International Journal of Molecular Sciences

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Open AccessReview

by Ziyuan Meng, Quanxia Lv, Jun Lu, Houzong Yao, Xiaoqing Lv, Feng Jiang, Aiping Lu and Ge Zhang

Int. J. Mol. Sci. 2016, 17(5), 796; https://doi.org/10.3390/ijms17050796 - 23 May 2016

Cited by 77 | Viewed by 12129

Abstract

Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule [...] Read more.

Paclitaxel is an anti-tumor agent with remarkable anti-tumor activity and wide clinical uses. However, it is also faced with various challenges especially for its poor water solubility and low selectivity for the target. To overcome these disadvantages of paclitaxel, approaches using small molecule modifications and macromolecule modifications have been developed by many research groups from all over the world. In this review, we discuss the different strategies especially prodrug strategies that are currently used to make paclitaxel more effective. Full article

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

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Open AccessArticle

Cold-Induced Browning Dynamically Alters the Expression Profiles of Inflammatory Adipokines with Tissue Specificity in Mice

by Xiao Luo, Ru Jia, Qiangling Zhang, Bo Sun and Jianqun Yan

Int. J. Mol. Sci. 2016, 17(5), 795; https://doi.org/10.3390/ijms17050795 - 23 May 2016

Cited by 22 | Viewed by 6167

Abstract

Cold exposure or β₃-adrenoceptor agonist treatment induces the adipose tissues remodeling, relevant for beige adipogenesis within white adipose tissue (WAT). It remains unclear whether this process influences inflammatory adipokines expression in adipose tissues. We determine the temporal profile of cold or [...] Read more.

Cold exposure or β₃-adrenoceptor agonist treatment induces the adipose tissues remodeling, relevant for beige adipogenesis within white adipose tissue (WAT). It remains unclear whether this process influences inflammatory adipokines expression in adipose tissues. We determine the temporal profile of cold or β₃-adrenoceptor agonist (CL316,243)-induced changes in the expression of inflammatory adipokines in adipose tissues in mice or primary mice adipocytes. Male C57BL/6J mice at eight weeks old were exposed to 4 °C for 1–5 days. Interscapular brown adipose tissue (iBAT), inguinal subcutaneous WAT (sWAT) and epididymal WAT (eWAT) were harvested for gene and protein expression analysis. In addition, cultured primary mice brown adipocyte (BA) and white adipocyte (WA) treated with or without CL316,243 were harvested for gene expression analysis. The inflammatory adipokines expressed significantly higher in WAT than BAT at baseline. They were rapidly changed in iBAT, while down-regulated in sWAT and up-regulated in eWAT during the cold acclimation. Upon CL316,243 treatment, detected inflammatory adipokines except Leptin were transiently increased in both BA and WA. Our in vivo and in vitro data demonstrate that the browning process alters the inflammatory adipokines expression in adipose tissues, which is acutely responded to in iBAT, dynamically decreased in sWAT whilst increased in eWAT for compensation. Full article

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

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Open AccessReview

Gibberellic Acid: A Key Phytohormone for Spikelet Fertility in Rice Grain Production

by Choon-Tak Kwon and Nam-Chon Paek

Int. J. Mol. Sci. 2016, 17(5), 794; https://doi.org/10.3390/ijms17050794 - 23 May 2016

Cited by 48 | Viewed by 9935

Abstract

The phytohormone gibberellic acid (GA) has essential signaling functions in multiple processes during plant development. In the “Green Revolution”, breeders developed high-yield rice cultivars that exhibited both semi-dwarfism and altered GA responses, thus improving grain production. Most studies of GA have concentrated on [...] Read more.

The phytohormone gibberellic acid (GA) has essential signaling functions in multiple processes during plant development. In the “Green Revolution”, breeders developed high-yield rice cultivars that exhibited both semi-dwarfism and altered GA responses, thus improving grain production. Most studies of GA have concentrated on germination and cell elongation, but GA also has a pivotal role in floral organ development, particularly in stamen/anther formation. In rice, GA signaling plays an important role in spikelet fertility; however, the molecular genetic and biochemical mechanisms of GA in male fertility remain largely unknown. Here, we review recent progress in understanding the network of GA signaling and its connection with spikelet fertility, which is tightly associated with grain productivity in cereal crops. Full article

(This article belongs to the Special Issue Metabolomics in the Plant Sciences)

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Open AccessReview

The Role of Proanthocyanidins Complex in Structure and Nutrition Interaction in Alfalfa Forage

by Arjan Jonker and Peiqiang Yu

Int. J. Mol. Sci. 2016, 17(5), 793; https://doi.org/10.3390/ijms17050793 - 23 May 2016

Cited by 28 | Viewed by 5793

Abstract

Alfalfa (Medicago sativa L.) is one of the main forages grown in the world. Alfalfa is a winter hardy, drought tolerant, N-fixing legume with a good longevity, high yield, high nutrient levels, high digestibility, unique structural to non-structural components ratio, high dry [...] Read more.

Alfalfa (Medicago sativa L.) is one of the main forages grown in the world. Alfalfa is a winter hardy, drought tolerant, N-fixing legume with a good longevity, high yield, high nutrient levels, high digestibility, unique structural to non-structural components ratio, high dry matter intake, and high animal productivity per hectare. However, its main limitation is its excessively rapid initial rate of protein degradation in the rumen, which results in pasture bloat and inefficient use of protein with consequent excessive excretions of nitrogen into the environment. Proanthocyanidins are secondary plant metabolites that can bind with protein and thereby reduce the rate and extent of ruminal protein degradation. However, these secondary metabolites do not accumulate in alfalfa. This review aims to firstly describe the events involved in the rapid release of protein from alfalfa and its effect on ruminant nutrition, environmental pollution, and pasture bloat; secondly, to describe occurrence, structure, functions and benefits of moderate amounts of proanthocyanidin; and finally, to describe the development of alfalfa which accumulates moderate amounts of proanthocyanidins. The emphasis of this review focuses on the role of proanthocyanidins compounds in structure and nutrition interaction in ruminant livestock systems. Full article

(This article belongs to the Section Molecular Plant Sciences)

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Open AccessCommunication

A Novel Technique to Detect EGFR Mutations in Lung Cancer

by Yuanbin Liu, Ting Lei, Zhiyu Liu, Yanbin Kuang, Jianxin Lyu and Qi Wang

Int. J. Mol. Sci. 2016, 17(5), 792; https://doi.org/10.3390/ijms17050792 - 23 May 2016

Cited by 27 | Viewed by 8987

Abstract

Epidermal growth factor receptor (EGFR) gene mutations occur in multiple human cancers; therefore, the detection of EGFR mutations could lead to early cancer diagnosis. This study describes a novel EGFR mutation detection technique. Compared to direct DNA sequencing detection methods, this [...] Read more.

Epidermal growth factor receptor (EGFR) gene mutations occur in multiple human cancers; therefore, the detection of EGFR mutations could lead to early cancer diagnosis. This study describes a novel EGFR mutation detection technique. Compared to direct DNA sequencing detection methods, this method is based on allele-specific amplification (ASA), recombinase polymerase amplification (RPA), peptide nucleic acid (PNA), and SYBR Green I (SYBR), referred to as the AS-RPA-PNA-SYBR (ARPS) system. The principle of this technique is based on three continuous steps: ASA or ASA combined with PNA to prevent non-target sequence amplification (even single nucleotide polymorphisms, SNPs), the rapid amplification advantage of RPA, and appropriate SYBR Green I detection (the samples harboring EGFR mutations show a green signal). Using this method, the EGFR 19Del(2) mutation was detected in 5 min, while the EGFR L858R mutation was detected in 10 min. In this study, the detection of EGFR mutations in clinical samples using the ARPS system was compatible with that determined by polymerase chain reaction (PCR) and DNA sequencing methods. Thus, this newly developed methodology that uses the ARPS system with appropriate primer sets is a rapid, reliable, and practical way to assess EGFR mutations in clinical samples. Full article

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

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Open AccessReview

Circulating MicroRNAs as Biomarkers in Biliary Tract Cancers

by Pablo Letelier, Ismael Riquelme, Alfonso H. Hernández, Neftalí Guzmán, Jorge G. Farías and Juan Carlos Roa

Int. J. Mol. Sci. 2016, 17(5), 791; https://doi.org/10.3390/ijms17050791 - 23 May 2016

Cited by 37 | Viewed by 9001

Abstract

Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative exploration due to brush cytology havinga low sensitivity and the standard markers, such as carcinoembryonic antigen (CEA) [...] Read more.

Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative exploration due to brush cytology havinga low sensitivity and the standard markers, such as carcinoembryonic antigen (CEA) and carbohydrate 19-9 (CA19-9), not having enough sensitivity nor specificity to be used in a differential diagnosis and early stage detection. Thus, better non-invasive methods that can distinguish between normal and pathological tissue are needed. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules of ~20–22 nucleotides that regulate relevant physiological mechanisms and can also be involved in carcinogenesis. Recent studies have demonstrated that miRNAs are detectable in multiple body fluids, showing great stability, either free or trapped in circulating microvesicles, such as exosomes. miRNAs are ideal biomarkers that may be used in screening and prognosis in biliary tract cancers, aiding also in the clinical decisions at different stages of cancer treatment. This review highlights the progress in the analysis of circulating miRNAs in serum, plasma and bile as potential diagnostic and prognostic markers of BTCs. Full article

(This article belongs to the Special Issue MicroRNA in Various Disease States as Biomarkers)

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Open AccessArticle

Analysis of 2-(2-Phenylethyl)chromones by UPLC-ESI-QTOF-MS and Multivariate Statistical Methods in Wild and Cultivated Agarwood

by Yuanbin Li, Nan Sheng, Lingli Wang, Shijie Li, Jiannan Chen and Xiaoping Lai

Int. J. Mol. Sci. 2016, 17(5), 771; https://doi.org/10.3390/ijms17050771 - 23 May 2016

Cited by 31 | Viewed by 7025

Abstract

Agarwood is the fragrant resinous material mainly formed from species of Aquilaria. 2-(2-phenylethyl)chromones, especially the highly oxidized 5,6,7,8-tetrahydro-2-(2-phenylethyl)chromones, are the main representative compounds from agarwood. It is important to determine whether agarwood in trade is from cultivated trees or natural trees in [...] Read more.

Agarwood is the fragrant resinous material mainly formed from species of Aquilaria. 2-(2-phenylethyl)chromones, especially the highly oxidized 5,6,7,8-tetrahydro-2-(2-phenylethyl)chromones, are the main representative compounds from agarwood. It is important to determine whether agarwood in trade is from cultivated trees or natural trees in the Convention on the International Trade in Endangered Species (CITES). We characterized the 2-(2-phenylethyl)chromones in agarwood by ultra-performance liquid chromatography coupled with electrospray ionization mass spectrometry (UPLC–ESI-QTOF-MS) and differentiated wild from cultivated agarwood by metabolomic analysis. A total of 141 chromones including 50 potentially new compounds were evaluated as belonging to four structural classes (unoxidized 2-(2-phenylethyl)chromones, 5,6,7,8-tetrahydro-2-(2-phenylethyl)-chromones, bi-2-(2-phenylethyl)chromones, and tri-2-(2-phenylethyl)chromones). The metabolic difference between wild and cultivated agarwood was analyzed by component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Fourteen markers of metabolisms in wild and cultivated agarwood were constructed (e.g., 6,7-dimethoxy-2-(2-phenylethyl)chromone, 6,8-dihydroxy-2-(2-phenylethyl)chromone, 6-methoxy-2-(2-phenylethyl)chromone, etc.). These results indicated that UPLC–ESI-QTOF-MS-based metabonomics analysis in agarwood may be useful for distinguishing wild agarwood from cultivated agarwood. Full article

(This article belongs to the Special Issue Metabolomics in the Plant Sciences)

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Open AccessArticle

Variability in Immunohistochemical Detection of Programmed Death Ligand 1 (PD-L1) in Cancer Tissue Types

by Giosuè Scognamiglio, Anna De Chiara, Maurizio Di Bonito, Fabiana Tatangelo, Nunzia Simona Losito, Annamaria Anniciello, Rossella De Cecio, Crescenzo D’Alterio, Stefania Scala, Monica Cantile and Gerardo Botti

Int. J. Mol. Sci. 2016, 17(5), 790; https://doi.org/10.3390/ijms17050790 - 21 May 2016

Cited by 36 | Viewed by 7378

Abstract

In normal cell physiology, programmed death 1 (PD-1) and its ligand, PD-L1, play an immunoregulatory role in T-cell activation, tolerance, and immune-mediated tissue damage. The PD-1/PD-L1 pathway also plays a critical role in immune escape of tumor cells and has been demonstrated to [...] Read more.

In normal cell physiology, programmed death 1 (PD-1) and its ligand, PD-L1, play an immunoregulatory role in T-cell activation, tolerance, and immune-mediated tissue damage. The PD-1/PD-L1 pathway also plays a critical role in immune escape of tumor cells and has been demonstrated to correlate with a poor prognosis of patients with several types of cancer. However, recent reports have revealed that the immunohistochemical (IHC) expression of the PD-L1 in tumor cells is not uniform for the use of different antibodies clones, with variable specificity, often doubtful topographical localization, and with a score not uniquely defined. The purpose of this study was to analyze the IHC expression of PD-L1 on a large series of several human tumors to correctly define its staining in different tumor tissues. Full article

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

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Open AccessReview

Functions of miRNAs during Mammalian Heart Development

by Shun Yan and Kai Jiao

Int. J. Mol. Sci. 2016, 17(5), 789; https://doi.org/10.3390/ijms17050789 - 21 May 2016

Cited by 38 | Viewed by 6027

Abstract

MicroRNAs (miRNAs) play essential roles during mammalian heart development and have emerged as attractive therapeutic targets for cardiovascular diseases. The mammalian embryonic heart is mainly derived from four major cell types during development. These include cardiomyocytes, endocardial cells, epicardial cells, and neural crest [...] Read more.

MicroRNAs (miRNAs) play essential roles during mammalian heart development and have emerged as attractive therapeutic targets for cardiovascular diseases. The mammalian embryonic heart is mainly derived from four major cell types during development. These include cardiomyocytes, endocardial cells, epicardial cells, and neural crest cells. Recent data have identified various miRNAs as critical regulators of the proper differentiation, proliferation, and survival of these cell types. In this review, we briefly introduce the contemporary understanding of mammalian cardiac development. We also focus on recent developments in the field of cardiac miRNAs and their functions during the development of different cell types. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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Open AccessArticle

Extraction Optimization, Preliminary Characterization and Bioactivities in Vitro of Ligularia hodgsonii Polysaccharides

by Xueping Song and Jun Tang

Int. J. Mol. Sci. 2016, 17(5), 788; https://doi.org/10.3390/ijms17050788 - 21 May 2016

Cited by 22 | Viewed by 5573

Abstract

The optimization extraction, preliminary characterization and bioactivities of Ligularia hodgsonii polysaccharides were investigated. Based on single-factor experiments and orthogonal array test, the optimum extraction conditions were obtained as follows: extraction time 3 h, temperature 85 °C, water/raw material ratio 36. Further Sevag deproteinization [...] Read more.

The optimization extraction, preliminary characterization and bioactivities of Ligularia hodgsonii polysaccharides were investigated. Based on single-factor experiments and orthogonal array test, the optimum extraction conditions were obtained as follows: extraction time 3 h, temperature 85 °C, water/raw material ratio 36. Further Sevag deproteinization and dialysis yielded the dialyzed Ligularia hodgsonii polysaccharides (DLHP, 19.2 ± 1.4 mg/g crude herb). Compositional analysis, size-exclusion chromatography connected with multi-angle laser light-scattering and refractive index (SEC-MALLS-RI), Fourier transform infrared (FT-IR) and ¹H nuclear magnetic resonance (NMR) spectroscopy were employed for characterization of the polysaccharides. DLHP was found to have a major component with a weight-average molecular weight of 1.17 × 10⁵ Da, mainly comprising of glucose, galactose, arabinose, mannose, rhamnose, glucuronic acid and galacturonic acid. By in vitro antioxidant activity assays, DLHP presented remarkable scavenging capacities towards 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and hydroxyl radicals, and ferrous ions chelating ability. Moreover, it exhibited appreciable anti-hyperglycemic activity as demonstrated by differential inhibition of α-glucosidase and α-amylase. The results indicated that DLHP could potentially be a resource for antioxidant and hypoglycemic agents. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessArticle

Functional and Biochemical Characterization of Three Recombinant Human Glucose-6-Phosphate Dehydrogenase Mutants: Zacatecas, Vanua-Lava and Viangchan

by Saúl Gómez-Manzo, Jaime Marcial-Quino, America Vanoye-Carlo, Hugo Serrano-Posada, Abigail González-Valdez, Víctor Martínez-Rosas, Beatriz Hernández-Ochoa, Edgar Sierra-Palacios, Rosa Angélica Castillo-Rodríguez, Miguel Cuevas-Cruz, Eduardo Rodríguez-Bustamante and Roberto Arreguin-Espinosa

Int. J. Mol. Sci. 2016, 17(5), 787; https://doi.org/10.3390/ijms17050787 - 21 May 2016

Cited by 23 | Viewed by 7846

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency in humans causes severe disease, varying from mostly asymptomatic individuals to patients showing neonatal jaundice, acute hemolysis episodes or chronic nonspherocytic hemolytic anemia. In order to understand the effect of the mutations in G6PD gene function and its relation [...] Read more.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency in humans causes severe disease, varying from mostly asymptomatic individuals to patients showing neonatal jaundice, acute hemolysis episodes or chronic nonspherocytic hemolytic anemia. In order to understand the effect of the mutations in G6PD gene function and its relation with G6PD deficiency severity, we report the construction, cloning and expression as well as the detailed kinetic and stability characterization of three purified clinical variants of G6PD that present in the Mexican population: G6PD Zacatecas (Class I), Vanua-Lava (Class II) and Viangchan (Class II). For all the G6PD mutants, we obtained low purification yield and altered kinetic parameters compared with Wild Type (WT). Our results show that the mutations, regardless of the distance from the active site where they are located, affect the catalytic properties and structural parameters and that these changes could be associated with the clinical presentation of the deficiency. Specifically, the structural characterization of the G6PD Zacatecas mutant suggests that the R257L mutation have a strong effect on the global stability of G6PD favoring an unstable active site. Using computational analysis, we offer a molecular explanation of the effects of these mutations on the active site. Full article

(This article belongs to the Collection Computational, Structural and Spectroscopic Studies of Enzyme Mechanisms, Inhibition and Dynamics)

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Open AccessReview

Marine Antimicrobial Peptides: Nature Provides Templates for the Design of Novel Compounds against Pathogenic Bacteria

by Annarita Falanga, Lucia Lombardi, Gianluigi Franci, Mariateresa Vitiello, Maria Rosaria Iovene, Giancarlo Morelli, Massimiliano Galdiero and Stefania Galdiero

Int. J. Mol. Sci. 2016, 17(5), 785; https://doi.org/10.3390/ijms17050785 - 21 May 2016

Cited by 103 | Viewed by 10846

Abstract

The discovery of antibiotics for the treatment of bacterial infections brought the idea that bacteria would no longer endanger human health. However, bacterial diseases still represent a worldwide treat. The ability of microorganisms to develop resistance, together with the indiscriminate use of antibiotics, [...] Read more.

The discovery of antibiotics for the treatment of bacterial infections brought the idea that bacteria would no longer endanger human health. However, bacterial diseases still represent a worldwide treat. The ability of microorganisms to develop resistance, together with the indiscriminate use of antibiotics, is mainly responsible for this situation; thus, resistance has compelled the scientific community to search for novel therapeutics. In this scenario, antimicrobial peptides (AMPs) provide a promising strategy against a wide array of pathogenic microorganisms, being able to act directly as antimicrobial agents but also being important regulators of the innate immune system. This review is an attempt to explore marine AMPs as a rich source of molecules with antimicrobial activity. In fact, the sea is poorly explored in terms of AMPs, but it represents a resource with plentiful antibacterial agents performing their role in a harsh environment. For the application of AMPs in the medical field limitations correlated to their peptide nature, their inactivation by environmental pH, presence of salts, proteases, or other components have to be solved. Thus, these peptides may act as templates for the design of more potent and less toxic compounds. Full article

(This article belongs to the Special Issue Drug Delivery and Antimicrobial Agents)

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Open AccessArticle

Novel Zinc(II) Complexes [Zn(atc-Et)₂] and [Zn(atc-Ph)₂]: In Vitro and in Vivo Antiproliferative Studies

by Erica De O. Lopes, Carolina G. de Oliveira, Patricia B. da Silva, Carlos E. Eismann, Carlos A. Suárez, Amauri A. Menegário, Clarice Q. F. Leite, Victor M. Deflon and Fernando R. Pavan

Int. J. Mol. Sci. 2016, 17(5), 781; https://doi.org/10.3390/ijms17050781 - 21 May 2016

Cited by 22 | Viewed by 6370

Abstract

Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn^II) thiosemicarbazone complexes [Zn(atc-Et)₂] (1) and [Zn(atc-Ph)₂] (2 [...] Read more.

Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn^II) thiosemicarbazone complexes [Zn(atc-Et)₂] (1) and [Zn(atc-Ph)₂] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Open AccessArticle

An Eco-Friendly Ultrasound-Assisted Synthesis of Novel Fluorinated Pyridinium Salts-Based Hydrazones and Antimicrobial and Antitumor Screening

by Nadjet Rezki, Salsabeel A. Al-Sodies, Mohamed R. Aouad, Sanaa Bardaweel, Mouslim Messali and El Sayed H. El Ashry

Int. J. Mol. Sci. 2016, 17(5), 766; https://doi.org/10.3390/ijms17050766 - 21 May 2016

Cited by 28 | Viewed by 5961

Abstract

The present work reports an efficient synthesis of fluorinated pyridinium salts-based hydrazones under both conventional and eco-friendly ultrasound procedures. The synthetic approach first involves the preparation of halogenated pyridinium salts through the condensation of isonicotinic acid hydrazide (1) with p-fluorobenzaldehyde [...] Read more.

The present work reports an efficient synthesis of fluorinated pyridinium salts-based hydrazones under both conventional and eco-friendly ultrasound procedures. The synthetic approach first involves the preparation of halogenated pyridinium salts through the condensation of isonicotinic acid hydrazide (1) with p-fluorobenzaldehyde (2) followed by the nucleophilic alkylation of the resulting N-(4-fluorobenzylidene)isonicotinohydrazide (3) with a different alkyl iodide. The iodide counteranion of 5–10 was subjected to an anion exchange metathesis reaction in the presence of an excess of the appropriate metal salts to afford a new series of fluorinated pyridinium salts tethering a hydrazone linkage 11–40. Ultrasound irradiation led to higher yields in considerably less time than the conventional methods. The newly synthesized ILs were well-characterized with FT-IR, ¹H NMR, ¹³C NMR, ¹¹B, ¹⁹F, ³¹P and mass spectral analyses. The ILs were also screened for their antimicrobial and antitumor activities. Within the series, the salts tethering fluorinated counter anions 11–13, 21–23, 31–33 and 36–38 were found to be more potent against all bacterial and fungal strains at MIC 4–8 µg/mL. The in vitro antiproliferative activity was also investigated against four tumor cell lines (human ductal breast epithelial tumor T47D, human breast adenocarcinoma MCF-7, human epithelial carcinoma HeLa and human epithelial colorectal adenocarcinoma Caco-2) using the MTT assay, which revealed that promising antitumor activity was exhibited by compounds 5, 12 and 14. Full article

(This article belongs to the Special Issue Ionic Liquids 2016 and Selected Papers from ILMAT III)

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Open AccessArticle

Expression Patterns and Functional Novelty of Ribonuclease 1 in Herbivorous Megalobrama amblycephala

by Han Liu and Weimin Wang

Int. J. Mol. Sci. 2016, 17(5), 786; https://doi.org/10.3390/ijms17050786 - 20 May 2016

Cited by 5 | Viewed by 5263

Abstract

Ribonuclease 1 (RNase1) is an important digestive enzyme that has been used to study the molecular evolutionary and plant-feeding adaptation of mammals. However, the expression patterns and potential biological function of RNase1 in herbivorous fish is not known. Here, we identified RNase1 from [...] Read more.

Ribonuclease 1 (RNase1) is an important digestive enzyme that has been used to study the molecular evolutionary and plant-feeding adaptation of mammals. However, the expression patterns and potential biological function of RNase1 in herbivorous fish is not known. Here, we identified RNase1 from five fish species and illuminated the functional diversification and expression of RNase1 in herbivorous Megalobrama amblycephala. The five identified fish RNase1 genes all have the signature motifs of the RNase A superfamily. No expression of Ma-RNase1 was detected in early developmental stages but a weak expression was detected at 120 and 144 hours post-fertilization (hpf). Ma-RNase1 was only expressed in the liver and heart of one-year-old fish but strongly expressed in the liver, spleen, gut, kidney and testis of two-year-old fish. Moreover, the immunostaining localized RNase1 production to multiple tissues of two-year-old fish. A biological functional analysis of the recombinant protein demonstrated that M. amblycephala RNase1 had a relatively strong ribonuclease activity at its optimal pH 6.1, which is consistent with the pH of its intestinal microenvironment. Collectively, these results clearly show that Ma-RNase1 protein has ribonuclease activity and the expression patterns of Ma-RNase1 are dramatically different in one year and two-year-old fish, suggesting the functional differentiation during fish growing. Full article

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

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Open AccessArticle

Impact of Faba Bean-Seed Rhizobial Inoculation on Microbial Activity in the Rhizosphere Soil during Growing Season

by Anna Siczek and Jerzy Lipiec

Int. J. Mol. Sci. 2016, 17(5), 784; https://doi.org/10.3390/ijms17050784 - 20 May 2016

Cited by 28 | Viewed by 6819

Abstract

Inoculation of legume seeds with Rhizobium affects soil microbial community and processes, especially in the rhizosphere. This study aimed at assessing the effect of Rhizobium inoculation on microbial activity in the faba bean rhizosphere during the growing season in a field experiment on [...] Read more.

Inoculation of legume seeds with Rhizobium affects soil microbial community and processes, especially in the rhizosphere. This study aimed at assessing the effect of Rhizobium inoculation on microbial activity in the faba bean rhizosphere during the growing season in a field experiment on a Haplic Luvisol derived from loess. Faba bean (Vicia faba L.) seeds were non-inoculated (NI) or inoculated (I) with Rhizobium leguminosarum bv. viciae and sown. The rhizosphere soil was analyzed for the enzymatic activities of dehydrogenases, urease, protease and acid phosphomonoesterase, and functional diversity (catabolic potential) using the Average Well Color Development, Shannon-Weaver, and Richness indices following the community level physiological profiling from Biolog EcoPlate™. The analyses were done on three occasions corresponding to the growth stages of: 5–6 leaf, flowering, and pod formation. The enzymatic activities were higher in I than NI (p < 0.05) throughout the growing season. However, none of the functional diversity indices differed significantly under both treatments, regardless of the growth stage. This work showed that the functional diversity of the microbial communities was a less sensitive tool than enzyme activities in assessment of rhizobial inoculation effects on rhizosphere microbial activity. Full article

(This article belongs to the Special Issue Molecular Signals in Nodulation Control)

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Open AccessArticle

Quantitative Metabolomic Analysis of Urinary Citrulline and Calcitroic Acid in Mice after Exposure to Various Types of Ionizing Radiation

by Maryam Goudarzi, Siddheshwar Chauthe, Steven J. Strawn, Waylon M. Weber, David J. Brenner and Albert J. Fornace

Int. J. Mol. Sci. 2016, 17(5), 782; https://doi.org/10.3390/ijms17050782 - 20 May 2016

Cited by 12 | Viewed by 6093

Abstract

With the safety of existing nuclear power plants being brought into question after the Fukushima disaster and the increased level of concern over terrorism-sponsored use of improvised nuclear devices, it is more crucial to develop well-defined radiation injury markers in easily accessible biofluids [...] Read more.

With the safety of existing nuclear power plants being brought into question after the Fukushima disaster and the increased level of concern over terrorism-sponsored use of improvised nuclear devices, it is more crucial to develop well-defined radiation injury markers in easily accessible biofluids to help emergency-responders with injury assessment during patient triage. Here, we focused on utilizing ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to identify and quantitate the unique changes in the urinary excretion of two metabolite markers, calcitroic acid and citrulline, in mice induced by different forms of irradiation; X-ray irradiation at a low dose rate (LDR) of 3.0 mGy/min and a high dose rate (HDR) of 1.1 Gy/min, and internal exposure to Cesium-137 (¹³⁷Cs) and Strontium-90 (⁹⁰Sr). The multiple reaction monitoring analysis showed that, while exposure to ¹³⁷Cs and ⁹⁰Sr induced a statistically significant and persistent decrease, similar doses of X-ray beam at the HDR had the opposite effect, and the LDR had no effect on the urinary levels of these two metabolites. This suggests that the source of exposure and the dose rate strongly modulate the in vivo metabolomic injury responses, which may have utility in clinical biodosimetry assays for the assessment of exposure in an affected population. This study complements our previous investigations into the metabolomic profile of urine from mice internally exposed to ⁹⁰Sr and ¹³⁷Cs and to X-ray beam radiation. Full article

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

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Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules

by Annayya Aroor, Marcin Zuberek, Cornel Duta, Alex Meuth, James R. Sowers, Adam Whaley-Connell and Ravi Nistala

Int. J. Mol. Sci. 2016, 17(5), 780; https://doi.org/10.3390/ijms17050780 - 20 May 2016

Cited by 32 | Viewed by 6365

Abstract

Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is [...] Read more.

Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT₁R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10⁻⁸ M) treatment of T35OK-AT₁R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT₁R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression. Full article

(This article belongs to the Special Issue Advances in Chronic Kidney Disease)

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Open AccessEditorial

International Journal of Molecular Sciences 2016 Best Paper Award

by International Journal of Molecular Sciences Editorial Office

Int. J. Mol. Sci. 2016, 17(5), 777; https://doi.org/10.3390/ijms17050777 - 20 May 2016

Cited by 7 | Viewed by 8597

Abstract

The Editors of the International Journal of Molecular Sciences have established the Best Paper Award to recognize the most outstanding articles published in the areas of molecular biology, molecular physics and chemistry that have been published in the International Journal of Molecular Sciences.[...] [...] Read more.

The Editors of the International Journal of Molecular Sciences have established the Best Paper Award to recognize the most outstanding articles published in the areas of molecular biology, molecular physics and chemistry that have been published in the International Journal of Molecular Sciences.[...] Full article

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Open AccessArticle

Integrated Analysis of Expression Profile Based on Differentially Expressed Genes in Middle Cerebral Artery Occlusion Animal Models

by Huaqiang Zhou, Zeting Qiu, Shaowei Gao, Qinchang Chen, Si Li, Wulin Tan, Xiaochen Liu and Zhongxing Wang

Int. J. Mol. Sci. 2016, 17(5), 776; https://doi.org/10.3390/ijms17050776 - 20 May 2016

Cited by 12 | Viewed by 6635

Abstract

Stroke is one of the most common causes of death, only second to heart disease. Molecular investigations about stroke are in acute shortage nowadays. This study is intended to explore a gene expression profile after brain ischemia reperfusion. Meta-analysis, differential expression analysis, and [...] Read more.

Stroke is one of the most common causes of death, only second to heart disease. Molecular investigations about stroke are in acute shortage nowadays. This study is intended to explore a gene expression profile after brain ischemia reperfusion. Meta-analysis, differential expression analysis, and integrated analysis were employed on an eight microarray series. We explored the functions and pathways of target genes in gene ontology (GO) enrichment analysis and constructed a protein-protein interaction network. Meta-analysis identified 360 differentially expressed genes (DEGs) for Mus musculus and 255 for Rattus norvegicus. Differential expression analysis identified 44 DEGs for Mus musculus and 21 for Rattus norvegicus. Timp1 and Lcn2 were overexpressed in both species. The cytokine-cytokine receptor interaction and chemokine signaling pathway were highly enriched for the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. We have exhibited a global view of the potential molecular differences between middle cerebral artery occlusion (MCAO) animal model and sham for Mus musculus or Rattus norvegicus, including the biological process and enriched pathways in DEGs. This research helps contribute to a clearer understanding of the inflammation process and accurate identification of ischemic infarction stages, which might be transformed into a therapeutic approach. Full article

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

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Open AccessReview

The Natural Course of Non-Alcoholic Fatty Liver Disease

by Luis Calzadilla Bertot and Leon Anton Adams

Int. J. Mol. Sci. 2016, 17(5), 774; https://doi.org/10.3390/ijms17050774 - 20 May 2016

Cited by 465 | Viewed by 22111

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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Open AccessArticle

Polymeric Nanoparticle-Based Photodynamic Therapy for Chronic Periodontitis in Vivo

by Laura Marise De Freitas, Giovana Maria Fioramonti Calixto, Marlus Chorilli, Juçaíra Stella M. Giusti, Vanderlei Salvador Bagnato, Nikolaos S. Soukos, Mansoor M. Amiji and Carla Raquel Fontana

Int. J. Mol. Sci. 2016, 17(5), 769; https://doi.org/10.3390/ijms17050769 - 20 May 2016

Cited by 84 | Viewed by 10346

Abstract

Antimicrobial photodynamic therapy (aPDT) is increasingly being explored for treatment of periodontitis. Here, we investigated the effect of aPDT on human dental plaque bacteria in suspensions and biofilms in vitro using methylene blue (MB)-loaded poly(lactic-co-glycolic) (PLGA) nanoparticles (MB-NP) and red light [...] Read more.

Antimicrobial photodynamic therapy (aPDT) is increasingly being explored for treatment of periodontitis. Here, we investigated the effect of aPDT on human dental plaque bacteria in suspensions and biofilms in vitro using methylene blue (MB)-loaded poly(lactic-co-glycolic) (PLGA) nanoparticles (MB-NP) and red light at 660 nm. The effect of MB-NP-based aPDT was also evaluated in a clinical pilot study with 10 adult human subjects with chronic periodontitis. Dental plaque samples from human subjects were exposed to aPDT—in planktonic and biofilm phases—with MB or MB-NP (25 µg/mL) at 20 J/cm² in vitro. Patients were treated either with ultrasonic scaling and scaling and root planing (US + SRP) or ultrasonic scaling + SRP + aPDT with MB-NP (25 µg/mL and 20 J/cm²) in a split-mouth design. In biofilms, MB-NP eliminated approximately 25% more bacteria than free MB. The clinical study demonstrated the safety of aPDT. Both groups showed similar improvements of clinical parameters one month following treatments. However, at three months ultrasonic SRP + aPDT showed a greater effect (28.82%) on gingival bleeding index (GBI) compared to ultrasonic SRP. The utilization of PLGA nanoparticles encapsulated with MB may be a promising adjunct in antimicrobial periodontal treatment. Full article

(This article belongs to the Special Issue Drug Delivery and Antimicrobial Agents)

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Open AccessRetraction

RETRACTED: Xu, et al. Tanshinone IIA Pretreatment Renders Free Flaps against Hypoxic Injury through Activating Wnt Signaling and Upregulating Stem Cell-Related Biomarkers. Int. J. Mol. Sci. 2014, 15, 18117–18130

by International Journal of Molecular Sciences Editorial Office

Int. J. Mol. Sci. 2016, 17(5), 768; https://doi.org/10.3390/ijms17050768 - 20 May 2016

Cited by 2 | Viewed by 3742

Abstract

We have been made aware that text, ﬁgures and experimental data reported in the title paper [...] Full article

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Open AccessArticle

Development of Therapeutic Chimeric Uricase by Exon Replacement/Restoration and Site-Directed Mutagenesis

by Guangrong Xie, Weizhen Yang, Jing Chen, Miaomiao Li, Nan Jiang, Baixue Zhao, Si Chen, Min Wang and Jianhua Chen

Int. J. Mol. Sci. 2016, 17(5), 764; https://doi.org/10.3390/ijms17050764 - 20 May 2016

Cited by 10 | Viewed by 5928

Abstract

The activity of urate oxidase was lost during hominoid evolution, resulting in high susceptibility to hyperuricemia and gout in humans. In order to develop a more “human-like” uricase for therapeutic use, exon replacement/restoration and site-directed mutagenesis were performed to obtain porcine–human uricase with [...] Read more.

The activity of urate oxidase was lost during hominoid evolution, resulting in high susceptibility to hyperuricemia and gout in humans. In order to develop a more “human-like” uricase for therapeutic use, exon replacement/restoration and site-directed mutagenesis were performed to obtain porcine–human uricase with higher homology to deduced human uricase (dHU) and increased uricolytic activity. In an exon replacement study, substitution of exon 6 in wild porcine uricase (wPU) gene with corresponding exon in dhu totally abolished its activity. Substitutions of exon 5, 3, and 1–2 led to 85%, 60%, and 45% loss of activity, respectively. However, replacement of exon 4 and 7–8 did not significantly change the enzyme activity. When exon 5, 6, and 3 in dhu were replaced by their counterparts in wpu, the resulting chimera H_1-2P₃H₄P_5-6H_7-8 was active, but only about 28% of wPU. Multiple sequence alignment and homology modeling predicted that mutations of E24D and E83G in H_1-2P₃H₄P_5-6H_7-8 were favorable for further increase of its activity. After site-directed mutagenesis, H_1-2P₃H₄P_5-6H_7-8 (E24D & E83G) with increased homology (91.45%) with dHU and higher activity and catalytic efficiency than the FDA-approved porcine–baboon chimera (PBC) was obtained. It showed optimum activity at pH 8.5 and 35 °C and was stable in a pH range of 6.5–11.0 and temperature range of 20–40 °C. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Degree of Conversion and BisGMA, TEGDMA, UDMA Elution from Flowable Bulk Fill Composites

by Edina Lempel, Zsuzsanna Czibulya, Bálint Kovács, József Szalma, Ákos Tóth, Sándor Kunsági-Máté, Zoltán Varga and Katalin Böddi

Int. J. Mol. Sci. 2016, 17(5), 732; https://doi.org/10.3390/ijms17050732 - 20 May 2016

Cited by 72 | Viewed by 8760

Abstract

The degree of conversion (DC) and the released bisphenol A diglycidyl ether dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA) and urethane dimethacrylate (UDMA) monomers of bulk-fill composites compared to that of conventional flowable ones were assessed using micro-Raman spectroscopy and high performance liquid chromatography [...] Read more.

The degree of conversion (DC) and the released bisphenol A diglycidyl ether dimethacrylate (BisGMA), triethylene glycol dimethacrylate (TEGDMA) and urethane dimethacrylate (UDMA) monomers of bulk-fill composites compared to that of conventional flowable ones were assessed using micro-Raman spectroscopy and high performance liquid chromatography (HPLC). Four millimeter-thick samples were prepared from SureFil SDR Flow (SDR), X-tra Base (XB), Filtek Bulk Fill (FBF) and two and four millimeter samples from Filtek Ultimate Flow (FUF). They were measured with micro-Raman spectroscopy to determine the DC% of the top and the bottom surfaces. The amount of released monomers in 75% ethanol extraction media was measured with HPLC. The differences between the top and bottom DC% were significant for each material. The mean DC values were in the following order for the bottom surfaces: SDR_4mm_20s > FUF_2mm_20s > XB_4mm_20s > FBF_4mm_20s > XB_4mm_10s > FBF_4mm_10s > FUF_4mm_20s. The highest rate in the amount of released BisGMA and TEGDMA was found from the 4 mm-thick conventional flowable FUF. Among bulk-fills, FBF showed a twenty times higher amount of eluted UDMA and twice more BisGMA; meanwhile, SDR released a significantly higher amount of TEGDMA. SDR bulk-fill showed significantly higher DC%; meanwhile XB, FBF did not reach the same level DC, as that of the 2 mm-thick conventional composite at the bottom surface. Conventional flowable composites showed a higher rate of monomer elution compared to the bulk-fills, except FBF, which showed a high amount of UDMA release. Full article

(This article belongs to the Special Issue Molecular Research on Dental Materials and Biomaterials)

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Open AccessArticle

Ruthenium Complexes Induce HepG2 Human Hepatocellular Carcinoma Cell Apoptosis and Inhibit Cell Migration and Invasion through Regulation of the Nrf2 Pathway

by Yiyu Lu, Ting Shen, Hua Yang and Weiguang Gu

Int. J. Mol. Sci. 2016, 17(5), 775; https://doi.org/10.3390/ijms17050775 - 19 May 2016

Cited by 34 | Viewed by 7055

Abstract

Ruthenium (Ru) complexes are currently the focus of substantial interest because of their potential application as chemotherapeutic agents with broad anticancer activities. This study investigated the in vitro and in vivo anticancer activities and mechanisms of two Ru complexes—2,3,7,8,12,13,17,18-Octaethyl-21H,23H-porphine Ru(II) carbonyl (Ru1) and [...] Read more.

Ruthenium (Ru) complexes are currently the focus of substantial interest because of their potential application as chemotherapeutic agents with broad anticancer activities. This study investigated the in vitro and in vivo anticancer activities and mechanisms of two Ru complexes—2,3,7,8,12,13,17,18-Octaethyl-21H,23H-porphine Ru(II) carbonyl (Ru1) and 5,10,15,20-Tetraphenyl-21H,23H-porphine Ru(II) carbonyl (Ru2)—against human hepatocellular carcinoma (HCC) cells. These Ru complexes effectively inhibited the cellular growth of three human hepatocellular carcinoma (HCC) cells, with IC₅₀ values ranging from 2.7–7.3 μM. In contrast, the complexes exhibited lower toxicity towards L02 human liver normal cells with IC₅₀ values of 20.4 and 24.8 μM, respectively. Moreover, Ru2 significantly inhibited HepG2 cell migration and invasion, and these effects were dose-dependent. The mechanistic studies demonstrated that Ru2 induced HCC cell apoptosis, as evidenced by DNA fragmentation and nuclear condensation, which was predominately triggered via caspase family member activation. Furthermore, HCC cell treatment significantly decreased the expression levels of Nrf2 and its downstream effectors, NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1). Ru2 also exhibited potent in vivo anticancer efficacy in a tumor-bearing nude mouse model, as demonstrated by a time- and dose-dependent inhibition on tumor growth. The results demonstrate the therapeutic potential of Ru complexes against HCC via Nrf2 pathway regulation. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Open AccessArticle

Predicting MicroRNA Biomarkers for Cancer Using Phylogenetic Tree and Microarray Analysis

by Hsiuying Wang

Int. J. Mol. Sci. 2016, 17(5), 773; https://doi.org/10.3390/ijms17050773 - 19 May 2016

Cited by 26 | Viewed by 7932

Abstract

MicroRNAs (miRNAs) are shown to be involved in the initiation and progression of cancers in the literature, and the expression of miRNAs is used as an important cancer prognostic tool. The aim of this study is to predict high-confidence miRNA biomarkers for cancer. [...] Read more.

MicroRNAs (miRNAs) are shown to be involved in the initiation and progression of cancers in the literature, and the expression of miRNAs is used as an important cancer prognostic tool. The aim of this study is to predict high-confidence miRNA biomarkers for cancer. We adopt a method that combines miRNA phylogenetic structure and miRNA microarray data analysis to discover high-confidence miRNA biomarkers for colon, prostate, pancreatic, lung, breast, bladder and kidney cancers. There are 53 miRNAs selected through this method that either have potential to involve a single cancer’s development or to involve several cancers’ development. These miRNAs can be used as high-confidence miRNA biomarkers of these seven investigated cancers for further experiment validation. miR-17, miR-20, miR-106a, miR-106b, miR-92, miR-25, miR-16, miR-195 and miR-143 are selected to involve a single cancer’s development in these seven cancers. They have the potential to be useful miRNA biomarkers when the result can be confirmed by experiments. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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Open AccessArticle

A Study of Single Nucleotide Polymorphisms of the SLC19A1/RFC1 Gene in Subjects with Autism Spectrum Disorder

by Naila Al Mahmuda, Shigeru Yokoyama, Jian-Jun Huang, Li Liu, Toshio Munesue, Hideo Nakatani, Kenshi Hayashi, Kunimasa Yagi, Masakazu Yamagishi and Haruhiro Higashida

Int. J. Mol. Sci. 2016, 17(5), 772; https://doi.org/10.3390/ijms17050772 - 19 May 2016

Cited by 12 | Viewed by 6195

Abstract

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate–methionine cycle may play a key role in the etiology of [...] Read more.

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate–methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16–0.91, p = 0.0394; Fisher’s exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study. Full article

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

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Open AccessArticle

Downregulation of Runx2 by 1,25-Dihydroxyvitamin D₃ Induces the Transdifferentiation of Osteoblasts to Adipocytes

by Jung Ha Kim, Semun Seong, Kabsun Kim, Inyoung Kim, Byung-Chul Jeong and Nacksung Kim

Int. J. Mol. Sci. 2016, 17(5), 770; https://doi.org/10.3390/ijms17050770 - 19 May 2016

Cited by 14 | Viewed by 6678

Abstract

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) indirectly stimulates bone formation, but little is known about its direct effect on bone formation. In this study, we observed that 1,25(OH)₂D₃ enhances adipocyte differentiation, but inhibits osteoblast differentiation during osteogenesis. The [...] Read more.

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) indirectly stimulates bone formation, but little is known about its direct effect on bone formation. In this study, we observed that 1,25(OH)₂D₃ enhances adipocyte differentiation, but inhibits osteoblast differentiation during osteogenesis. The positive role of 1,25(OH)₂D₃ in adipocyte differentiation was confirmed when murine osteoblasts were cultured in adipogenic medium. Additionally, 1,25(OH)₂D₃ enhanced the expression of adipocyte marker genes, but inhibited the expression of osteoblast marker genes in osteoblasts. The inhibition of osteoblast differentiation and promotion of adipocyte differentiation mediated by 1,25(OH)₂D₃ were compensated by Runx2 overexpression. Our results suggest that 1,25(OH)₂D₃ induces the transdifferentiation of osteoblasts to adipocytes via Runx2 downregulation in osteoblasts. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

How Diet Intervention via Modulation of DNA Damage Response through MicroRNAs May Have an Effect on Cancer Prevention and Aging, an in Silico Study

by Felicia Carotenuto, Maria C. Albertini, Dario Coletti, Alessandra Vilmercati, Luigi Campanella, Zbigniew Darzynkiewicz and Laura Teodori

Int. J. Mol. Sci. 2016, 17(5), 752; https://doi.org/10.3390/ijms17050752 - 19 May 2016

Cited by 18 | Viewed by 6580

Abstract

The DNA damage response (DDR) is a molecular mechanism that cells have evolved to sense DNA damage (DD) to promote DNA repair, or to lead to apoptosis, or cellular senescence if the damage is too extensive. Recent evidence indicates that microRNAs (miRs) play [...] Read more.

The DNA damage response (DDR) is a molecular mechanism that cells have evolved to sense DNA damage (DD) to promote DNA repair, or to lead to apoptosis, or cellular senescence if the damage is too extensive. Recent evidence indicates that microRNAs (miRs) play a critical role in the regulation of DDR. Dietary bioactive compounds through miRs may affect activity of numerous genes. Among the most studied bioactive compounds modulating expression of miRs are epi-gallocatechin-3-gallate, curcumin, resveratrol and n3-polyunsaturated fatty acids. To compare the impact of these dietary compounds on DD/DDR network modulation, we performed a literature search and an in silico analysis by the DIANA-mirPathv3 software. The in silico analysis allowed us to identify pathways shared by different miRs involved in DD/DDR vis-à-vis the specific compounds. The results demonstrate that certain miRs (e.g., -146, -21) play a central role in the interplay among DD/DDR and the bioactive compounds. Furthermore, some specific pathways, such as “fatty acids biosynthesis/metabolism”, “extracellular matrix-receptor interaction” and “signaling regulating the pluripotency of stem cells”, appear to be targeted by most miRs affected by the studied compounds. Since DD/DDR and these pathways are strongly related to aging and carcinogenesis, the present in silico results of our study suggest that monitoring the induction of specific miRs may provide the means to assess the antiaging and chemopreventive properties of particular dietary compounds. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)

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