International Journal of Molecular Sciences

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Open AccessArticle

Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives

by Saleh A. Bahashwan, Ahmed A. Fayed, Mohamed A. Ramadan, Abd El-Galil E. Amr and Naif O. Al-Harbi

Int. J. Mol. Sci. 2014, 15(11), 21587-21602; https://doi.org/10.3390/ijms151121587 - 24 Nov 2014

Cited by 17 | Viewed by 6175

Abstract

A series of substituted pyrazole, triazole and thiazole derivatives (2–13) were synthesized from 1-(naphtho[1,2-d]thiazol-2-yl)hydrazine as starting material and evaluated as androgen receptor antagonists and anti-prostate cancer agents. The newly synthesized compounds showed potent androgen receptor antagonists and [...] Read more.

A series of substituted pyrazole, triazole and thiazole derivatives (2–13) were synthesized from 1-(naphtho[1,2-d]thiazol-2-yl)hydrazine as starting material and evaluated as androgen receptor antagonists and anti-prostate cancer agents. The newly synthesized compounds showed potent androgen receptor antagonists and anti-prostate cancer activities with low toxicity (lethal dose 50 (LD₅₀)) comparable to Bicalutamide as reference drug. The structures of newly synthesized compounds were confirmed by IR, ¹H-NMR, ¹³C-NMR, and MS spectral data and elemental analysis. The detailed synthesis, spectroscopic data, LD₅₀ values and pharmacological activities of the synthesized compounds are reported. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

MicroRNA Signatures as Biomarkers and Therapeutic Target for CNS Embryonal Tumors: The Pros and the Cons

by Tarek Shalaby, Giulio Fiaschetti, Martin Baumgartner and Michael A. Grotzer

Int. J. Mol. Sci. 2014, 15(11), 21554-21586; https://doi.org/10.3390/ijms151121554 - 24 Nov 2014

Cited by 31 | Viewed by 8426

Abstract

Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients’ response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors [...] Read more.

Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients’ response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5–10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs) in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets. Full article

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

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Open AccessArticle

Some Characteristics of Free Cell Population in the Airways of Rats after Intratracheal Instillation of Copper-Containing Nano-Scale Particles

by Larisa I. Privalova, Boris A. Katsnelson, Nadezhda V. Loginova, Vladimir B. Gurvich, Vladimir Y. Shur, Yakov B. Beikin, Marina P. Sutunkova, Ilzira A. Minigalieva, Ekaterina V. Shishkina, Svetlana V. Pichugova, Ludmila G. Tulakina and Svetlana V. Beljayeva

Int. J. Mol. Sci. 2014, 15(11), 21538-21553; https://doi.org/10.3390/ijms151121538 - 24 Nov 2014

Cited by 18 | Viewed by 6282

Abstract

We used stable water suspensions of copper oxide particles with mean diameter 20 nm and of particles containing copper oxide and element copper with mean diameter 340 nm to assess the pulmonary phagocytosis response of rats to a single intratracheal instillation of these [...] Read more.

We used stable water suspensions of copper oxide particles with mean diameter 20 nm and of particles containing copper oxide and element copper with mean diameter 340 nm to assess the pulmonary phagocytosis response of rats to a single intratracheal instillation of these suspensions using optical, transmission electron, and semi-contact atomic force microscopy and biochemical indices measured in the bronchoalveolar lavage fluid. Although both nano and submicron ultrafine particles were adversely bioactive, the former were found to be more toxic for lungs as compared with the latter while evoking more pronounced defense recruitment of alveolar macrophages and especially of neutrophil leukocytes and more active phagocytosis. Based on our results and literature data, we consider both copper solubilization and direct contact with cellular organelles (mainly, mitochondria) of persistent particles internalized by phagocytes as probable mechanisms of their cytotoxicity. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles 2014)

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Open AccessReview

Therapeutic Phytogenic Compounds for Obesity and Diabetes

by Hee Soong Jung, Yun Lim and Eun-Kyoung Kim

Int. J. Mol. Sci. 2014, 15(11), 21505-21537; https://doi.org/10.3390/ijms151121505 - 21 Nov 2014

Cited by 26 | Viewed by 11271

Abstract

Natural compounds have been used to develop drugs for many decades. Vast diversities and minimum side effects make natural compounds a good source for drug development. However, the composition and concentrations of natural compounds can vary. Despite this inconsistency, half of the Food [...] Read more.

Natural compounds have been used to develop drugs for many decades. Vast diversities and minimum side effects make natural compounds a good source for drug development. However, the composition and concentrations of natural compounds can vary. Despite this inconsistency, half of the Food and Drug Administration (FDA)-approved pharmaceuticals are natural compounds or their derivatives. Therefore, it is essential to continuously investigate natural compounds as sources of new pharmaceuticals. This review provides comprehensive information and analysis on natural compounds from plants (phytogenic compounds) that may serve as anti-obesity and/or anti-diabetes therapeutics. Our growing understanding and further exploration of the mechanisms of action of the phytogenic compounds may afford opportunities for development of therapeutic interventions in metabolic diseases. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals in Functional Foods for Cancer Prevention)

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Open AccessArticle

Hepatoma-Derived Growth Factor Upregulation Is Correlated with Prognostic Factors of Early-Stage Cervical Adenocarcinoma

by Ching-Chou Tsai, Shun-Chen Huang, Ming Hong Tai, Chan-Chao Chang Chien, Chao-Cheng Huang and Yi-Chiang Hsu

Int. J. Mol. Sci. 2014, 15(11), 21492-21504; https://doi.org/10.3390/ijms151121492 - 21 Nov 2014

Cited by 18 | Viewed by 5584

Abstract

Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor that plays an important role in the progression of different types of cancer. A total of 63 patients with early-stage cervical adenocarcinoma (Cx) were enrolled in this retrospective study. The expression of HDGF was [...] Read more.

Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor that plays an important role in the progression of different types of cancer. A total of 63 patients with early-stage cervical adenocarcinoma (Cx) were enrolled in this retrospective study. The expression of HDGF was significantly increased compared with adjacent non-tumor tissue samples (p < 0.001). Moreover, elevated nuclear HDGF levels were correlated with lymph-vascular space invasion (LVSI; p < 0.05), lymph node metastasis (LNM; p < 0.001), recurrence (p < 0.001) and advanced grade (AG; p < 0.001). The growth of cervical cancer cells (Hela cells) was enhanced by HDGF treatment. The HDGF mRNA and protein level were significantly higher in malignant cervical cancer cells compared with primary ones. By adenovirus gene delivery, HDGF overexpression enhanced, whereas HDGF knockdown perturbed the tumorigenic behaviors of cervical cancer cells. HDGF overexpression is common in early-stage cervical adenocarcinoma and is involved in the carcinogenesis of cervical adenocarcinoma. Cytoplasmic HDGF expression is strongly correlated with pelvic lymph node metastasis and recurrence, indicating that HDGF may serve as a novel prognostic marker for patients with Cx. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Assessing the Accuracy of Quantitative Molecular Microbial Profiling

by Denise M. O'Sullivan, Thomas Laver, Sasithon Temisak, Nicholas Redshaw, Kathryn A. Harris, Carole A. Foy, David J. Studholme and Jim F. Huggett

Int. J. Mol. Sci. 2014, 15(11), 21476-21491; https://doi.org/10.3390/ijms151121476 - 21 Nov 2014

Cited by 15 | Viewed by 10514

Abstract

The application of high-throughput sequencing in profiling microbial communities is providing an unprecedented ability to investigate microbiomes. Such studies typically apply one of two methods: amplicon sequencing using PCR to target a conserved orthologous sequence (typically the 16S ribosomal RNA gene) or whole [...] Read more.

The application of high-throughput sequencing in profiling microbial communities is providing an unprecedented ability to investigate microbiomes. Such studies typically apply one of two methods: amplicon sequencing using PCR to target a conserved orthologous sequence (typically the 16S ribosomal RNA gene) or whole (meta)genome sequencing (WGS). Both methods have been used to catalog the microbial taxa present in a sample and quantify their respective abundances. However, a comparison of the inherent precision or bias of the different sequencing approaches has not been performed. We previously developed a metagenomic control material (MCM) to investigate error when performing different sequencing strategies. Amplicon sequencing using four different primer strategies and two 16S rRNA regions was examined (Roche 454 Junior) and compared to WGS (Illumina HiSeq). All sequencing methods generally performed comparably and in good agreement with organism specific digital PCR (dPCR); WGS notably demonstrated very high precision. Where discrepancies between relative abundances occurred they tended to differ by less than twofold. Our findings suggest that when alternative sequencing approaches are used for microbial molecular profiling they can perform with good reproducibility, but care should be taken when comparing small differences between distinct methods. This work provides a foundation for future work comparing relative differences between samples and the impact of extraction methods. We also highlight the value of control materials when conducting microbial profiling studies to benchmark methods and set appropriate thresholds. Full article

(This article belongs to the Special Issue Metagenomics: a Powerful Lens Viewing the Microbial World)

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Open AccessEditorial

Editorial: Biodegradable Materials

by Carl Schaschke and Jean-Luc Audic

Int. J. Mol. Sci. 2014, 15(11), 21468-21475; https://doi.org/10.3390/ijms151121468 - 21 Nov 2014

Cited by 16 | Viewed by 7144

Abstract

This Special Issue “Biodegradable Materials” features research and review papers concerning recent advances on the development, synthesis, testing and characterisation of biomaterials. These biomaterials, derived from natural and renewable sources, offer a potential alternative to existing non-biodegradable materials with application to the food [...] Read more.

This Special Issue “Biodegradable Materials” features research and review papers concerning recent advances on the development, synthesis, testing and characterisation of biomaterials. These biomaterials, derived from natural and renewable sources, offer a potential alternative to existing non-biodegradable materials with application to the food and biomedical industries amongst many others. In this Special Issue, the work is expanded to include the combined use of fillers that can enhance the properties of biomaterials prepared as films. The future application of these biomaterials could have an impact not only at the economic level, but also for the improvement of the environment. Full article

(This article belongs to the Special Issue Biodegradable Materials)

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Open AccessArticle

Reactivation of Hepatitis B Virus in Hematopoietic Stem Cell Transplant Recipients in Japan: Efficacy of Nucleos(t)ide Analogues for Prevention and Treatment

by Shingo Nakamoto, Tatsuo Kanda, Chiaki Nakaseko, Emiko Sakaida, Chikako Ohwada, Masahiro Takeuchi, Yusuke Takeda, Naoya Mimura, Tohru Iseki, Shuang Wu, Makoto Arai, Fumio Imazeki, Kengo Saito, Hiroshi Shirasawa and Osamu Yokosuka

Int. J. Mol. Sci. 2014, 15(11), 21455-21467; https://doi.org/10.3390/ijms151121455 - 21 Nov 2014

Cited by 36 | Viewed by 7311

Abstract

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis [...] Read more.

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined ≥1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined ≥1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t)ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with NUCs, and fortunately none developed acute liver failure. In 5 (6.0%) of 83 anti-HBc and/or anti-HBs-positive recipients, HBV reactivation occurred. None of 157 (0%) recipients without HBsAg, anti-HBs or anti-HBc experienced HBV reactivation. In HSCT recipients, HBV reactivation is a common event in HBsAg-positive recipients, or in HBsAg-negative recipients with anti-HBc and/or anti-HBs. Further attention should be paid to HSCT recipients with previous exposure to HBV. Full article

(This article belongs to the Special Issue Viral Hepatitis Research)

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Open AccessArticle

Epidermal Growth Factor Receptor Transactivation Is Required for Mitogen-Activated Protein Kinase Activation by Muscarinic Acetylcholine Receptors in HaCaT Keratinocytes

by Wymke Ockenga, Sina Kühne, Simone Bocksberger, Antje Banning and Ritva Tikkanen

Int. J. Mol. Sci. 2014, 15(11), 21433-21454; https://doi.org/10.3390/ijms151121433 - 21 Nov 2014

Cited by 18 | Viewed by 9515

Abstract

Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are [...] Read more.

Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are expressed, but M₁ and M₃ are the subtypes involved in mitogenic signaling. Stimulation with the cholinergic agonist carbachol leads to activation of the MAP kinase extracellular signal regulated kinase, together with the protein kinase Akt. The activation is fully dependent on the transactivation of the epidermal growth factor receptor (EGFR), which even appears to be the sole pathway for the muscarinic receptors to facilitate MAP kinase activation in HaCaT cells. The transactivation pathway involves a triple-membrane-passing process, based on activation of matrix metalloproteases, and extracellular ligand release; whereas phosphatidylinositol 3-kinase, Src family kinases or protein kinase C do not appear to be involved in MAP kinase activation. Furthermore, phosphorylation, ubiquitination and endocytosis of the EGF receptor after cholinergic transactivation are different from that induced by a direct stimulation with EGF, suggesting that ligands other than EGF itself mediate the cholinergic transactivation. Full article

(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)

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Open AccessArticle

The Daidzein Metabolite, 6,7,4'-Trihydroxyisoflavone, Is a Novel Inhibitor of PKCα in Suppressing Solar UV-Induced Matrix Metalloproteinase 1

by Tae-Gyu Lim, Jong-Eun Kim, Sung-Young Lee, Jun Seong Park, Myung Hun Yeom, Hanyong Chen, Ann M. Bode, Zigang Dong and Ki Won Lee

Int. J. Mol. Sci. 2014, 15(11), 21419-21432; https://doi.org/10.3390/ijms151121419 - 19 Nov 2014

Cited by 22 | Viewed by 8835

Abstract

Soy isoflavone is an attractive source of functional cosmetic materials with anti-wrinkle, whitening and skin hydration effects. After consumption, the majority of soy isoflavones are converted to their metabolites in the human gastrointestinal tract. To understand the physiological impact of soy isoflavone on [...] Read more.

Soy isoflavone is an attractive source of functional cosmetic materials with anti-wrinkle, whitening and skin hydration effects. After consumption, the majority of soy isoflavones are converted to their metabolites in the human gastrointestinal tract. To understand the physiological impact of soy isoflavone on the human body, it is necessary to evaluate and address the biological function of its metabolites. In this study, we investigated the effect of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), a major metabolite of daidzein, against solar UV (sUV)-induced matrix metalloproteinases (MMPs) in normal human dermal fibroblasts. MMPs play a critical role in the degradation of collagen in skin, thereby accelerating the aging process of skin. The mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MKK)3/6/p38 and MKK4/c-Jun N-terminal kinases (JNK) signaling pathways are known to modulate MMP-1 function, and their activation by sUV was significantly reduced by 6,7,4'-THIF pretreatment. Our results also indicated that the enzyme activity of protein kinase C (PKC)α, an upstream regulator of MKKs signaling, is suppressed by 6,7,4'-THIF using the in vitro kinase assay. Furthermore, the direct interaction between 6,7,4'-THIF and endogenous PKCα was confirmed using the pull-down assay. Not only sUV-induced MMP-1 expression, but also sUV-induced signaling pathway activation were decreased in PKCα knockdown cells. Overall, we elucidated the inhibitory effect of 6,7,4'-THIF on sUV-induced MMPs and suggest PKCα as its direct molecular target. Full article

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

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Open AccessArticle

Nicotinic Acid Increases Adiponectin Secretion from Differentiated Bovine Preadipocytes through G-Protein Coupled Receptor Signaling

by Christina Kopp, Afshin Hosseini, Shiva P. Singh, Petra Regenhard, Hamed Khalilvandi-Behroozyar, Helga Sauerwein and Manfred Mielenz

Int. J. Mol. Sci. 2014, 15(11), 21401-21418; https://doi.org/10.3390/ijms151121401 - 18 Nov 2014

Cited by 34 | Viewed by 6654

Abstract

The transition period in dairy cows (3 weeks prepartum until 3 weeks postpartum) is associated with substantial mobilization of energy stores, which is often associated with metabolic diseases. Nicotinic acid (NA) is an antilipolytic and lipid-lowering compound used to treat dyslipidaemia in humans, [...] Read more.

The transition period in dairy cows (3 weeks prepartum until 3 weeks postpartum) is associated with substantial mobilization of energy stores, which is often associated with metabolic diseases. Nicotinic acid (NA) is an antilipolytic and lipid-lowering compound used to treat dyslipidaemia in humans, and it also reduces non-esterified fatty acids in cattle. In mice the G-protein coupled receptor 109A (GPR109A) ligand NA positively affects the secretion of adiponectin, an important modulator of glucose and fat metabolism. In cattle, the corresponding data linking NA to adiponectin are missing. Our objective was to examine the effects of NA on adiponectin and AMPK protein abundance and the expression of mRNAs of related genes such as chemerin, an adipokine that enhances adiponectin secretion in vitro. Differentiated bovine adipocytes were incubated with pertussis toxin (PTX) to verify the involvement of GPR signaling, and treated with 10 or 15 µM NA for 12 or 24 h. NA increased adiponectin concentrations (p ≤ 0.001) and the mRNA abundances of GPR109A (p ≤ 0.05) and chemerin (p ≤ 0.01). Pre-incubation with PTX reduced the adiponectin response to NA (p ≤ 0.001). The NA-stimulated secretion of adiponectin and the mRNA expression of chemerin in the bovine adipocytes were suggestive of GPR signaling-dependent improved insulin sensitivity and/or adipocyte metabolism in dairy cows. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Structure–Biological Function Relationship Extended to Mitotic Arrest-Deficient 2-Like Protein Mad2 Native and Mutants-New Opportunity for Genetic Disorder Control

by Speranta Avram, Adina Milac, Maria Mernea, Dan Mihailescu, Mihai V. Putz and Catalin Buiu

Int. J. Mol. Sci. 2014, 15(11), 21381-21400; https://doi.org/10.3390/ijms151121381 - 18 Nov 2014

Cited by 4 | Viewed by 6015

Abstract

Overexpression of mitotic arrest-deficient proteins Mad1 and Mad2, two components of spindle assembly checkpoint, is a risk factor for chromosomal instability (CIN) and a trigger of many genetic disorders. Mad2 transition from inactive open (O-Mad2) to active closed (C-Mad2) conformations or Mad2 binding [...] Read more.

Overexpression of mitotic arrest-deficient proteins Mad1 and Mad2, two components of spindle assembly checkpoint, is a risk factor for chromosomal instability (CIN) and a trigger of many genetic disorders. Mad2 transition from inactive open (O-Mad2) to active closed (C-Mad2) conformations or Mad2 binding to specific partners (cell-division cycle protein 20 (Cdc20) or Mad1) were targets of previous pharmacogenomics studies. Here, Mad2 binding to Cdc20 and the interconversion rate from open to closed Mad2 were predicted and the molecular features with a critical contribution to these processes were determined by extending the quantitative structure-activity relationship (QSAR) method to large-size proteins such as Mad2. QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes. The most relevant descriptors identified for predicting Mad2 native and mutants action mechanism and their involvement in genetic disorders are the steric (van der Waals area and solvent accessible area and their subdivided) and energetic van der Waals energy descriptors. The reliability of our QSAR models is indicated by significant values of statistical coefficients: Cross-validated correlation q² (0.53–0.65) and fitted correlation r² (0.82–0.90). Moreover, based on established QSAR equations, we rationally design and analyze nine de novo Mad2 mutants as possible promoters of CIN. Full article

(This article belongs to the Special Issue Chemical Bond and Bonding 2015)

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Open AccessReview

Small Molecule Membrane Transporters in the Mammalian Podocyte: A Pathogenic and Therapeutic Target

by Cristina Zennaro, Mary Artero, Vittorio Di Maso and Michele Carraro

Int. J. Mol. Sci. 2014, 15(11), 21366-21380; https://doi.org/10.3390/ijms151121366 - 18 Nov 2014

Cited by 5 | Viewed by 6814

Abstract

The intriguingly complex glomerular podocyte has been a recent object of intense study. Researchers have sought to understand its role in the pathogenesis of common proteinuric diseases such as minimal change disease and focal segmental glomerular sclerosis. In particular, considerable effort has been [...] Read more.

The intriguingly complex glomerular podocyte has been a recent object of intense study. Researchers have sought to understand its role in the pathogenesis of common proteinuric diseases such as minimal change disease and focal segmental glomerular sclerosis. In particular, considerable effort has been directed towards the anatomic and functional barrier to macromolecular filtration provided by the secondary foot processes, but little attention has been paid to the potential of podocytes to handle plasma proteins beyond the specialization of the slit diaphragm. Renal membrane transporters in the proximal tubule have been extensively studied for decades, particularly in relation to drug metabolism and elimination. Recently, uptake and efflux transporters for small organic molecules have also been found in the glomerular podocyte, and we and others have found that these transporters can engage not only common pharmaceuticals but also injurious endogenous and exogenous agents. We have also found that the activity of podocyte transporters can be manipulated to inhibit pathogen uptake and efflux. It is conceivable that podocyte transporters may play a role in disease pathogenesis and may be a target for future drug development. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Multigenerational Study of Chemically Induced Cytotoxicity and Proliferation in Cultures of Human Proximal Tubular Cells

by Lawrence H. Lash, David A. Putt and Bavneet Benipal

Int. J. Mol. Sci. 2014, 15(11), 21348-21365; https://doi.org/10.3390/ijms151121348 - 18 Nov 2014

Cited by 4 | Viewed by 5195

Abstract

Primary cultures of human proximal tubular (hPT) cells are a useful experimental model to study transport, metabolism, cytotoxicity, and effects on gene expression of a diverse array of drugs and environmental chemicals because they are derived directly from the in vivo human kidney. [...] Read more.

Primary cultures of human proximal tubular (hPT) cells are a useful experimental model to study transport, metabolism, cytotoxicity, and effects on gene expression of a diverse array of drugs and environmental chemicals because they are derived directly from the in vivo human kidney. To extend the model to investigate longer-term processes, primary cultures (P0) were passaged for up to four generations (P1–P4). hPT cells retained epithelial morphology and stained positively for cytokeratins through P4, although cell growth and proliferation successively slowed with each passage. Necrotic cell death due to the model oxidants tert-butyl hydroperoxide (tBH) and methyl vinyl ketone (MVK) increased with increasing passage number, whereas that due to the selective nephrotoxicant S-(1,2-dichlorovinyl)-l-cysteine (DCVC) was modest and did not change with passage number. Mitochondrial activity was lower in P2–P4 cells than in either P0 or P1 cells. P1 and P2 cells were most sensitive to DCVC-induced apoptosis. DCVC also increased cell proliferation most prominently in P1 and P2 cells. Modest differences with respect to passage number and response to DCVC exposure were observed in expression of three key proteins (Hsp27, GADD153, p53) involved in stress response. Hence, although there are some modest differences in function with passage, these results support the use of multiple generations of hPT cells as an experimental model. Full article

(This article belongs to the Special Issue Renal Toxicology—Epidemiology and Mechanisms)

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Open AccessArticle

Se-Methylselenocysteine Inhibits Apoptosis Induced by Clusterin Knockdown in Neuroblastoma N2a and SH-SY5Y Cell Lines

by Chao Wang, Zhenyu Zeng, Qiong Liu, Renli Zhang and Jiazuan Ni

Int. J. Mol. Sci. 2014, 15(11), 21331-21347; https://doi.org/10.3390/ijms151121331 - 18 Nov 2014

Cited by 5 | Viewed by 7447

Abstract

Apoptosis, as a programmed cell death process, is essential for the maintenance of tissue function in organisms. Alteration of this process is linked to many diseases. Over-expression of clusterin (Clu) can antagonize apoptosis in various cells. Selenium (Se) is an essential trace element [...] Read more.

Apoptosis, as a programmed cell death process, is essential for the maintenance of tissue function in organisms. Alteration of this process is linked to many diseases. Over-expression of clusterin (Clu) can antagonize apoptosis in various cells. Selenium (Se) is an essential trace element for human health. Its biological function is also associated with cell apoptosis. To explore the function of Clu and the impact of Se in the process of apoptosis, several short-hairpin RNAs (shRNA) were designed for the construction of two sets of recombinant plasmids: one set for plasmid-transfection of mouse neuroblastoma N2a cells (N2a cells); and the other set for lentiviral infection of human neuroblastoma SH-SY5Y cells (SH-SY5Y cells). These shRNAs specifically and efficiently interfered with the intracellular expression of Clu at both the mRNA and protein levels. The Clu-knockdown cells showed apoptosis-related features, including down-regulation of antioxidative capacity and the Bcl-2/Bax ratio and up-regulation of caspase-8 activity. Se-methylselenocysteine (MSC) at an optimum concentration of 1 μM could reverse the alteration in antioxidative capacity, Bcl2/Bax ratio and caspase-8 activity caused by Clu-knockdown, thus inhibiting apoptosis and maintaining cell viability. The results hereby imply the potentiality of Clu and Se in neuroprotection. Full article

(This article belongs to the Special Issue RNA Interference)

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Open AccessArticle

Inhibition of p53 deSUMOylation Exacerbates Puromycin Aminonucleoside-Induced Apoptosis in Podocytes

by Lingyu Wang, Jingwei Zhu, Ming Fang, Tuaner Zhang, Hua Xie, Nan Wang, Nan Shen, Hui Guo, Bo Fu and Hongli Lin

Int. J. Mol. Sci. 2014, 15(11), 21314-21330; https://doi.org/10.3390/ijms151121314 - 18 Nov 2014

Cited by 20 | Viewed by 7153

Abstract

Apoptosis is a major cause of reduced podocyte numbers, which leads to proteinuria and/or glomerulosclerosis. Emerging evidence has indicated that deSUMOylation, a dynamic post-translational modification that reverses SUMOylation, is involved in the apoptosis of Burkitt’s lymphoma cells and cardiomyocytes; however, the impact of [...] Read more.

Apoptosis is a major cause of reduced podocyte numbers, which leads to proteinuria and/or glomerulosclerosis. Emerging evidence has indicated that deSUMOylation, a dynamic post-translational modification that reverses SUMOylation, is involved in the apoptosis of Burkitt’s lymphoma cells and cardiomyocytes; however, the impact of deSUMOylation on podocyte apoptosis remains unexplored. The p53 protein plays a major role in the pathogenesis of podocyte apoptosis, and p53 can be SUMOylated. Therefore, in the present study, we evaluated the effect of p53 deSUMOylation, which is regulated by sentrin/SUMO-specific protease 1 (SENP1), on podocyte apoptosis. Our results showed that SENP1 deficiency significantly increases puromycin aminonucleoside (PAN)-induced podocyte apoptosis. Moreover, SENP1 knockdown results in the accumulation of SUMOylated p53 protein and the increased expression of the p53 target pro-apoptotic genes, BAX, Noxa and PUMA, in podocytes during PAN stimulation. Thus, SENP1 may be essential for preventing podocyte apoptosis, at least partly through regulating the functions of p53 protein via deSUMOylation. The regulation of deSUMOylation may provide a novel strategy for the treatment of glomerular disorders that involve podocyte apoptosis. Full article

(This article belongs to the Collection Programmed Cell Death and Apoptosis)

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Open AccessArticle

Dexamethasone Improves Heat Stroke-Induced Multiorgan Dysfunction and Damage in Rats

by Chia-Chyuan Liu, Mei-Fen Shih, Yi-Szu Wen, Ying-Hsiu Lai and Tsai-Hsiu Yang

Int. J. Mol. Sci. 2014, 15(11), 21299-21313; https://doi.org/10.3390/ijms151121299 - 18 Nov 2014

Cited by 16 | Viewed by 6671

Abstract

Dexamethasone (DXM) is known as an immunosuppressive drug used for inflammation control. In the present study, we attempted to examine whether DXM administration could attenuate the hypercoagulable state and the overproduction of pro-inflammatory cytokines, improve arterial hypotension, cerebral ischemia and damage, and vital [...] Read more.

Dexamethasone (DXM) is known as an immunosuppressive drug used for inflammation control. In the present study, we attempted to examine whether DXM administration could attenuate the hypercoagulable state and the overproduction of pro-inflammatory cytokines, improve arterial hypotension, cerebral ischemia and damage, and vital organ failure in a rat model of heat stroke. The results indicated that all the rats suffering from heat stroke showed high serum levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), accompanied with increased prothrombin time, activated partial thromboplastin time and D-D dimer, and decreased protein C. During the induction period of heat stroke, plasma levels of blood urea nitrogen (BUN), creatinine, glutamic oxaloacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), and alkaline phosphatase (ALP), were consistently increased. High striatal levels of glycerol, glutamate, and lactate/pyruvate were simultaneously detected. On the contrary, the mean arterial pressure, plasma levels of interleukin-10 (IL-10), and local cerebral blood flow at the striatum were all decreased. Importantly, intravenous administration of DXM substantially ameliorated the circulatory dysfunction, systematic inflammation, hypercoagulable state, cerebral ischemia and damage during the induction period of heat stroke. These findings demonstrated that DXM may be an alternative therapy that can ameliorate heat stroke victims by attenuating activated coagulation, systemic inflammation, and vital organ ischemia/injury during heat stroke. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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Enhanced Levels of Interleukin-8 Are Associated with Hepatitis B Virus Infection and Resistance to Interferon-Alpha Therapy

by Kai Yang, Shi-He Guan, Hao Zhang, Ying Pan, Yuan-Yuan Wu, Ai-Hua Wang and Bei-Bei Sun

Int. J. Mol. Sci. 2014, 15(11), 21286-21298; https://doi.org/10.3390/ijms151121286 - 17 Nov 2014

Cited by 19 | Viewed by 6401

Abstract

The objective of this study was to analyze the expression levels of IL-8 in serum and liver tissues from patients with chronic hepatitis B (CHB) infection and to investigate whether IL-8 may antagonize interferon-alpha (IFN-α) antiviral activity against HBV. IL-8 expression in serum [...] Read more.

The objective of this study was to analyze the expression levels of IL-8 in serum and liver tissues from patients with chronic hepatitis B (CHB) infection and to investigate whether IL-8 may antagonize interferon-alpha (IFN-α) antiviral activity against HBV. IL-8 expression in serum was determined by enzyme linked immunosorbent assay (ELISA), and fluorescence-based quantitative real-time PCR (RT-qPCR) was used to measure IL-8 mRNA in peripheral blood mononuclear cells (PBMCs) in patients with CHB. IL-8 protein expression was detected in liver biopsy tissues by immunohistochemistry. In addition, the differences in serum IL-8 and PBMCs mRNA levels were also observed in patients with different anti-viral responses to IFN-α. Compared to normal controls, serum IL-8 protein and mRNA levels were increased in CHB patients, IL-8 levels were positively correlated with the severity of liver inflammation/fibrosis. Moreover, serum IL-8 protein and mRNA levels were positively correlated with serum alanine aminotransferase (ALT) level and negatively correlated with serum prealbumin (PA) level. IL-8 expression was mainly located in portal area of liver tissues and was increased with the severity of liver inflammation and fibrosis stage. The expression serum and mRNA levels of IL-8 in the CHB patients with a complete response to IFN-α are significantly lower than that of the patients with non-response to IFN-α treatment. It is suggested that IL-8 might play important roles in the pathogenesis of CHB. Moreover, interferon resistance may be related to the up-regulation of IL-8 expression in the patients did not respond to IFN-α treatment. Full article

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

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Open AccessReview

Acquiring Chondrocyte Phenotype from Human Mesenchymal Stem Cells under Inflammatory Conditions

by Masahiro Kondo, Kunihiro Yamaoka and Yoshiya Tanaka

Int. J. Mol. Sci. 2014, 15(11), 21270-21285; https://doi.org/10.3390/ijms151121270 - 17 Nov 2014

Cited by 22 | Viewed by 12527

Abstract

An inflammatory milieu breaks down the cartilage matrix and induces chondrocyte apoptosis, resulting in cartilage destruction in patients with cartilage degenerative diseases, such as rheumatoid arthritis or osteoarthritis. Because of the limited regenerative ability of chondrocytes, defects in cartilage are irreversible and difficult [...] Read more.

An inflammatory milieu breaks down the cartilage matrix and induces chondrocyte apoptosis, resulting in cartilage destruction in patients with cartilage degenerative diseases, such as rheumatoid arthritis or osteoarthritis. Because of the limited regenerative ability of chondrocytes, defects in cartilage are irreversible and difficult to repair. Mesenchymal stem cells (MSCs) are expected to be a new tool for cartilage repair because they are present in the cartilage and are able to differentiate into multiple lineages of cells, including chondrocytes. Although clinical trials using MSCs for patients with cartilage defects have already begun, its efficacy and repair mechanisms remain unknown. A PubMed search conducted in October 2014 using the following medical subject headings (MeSH) terms: mesenchymal stromal cells, chondrogenesis, and cytokines resulted in 204 articles. The titles and abstracts were screened and nine articles relevant to “inflammatory” cytokines and “human” MSCs were identified. Herein, we review the cell biology and mechanisms of chondrocyte phenotype acquisition from human MSCs in an inflammatory milieu and discuss the clinical potential of MSCs for cartilage repair. Full article

(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)

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Nickel Nanoparticles Exposure and Reproductive Toxicity in Healthy Adult Rats

by Lu Kong, Meng Tang, Ting Zhang, Dayong Wang, Ke Hu, Weiqi Lu, Chao Wei, Geyu Liang and Yuepu Pu

Int. J. Mol. Sci. 2014, 15(11), 21253-21269; https://doi.org/10.3390/ijms151121253 - 17 Nov 2014

Cited by 156 | Viewed by 14329

Abstract

Nickel is associated with reproductive toxicity. However, the reproductive toxicity of nickel nanoparticles (Ni NPs) is unclear. Our goal was to determine the association between nickel nanoparticle exposure and reproductive toxicity. According to the one-generation reproductive toxicity standard, rats were exposed to nickel [...] Read more.

Nickel is associated with reproductive toxicity. However, the reproductive toxicity of nickel nanoparticles (Ni NPs) is unclear. Our goal was to determine the association between nickel nanoparticle exposure and reproductive toxicity. According to the one-generation reproductive toxicity standard, rats were exposed to nickel nanoparticles by gavage and we selected indicators including sex hormone levels, sperm motility, histopathology, and reproductive outcome etc. Experimental results showed nickel nanoparticles increased follicle stimulating hormone (FSH) and luteinizing hormone (LH), and lowered etradiol (E₂) serum levels at a dose of 15 and 45 mg/kg in female rats. Ovarian lymphocytosis, vascular dilatation and congestion, inflammatory cell infiltration, and increase in apoptotic cells were found in ovary tissues in exposure groups. For male rats, the weights decreased gradually, the ratio of epididymis weight over body weight increased, the motility of rat sperm changed, and the levels of FSH and testosterone (T) diminished. Pathological results showed the shedding of epithelial cells of raw seminiferous tubule, disordered arrangement of cells in the tube, and the appearance of cell apoptosis and death in the exposure group. At the same time, Ni NPs resulted in a change of the reproductive index and the offspring development of rats. Further research is needed to elucidate exposure to human populations and mechanism of actions. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles 2014)

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From Plasminogen to Plasmin: Role of Plasminogen Receptors in Human Cancer

by Miroslava Didiasova, Lukasz Wujak, Malgorzata Wygrecka and Dariusz Zakrzewicz

Int. J. Mol. Sci. 2014, 15(11), 21229-21252; https://doi.org/10.3390/ijms151121229 - 17 Nov 2014

Cited by 60 | Viewed by 13342

Abstract

Cell surface-associated proteolysis mediated by plasmin (PLA) is an essential feature of wound healing, angiogenesis and cell invasion, processes that are dysregulated in cancer development, progression and systemic spread. The generation of PLA, initiated by the binding of its precursor plasminogen (PLG) to [...] Read more.

Cell surface-associated proteolysis mediated by plasmin (PLA) is an essential feature of wound healing, angiogenesis and cell invasion, processes that are dysregulated in cancer development, progression and systemic spread. The generation of PLA, initiated by the binding of its precursor plasminogen (PLG) to the cell surface, is regulated by an array of activators, inhibitors and receptors. In this review, we will highlight the importance of the best-characterized components of the PLG/PLA cascade in the pathogenesis of cancer focusing on the role of the cell surface-PLG receptors (PLG-R). PLG-R overexpression has been associated with poor prognosis of cancer patients and resistance to chemotherapy. We will also discuss recent findings on the molecular mechanisms regulating cell surface expression and distribution of PLG-R. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Molecular Characterization of the BMP7 Gene and Its Potential Role in Shell Formation in Pinctada martensii

by Fang Yan, Shaojie Luo, Yu Jiao, Yuewen Deng, Xiaodong Du, Ronglian Huang, Qingheng Wang and Weiyao Chen

Int. J. Mol. Sci. 2014, 15(11), 21215-21228; https://doi.org/10.3390/ijms151121215 - 17 Nov 2014

Cited by 30 | Viewed by 6345

Abstract

Bone morphogenetic protein 7 (BMP7), also called osteogenetic protein-1, can induce bone formation. In this study, the obtained full-length cDNA of BMP7 from Pinctada martensii (Pm-BMP7) was 2972 bp, including a 5'-untranslated region (UTR) of 294 bp, an open reading fragment of 1290 [...] Read more.

Bone morphogenetic protein 7 (BMP7), also called osteogenetic protein-1, can induce bone formation. In this study, the obtained full-length cDNA of BMP7 from Pinctada martensii (Pm-BMP7) was 2972 bp, including a 5'-untranslated region (UTR) of 294 bp, an open reading fragment of 1290 bp encoding a 429 amino acid polypeptide and a 3'-UTR of 1388 bp. The deduced protein sequence of Pm-BMP7 contained a signal peptide, a pro-domain and a mature peptide. The mature peptide consisted of 135 amino acids and included a transforming growth factor β family domain with six shared cysteine residues. The protein sequence of Pm-BMP7 showed 66% identity with that from Crassostrea gigas. Two unigenes encoding Pm-BMPRI (Pm-BMP receptor I) and Pm-BMPRII were obtained from the transcriptome database of P. martensii. Tissue expression analysis demonstrated Pm-BMP7 and Pm-BMPRI were highly expressed in the mantle (shell formation related-tissue), while Pm-BMPRII was highly expressed in the foot. After inhibiting Pm-BMP7 expression using RNA interference (RNAi) technology, Pm-BMP7 mRNA was significantly down-regulated (p < 0.05) in the mantle pallium (nacre formation related-tissue) and the mantle edge (prismatic layer formation related-tissue). The microstructure, observed using a scanning electron microscope, indicated a disordered growth status in the nacre and obvious holes in the prismatic layer in the dsRNA-Pm-BMP7 injected-group. These results suggest that Pm-BMP7 plays a crucial role in the nacre and prismatic layer formation process of the shell. Full article

(This article belongs to the Section Biochemistry)

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Plasma Levels of Homocysteine and Cysteine Increased in Pediatric NAFLD and Strongly Correlated with Severity of Liver Damage

by Anna Pastore, Anna Alisi, Gianna Di Giovamberardino, Annalisa Crudele, Sara Ceccarelli, Nadia Panera, Carlo Dionisi-Vici and Valerio Nobili

Int. J. Mol. Sci. 2014, 15(11), 21202-21214; https://doi.org/10.3390/ijms151121202 - 17 Nov 2014

Cited by 89 | Viewed by 10626

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of metabolic abnormalities ranging from simple triglyceride accumulation in the hepatocytes to hepatic steatosis with inflammation, ballooning and fibrosis. It has been demonstrated that the pathogenesis of NAFLD involves increased oxidative stress, with consumption of [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of metabolic abnormalities ranging from simple triglyceride accumulation in the hepatocytes to hepatic steatosis with inflammation, ballooning and fibrosis. It has been demonstrated that the pathogenesis of NAFLD involves increased oxidative stress, with consumption of the major cellular antioxidant, glutathione (GSH). Liver has a fundamental role in sulfur compound metabolism, although the data reported on plasma thiols status in NAFLD are conflicting. We recruited 63 NAFLD patients, and we analyzed all plasma thiols, such as homocysteine (Hcy), cysteine (Cys), cysteinylglycine (CysGly) and GSH, by high-performance liquid chromatography (HPLC) with fluorescence detection. Hcy, Cys and CysGly plasma levels increased in NAFLD patients (p < 0.0001); whereas GSH levels were decreased in NAFLD patients when compared to controls (p < 0.0001). On the contrary, patients with steatohepatitis exhibited lower levels of Hcy and Cys than subjects without. Furthermore, a positive correlation was found between Hcy and Cys and the presence of fibrosis in children with NAFLD. Taken together, these data demonstrated a defective hepatic sulfur metabolism in children with NAFLD, and that high levels of Hcy and Cys probably correlates with a pattern of more severe histological liver damage, due to mechanisms that require further studies. Full article

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

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The Stability of G6PD Is Affected by Mutations with Different Clinical Phenotypes

by Saúl Gómez-Manzo, Jessica Terrón-Hernández, Ignacio De la Mora-De la Mora, Abigail González-Valdez, Jaime Marcial-Quino, Itzhel García-Torres, America Vanoye-Carlo, Gabriel López-Velázquez, Gloria Hernández-Alcántara, Jesús Oria-Hernández, Horacio Reyes-Vivas and Sergio Enríquez-Flores

Int. J. Mol. Sci. 2014, 15(11), 21179-21201; https://doi.org/10.3390/ijms151121179 - 17 Nov 2014

Cited by 59 | Viewed by 7801

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency worldwide, causing a wide spectrum of conditions with severity classified from the mildest (Class IV) to the most severe (Class I). To correlate mutation sites in the G6PD with the resulting phenotypes, we [...] Read more.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency worldwide, causing a wide spectrum of conditions with severity classified from the mildest (Class IV) to the most severe (Class I). To correlate mutation sites in the G6PD with the resulting phenotypes, we studied four naturally occurring G6PD variants: Yucatan, Nashville, Valladolid and Mexico City. For this purpose, we developed a successful over-expression method that constitutes an easier and more precise method for obtaining and characterizing these enzymes. The k_cat (catalytic constant) of all the studied variants was lower than in the wild-type. The structural rigidity might be the cause and the most evident consequence of the mutations is their impact on protein stability and folding, as can be observed from the protein yield, the T₅₀ (temperature where 50% of its original activity is retained) values, and differences on hydrophobic regions. The mutations corresponding to more severe phenotypes are related to the structural NADP⁺ region. This was clearly observed for the Classes III and II variants, which became more thermostable with increasing NADP⁺, whereas the Class I variants remained thermolabile. The mutations produce repulsive electric charges that, in the case of the Yucatan variant, promote increased disorder of the C-terminus and consequently affect the binding of NADP⁺, leading to enzyme instability. Full article

(This article belongs to the Section Biochemistry)

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Cobalt Alleviates GA-Induced Programmed Cell Death in Wheat Aleurone Layers via the Regulation of H₂O₂ Production and Heme Oxygenase-1 Expression

by Mingzhu Wu, Jiale Li, Fangquan Wang, Feng Li, Jun Yang and Wenbiao Shen

Int. J. Mol. Sci. 2014, 15(11), 21155-21178; https://doi.org/10.3390/ijms151121155 - 14 Nov 2014

Cited by 6 | Viewed by 6245

Abstract

Heme oxygenase-1 (HO-1) and hydrogen peroxide (H₂O₂) are key signaling molecules that are produced in response to various environmental stimuli. Here, we demonstrate that cobalt is able to delay gibberellic acid (GA)-induced programmed cell death (PCD) in wheat aleurone [...] Read more.

Heme oxygenase-1 (HO-1) and hydrogen peroxide (H₂O₂) are key signaling molecules that are produced in response to various environmental stimuli. Here, we demonstrate that cobalt is able to delay gibberellic acid (GA)-induced programmed cell death (PCD) in wheat aleurone layers. A similar response was observed when samples were pretreated with carbon monoxide (CO) or bilirubin (BR), two end-products of HO catalysis. We further observed that increased HO-1 expression played a role in the cobalt-induced alleviation of PCD. The application of HO-1-specific inhibitor, zinc protoporphyrin-IX (ZnPPIX), substantially prevented the increases of HO-1 activity and the alleviation of PCD triggered by cobalt. The stimulation of HO-1 expression, and alleviation of PCD might be caused by the initial H₂O₂ production induced by cobalt. qRT-PCR and enzymatic assays revealed that cobalt-induced gene expression and the corresponding activities of superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX), three enzymes that metabolize reactive oxygen species, were consistent with the H₂O₂ accumulation during GA treatment. These cobalt responses were differentially blocked by co-treatment with ZnPPIX. We therefore suggest that HO-1 functions in the cobalt-triggered alleviation of PCD in wheat aleurone layers, which is also dependent on the enhancement of the activities of antioxidant enzymes. Full article

(This article belongs to the Section Biochemistry)

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The eTOX Data-Sharing Project to Advance in Silico Drug-Induced Toxicity Prediction

by Montserrat Cases, Katharine Briggs, Thomas Steger-Hartmann, François Pognan, Philippe Marc, Thomas Kleinöder, Christof H. Schwab, Manuel Pastor, Jörg Wichard and Ferran Sanz

Int. J. Mol. Sci. 2014, 15(11), 21136-21154; https://doi.org/10.3390/ijms151121136 - 14 Nov 2014

Cited by 53 | Viewed by 11755

Abstract

The high-quality in vivo preclinical safety data produced by the pharmaceutical industry during drug development, which follows numerous strict guidelines, are mostly not available in the public domain. These safety data are sometimes published as a condensed summary for the few compounds that [...] Read more.

The high-quality in vivo preclinical safety data produced by the pharmaceutical industry during drug development, which follows numerous strict guidelines, are mostly not available in the public domain. These safety data are sometimes published as a condensed summary for the few compounds that reach the market, but the majority of studies are never made public and are often difficult to access in an automated way, even sometimes within the owning company itself. It is evident from many academic and industrial examples, that useful data mining and model development requires large and representative data sets and careful curation of the collected data. In 2010, under the auspices of the Innovative Medicines Initiative, the eTOX project started with the objective of extracting and sharing preclinical study data from paper or pdf archives of toxicology departments of the 13 participating pharmaceutical companies and using such data for establishing a detailed, well-curated database, which could then serve as source for read-across approaches (early assessment of the potential toxicity of a drug candidate by comparison of similar structure and/or effects) and training of predictive models. The paper describes the efforts undertaken to allow effective data sharing intellectual property (IP) protection and set up of adequate controlled vocabularies) and to establish the database (currently with over 4000 studies contributed by the pharma companies corresponding to more than 1400 compounds). In addition, the status of predictive models building and some specific features of the eTOX predictive system (eTOXsys) are presented as decision support knowledge-based tools for drug development process at an early stage. Full article

(This article belongs to the Special Issue Computational Toxicology: Predicting Potential Toxicity of Drugs and Therapeutics)

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Bioactive Peptides in Cereals and Legumes: Agronomical, Biochemical and Clinical Aspects

by Marco Malaguti, Giovanni Dinelli, Emanuela Leoncini, Valeria Bregola, Sara Bosi, Arrigo F. G. Cicero and Silvana Hrelia

Int. J. Mol. Sci. 2014, 15(11), 21120-21135; https://doi.org/10.3390/ijms151121120 - 14 Nov 2014

Cited by 147 | Viewed by 11389

Abstract

Cereals and legumes are key components of a healthy and balanced diet. Accordingly, many national nutritional guidelines emphasize their health promoting properties by placing them at the base of nutritional food pyramids. This concept is further validated by the observed correlation between a [...] Read more.

Cereals and legumes are key components of a healthy and balanced diet. Accordingly, many national nutritional guidelines emphasize their health promoting properties by placing them at the base of nutritional food pyramids. This concept is further validated by the observed correlation between a lower risk and occurrence of chronic diseases and the adherence to dietary patterns, like the Mediterranean diet, in which cereal grains, legumes and derived products represent a staple food. In the search for a dietary approach to control/prevent chronic degenerative diseases, protein derived bioactive peptides may represent one such source of health-enhancing components. These peptides may already be present in foods as natural components or may derive from hydrolysis by chemical or enzymatic treatments (digestion, hydrolysis or fermentation). Many reports are present in the literature regarding the bioactivity of peptides in vitro and a wide range of activities has been described, including antimicrobial properties, blood pressure-lowering (ACE inhibitory) effects, cholesterol-lowering ability, antithrombotic and antioxidant activities, enhancement of mineral absorption/bioavailability, cyto- or immunomodulatory effects, and opioid-like activities. However it is difficult to translate these observed effects to human. In fact, the active peptide may be degraded during digestion, or may not be absorbed or reach the target tissues at a concentration necessary to exert its function. This review will focus on bioactive peptides identified in cereals and legumes, from an agronomical and biochemical point of view, including considerations about requirements for the design of appropriate clinical trials necessary for the assessment of their nutraceutical effect in vivo. Full article

(This article belongs to the Special Issue Bioactive Proteins and Peptides Derived from Food)

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Growth Suppression of Colorectal Cancer by Plant-Derived Multiple mAb CO17-1A × BR55 via Inhibition of ERK1/2 Phosphorylation

by Dong Hoon Kwak, Ghislain Moussavou, Ju Hyoung Lee, Sung Youn Heo, Kisung Ko, Kyung-A Hwang, Seung-Joo Jekal and Young-Kug Choo

Int. J. Mol. Sci. 2014, 15(11), 21105-21119; https://doi.org/10.3390/ijms151121105 - 14 Nov 2014

Cited by 1 | Viewed by 6984

Abstract

We have generated the transgenic Tabaco plants expressing multiple monoclonal antibody (mAb) CO7-1A × BR55 by cross-pollinating with mAb CO17-1A and mAb BR55. We have demonstrated the anti-cancer effect of plant-derived multiple mAb CO17-1A × BR55. We find that co-treatment of colorectal mAbs [...] Read more.

We have generated the transgenic Tabaco plants expressing multiple monoclonal antibody (mAb) CO7-1A × BR55 by cross-pollinating with mAb CO17-1A and mAb BR55. We have demonstrated the anti-cancer effect of plant-derived multiple mAb CO17-1A × BR55. We find that co-treatment of colorectal mAbs (anti-epithelial cellular adhesion molecule (EpCAM), plant-derived monoclonal antibody (mAb^P) CO17-1A and mAb^P CO17-1A × BR55) with RAW264.7 cells significantly inhibited the cell growth in SW620 cancer cells. In particular, multi mAb^P CO17-1A × BR55 significantly and efficiently suppressed the growth of SW620 cancer cells compared to another mAbs. Apoptotic death-positive cells were significantly increased in the mAb^P CO17-1A × BR55-treated. The mAb^P CO17-1A × BR55 treatment significantly decreased the expression of B-Cell lymphoma-2 (BCl-2), but the expression of Bcl-2-associated X protein (Bax), and cleaved caspase-3 were markedly increased. In vivo, the mAb^P CO17-1A × BR55 significantly and efficiently inhibited the growth of colon tumors compared to another mAbs. The apoptotic cell death and inhibition of pro-apoptotic proteins expression were highest by treatment with mAb^P CO17-1A × BR55. In addition, the mAb^P CO17-1A × BR55 significantly inhibited the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in cancer cells and tumors. Therefore, this study results suggest that multiple mAb^P CO17-1A × BR55 has a significant effect on apoptosis-mediated anticancer by suppression of ERK1/2 phosphorylation in colon cancer compared to another mAbs. In light of these results, further clinical investigation should be conducted on mAb^P CO17-1A × BR55 to determine its possible chemopreventive and/or therapeutic efficacy against human colon cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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Effects of Melatonin on the Proliferation and Apoptosis of Sheep Granulosa Cells under Thermal Stress

by Yao Fu, Chang-Jiu He, Peng-Yun Ji, Zhi-Yong Zhuo, Xiu-Zhi Tian, Feng Wang, Dun-Xian Tan and Guo-Shi Liu

Int. J. Mol. Sci. 2014, 15(11), 21090-21104; https://doi.org/10.3390/ijms151121090 - 14 Nov 2014

Cited by 57 | Viewed by 7536

Abstract

The cross-talk between oocyte and somatic cells plays a crucial role in the regulation of follicular development and oocyte maturation. As a result, granulosa cell apoptosis causes follicular atresia. In this study, sheep granulosa cells were cultured under thermal stress to induce apoptosis, [...] Read more.

The cross-talk between oocyte and somatic cells plays a crucial role in the regulation of follicular development and oocyte maturation. As a result, granulosa cell apoptosis causes follicular atresia. In this study, sheep granulosa cells were cultured under thermal stress to induce apoptosis, and melatonin (MT) was examined to evaluate its potential effects on heat-induced granulosa cell injury. The results demonstrated that the Colony Forming Efficiency (CFE) of granulosa cells was significantly decreased (heat 19.70% ± 1.29% vs. control 26.96% ± 1.81%, p < 0.05) and the apoptosis rate was significantly increased (heat 56.16% ± 13.95% vs. control 22.80% ± 12.16%, p < 0.05) in granulosa cells with thermal stress compared with the control group. Melatonin (10⁻⁷ M) remarkably reduced the negative effects caused by thermal stress in the granulosa cells. This reduction was indicated by the improved CFE and decreased apoptotic rate of these cells. The beneficial effects of melatonin on thermal stressed granulosa cells were not inhibited by its membrane receptor antagonist luzindole. A mechanistic exploration indicated that melatonin (10⁻⁷ M) down-regulated p53 and up-regulated Bcl-2 and LHR gene expression of granulosa cells under thermal stress. This study provides evidence for the molecular mechanisms of the protective effects of melatonin on granulosa cells during thermal stress. Full article

(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)

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Boric Ester-Type Molten Salt via Dehydrocoupling Reaction

by Noriyoshi Matsumi, Yoshiyuki Toyota, Prerna Joshi, Puhup Puneet, Raman Vedarajan and Toshihiro Takekawa

Int. J. Mol. Sci. 2014, 15(11), 21080-21089; https://doi.org/10.3390/ijms151121080 - 14 Nov 2014

Cited by 1 | Viewed by 7359

Abstract

Novel boric ester-type molten salt was prepared using 1-(2-hydroxyethyl)-3-methylimidazolium chloride as a key starting material. After an ion exchange reaction of 1-(2-hydroxyethyl)-3-methylimidazolium chloride with lithium (bis-(trifluoromethanesulfonyl) imide) (LiNTf₂), the resulting 1-(2-hydroxyethyl)-3-methylimidazolium NTf₂ was reacted with 9-borabicyclo[3.3.1]nonane (9-BBN) to [...] Read more.

Novel boric ester-type molten salt was prepared using 1-(2-hydroxyethyl)-3-methylimidazolium chloride as a key starting material. After an ion exchange reaction of 1-(2-hydroxyethyl)-3-methylimidazolium chloride with lithium (bis-(trifluoromethanesulfonyl) imide) (LiNTf₂), the resulting 1-(2-hydroxyethyl)-3-methylimidazolium NTf₂ was reacted with 9-borabicyclo[3.3.1]nonane (9-BBN) to give the desired boric ester-type molten salt in a moderate yield. The structure of the boric ester-type molten salt was supported by ¹H-, ¹³C-, ¹¹B- and ¹⁹F-NMR spectra. In the presence of two different kinds of lithium salts, the matrices showed an ionic conductivity in the range of 1.1 × 10⁻⁴–1.6 × 10⁻⁵ S cm⁻¹ at 51 °C. This was higher than other organoboron molten salts ever reported. Full article

(This article belongs to the Special Issue Green Chemistry and the Biorefinery)

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Int. J. Mol. Sci., Volume 15, Issue 11 (November 2014) – 130 articles , Pages 19330-21602

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