International Journal of Molecular Sciences

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Open AccessArticle

Exploring the Role of Different Neonatal Nutrition Regimens during the First Week of Life by Urinary GC-MS Metabolomics

by Angelica Dessì, Antonio Murgia, Rocco Agostino, Maria Grazia Pattumelli, Andrea Schirru, Paola Scano, Vassilios Fanos and Pierluigi Caboni

Int. J. Mol. Sci. 2016, 17(2), 265; https://doi.org/10.3390/ijms17020265 - 22 Feb 2016

Cited by 45 | Viewed by 6888

Abstract

In this study, a gas-chromatography mass spectrometry (GC-MS) metabolomics study was applied to examine urine metabolite profiles of different classes of neonates under different nutrition regimens. The study population included 35 neonates, exclusively either breastfed or formula milk fed, in a seven-day timeframe. [...] Read more.

In this study, a gas-chromatography mass spectrometry (GC-MS) metabolomics study was applied to examine urine metabolite profiles of different classes of neonates under different nutrition regimens. The study population included 35 neonates, exclusively either breastfed or formula milk fed, in a seven-day timeframe. Urine samples were collected from intrauterine growth restriction (IUGR), large for gestational age (LGA), and appropriate gestational age (AGA) neonates. At birth, IUGR and LGA neonates showed similarities in their urine metabolite profiles that differed from AGA. When neonates started milk feeding, their metabolite excretion profile was strongly characterized by the different diet regimens. After three days of formula milk nutrition, urine had higher levels of glucose, galactose, glycine and myo-inositol, while up-regulated aconitic acid, aminomalonic acid and adipic acid were found in breast milk fed neonates. At seven days, neonates fed with formula milk shared higher levels of pseudouridine with IUGR and LGA at birth. Breastfed neonates shared up-regulated pyroglutamic acid, citric acid, and homoserine, with AGA at birth. The role of most important metabolites is herein discussed. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Benzyl Isothiocyanate Inhibits Prostate Cancer Development in the Transgenic Adenocarcinoma Mouse Prostate (TRAMP) Model, Which Is Associated with the Induction of Cell Cycle G1 Arrest

by Han Jin Cho, Do Young Lim, Gyoo Taik Kwon, Ji Hee Kim, Zunnan Huang, Hyerim Song, Yoon Sin Oh, Young-Hee Kang, Ki Won Lee, Zigang Dong and Jung Han Yoon Park

Int. J. Mol. Sci. 2016, 17(2), 264; https://doi.org/10.3390/ijms17020264 - 22 Feb 2016

Cited by 22 | Viewed by 7235

Abstract

Benzyl isothiocyanate (BITC) is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables, and has been shown to have anti-tumor properties. In the present study, we investigated whether BITC inhibits the development of prostate cancer in the transgenic adenocarcinoma mouse prostate [...] Read more.

Benzyl isothiocyanate (BITC) is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables, and has been shown to have anti-tumor properties. In the present study, we investigated whether BITC inhibits the development of prostate cancer in the transgenic adenocarcinoma mouse prostate (TRAMP) mice. Five-week old, male TRAMP mice and their nontransgenic littermates were gavage-fed with 0, 5, or 10 mg/kg of BITC every day for 19 weeks. The weight of the genitourinary tract increased markedly in TRAMP mice and this increase was suppressed significantly by BITC feeding. H and E staining of the dorsolateral lobes of the prostate demonstrated that well-differentiated carcinoma (WDC) was a predominant feature in the TRAMP mice. The number of lobes with WDC was reduced by BITC feeding while that of lobes with prostatic intraepithelial neoplasia was increased. BITC feeding reduced the number of cells expressing Ki67 (a proliferation marker), cyclin A, cyclin D1, and cyclin-dependent kinase (CDK)2 in the prostatic tissue. In vitro cell culture results revealed that BITC decreased DNA synthesis, as well as CDK2 and CDK4 activity in TRAMP-C2 mouse prostate cancer cells. These results indicate that inhibition of cell cycle progression contributes to the inhibition of prostate cancer development in TRAMP mice treated with BITC. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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Open AccessReview

Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease

by Ana Dinca, Wei-Ming Chien and Michael T. Chin

Int. J. Mol. Sci. 2016, 17(2), 263; https://doi.org/10.3390/ijms17020263 - 22 Feb 2016

Cited by 124 | Viewed by 9880

Abstract

Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the [...] Read more.

Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa). Recombinant proteins that include a CPP tag to promote intracellular delivery show promise as therapeutic agents with encouraging success rates in both animal and human trials. This review highlights recent advances in protein-CPP therapy and discusses optimization strategies and potential detrimental effects. Full article

(This article belongs to the Special Issue Cell-Penetrating Peptides)

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Open AccessArticle

Identification and Evolution of Functional Alleles of the Previously Described Pollen Specific Myrosinase Pseudogene AtTGG6 in Arabidopsis thaliana

by Lili Fu, Bingying Han, Deguan Tan, Meng Wang, Mei Ding and Jiaming Zhang

Int. J. Mol. Sci. 2016, 17(2), 262; https://doi.org/10.3390/ijms17020262 - 22 Feb 2016

Cited by 6 | Viewed by 5159

Abstract

Myrosinases are β-thioglucoside glucohydrolases and serve as defense mechanisms against insect pests and pathogens by producing toxic compounds. AtTGG6 in Arabidopsis thaliana was previously reported to be a myrosinase pseudogene but specifically expressed in pollen. However, we found that AlTGG6, an ortholog [...] Read more.

Myrosinases are β-thioglucoside glucohydrolases and serve as defense mechanisms against insect pests and pathogens by producing toxic compounds. AtTGG6 in Arabidopsis thaliana was previously reported to be a myrosinase pseudogene but specifically expressed in pollen. However, we found that AlTGG6, an ortholog to AtTGG6 in A. lyrata (an outcrossing relative of A. thaliana) was functional, suggesting that functional AtTGG6 alleles may still exist in A. thaliana. AtTGG6 alleles in 29 A. thaliana ecotypes were cloned and sequenced. Results indicate that ten alleles were functional and encoded Myr II type myrosinase of 512 amino acids, and myrosinase activity was confirmed by overexpressing AtTGG6 in Pichia pastoris. However, the 19 other ecotypes had disabled alleles with highly polymorphic frame-shift mutations and diversified sequences. Thirteen frame-shift mutation types were identified, which occurred independently many times in the evolutionary history within a few thousand years. The functional allele was expressed specifically in pollen similar to the disabled alleles but at a higher expression level, suggesting its role in defense of pollen against insect pests such as pollen beetles. However, the defense function may have become less critical after A. thaliana evolved to self-fertilization, and thus resulted in loss of function in most ecotypes. Full article

(This article belongs to the Special Issue Gene–Environment Interactions)

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Open AccessArticle

Cloning and Characterization of a Flavonoid 3′-Hydroxylase Gene from Tea Plant (Camellia sinensis)

by Tian-Shan Zhou, Rui Zhou, You-Ben Yu, Yao Xiao, Dong-Hua Li, Bin Xiao, Oliver Yu and Ya-Jun Yang

Int. J. Mol. Sci. 2016, 17(2), 261; https://doi.org/10.3390/ijms17020261 - 22 Feb 2016

Cited by 40 | Viewed by 8465

Abstract

Tea leaves contain abundant flavan-3-ols, which include dihydroxylated and trihydroxylated catechins. Flavonoid 3′-hydroxylase (F3′H: EC 1.14.13.21) is one of the enzymes in the establishment of the hydroxylation pattern. A gene encoding F3′H, designated as CsF3′H, was isolated from Camellia sinensis [...] Read more.

Tea leaves contain abundant flavan-3-ols, which include dihydroxylated and trihydroxylated catechins. Flavonoid 3′-hydroxylase (F3′H: EC 1.14.13.21) is one of the enzymes in the establishment of the hydroxylation pattern. A gene encoding F3′H, designated as CsF3′H, was isolated from Camellia sinensis with a homology-based cloning technique and deposited in the GenBank (GenBank ID: KT180309). Bioinformatic analysis revealed that CsF3′H was highly homologous with the characterized F3′Hs from other plant species. Four conserved cytochrome P450-featured motifs and three F3′H-specific conserved motifs were discovered in the protein sequence of CsF3′H. Enzymatic analysis of the heterologously expressed CsF3′H in yeast demonstrated that tea F3′H catalyzed the 3′-hydroxylation of naringenin, dihydrokaempferol and kaempferol. Apparent K_m values for these substrates were 17.08, 143.64 and 68.06 μM, and their apparent V_max values were 0.98, 0.19 and 0.44 pM·min⁻¹, respectively. Transcription level of CsF3′H in the new shoots, during tea seed germination was measured, along with that of other key genes for flavonoid biosynthesis using real-time PCR technique. The changes in 3′,4′-flavan-3-ols, 3′,4′,5′-flavan-3-ols and flavan-3-ols, were consistent with the expression level of CsF3′H and other related genes in the leaves. In the study of nitrogen supply for the tea plant growth, our results showed the expression level of CsF3′H and all other tested genes increased in response to nitrogen depletion after 12 days of treatment, in agreement with a corresponding increase in 3′,4′-catechins, 3′,4′,5′-catechins and flavan 3-ols content in the leaves. All these results suggest the importance of CsF3′H in the biosynthesis of 3′,4′-catechins, 3′,4′,5′-catechins and flavan 3-ols in tea leaves. Full article

(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism 2015)

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Open AccessArticle

Chalcone-Induced Apoptosis through Caspase-Dependent Intrinsic Pathways in Human Hepatocellular Carcinoma Cells

by Rodrigo Ramirez-Tagle, Carlos A. Escobar, Valentina Romero, Ignacio Montorfano, Ricardo Armisén, Vincenzo Borgna, Emanuel Jeldes, Luis Pizarro, Felipe Simon and Cesar Echeverria

Int. J. Mol. Sci. 2016, 17(2), 260; https://doi.org/10.3390/ijms17020260 - 22 Feb 2016

Cited by 33 | Viewed by 7119

Abstract

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide. Chemoprevention of HCC can be achieved through the use of natural or synthetic compounds that reverse, suppress or prevent the development of cancer progression. In this study, we investigated the antiproliferative [...] Read more.

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide. Chemoprevention of HCC can be achieved through the use of natural or synthetic compounds that reverse, suppress or prevent the development of cancer progression. In this study, we investigated the antiproliferative effects and the mechanism of action of two compounds, 2,3,4′-trimethoxy-2′-hydroxy-chalcone (CH1) and 3′-bromo-3,4-dimethoxy-chalcone (CH2), over human hepatoma cells (HepG2 and Huh-7) and cultured mouse hepatocytes (HepM). Cytotoxic effects were observed over the HepG2 and Huh-7, and no effects were observed over the HepM. For HepG2 cells, treated separately with each chalcone, typical apoptotic laddering and nuclear condensation were observed. Additionally, the caspases and Bcl-2 family proteins activation by using Western blotting and immunocytochemistry were studied. Caspase-8 was not activated, but caspase-3 and -9 were both activated by chalcones in HepG2 cells. Chalcones also induced reactive oxygen species (ROS) accumulation after 4, 8 and 24 h of treatment in HepG2 cells. These results suggest that apoptosis in HepG2 was induced through: (i) a caspase-dependent intrinsic pathway; and (ii) by alterations in the cellular levels of Bcl-2 family proteins, and also, that the chalcone moiety could be a potent candidate as novel anticancer agents acting on human hepatomas. Full article

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

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Open AccessArticle

Synthetic Human TLR9-LRR11 Peptide Attenuates TLR9 Signaling by Binding to and thus Decreasing Internalization of CpG Oligodeoxynucleotides

by Xichun Pan, Bin Li, Mei Kuang, Xin Liu, Yanyan Cen, Rongxin Qin, Guofu Ding, Jiang Zheng and Hong Zhou

Int. J. Mol. Sci. 2016, 17(2), 242; https://doi.org/10.3390/ijms17020242 - 22 Feb 2016

Cited by 30 | Viewed by 6170

Abstract

Toll-like receptor (TLR) 9 is an endosomal receptor recognizing bacterial DNA/CpG-containing oligodeoxynucleotides (CpG ODN). Blocking CpG ODN/TLR9 activity represents a strategy for therapeutic prevention of immune system overactivation. Herein, we report that a synthetic peptide (SP) representing the leucine-rich repeat 11 subdomain of [...] Read more.

Toll-like receptor (TLR) 9 is an endosomal receptor recognizing bacterial DNA/CpG-containing oligodeoxynucleotides (CpG ODN). Blocking CpG ODN/TLR9 activity represents a strategy for therapeutic prevention of immune system overactivation. Herein, we report that a synthetic peptide (SP) representing the leucine-rich repeat 11 subdomain of the human TLR9 extracellular domain could attenuate CpG ODN/TLR9 activity in RAW264.7 cells by binding to CpG ODN and decreasing its internalization. Our results demonstrate that preincubation with SP specifically inhibited CpG ODN- but not lipopolysaccharide (LPS)- and lipopeptide (PAM3CSK4)-stimulated TNF-α and IL-6 release. Preincubation of SP with CpG ODN dose-dependently decreased TLR9-driven phosphorylation of IκBα and ERK and activation of NF-κB/p65. Moreover, SP dose-dependently decreased FAM-labeled CpG ODN internalization, whereas non-labeled CpG ODN reversed the inhibition. The K_D value of SP-CpG ODN binding was within the micromolar range. Our results demonstrated that SP was a specific inhibitor of CpG ODN/TLR9 activity via binding to CpG ODN, leading to reduced ODN internalization and decreased activation of subsequent pathways within cells. Thus, SP could be used as a potential CpG ODN antagonist to block TLR9 signaling. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Transcriptome-Based Identification of Differently Expressed Genes from Xanthomonas oryzae pv. oryzae Strains Exhibiting Different Virulence in Rice Varieties

by Tae-Hwan Noh, Eun-Sung Song, Hong-Il Kim, Mi-Hyung Kang and Young-Jin Park

Int. J. Mol. Sci. 2016, 17(2), 259; https://doi.org/10.3390/ijms17020259 - 19 Feb 2016

Cited by 6 | Viewed by 6533

Abstract

Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight (BB) in rice (Oryza sativa L.). In this study, we investigated the genome-wide transcription patterns of two Xoo strains (KACC10331 and HB1009), which showed different virulence patterns against eight rice cultivars, including [...] Read more.

Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight (BB) in rice (Oryza sativa L.). In this study, we investigated the genome-wide transcription patterns of two Xoo strains (KACC10331 and HB1009), which showed different virulence patterns against eight rice cultivars, including IRBB21 (carrying Xa21). In total, 743 genes showed a significant change (p-value < 0.001 in t-tests) in their mRNA expression levels in the HB1009 (K3a race) strain compared with the Xoo KACC10331 strain (K1 race). Among them, four remarkably enriched GO terms, DNA binding, transposition, cellular nitrogen compound metabolic process, and cellular macromolecule metabolic process, were identified in the upregulated genes. In addition, the expression of 44 genes was considerably higher (log2 fold changes > 2) in the HB1009 (K3a race) strain than in the Xoo KACC10331 (K1 race) strain. Furthermore, 13 and 12 genes involved in hypersensitive response and pathogenicity (hrp) and two-component regulatory systems (TCSs), respectively, were upregulated in the HB1009 (K3a race) strain compared with the Xoo KACC10331 (K1 race) strain, which we determined using either quantitative real-time PCR analysis or next-generation RNA sequencing. These results will be helpful to improve our understanding of Xoo and to gain a better insight into the Xoo–rice interactions. Full article

(This article belongs to the Special Issue Microbial Genomics and Metabolomics)

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Open AccessArticle

In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

by Jian Li, Nan Zhou, Peiling Cai and Jinku Bao

Int. J. Mol. Sci. 2016, 17(2), 258; https://doi.org/10.3390/ijms17020258 - 19 Feb 2016

Cited by 25 | Viewed by 7104

Abstract

Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed [...] Read more.

Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8) and amber score (−51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development. Full article

(This article belongs to the Special Issue Molecule- and Cell-Targeted Drug Design and Screening and Identification of Natural Product)

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Open AccessArticle

Deletion of Phytochelatin Synthase Modulates the Metal Accumulation Pattern of Cadmium Exposed C. elegans

by Yona J. Essig, Samuel M. Webb and Stephen R. Stürzenbaum

Int. J. Mol. Sci. 2016, 17(2), 257; https://doi.org/10.3390/ijms17020257 - 19 Feb 2016

Cited by 15 | Viewed by 5445

Abstract

Environmental metal pollution is a growing health risk to flora and fauna. It is therefore important to fully elucidate metal detoxification pathways. Phytochelatin synthase (PCS), an enzyme involved in the biosynthesis of phytochelatins (PCs), plays an important role in cadmium detoxification. The PCS [...] Read more.

Environmental metal pollution is a growing health risk to flora and fauna. It is therefore important to fully elucidate metal detoxification pathways. Phytochelatin synthase (PCS), an enzyme involved in the biosynthesis of phytochelatins (PCs), plays an important role in cadmium detoxification. The PCS and PCs are however not restricted to plants, but are also present in some lower metazoans. The model nematode Caenorhabditis elegans, for example, contains a fully functional phytochelatin synthase and phytochelatin pathway. By means of a transgenic nematode strain expressing a pcs-1 promoter-tagged GFP (pcs-1::GFP) and a pcs-1 specific qPCR assay, further evidence is presented that the expression of the C. elegans phytochelatin synthase gene (pcs-1) is transcriptionally non-responsive to a chronic (48 h) insult of high levels of zinc (500 μM) or acute (3 h) exposures to high levels of cadmium (300 μM). However, the accumulation of cadmium, but not zinc, is dependent on the pcs-1 status of the nematode. Synchrotron based X-ray fluorescence imaging uncovered that the cadmium body burden increased significantly in the pcs-1(tm1748) knockout allele. Taken together, this suggests that whilst the transcription of pcs-1 may not be mediated by an exposure zinc or cadmium, it is nevertheless an integral part of the cadmium detoxification pathway in C. elegans. Full article

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

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Open AccessReview

Recent Advances in Disease Modeling and Drug Discovery for Diabetes Mellitus Using Induced Pluripotent Stem Cells

by Mohammed Kawser Hossain, Ahmed Abdal Dayem, Jihae Han, Subbroto Kumar Saha, Gwang-Mo Yang, Hye Yeon Choi and Ssang-Goo Cho

Int. J. Mol. Sci. 2016, 17(2), 256; https://doi.org/10.3390/ijms17020256 - 19 Feb 2016

Cited by 27 | Viewed by 10061

Abstract

Diabetes mellitus (DM) is a widespread metabolic disease with a progressive incidence of morbidity and mortality worldwide. Despite extensive research, treatment options for diabetic patients remains limited. Although significant challenges remain, induced pluripotent stem cells (iPSCs) have the capacity to differentiate into any [...] Read more.

Diabetes mellitus (DM) is a widespread metabolic disease with a progressive incidence of morbidity and mortality worldwide. Despite extensive research, treatment options for diabetic patients remains limited. Although significant challenges remain, induced pluripotent stem cells (iPSCs) have the capacity to differentiate into any cell type, including insulin-secreting pancreatic β cells, highlighting its potential as a treatment option for DM. Several iPSC lines have recently been derived from both diabetic and healthy donors. Using different reprogramming techniques, iPSCs were differentiated into insulin-secreting pancreatic βcells. Furthermore, diabetes patient-derived iPSCs (DiPSCs) are increasingly being used as a platform to perform cell-based drug screening in order to develop DiPSC-based cell therapies against DM. Toxicity and teratogenicity assays based on iPSC-derived cells can also provide additional information on safety before advancing drugs to clinical trials. In this review, we summarize recent advances in the development of techniques for differentiation of iPSCs or DiPSCs into insulin-secreting pancreatic β cells, their applications in drug screening, and their role in complementing and replacing animal testing in clinical use. Advances in iPSC technologies will provide new knowledge needed to develop patient-specific iPSC-based diabetic therapies. Full article

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

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Open AccessArticle

Prenylated Flavonoids from Cudrania tricuspidata Suppress Lipopolysaccharide-Induced Neuroinflammatory Activities in BV2 Microglial Cells

by Dong-Cheol Kim, Chi-Su Yoon, Tran Hong Quang, Wonmin Ko, Jong-Su Kim, Hyuncheol Oh and Youn-Chul Kim

Int. J. Mol. Sci. 2016, 17(2), 255; https://doi.org/10.3390/ijms17020255 - 19 Feb 2016

Cited by 29 | Viewed by 6535

Abstract

In Korea and China, Cudrania tricuspidata Bureau (Moraceae) is an important traditional medicinal plant used to treat lumbago, hemoptysis, and contusions. The C. tricuspidata methanol extract suppressed both production of NO and PGE₂ in BV2 microglial cells. Cudraflavanone D (1), isolated from [...] Read more.

In Korea and China, Cudrania tricuspidata Bureau (Moraceae) is an important traditional medicinal plant used to treat lumbago, hemoptysis, and contusions. The C. tricuspidata methanol extract suppressed both production of NO and PGE₂ in BV2 microglial cells. Cudraflavanone D (1), isolated from this extract, remarkably suppressed the protein expression of inducible NO synthase and cyclooxygenase-2, and decreased the levels of NO and PGE₂ in BV2 microglial cells exposed to lipopolysaccharide. Cudraflavanone D (1) also decreased IL-6, TNF-α, IL-12, and IL-1β production, blocked nuclear translocation of NF-κB heterodimers (p50 and p65) by interrupting the degradation and phosphorylation of inhibitor of IκB-α, and inhibited NF-κB binding. In addition, cudraflavanone D (1) suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. This study indicated that cudraflavanone D (1) can be a potential drug candidate for the cure of neuroinflammation. Full article

(This article belongs to the Special Issue Plant-Derived Pharmaceuticals by Molecular Farming 2016)

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Open AccessArticle

Effect of the Solvent Temperatures on Dynamics of Serine Protease Proteinase K

by Peng Sang, Qiong Yang, Xing Du, Nan Yang, Li-Quan Yang, Xing-Lai Ji, Yun-Xin Fu, Zhao-Hui Meng and Shu-Qun Liu

Int. J. Mol. Sci. 2016, 17(2), 254; https://doi.org/10.3390/ijms17020254 - 19 Feb 2016

Cited by 21 | Viewed by 6151

Abstract

To obtain detailed information about the effect of the solvent temperatures on protein dynamics, multiple long molecular dynamics (MD) simulations of serine protease proteinase K with the solute and solvent coupled to different temperatures (either 300 or 180 K) have been performed. Comparative [...] Read more.

To obtain detailed information about the effect of the solvent temperatures on protein dynamics, multiple long molecular dynamics (MD) simulations of serine protease proteinase K with the solute and solvent coupled to different temperatures (either 300 or 180 K) have been performed. Comparative analyses demonstrate that the internal flexibility and mobility of proteinase K are strongly dependent on the solvent temperatures but weakly on the protein temperatures. The constructed free energy landscapes (FELs) at the high solvent temperatures exhibit a more rugged surface, broader spanning range, and higher minimum free energy level than do those at the low solvent temperatures. Comparison between the dynamic hydrogen bond (HB) numbers reveals that the high solvent temperatures intensify the competitive HB interactions between water molecules and protein surface atoms, and this in turn exacerbates the competitive HB interactions between protein internal atoms, thus enhancing the conformational flexibility and facilitating the collective motions of the protein. A refined FEL model was proposed to explain the role of the solvent mobility in facilitating the cascade amplification of microscopic motions of atoms and atomic groups into the global collective motions of the protein. Full article

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

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Open AccessArticle

Assessment of Radiation Induced Therapeutic Effect and Cytotoxicity in Cancer Patients Based on Transcriptomic Profiling

by Sajjad Karim, Zeenat Mirza, Adeel G. Chaudhary, Adel M. Abuzenadah, Mamdooh Gari and Mohammed H. Al-Qahtani

Int. J. Mol. Sci. 2016, 17(2), 250; https://doi.org/10.3390/ijms17020250 - 19 Feb 2016

Cited by 17 | Viewed by 7393

Abstract

Toxicity induced by radiation therapy is a curse for cancer patients undergoing treatment. It is imperative to understand and define an ideal condition where the positive effects notably outweigh the negative. We used a microarray meta-analysis approach to measure global gene-expression before and [...] Read more.

Toxicity induced by radiation therapy is a curse for cancer patients undergoing treatment. It is imperative to understand and define an ideal condition where the positive effects notably outweigh the negative. We used a microarray meta-analysis approach to measure global gene-expression before and after radiation exposure. Bioinformatic tools were used for pathways, network, gene ontology and toxicity related studies. We found 429 differentially expressed genes at fold change >2 and p-value <0.05. The most significantly upregulated genes were synuclein alpha (SNCA), carbonic anhydrase I (CA1), X-linked Kx blood group (XK), glycophorin A and B (GYPA and GYPB), and hemogen (HEMGN), while downregulated ones were membrane-spanning 4-domains, subfamily A member 1 (MS4A1), immunoglobulin heavy constant mu (IGHM), chemokine (C-C motif) receptor 7 (CCR7), BTB and CNC homology 1 transcription factor 2 (BACH2), and B-cell CLL/lymphoma 11B (BCL11B). Pathway analysis revealed calcium-induced T lymphocyte apoptosis and the role of nuclear factor of activated T-cells (NFAT) in regulation of the immune response as the most inhibited pathways, while apoptosis signaling was significantly activated. Most of the normal biofunctions were significantly decreased while cell death and survival process were activated. Gene ontology enrichment analysis revealed the immune system process as the most overrepresented group under the biological process category. Toxicity function analysis identified liver, kidney and heart to be the most affected organs during and after radiation therapy. The identified biomarkers and alterations in molecular pathways induced by radiation therapy should be further investigated to reduce the cytotoxicity and development of fatigue. Full article

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

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Open AccessReview

Energy Metabolism Plays a Critical Role in Stem Cell Maintenance and Differentiation

by Chenxia Hu, Linxiao Fan, Panpan Cen, Ermei Chen, Zhengyi Jiang and Lanjuan Li

Int. J. Mol. Sci. 2016, 17(2), 253; https://doi.org/10.3390/ijms17020253 - 18 Feb 2016

Cited by 94 | Viewed by 11155

Abstract

Various stem cells gradually turned to be critical players in tissue engineering and regenerative medicine therapies. Current evidence has demonstrated that in addition to growth factors and the extracellular matrix, multiple metabolic pathways definitively provide important signals for stem cell self-renewal and differentiation. [...] Read more.

Various stem cells gradually turned to be critical players in tissue engineering and regenerative medicine therapies. Current evidence has demonstrated that in addition to growth factors and the extracellular matrix, multiple metabolic pathways definitively provide important signals for stem cell self-renewal and differentiation. In this review, we mainly focus on a detailed overview of stem cell metabolism in vitro. In stem cell metabolic biology, the dynamic balance of each type of stem cell can vary according to the properties of each cell type, and they share some common points. Clearly defining the metabolic flux alterations in stem cells may help to shed light on stemness features and differentiation pathways that control the fate of stem cells. Full article

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

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Open AccessArticle

Metabolic Activity of Radish Sprouts Derived Isothiocyanates in Drosophila melanogaster

by Nieves Baenas, Stefanie Piegholdt, Anke Schloesser, Diego A. Moreno, Cristina García-Viguera, Gerald Rimbach and Anika E. Wagner

Int. J. Mol. Sci. 2016, 17(2), 251; https://doi.org/10.3390/ijms17020251 - 18 Feb 2016

Cited by 50 | Viewed by 9553

Abstract

We used Drosophila melanogaster as a model system to study the absorption, metabolism and potential health benefits of plant bioactives derived from radish sprouts (Raphanus sativus cv. Rambo), a Brassicaceae species rich in glucosinolates and other phytochemicals. Flies were subjected to a [...] Read more.

We used Drosophila melanogaster as a model system to study the absorption, metabolism and potential health benefits of plant bioactives derived from radish sprouts (Raphanus sativus cv. Rambo), a Brassicaceae species rich in glucosinolates and other phytochemicals. Flies were subjected to a diet supplemented with lyophilized radish sprouts (10.6 g/L) for 10 days, containing high amounts of glucoraphenin and glucoraphasatin, which can be hydrolyzed by myrosinase to the isothiocyanates sulforaphene and raphasatin, respectively. We demonstrate that Drosophila melanogaster takes up and metabolizes isothiocyanates from radish sprouts through the detection of the metabolite sulforaphane-cysteine in fly homogenates. Moreover, we report a decrease in the glucose content of flies, an upregulation of spargel expression, the Drosophila homolog of the mammalian PPARγ-coactivator 1 α, as well as the inhibition of α-amylase and α-glucosidase in vitro. Overall, we show that the consumption of radish sprouts affects energy metabolism in Drosophila melanogaster which is reflected by lower glucose levels and an increased expression of spargel, a central player in mitochondrial biogenesis. These processes are often affected in chronic diseases associated with aging, including type II diabetes mellitus. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Antinociceptive and Anti-Inflammatory Effects of Zerumbone against Mono-Iodoacetate-Induced Arthritis

by Ting-Yi Chien, Steven Kuan-Hua Huang, Chia-Jung Lee, Po-Wei Tsai and Ching-Chiung Wang

Int. J. Mol. Sci. 2016, 17(2), 249; https://doi.org/10.3390/ijms17020249 - 18 Feb 2016

Cited by 41 | Viewed by 7418

Abstract

The fresh rhizome of Zingiber zerumbet Smith (Zingiberaceae) is used as a food flavoring and also serves as a folk medicine as an antipyretic and for analgesics in Taiwan. Zerumbone, a monocyclic sesquiterpene was isolated from the rhizome of Z. zerumbet and is [...] Read more.

The fresh rhizome of Zingiber zerumbet Smith (Zingiberaceae) is used as a food flavoring and also serves as a folk medicine as an antipyretic and for analgesics in Taiwan. Zerumbone, a monocyclic sesquiterpene was isolated from the rhizome of Z. zerumbet and is the major active compound. In this study, the anti-inflammatory and antinociceptive effects of zerumbone on arthritis were explored using in vitro and in vivo models. Results showed that zerumbone inhibited inducible nitric oxide (NO) synthase (iNOS), cyclooxygenase (COX)-2 expressions, and NO and prostaglandin E₂ (PGE₂) production, but induced heme oxygenase (HO)-1 expression in a dose-dependent manner in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. When zerumbone was co-treated with an HO-1 inhibitor (tin protoporphyrin (SnPP)), the NO inhibitory effects of zerumbone were recovered. The above results suggest that zerumbone inhibited iNOS and COX-2 through induction of the HO-1 pathway. Moreover, matrix metalloproteinase (MMP)-13 and COX-2 expressions of interleukin (IL)-1β-stimulated primary rat chondrocytes were inhibited by zerumbone. In an in vivo assay, an acetic acid-induced writhing response in mice was significantly reduced by treatment with zerumbone. Furthermore, zerumbone reduced paw edema and the pain response in a mono-iodoacetate (MIA)-induced rat osteoarthritis model. Therefore, we suggest that zerumbone possesses anti-inflammatory and antinociceptive effects which indicate zerumbone could be a potential candidate for osteoarthritis treatment. Full article

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

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Open AccessArticle

Hinokitiol Inhibits Melanogenesis via AKT/mTOR Signaling in B16F10 Mouse Melanoma Cells

by Yu-Tzu Tsao, Yu-Fen Huang, Chun-Yu Kuo, Yu-Chiang Lin, Wei-Cheng Chiang, Wei-Kuang Wang, Chia-Wei Hsu and Che-Hsin Lee

Int. J. Mol. Sci. 2016, 17(2), 248; https://doi.org/10.3390/ijms17020248 - 18 Feb 2016

Cited by 28 | Viewed by 9745

Abstract

H inokitiol purified from the heartwood of cupressaceous plants has had various biological functions of cell differentiation and growth. Hinokitiol has been demonstrated as having an important role in anti-inflammation and anti-bacteria effect, suggesting that it is potentially useful in therapies for hyperpigmentation. [...] Read more.

H inokitiol purified from the heartwood of cupressaceous plants has had various biological functions of cell differentiation and growth. Hinokitiol has been demonstrated as having an important role in anti-inflammation and anti-bacteria effect, suggesting that it is potentially useful in therapies for hyperpigmentation. Previously, hinokitiol inhibited the production of melanin by inhibiting tyrosinase activity. The autophagic signaling pathway can induce hypopigmentation. This study is warranted to investigate the mechanism of hinokitiol-induced hypopigmentation through autophagy in B16F10 melanoma cells. The melanin contents and expression of microthphalmia associated transcription factor (MITF) and tyrosinase were inhibited by treatment with hinokitiol. Moreover, the phosphorylation of the protein express levels of phospho-protein kinase B (P-AKT) and phospho-mammalian targets of rapamycin (P-mTOR) were reduced after hinokitiol treatment. In addition, the microtubule associated protein 1 light chain 3 (LC3) -II and beclin 1 (autophagic markers) were increased after the B16F10 cell was treated with hinokitiol. Meanwhile, hinokitiol decreased cellular melanin contents in a dose-dependent manner. These findings establish that hinokitiol inhibited melanogenesis through the AKT/mTOR signaling pathway. Full article

(This article belongs to the Special Issue Biochemistry and Mechanisms of Melanogenesis)

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Open AccessReview

Systems Pharmacology in Small Molecular Drug Discovery

by Wei Zhou, Yonghua Wang, Aiping Lu and Ge Zhang

Int. J. Mol. Sci. 2016, 17(2), 246; https://doi.org/10.3390/ijms17020246 - 18 Feb 2016

Cited by 112 | Viewed by 15337

Abstract

Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that [...] Read more.

Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

The Potential of Plant Phenolics in Prevention and Therapy of Skin Disorders

by Magdalena Działo, Justyna Mierziak, Urszula Korzun, Marta Preisner, Jan Szopa and Anna Kulma

Int. J. Mol. Sci. 2016, 17(2), 160; https://doi.org/10.3390/ijms17020160 - 18 Feb 2016

Cited by 512 | Viewed by 27713

Abstract

Phenolic compounds constitute a group of secondary metabolites which have important functions in plants. Besides the beneficial effects on the plant host, phenolic metabolites (polyphenols) exhibit a series of biological properties that influence the human in a health-promoting manner. Evidence suggests that people [...] Read more.

Phenolic compounds constitute a group of secondary metabolites which have important functions in plants. Besides the beneficial effects on the plant host, phenolic metabolites (polyphenols) exhibit a series of biological properties that influence the human in a health-promoting manner. Evidence suggests that people can benefit from plant phenolics obtained either by the diet or through skin application, because they can alleviate symptoms and inhibit the development of various skin disorders. Due to their natural origin and low toxicity, phenolic compounds are a promising tool in eliminating the causes and effects of skin aging, skin diseases, and skin damage, including wounds and burns. Polyphenols also act protectively and help prevent or attenuate the progression of certain skin disorders, both embarrassing minor problems (e.g., wrinkles, acne) or serious, potentially life-threatening diseases such as cancer. This paper reviews the latest reports on the potential therapy of skin disorders through treatment with phenolic compounds, considering mostly a single specific compound or a combination of compounds in a plant extract. Full article

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

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Open AccessArticle

Investigation of the Antiproliferative Properties of Natural Sesquiterpenes from Artemisia asiatica and Onopordum acanthium on HL-60 Cells in Vitro

by Judit Molnár, Gábor J. Szebeni, Boglárka Csupor-Löffler, Zsuzsanna Hajdú, Thomas Szekeres, Philipp Saiko, Imre Ocsovszki, László G. Puskás, Judit Hohmann and István Zupkó

Int. J. Mol. Sci. 2016, 17(2), 83; https://doi.org/10.3390/ijms17020083 - 17 Feb 2016

Cited by 18 | Viewed by 6645

Abstract

Plants and plant extracts play a crucial role in the research into novel antineoplastic agents. Four sesquiterpene lactones, artecanin (1), 3β-chloro-4α,10α-dihydroxy-1α,2α-epoxy-5α,7αH-guaia-11(13)-en-12,6α-olide (2), iso-seco-tanapartholide 3-O-methyl ether (3) and 4β,15-dihydro-3-dehydrozaluzanin C (4), were isolated from two [...] Read more.

Plants and plant extracts play a crucial role in the research into novel antineoplastic agents. Four sesquiterpene lactones, artecanin (1), 3β-chloro-4α,10α-dihydroxy-1α,2α-epoxy-5α,7αH-guaia-11(13)-en-12,6α-olide (2), iso-seco-tanapartholide 3-O-methyl ether (3) and 4β,15-dihydro-3-dehydrozaluzanin C (4), were isolated from two traditionally used Asteraceae species (Onopordum acanthium and Artemisia asiatica). When tested for antiproliferative action on HL-60 leukemia cells, these compounds exhibited reasonable IC₅₀ values in the range 3.6–13.5 μM. Treatment with the tested compounds resulted in a cell cycle disturbance characterized by increases in the G1 and G2/M populations, while there was a decrease in the S phase. Additionally, 1–3 elicited increases in the hypodiploid (subG1) population. The compounds elicited concentration-dependent chromatin condensation and disruption of the membrane integrity, as revealed by Hoechst 33258–propidium staining. Treatment for 24 h resulted in significant increases in activity of caspases-3 and -9, indicating that the tested sesquiterpenes induced the mitochondrial pathway of apoptosis. The proapoptotic properties of the sesquiterpene lactones were additionally demonstrated withannexin V staining. Compounds 1 and 2 increased the Bax/Bcl-2 expression and decreased the expressions of CDK1 and cyclin B2, as determined at the mRNA level by means of RT-PCR. These experimental results indicate that sesquiterpene lactones may be regarded as potential starting structures for the development of novel anticancer agents. Full article

(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism 2015)

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Open AccessEditorial

Toward Precision Medicine: How Far Is the Goal?

by Gloria Ravegnini and Sabrina Angelini

Int. J. Mol. Sci. 2016, 17(2), 245; https://doi.org/10.3390/ijms17020245 - 17 Feb 2016

Cited by 5 | Viewed by 4781

Abstract

The accomplishment of the Human Genome Project, followed by the availability of high-throughput technologies, has led to an impressive change in biomedical research.[...] Full article

(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)

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Open AccessArticle

Therapeutic Effects of Erythroid Differentiation Regulator 1 on Imiquimod-Induced Psoriasis-Like Skin Inflammation

by Kyung Eun Kim, Younkyung Houh, Hyun Jeong Park and Daeho Cho

Int. J. Mol. Sci. 2016, 17(2), 244; https://doi.org/10.3390/ijms17020244 - 17 Feb 2016

Cited by 14 | Viewed by 7354

Abstract

Psoriasis is a common skin disease accompanied by chronic inflammation. In previous studies, erythroid differentiation regulator 1 (ERDR1) was shown to have a negative correlation with proinflammatory cytokine IL-18. However, the role of ERDR1 in the inflammatory skin disease psoriasis has not been [...] Read more.

Psoriasis is a common skin disease accompanied by chronic inflammation. In previous studies, erythroid differentiation regulator 1 (ERDR1) was shown to have a negative correlation with proinflammatory cytokine IL-18. However, the role of ERDR1 in the inflammatory skin disease psoriasis has not been evaluated. In this study, to investigate the role of ERDR1 in psoriasis, recombinant ERDR1 was injected intraperitoneally into a psoriasis mouse model. Recombinant ERDR1 (rERDR1) significantly alleviated the symptoms of psoriasis-like skin inflammation and reduced the mRNA of various psoriasis-related markers, including keratin 14, S100A8, and Th17-related cytokines IL-17 and IL-22, suggesting that rERDR1 exerts therapeutic effects on psoriasis via the regulation of Th17 functions. Additionally, the expression of CCL20, a well-known Th17 attracting chemokine, was determined. CCL20 expression significantly decreased in the rERDR1-injected group compared with the vehicle (PBS)-injected group. CCR6 expression in the psoriatic lesional skin was also decreased by rERDR1 administration, implying the inhibition of CCR6-expressing Th17 cell chemotaxis via the downregulation of CCL20. Taken together, this study provides the first evidence that ERDR1 may be a potential therapeutic target for psoriasis. Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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Open AccessArticle

Integrative Transcriptome, Genome and Quantitative Trait Loci Resources Identify Single Nucleotide Polymorphisms in Candidate Genes for Growth Traits in Turbot

by Diego Robledo, Carlos Fernández, Miguel Hermida, Andrés Sciara, José Antonio Álvarez-Dios, Santiago Cabaleiro, Rubén Caamaño, Paulino Martínez and Carmen Bouza

Int. J. Mol. Sci. 2016, 17(2), 243; https://doi.org/10.3390/ijms17020243 - 17 Feb 2016

Cited by 28 | Viewed by 7350

Abstract

Growth traits represent a main goal in aquaculture breeding programs and may be related to adaptive variation in wild fisheries. Integrating quantitative trait loci (QTL) mapping and next generation sequencing can greatly help to identify variation in candidate genes, which can result in [...] Read more.

Growth traits represent a main goal in aquaculture breeding programs and may be related to adaptive variation in wild fisheries. Integrating quantitative trait loci (QTL) mapping and next generation sequencing can greatly help to identify variation in candidate genes, which can result in marker-assisted selection and better genetic structure information. Turbot is a commercially important flatfish in Europe and China, with available genomic information on QTLs and genome mapping. Muscle and liver RNA-seq from 18 individuals was carried out to obtain gene sequences and markers functionally related to growth, resulting in a total of 20,447 genes and 85,344 single nucleotide polymorphisms (SNPs). Many growth-related genes and SNPs were identified and placed in the turbot genome and genetic map to explore their co-localization with growth-QTL markers. Forty-five SNPs on growth-related genes were selected based on QTL co-localization and relevant function for growth traits. Forty-three SNPs were technically feasible and validated in a wild Atlantic population, where 91% were polymorphic. The integration of functional and structural genomic resources in turbot provides a practical approach for QTL mining in this species. Validated SNPs represent a useful set of growth-related gene markers for future association, functional and population studies in this flatfish species. Full article

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

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Open AccessArticle

Delivery of Flavonoids and Saponins from Black Bean (Phaseolus vulgaris) Seed Coats Incorporated into Whole Wheat Bread

by Rocio A. Chávez-Santoscoy, Marco A. Lazo-Vélez, Sergio O. Serna-Sáldivar and Janet A. Gutiérrez-Uribe

Int. J. Mol. Sci. 2016, 17(2), 222; https://doi.org/10.3390/ijms17020222 - 17 Feb 2016

Cited by 24 | Viewed by 8348

Abstract

Cereal-based products can be used as vehicles for the delivery of relevant bioactive compounds since they are staple foods for most cultures throughout the world. The health promoting benefits of flavonoids and saponins contained in black bean seed coats have been previously described. [...] Read more.

Cereal-based products can be used as vehicles for the delivery of relevant bioactive compounds since they are staple foods for most cultures throughout the world. The health promoting benefits of flavonoids and saponins contained in black bean seed coats have been previously described. In the present work, the effect of adding flavonoids and saponins from black bean seed coat to the typical yeast-leavened whole wheat bread formulation in terms of bread features, organoleptic properties and phytochemical profile was studied. The retention of bioactive compounds was determined and the inhibitory effects of in vitro enzyme digested samples on two colon cancer cell lines (Caco-2 and HT29) was evaluated. The addition of bioactive compounds did not significantly affect baking properties or texture parameters. Among organoleptic properties of enriched breads, only crumb color was affected by the addition of bioactive compounds. However, the use of whole wheat flour partially masked the effect on color. More than 90% of added flavonoids and saponins and 80% of anthocyanins were retained in bread after baking. However, saponins were reduced more than 50% after the in vitro enzyme digestion. The black bean seed coat phytochemicals recovered after in vitro enzyme digestion of enriched breads significantly reduced by 20% the viability of colon cancer cells without affecting standard fibroblast cells (p < 0.05). Full article

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

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Deep Sequencing and Screening of Differentially Expressed MicroRNAs Related to Milk Fat Metabolism in Bovine Primary Mammary Epithelial Cells

by Binglei Shen, Liying Zhang, Chuanjiang Lian, Chunyan Lu, Yonghong Zhang, Qiqi Pan, Runjun Yang and Zhihui Zhao

Int. J. Mol. Sci. 2016, 17(2), 200; https://doi.org/10.3390/ijms17020200 - 17 Feb 2016

Cited by 36 | Viewed by 7038

Abstract

Milk fat is a key factor affecting milk quality and is also a major trait targeted in dairy cow breeding. To determine how the synthesis and the metabolism of lipids in bovine milk is regulated at the miRNA level, primary mammary epithelial cells [...] Read more.

Milk fat is a key factor affecting milk quality and is also a major trait targeted in dairy cow breeding. To determine how the synthesis and the metabolism of lipids in bovine milk is regulated at the miRNA level, primary mammary epithelial cells (pMEC) derived from two Chinese Holstein dairy cows that produced extreme differences in milk fat percentage were cultured by the method of tissue nubbles culture. Small RNA libraries were constructed from each of the two pMEC groups, and Solexa sequencing and bioinformatics analysis were then used to determine the abundance of miRNAs and their differential expression pattern between pMECs. Target genes and functional prediction of differentially expressed miRNAs by Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analysis illustrated their roles in milk fat metabolism. Results show that a total of 292 known miRNAs and 116 novel miRNAs were detected in both pMECs. Identification of known and novel miRNA candidates demonstrated the feasibility and sensitivity of sequencing at the cellular level. Additionally, 97 miRNAs were significantly differentially expressed between the pMECs. Finally, three miRNAs including bta-miR-33a, bta-miR-152 and bta-miR-224 whose predicted target genes were annotated to the pathway of lipid metabolism were screened and verified by real-time qPCR and Western-blotting experiments. This study is the first comparative profiling of the miRNA transcriptome in pMECs that produce different milk fat content. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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Open AccessBrief Report

Atypical Antipsychotics in the Treatment of Acute Bipolar Depression with Mixed Features: A Systematic Review and Exploratory Meta-Analysis of Placebo-Controlled Clinical Trials

by Michele Fornaro, Brendon Stubbs, Domenico De Berardis, Giampaolo Perna, Alessandro Valchera, Nicola Veronese, Marco Solmi and Licínia Ganança

Int. J. Mol. Sci. 2016, 17(2), 241; https://doi.org/10.3390/ijms17020241 - 16 Feb 2016

Cited by 42 | Viewed by 10080

Abstract

Evidence supporting the use of second generation antipsychotics (SGAs) in the treatment of acute depression with mixed features (MFs) associated with bipolar disorder (BD) is scarce and equivocal. Therefore, we conducted a systematic review and preliminary meta-analysis investigating SGAs in the treatment of [...] Read more.

Evidence supporting the use of second generation antipsychotics (SGAs) in the treatment of acute depression with mixed features (MFs) associated with bipolar disorder (BD) is scarce and equivocal. Therefore, we conducted a systematic review and preliminary meta-analysis investigating SGAs in the treatment of acute BD depression with MFs. Two authors independently searched major electronic databases from 1990 until September 2015 for randomized (placebo-) controlled trials (RCTs) or open-label clinical trials investigating the efficacy of SGAs in the treatment of acute bipolar depression with MFs. A random-effect meta-analysis calculating the standardized mean difference (SMD) between SGA and placebo for the mean baseline to endpoint change in depression as well as manic symptoms score was computed based on 95% confidence intervals (CI). Six RCTs and one open-label placebo-controlled studies (including post-hoc reports) representing 1023 patients were included. Participants received either ziprasidone, olanzapine, lurasidone, quetiapine or asenapine for an average of 6.5 weeks across the included studies. Meta-analysis with Duval and Tweedie adjustment for publication bias demonstrated that SGA resulted in significant improvements of (hypo-)manic symptoms of bipolar mixed depression as assessed by the means of the total scores of the Young Mania Rating Scale (YMRS) (SMD −0.74, 95% CI −1.20 to −0.28, n SGA = 907, control = 652). Meta-analysis demonstrated that participants in receipt of SGA (n = 979) experienced a large improvement in the Montgomery–Åsberg Depression Rating Scale (MADRS) scores (SMD −1.08, 95% CI −1.35 to −0.81, p < 0.001) vs. placebo (n = 678). Publication and measurement biases and relative paucity of studies. Overall, SGAs appear to offer favorable improvements in MADRS and YMRS scores vs. placebo. Nevertheless, given the preliminary nature of the present report, additional original studies are required to allow more reliable and clinically definitive conclusions. Full article

(This article belongs to the Special Issue Antipsychotics)

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Open AccessArticle

Role of miR-222-3p in c-Src-Mediated Regulation of Osteoclastogenesis

by Shinya Takigawa, Andy Chen, Qiaoqiao Wan, Sungsoo Na, Akihiro Sudo, Hiroki Yokota and Kazunori Hamamura

Int. J. Mol. Sci. 2016, 17(2), 240; https://doi.org/10.3390/ijms17020240 - 16 Feb 2016

Cited by 25 | Viewed by 6705

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that play a mostly post-transcriptional regulatory role in gene expression. Using RAW264.7 pre-osteoclast cells and genome-wide expression analysis, we identified a set of miRNAs that are involved in osteoclastogenesis. Based on in silico analysis, we specifically focused [...] Read more.

MicroRNAs (miRNAs) are small non-coding RNAs that play a mostly post-transcriptional regulatory role in gene expression. Using RAW264.7 pre-osteoclast cells and genome-wide expression analysis, we identified a set of miRNAs that are involved in osteoclastogenesis. Based on in silico analysis, we specifically focused on miR-222-3p and evaluated its role in osteoclastogenesis. The results show that the inhibitor of miR-222-3p upregulated the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and tartrate-resistant acid phosphatase (TRAP), while its mimicking agent downregulated their mRNA levels. Western blot analysis showed that its inhibitor increased the protein levels of TRAP and cathepsin K, while its mimicking agent decreased their levels. Genome-wide mRNA expression analysis in the presence and absence of receptor activator of nuclear factor κ-B ligand (RANKL) predicted c-Src as a potential regulatory target of miR-222-3p. Live cell imaging using a fluorescence resonance energy transfer (FRET) technique revealed that miR-222-3p acted as an inhibitor of c-Src activity, and a partial silencing of c-Src suppressed RANKL-induced expression of TRAP and cathepsin K, as well as the number of multi-nucleated osteoclasts and their pit formation. Collectively, the study herein demonstrates that miR-222-3p serves as an inhibitor of osteoclastogenesis and c-Src mediates its inhibition of cathepsin K and TRAP. Full article

(This article belongs to the Special Issue MicroRNA Regulation)

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Open AccessArticle

Food-Derived Bioactives Can Protect the Anti-Inflammatory Activity of Cortisol with Antioxidant-Dependent and -Independent Mechanisms

by Erik J. B. Ruijters, Guido R. M. M. Haenen, Mathijs Willemsen, Antje R. Weseler and Aalt Bast

Int. J. Mol. Sci. 2016, 17(2), 239; https://doi.org/10.3390/ijms17020239 - 15 Feb 2016

Cited by 12 | Viewed by 6699

Abstract

In chronic inflammatory diseases the anti-inflammatory effect of glucocorticoids (GCs) is often decreased, leading to GC resistance. Inflammation is related with increased levels of reactive oxygen species (ROS), leading to oxidative stress which is thought to contribute to the development of GC resistance. [...] Read more.

In chronic inflammatory diseases the anti-inflammatory effect of glucocorticoids (GCs) is often decreased, leading to GC resistance. Inflammation is related with increased levels of reactive oxygen species (ROS), leading to oxidative stress which is thought to contribute to the development of GC resistance. Plant-derived compounds such as flavonoids are known for their ability to protect against ROS. In this exploratory study we screened a broad range of food-derived bioactives for their antioxidant and anti-inflammatory effects in order to investigate whether their antioxidant effects are associated with the ability to preserve the anti-inflammatory effects of cortisol. The anti-inflammatory potency of the tested compounds was assessed by measuring the oxidative stress–induced GC resistance in human macrophage-like cells. Cells were pre-treated with H₂O₂ (800 µM) with and without bioactives and then exposed to lipopolysaccharides (LPS) (10 ng/mL) and cortisol (100 nM). The level of inflammation was deducted from the concentration of interleukin-8 (IL-8) in the medium. Intracellular oxidative stress was measured using the fluorescent probe 2′,7′-dichlorofluorescein (DCFH). We found that most of the dietary bioactives display antioxidant and anti-inflammatory action through the protection of the cortisol response. All compounds, except for quercetin, revealing antioxidant activity also protect the cortisol response. This indicates that the antioxidant activity of compounds plays an important role in the protection of the GC response. However, next to the antioxidant activity of the bioactives, other mechanisms also seem to be involved in this protective, anti-inflammatory effect. Full article

(This article belongs to the Special Issue Antioxidant 2.0——Redox Modulation by Food and Drugs)

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Open AccessArticle

The Chinese Herbal Medicine Formula mKG Suppresses Pulmonary Fibrosis of Mice Induced by Bleomycin

by Ying Gao, Li-Fu Yao, Yang Zhao, Li-Man Wei, Peng Guo, Meng Yu, Bo Cao, Tan Li, Hong Chen and Zhong-Mei Zou

Int. J. Mol. Sci. 2016, 17(2), 238; https://doi.org/10.3390/ijms17020238 - 15 Feb 2016

Cited by 24 | Viewed by 6977

Abstract

Pulmonary fibrosis (PF) is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal [...] Read more.

Pulmonary fibrosis (PF) is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicine, has a prominent anti-inflammatory effect. The present study is to explore the inhibitory effects of mKG on bleomycin (BLM)-induced pulmonary fibrosis in mice. mKG significantly decreased pulmonary alveolitis, fibrosis scores, and interleukin-6 (IL-6), interleukin-17 (IL-17), transforming growth factor-β (TGF-β) and hydroxyproline (HYP) levels in lung tissue of mice compared with BLM treatment. It markedly alleviated the increase of HYP content in the lung tissues and pathologic changes of pulmonary fibrosis caused by BLM instillation. In conclusion, mKG has an anti-fibrotic effect and might be employed as a therapeutic candidate agent for attenuating pulmonary fibrosis. Full article

(This article belongs to the Section Biochemistry)

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