⁵ National Centre for Tumor Diseases, Heidelberg 69120, Germany

Int. J. Mol. Sci. 2018, 19(3), 900; https://doi.org/10.3390/ijms19030900 - 19 Mar 2018

Cited by 19 | Viewed by 4916

Abstract

Breast cancer (BC) is the most common cancer among women and has high mortality rates. Early detection is supposed to be critical for the patient’s prognosis. In recent years, several studies have investigated global DNA methylation profiles and gene-specific DNA methylation in blood-based [...] Read more.

Breast cancer (BC) is the most common cancer among women and has high mortality rates. Early detection is supposed to be critical for the patient’s prognosis. In recent years, several studies have investigated global DNA methylation profiles and gene-specific DNA methylation in blood-based DNA to develop putative screening markers for cancer. However, most of the studies have not yet been validated. In our study, we analyzed the promoter methylation of RASSF1A and ATM in peripheral blood DNA of 229 sporadic patients and 151 healthy controls by the MassARRAY EpiTYPER assay. There were no significant differences in DNA methylation levels of RASSF1A and ATM between the sporadic BC cases and the healthy controls. Furthermore, we performed the Infinium HumanMethylation450 BeadChip (450K) array analysis using 48 sporadic BC cases and 48 healthy controls (cases and controls are the same from those of the MassARRAY EpiTYPER assay) and made a comparison with the published data. No significant differences were presented in DNA methylation levels of RASSF1A and ATM between the sporadic BC cases and the healthy controls. So far, the evidence for powerful blood-based methylation markers is still limited and the identified markers need to be further validated. Full article

(This article belongs to the Special Issue DNA Methylation)

13 pages, 1488 KiB

Open AccessArticle

Individual versus Combinatorial Effects of Silicon, Phosphate, and Iron Deficiency on the Growth of Lowland and Upland Rice Varieties

by Nanthana Chaiwong¹, Chanakan Prom-u-thai^1,*, Nadia Bouain², Benoit Lacombe² and Hatem Rouached^2,*

¹ Agronomy Division, Department of Plant and Soil Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai 50200, Thailand

² BPMP, Université de Montpellier, CNRS, INRA, SupAgro, 2 Place Pierre Viala, 34060 Montpellier, France

Int. J. Mol. Sci. 2018, 19(3), 899; https://doi.org/10.3390/ijms19030899 - 18 Mar 2018

Cited by 23 | Viewed by 5910

Abstract

Mineral nutrient homeostasis is essential for plant growth and development. Recent research has demonstrated that the occurrence of interactions among the mechanisms regulating the homeostasis of different nutrients in plants is a general rule rather than an exception. Therefore, it is important to [...] Read more.

Mineral nutrient homeostasis is essential for plant growth and development. Recent research has demonstrated that the occurrence of interactions among the mechanisms regulating the homeostasis of different nutrients in plants is a general rule rather than an exception. Therefore, it is important to understand how plants regulate the homeostasis of these elements and how multiple mineral nutrient signals are wired to influence plant growth. Silicon (Si) is not directly involved in plant metabolism but it is an essential element for a high and sustainable production of crops, especially rice, because of its high content in the total shoot dry weight. Although some mechanisms underlying the role of Si in plants responses to both abiotic and biotic stresses have been proposed, the involvement of Si in regulating plant growth in conditions where the availability of essential macro- and micronutrients changes remains poorly investigated. In this study, the existence of an interaction between Si, phosphate (Pi), and iron (Fe) availability was examined in lowland (Suphanburi 1, SPR1) and upland (Kum Hom Chiang Mai University, KH CMU) rice varieties. The effect of Si and/or Fe deficiency on plant growth, Pi accumulation, Pi transporter expression (OsPHO1;2), and Pi root-to-shoot translocation in these two rice varieties grown under individual or combinatorial nutrient stress conditions were determined. The phenotypic, physiological, and molecular data of this study revealed an interesting tripartite Pi-Fe-Si homeostasis interaction that influences plant growth in contrasting manners in the two rice varieties. These results not only reveal the involvement of Si in modulating rice growth through an interaction with essential micro- and macronutrients, but, more importantly, they opens new research avenues to uncover the molecular basis of Pi-Fe-Si signaling crosstalk in plants. Full article

(This article belongs to the Special Issue Regulation of Mineral Nutrients Homeostasis and Their Crosstalk in Plants)

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11 pages, 768 KiB

Open AccessReview

Understanding Splenomegaly in Myelofibrosis: Association with Molecular Pathogenesis

by Moo-Kon Song¹, Byeong-Bae Park^2,* and Ji-Eun Uhm²

¹ Department of Hematology-Oncology, Hanyang University Hanmaeum Changwon Hospital, Changwon 51497, Korea

² Division of Hematology-Oncology, Department of Internal Medicine, Hanyang University College of Medicine, Hanyang University Hospital, 222-1, Seongdong-Gu Wangsimni-Ro, Seoul 04763, Korea

Int. J. Mol. Sci. 2018, 19(3), 898; https://doi.org/10.3390/ijms19030898 - 18 Mar 2018

Cited by 39 | Viewed by 10536

Abstract

Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due [...] Read more.

Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM) microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen. Moreover, low Gata1 expression was found to be significantly associated with the EMH. Several gene mutations were found to be associated with significant splenomegaly in MF. In recent data, JAK2 V617F homozygous mutation was associated with a larger spleen size. In other data, CALR mutations in MF were signigicantly associated with longer larger splenomegaly-free survivals than others. In addition, MF patients with ≥1 mutations in AZXL1, EZH1 or IDH1/2 had significantly low spleen reduction response in ruxolitinib treatment. Developments of JAK inhibitors, such as ruxolitinib, pacritinib, momelotinib, and febratinib enabled the effective management in MF patients. Especially, significant spleen reduction responses of the drugs were demonstrated in several randomized clinical studies, although those could not eradicate allele burdens of MF. Full article

(This article belongs to the Special Issue Spleen: Crossroad between Immune System, Metabolic Asset and Endocrine Function)

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10 pages, 1496 KiB

Open AccessArticle

An Anion Conductance, the Essential Component of the Hydroxyl-Radical-Induced Ion Current in Plant Roots

by Igor Pottosin^1,2,*

, Isaac Zepeda-Jazo³

, Jayakumar Bose⁴ and Sergey Shabala²

¹ Centro Universitario de Investigaciones Biomédicas, Universidad de Colima; Av. 25 de julio 965, Villa de San Sebastian, Colima, Col. 28045, Mexico

² School of Land and Food, University of Tasmania, Private Bag 54, Hobart, Tas. 7001, Australia

³ Genómica Alimentaria, Universidad de La Ciénega del Estado de Michoacán de Ocampo, Av. Universidad 3000, Lomas de la Universidad, Sahuayo, Mich. 59103, Mexico

⁴ Australian Research Council Centre of Excellence in Plant Energy Biology, School of Agriculture, Food and Wine, University of Adelaide, Adelaide SA 5064, Australia

Int. J. Mol. Sci. 2018, 19(3), 897; https://doi.org/10.3390/ijms19030897 - 18 Mar 2018

Cited by 11 | Viewed by 4725

Abstract

Oxidative stress signaling is essential for plant adaptation to hostile environments. Previous studies revealed the essentiality of hydroxyl radicals (HO•)-induced activation of massive K⁺ efflux and a smaller Ca²⁺ influx as an important component of plant adaptation to a broad range [...] Read more.

Oxidative stress signaling is essential for plant adaptation to hostile environments. Previous studies revealed the essentiality of hydroxyl radicals (HO•)-induced activation of massive K⁺ efflux and a smaller Ca²⁺ influx as an important component of plant adaptation to a broad range of abiotic stresses. Such activation would modify membrane potential making it more negative. Contrary to these expectations, here, we provide experimental evidence that HO• induces a strong depolarization, from −130 to −70 mV, which could only be explained by a substantial HO•-induced efflux of intracellular anions. Application of Gd³⁺ and NPPB, non-specific blockers of cation and anion conductance, respectively, reduced HO•-induced ion fluxes instantaneously, implying a direct block of the dual conductance. The selectivity of an early instantaneous HO•-induced whole cell current fluctuated from more anionic to more cationic and vice versa, developing a higher cation selectivity at later times. The parallel electroneutral efflux of K⁺ and anions should underlie a substantial leak of the cellular electrolyte, which may affect the cell’s turgor and metabolic status. The physiological implications of these findings are discussed in the context of cell fate determination, and ROS and cytosolic K⁺ signaling. Full article

(This article belongs to the Special Issue Plasma-Membrane Transport)

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16 pages, 4021 KiB

Open AccessArticle

Study of Imidazolium Salt Derivatives as PIK3CA Inhibitors Using a Comprehensive in Silico Method

by Ming-yang Wang, Jing-wei Liang, Xin-yang Li, Kamara Mohamed Olounfeh

, Shi-long Li, Shan Wang, Lin Wang and Fan-hao Meng^*

School of Pharmacy, China Medical University, Shenyang 110122, China

Int. J. Mol. Sci. 2018, 19(3), 896; https://doi.org/10.3390/ijms19030896 - 18 Mar 2018

Cited by 8 | Viewed by 4696

Abstract

A series of imidazolium salt derivatives have demonstrated potent antitumor activity in prior research. A comprehensive in silicon method was carried out to identify the putative protein target and detailed structure-activity relationship of the compounds. The Topomer CoMFA and CoMSIA techniques were implemented [...] Read more.

A series of imidazolium salt derivatives have demonstrated potent antitumor activity in prior research. A comprehensive in silicon method was carried out to identify the putative protein target and detailed structure-activity relationship of the compounds. The Topomer CoMFA and CoMSIA techniques were implemented during the investigation to obtain the relationship between the properties of the substituent group and the contour map of around 77 compounds; the Topomer CoMFA and CoMSIA models were reliable with the statistical data. The protein–protein interaction network was constructed by combining the Pharmmapper platform and STRING database. After generating the sub-network, the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA with protein data bank ID: 3ZIM) was selected as the putative target of imidazolium salt derivatives. A docking study was carried out to correlate interactions of amino acids in protein active pockets surrounded by the ligand with contour maps generated by the structure-activity relationship method. Then the molecular dynamics simulations demonstrated that the imidazolium salt derivatives have potent binding capacity and stability to receptor 3ZIM, and the two ligand-receptor complex was stable in the last 2 ns. Finally, the ligand-based structure-activity relationship and receptor-based docking were combined together to identify the structural requirement of the imidazolium salt derivatives, which will be used to design and synthesize the novel PIK3CA inhibitors. Full article

(This article belongs to the Section Molecular Biophysics)

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13 pages, 2515 KiB

Open AccessArticle

Dietary Quercetin Attenuates Adipose Tissue Expansion and Inflammation and Alters Adipocyte Morphology in a Tissue-Specific Manner

by Laura A. Forney¹, Natalie R. Lenard², Laura K. Stewart^3,† and Tara M. Henagan^4,*,†

¹ Nutrient Sensing and Adipocyte Signaling Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA

² Biology Department, Franciscan Missionaries of Our Lady University, Baton Rouge, LA 70808, USA

³ School of Sport and Exercise Sciece, University of Northern Colorado, Greeley, CO, 80639, USA

⁴ Nutrition Science, Purdue University, West Lafayette, IN 47907, USA

^† These authors contributed equally as senior authors.

Int. J. Mol. Sci. 2018, 19(3), 895; https://doi.org/10.3390/ijms19030895 - 17 Mar 2018

Cited by 60 | Viewed by 9516

Abstract

Chronic inflammation in adipose tissue may contribute to depot-specific adipose tissue expansion, leading to obesity and insulin resistance. Dietary supplementation with quercetin or botanical extracts containing quercetin attenuates high fat diet (HFD)-induced obesity and insulin resistance and decreases inflammation. Here, we determined the [...] Read more.

Chronic inflammation in adipose tissue may contribute to depot-specific adipose tissue expansion, leading to obesity and insulin resistance. Dietary supplementation with quercetin or botanical extracts containing quercetin attenuates high fat diet (HFD)-induced obesity and insulin resistance and decreases inflammation. Here, we determined the effects of quercetin and red onion extract (ROE) containing quercetin on subcutaneous (inguinal, IWAT) vs. visceral (epididymal, EWAT) white adipose tissue morphology and inflammation in mice fed low fat, high fat, high fat plus 50 μg/day quercetin or high fat plus ROE containing 50 μg/day quercetin equivalents for 9 weeks. Quercetin and ROE similarly ameliorated HFD-induced increases in adipocyte size and decreases in adipocyte number in IWAT and EWAT. Furthermore, quercetin and ROE induced alterations in adipocyte morphology in IWAT. Quercetin and ROE similarly decreased HFD-induced IWAT inflammation. However, quercetin and red onion differentially affected HFD-induced EWAT inflammation, with quercetin decreasing and REO increasing inflammatory marker gene expression. Quercetin and REO also differentially regulated circulating adipokine levels. These results show that quercetin or botanical extracts containing quercetin induce white adipose tissue remodeling which may occur through inflammatory-related mechanisms. Full article

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

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14 pages, 1777 KiB

Open AccessArticle

Distinct Properties of Human M-CSF and GM-CSF Monocyte-Derived Macrophages to Simulate Pathological Lung Conditions In Vitro: Application to Systemic and Inflammatory Disorders with Pulmonary Involvement

by Alain Lescoat^1,2, Alice Ballerie^1,2, Yu Augagneur¹, Claudie Morzadec¹, Laurent Vernhet¹, Olivier Fardel^1,3

, Patrick Jégo^1,2, Stéphane Jouneau^1,4

and Valérie Lecureur^1,*

¹ Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, F-35000 Rennes, France

² Department of Internal Medicine, Rennes University Hospital, 35203 Rennes, France

³ Pôle Biologie, Rennes University Hospital, 35203 Rennes, France

⁴ Department of Respiratory Diseases, Rennes University Hospital, 35203 Rennes, France

Int. J. Mol. Sci. 2018, 19(3), 894; https://doi.org/10.3390/ijms19030894 - 17 Mar 2018

Cited by 40 | Viewed by 7425

Abstract

Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the [...] Read more.

Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc. Full article

(This article belongs to the Special Issue Macrophages in Inflammation)

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19 pages, 355 KiB

Open AccessReview

Treatment with Growth Hormone for Adults with Growth Hormone Deficiency Syndrome: Benefits and Risks

by Juan J. Díez^1,2, Susana Sangiao-Alvarellos^3,4

and Fernando Cordido^3,4,5,*

¹ Department of Endocrinology, Hospital Ramón y Cajal, 28034 Madrid, Spain

² Department of Medicine, University of Alcalá de Henares, 28034 Madrid, Spain

³ Faculty of Health Sciences, University of A Coruña, 15006 A Coruña, Spain

⁴ Instituto de Investigación Biomedica (INIBIC), University Hospital A Coruña, 15006 A Coruña, Spain

⁵ Department of Endocrinology, University Hospital A Coruña, Xubias de Arriba 84, 15006 A Coruña, Spain

Int. J. Mol. Sci. 2018, 19(3), 893; https://doi.org/10.3390/ijms19030893 - 17 Mar 2018

Cited by 63 | Viewed by 11307

Abstract

Pharmacological treatment of growth hormone deficiency (GHD) in adults began in clinical practice more than 20 years ago. Since then, a great volume of experience has been accumulated on its effects on the symptoms and biochemical alterations that characterize this hormonal deficiency. The [...] Read more.

Pharmacological treatment of growth hormone deficiency (GHD) in adults began in clinical practice more than 20 years ago. Since then, a great volume of experience has been accumulated on its effects on the symptoms and biochemical alterations that characterize this hormonal deficiency. The effects on body composition, muscle mass and strength, exercise capacity, glucose and lipid profile, bone metabolism, and quality of life have been fully demonstrated. The advance of knowledge has also taken place in the biological and molecular aspects of the action of this hormone in patients who have completed longitudinal growth. In recent years, several epidemiological studies have reported interesting information about the long-term effects of GH replacement therapy in regard to the possible induction of neoplasms and the potential development of diabetes. In addition, GH hormone receptor polymorphism could potentially influence GH therapy. Long-acting GH are under development to create a more convenient GH dosing profile, while retaining the excellent safety, efficacy, and tolerability of daily GH. In this article we compile the most recent data of GH replacement therapy in adults, as well as the molecular aspects that may condition a different sensitivity to this treatment. Full article

(This article belongs to the Special Issue Growth Hormone: Therapeutic Possibilities)

18 pages, 930 KiB

Open AccessReview

Health Risks of Hypovitaminosis D: A Review of New Molecular Insights

by Daniela Caccamo^*

, Sergio Ricca, Monica Currò and Riccardo Ientile

Department of Biomedical Sciences, Dental Sciences, and Morpho-functional Imaging, University of Messina, 98125 Messina, Italy

Int. J. Mol. Sci. 2018, 19(3), 892; https://doi.org/10.3390/ijms19030892 - 17 Mar 2018

Cited by 68 | Viewed by 11786

Abstract

Hypovitaminosis D has become a pandemic, being observed in all ethnicities and age groups worldwide. Environmental factors, such as increased air pollution and reduced ultraviolet B (UVB) irradiation, as well as lifestyle factors, i.e., decreased outdoor activities and/or poor intake of vitamin D-rich [...] Read more.

Hypovitaminosis D has become a pandemic, being observed in all ethnicities and age groups worldwide. Environmental factors, such as increased air pollution and reduced ultraviolet B (UVB) irradiation, as well as lifestyle factors, i.e., decreased outdoor activities and/or poor intake of vitamin D-rich food, are likely involved in the etiology of a dramatic reduction of vitamin D circulating levels. The insufficiency/deficiency of vitamin D has long been known for its association with osteoporosis and rickets. However, in the last few decades it has become a serious public health concern since it has been shown to be independently associated with various chronic pathological conditions such as cancer, coronary heart disease, neurological diseases, type II diabetes, autoimmune diseases, depression, with various inflammatory disorders, and with increased risk for all-cause mortality in the general population. Prevention strategies for these disorders have recently involved supplementation with either vitamin D2 or vitamin D3 or their analogs at required daily doses and tolerable upper-limit levels. This review will focus on the emerging evidence about non-classical biological functions of vitamin D in various disorders. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects and Therapeutic Uses)

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Int. J. Mol. Sci., Volume 19, Issue 3 (March 2018) – 278 articles

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