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Inadequate oxygen availability-for instance at high altitudes-leads to hippocampal neurodegeneration and memory impairment. Although oxidative stress is one factor, the mechanism underlying the effects of hypobaric hypoxia (HH) are unclear, and effective strategies for preventing the resultant damage to the brain are limited. In the present study, we demonstrate that ingesting dihydromyricetin (DM) protects against memory impairment in adult rats subjected to HH for 7 days, equivalent to an altitude of 5000 m above sea level. Moreover, DM treatment stimulated mitochondrial biogenesis and improved mitochondrial morphology and function, suppressed the generation of reactive oxygen species, and reduced lipid peroxidation in the hippocampus. In HT-22 cells exposed to hypoxic conditions, the neuroprotective effects of DM were shown to be exerted via attenuation of oxidative stress through sirtuin 3-induced forkhead box O3 deacetylation.

Diabetic angiopathy is a major diabetes-specific complication that often begins with endothelial dysfunction induced by hyperglycemia; however, the pathological mechanisms of this progression remain unclear. Ampelopsin is a natural flavonol that has strong antioxidant activity, but little information is available regarding its antidiabetic effect. This study focused on the effect of ampelopsin on hyperglycemia-induced oxidative damage and the underlying mechanism of this effect in human umbilical vein endothelial cells (HUVECs). We found that hyperglycemia impaired autophagy in HUVECs through the inhibition of AMP-activated protein kinase (AMPK), which directly led to endothelial cell damage. Ampelopsin significantly attenuated the detrimental effect of hyperglycemia-induced cell dysfunction in a concentration-dependent manner in HUVECs. Ampelopsin significantly upregulated LC3-II, Beclin1, and Atg5 protein levels but downregulated p62 protein levels in HUVECs. Transmission electron microscopy and confocal microscopy indicated that ampelopsin notably induced autophagosomes and LC3-II dots, respectively. Additionally, the autophagy-specific inhibitor 3-MA, as well as Atg5 and Beclin1 siRNA pretreatment, markedly attenuated ampelopsin-induced autophagy, which subsequently abolished the protective effect of ampelopsin against hyperglycemia in HUVECs. Moreover, ampelopsin also increased AMPK activity and inhibited mTOR (mammalian target of rapamycin) complex activation. Ampelopsin-induced autophagy was attenuated by the AMPK antagonist compound C but strengthened by the AMPK agonist AICAR (5-minoimidazole-4-carboxamide ribonucleotide). Furthermore, AMPK siRNA transfection eliminated ampelopsin's alleviation of cell injury induced by hyperglycemia. The protective effect of ampelopsin against hyperglycemia-induced cell damage, which functions by targeting autophagy via AMPK activation, makes it a promising pharmacological treatment for type-2 diabetes., (© 2015 International Union of Biochemistry and Molecular Biology.)

Insulin resistance in skeletal muscle is a key feature in the pathogenesis of type 2 diabetes (T2D) that often manifests early in its development. Pharmaceutical and dietary strategies have targeted insulin resistance to control T2D, and many natural products with excellent pharmacological properties are good candidates for the control or prevention of T2D. Dihydromyricetin (DHM) is a natural flavonol which provides a wide range of health benefits including anti-inflammatory and anti-tumor effects. However, little information is available regarding the effects of DHM on skeletal muscle insulin sensitivity as well as the underlying mechanisms. In the present study, we found that DHM activated insulin signaling and increased glucose uptake in skeletal muscle in vitro and in vivo. The expression of light chain 3, the degradation of sequestosome 1, and the formation of autophagosomes were also upregulated by DHM. DHM-induced insulin sensitivity improvement was significantly abolished in the presence of 3-methyladenine, bafilomycin A1, or Atg5 siRNA in C2C12 myotubes. Furthermore, DHM increased the levels of phosphorylated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), and Sirt3 in skeletal muscle in vitro and in vivo. Autophagy was inhibited in the presence of Sirt3 siRNA in C2C12 myotubes and in skeletal muscles from Sirt3-/- mice. Additionally, PGC-1α or AMPK siRNA transfection attenuated DHM-induced Sirt3 expression, thereby abrogating DHM-induced autophagy in C2C12 myotubes. In conclusion, DHM improved skeletal muscle insulin sensitivity by partially inducing autophagy via activation of the AMPK-PGC-1α-Sirt3 signaling pathway.

Ampelopsis grossedentata, a medicinal and edible plant, has been widely used in China for hundreds of years, and dihydromyricetin is the main active ingredient responsible for its various biological actions. We investigated the effects of dihydromyricetin on glucose and lipid metabolism, inflammatory mediators and several biomarkers in nonalcoholic fatty liver disease. In a double-blind clinical trial, sixty adult nonalcoholic fatty liver disease patients were randomly assigned to receive either two dihydromyricetin or two placebo capsules (150 mg) twice daily for three months. The serum levels of alanine, aspartate aminotransferase, γ-glutamyl transpeptidase, glucose, low-density lipoprotein-cholesterol and apolipoprotein B, and the homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly decreased in the dihydromyricetin group compared with the placebo group. In the dihydromyricetin group, the serum levels of tumor necrosis factor-alpha, cytokeratin-18 fragment and fibroblast growth factor 21 were decreased, whereas the levels of serum adiponectin were increased at the end of the study. We conclude that dihydromyricetin supplementation improves glucose and lipid metabolism as well as various biochemical parameters in patients with nonalcoholic fatty liver disease, and the therapeutic effects of dihydromyricetin are likely attributable to improved insulin resistance and decreases in the serum levels of tumor necrosis factor-alpha, cytokeratin-18, and fibroblast growth factor 21., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Chaenomeles speciosa fruit is a traditional herb medicine widely used in China. In this study, superfine powder of C. speciosa fruit (SCE), ground by supersonic nitrogen airflow at -140°C, was investigated to assess its in vitro antioxidant activity and in vivo antiphysical fatigue activity. SCE was homogenous (d < 10 μm) and rich in antioxidants like polyphenols, saponins, oleanolic acid, ursolic acid, ascorbic acid, and SOD. According to the in vitro experiments, SCE displayed promising antioxidant activity with powerful FARP, SC-DPPH, and SC-SAR activities. According to the in vivo experiments, rats supplemented with SCE had prolonged exhaustive swimming time (57%) compared to the nonsupplemented rats. Meanwhile, compared to the nonsupplemented rats, the SCE-supplemented rats had higher levels of blood glucose and liver and muscular glycogen and lower levels of LA and BUN. Lower MDA, higher antioxidant enzymes (SOD, CAT, and GSH-Px) activities, and upregulated Nrf2/ARE mediated antioxidant enzymes (HO-1, Trx, GCLM, and GCLC) expression were also detected in the supplemented group. This study indicates that SCE is a potent antioxidant and antifatigue agent, and SCE could be a promising raw material for the food and pharmaceutical industries.

It is well established that statins display potent anticancer activity in several types of proliferating tumor cells. However, how to promote the sensitivity of statins to mammary cancer is yet to be completely deciphered. The purpose of this study was to investigate whether breast cancer susceptibility gene 1 (BRCA1) overexpression sensitizes mammary cancer cells to statins. MCF-7 cells, which have only one wild-type BRCA1 allele, were transfected with pcDNA3-beta-HA-hsBRCA1 plasmids via liposomes to reconstitute BRCA1 overexpression human breast cancer cell line, and tumoral xenografts with BRCA1 overexpression were subsequently established in BALB/c nude mice. Then, the inhibitory activity of lovastatin on cancer cells and tumoral xenografts, and the underlying mechanism involving in cell-cycle regulatory proteins were analyzed. The proliferative ability of MCF-7 cells treated with lovastatin was reduced compared to normal, and further decreased in the presence of excess BRCA1, detected by methyl thiazolyl tetrazolium and flow cytometry techniques in vitro or by 5-bromodeoxyuridine incorporation in vivo. Additionally, the mRNA and protein expression of cyclin D1, cyclin-dependent kinase 4 (CDK4) and retinoblastoma protein (pRb), was further down-regulated under exposure to lovastatin in condition of BRCA1 overexpression, but the expression of p21WAF1/CIP1, a cyclin-dependent kinase inhibitor (CDKI), was further up-regulated, both in vitro and in vivo detected with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Moreover, we found the further reduced volume of tumoral xenografts treated with lovastatin in the presence of BRCA1 overexpression. Our results suggest that BRCA1 overexpression sensitizes cancer cells to lovastatin via regulation of cyclin D1-CDK4-p21WAF1/CIP1 pathway, which will provide an innovative experimental framework to study control of breast cancer cell proliferation.