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The type B trichothecene mycotoxin deoxynivalenol (DON), colloquially known as "vomitoxin", is the most commonly detected trichothecene in cereal-based foods, exerting acute and chronic toxic effects on animals and causing serious safety-related concerns. At the cellular and molecular levels, DON can inhibit macromolecule synthesis by binding to ribosomes and may disrupt cell proliferation, differentiation and apoptosis. However, the molecular mechanisms underlying the cytotoxicity of DON remain to be determined. Here, we identified β-catenin, the key signal transducer of the Wnt cascade, as a novel target of DON by quantitative real-time PCR and Western blot analysis in human embryonic kidney 293T and colorectal SW480 cells treated with DON at half IC 50 (50 ng/mL for HEK293T and 1 μg/mL for SW480). Further analysis showed that neither posttranslational modification nor nuclear accumulation of β-catenin was affected post DON treatment. Moreover, we found that the β-catenin-dependent canonical Wnt signaling pathway, which regulates many biological processes during embryonic development and adult tissue homeostasis, was involved in DON-induced inhibition of cell proliferation. Then, we determined that the β-catenin/c-Myc axis was essential for this process, as the DON-induced inhibition of cell proliferation was efficiently rescued by restoration of β-catenin or c-Myc levels. Our results advance the current understanding of the molecular toxicological mechanism of DON and provide a new perspective on strategies for the prevention and control of mycotoxins. [ABSTRACT FROM AUTHOR]

Melatonin reversed arginine vasopressin-induced apoptosis on H9c2 cardiomyoblasts by increasing Mst1-Nrf2 activity, yielding anti-oxidative enzyme up-regulation and lowered apoptosis; thus, it could serve as a potential heart failure treatment. [Display omitted] Heart failure patients have elevated arginine vasopressin (AVP) levels, which are involved in inducing peripheral vasoconstriction and cardiac hypertrophy. This hypertrophy, along with cardiomyocyte apoptosis, results from oxidative stress. Therefore, the antioxidant drug, melatonin (Mel), is commonly used to treat cardiac hypertrophy and apoptosis; however, whether it could alleviate AVP-induced myocardial injury remains to be addressed. In this study, high AVP doses were found to induce H9c2 cardiomyoblast apoptosis, demonstrated by increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, pro-apoptotic B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) up-regulation, and anti-apoptotic Bcl-2 downregulation. This AVP-induced apoptotic increase, along with lowered cell viability, was also associated with higher reactive oxygen species (ROS) levels and lowered mitochondrial membrane potentials (MMP), which were all reversed upon Mel administration. Further investigations found that apoptosis, ROS, and MMP outcomes under high AVP were associated with Mst1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway suppression, yielding mitochondrial dysfunction, and Mel reversed them via promoting Mst1 phosphorylation, which then activated Nrf2 to increase anti-oxidative enzyme production. These findings were supported by siRNA gene suppression, where knocking down either Nrf2 or Mst1 abrogated the anti-apoptotic effects of Mel in cardiomyoblasts. Therefore, Mel could reduce cardiomyoblast apoptosis under high AVP levels, via Mst1-Nrf2 pathway re-activation, to enhance anti-oxidative responses. [ABSTRACT FROM AUTHOR]

Currently, there is lack of cure or disease-modifying treatment for Alzheimer’s disease (AD). Chinese herbal medicine (CHM) is purported to ameliorate AD progression, perhaps by promoting hippocampal neurogenesis. Here, we conducted an updated systematic review to investigate the efficacy and safety of CHM for AD based on high-quality randomized controlled trials (RCTs) and reviewed its possible mechanisms of neurogenesis according to animal-based researches. Twenty eligible studies with 1767 subjects were identified in eight database searches from inception to February 2017. The studies investigated the CHM versus placebo (n = 3), CHM versus donepezil (n = 9 with 10 comparisons), CHM plus donepezil versus donepezil (n = 3), CHM versus a basic treatment (n = 3), and CHM plus basic treatment versus basic treatment (n = 2). Adverse events were reported in 11 studies, analyzed but not observed in 3 studies, and not analyzed in 6 studies. The main findings of present study are that CHM as adjuvant therapy exerted an additive anti-AD benefit, whereas the efficacy of CHM as a monotherapy was inconclusive. Additionally, CHMs were generally safe and well tolerated in AD patients. Active molecules in frequent constituents of CHMs can alter multiple critical signaling pathways regulating neurogenesis. Thus, the present evidence supports, to a limited extent, the conclusion that CHM can be recommended for routine use in AD patients and its possible mechanism enhances adult hippocampal neurogenesis through activating the multi-signal pathways. [ABSTRACT FROM AUTHOR]