Previous studies have postulated the association between oxidative stress and Type 2 diabetes. Considering the long pre-diabetic period with IGR (impaired glucose regulation) and its high risk of developing diabetes, to test this hypothesis, we have investigated oxidative stress pathways and DNA damage in patients with IGR and newly diagnosed Type 2 diabetes. The study population consisted of 92 subjects with NGT (normal glucose tolerance), 78 patients with IGR and 113 patients with newly diagnosed diabetes. Plasma MDA (malondialdehyde) and TAC (total antioxidative capacity) status, erythrocyte GSH content and SOD (superoxide dismutase) activity were determined. A comet assay was employed to evaluate DNA damage. Compared with subjects with NGT, patients with IGR had reduced erythrocyte SOD activity. Patients with diabetes had a higher plasma MDA concentration, but a lower plasma TAC level and erythrocyte SOD activity, than the NGT group. Correlation analysis revealed a strong positive association between IR (insulin resistance) and MDA concentration, but negative correlations with TAC status and SOD activity. With respect to beta-cell function, a positive association with TAC status and an inverse correlation with GSH respectively, were observed. The comet assay revealed slight DNA damage in patients with IGR, which was increased in patients with diabetes. Significant correlations were observed between DNA damage and hyperglycaemia, IR and beta-cell dysfunction. In conclusion, the results of the present study suggest that hyperglycaemia in an IGR state caused the predominance of oxidative stress over antioxidative defence systems, leading to oxidative DNA damage, which possibly contributed to pancreatic beta-cell dysfunction, IR and more pronounced hyperglycaemia. This vicious circle finally induced the deterioration to diabetes.

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The aim of this study was to investigate the changes in hepatic oxidative phosphorylation (OXPHOS) complexes (COs) in patients and cows with non‐alcoholic steatohepatitis (NASH) and to investigate the mechanism that links mitochondrial dysfunction and hepatic insulin resistance induced by non‐esterified fatty acids (NEFAs). Patients and cows with NASH displayed high blood NEFAs, TNF‐α and IL‐6 concentrations, mitochondrial dysfunction and insulin resistance. The protein levels of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), mitofusin‐2 (Mfn‐2) and OXPHOS complexes (human: COI and COIII; cow: COI‐IV) were significantly decreased in patients and cows with NASH. NEFA treatment significantly impaired mitochondrial function and, increased reactive oxygen species (ROS) production, and excessive ROS overactivated the JNK and p38MAPK pathways and induced insulin resistance in cow hepatocytes. PGC‐1α and Mfn‐2 overexpression significantly decreased the NEFA‐induced ROS production and TNF‐α and IL‐6 mRNA expressions, reversed the inhibitory effect of NEFAs on mitochondrial function and attenuated the overactivation of the ROS‐JNK/p38MAPK pathway, alleviated insulin resistance induced by NEFAs in cow hepatocytes and HepG2 cells. These findings indicate that NEFAs induce mitochondrial dysfunction and insulin resistance mediated by the ROS‐JNK/p38MAPK pathway. PGC‐1α or Mfn‐2 overexpression reversed the lipotoxicity of NEFAs on mitochondrial dysfunction and insulin resistance. Our study clarified the mechanism that links hepatic mitochondrial dysfunction and insulin resistance in NASH.

Angiotensin converting enzyme (ACE) inhibitory peptides are biologically active peptides that play a very important role in blood pressure regulation. In previous experiments, we obtained an ACE inhibitory peptide Val-Leu-Pro-Val-Pro (VLPVP) by DNA recombinant technology. The purpose of this study was to examine the bidirectional transport of VLPVP by using the human intestinal Caco-2 monolayers. The permeability coefficient ( P app) values of VLPVP over 4-8 mmol/L ranged from 7.44 x 10(-8) to 1.35 x 10(-6) cm/s for apical (AP) to basolateral (BL) transport, while the P app values for BL to AP flux were significantly lower than those for the AP to BL flux, with efflux ratio values of 0.74-0.13 over 4-8 mM. Preincubation of the paracellular transport enhancer (sodium deoxycholate), the inhibitor of multidrug resistant protein (MK-571), or sodium azide stimulated efflux of VLPVP significantly ( p < 0.01); these results indicate that the transport of VLPVP across Caco-2 monolayers was involved in paracellular diffusion and MRP2 transport.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5–10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5–15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30–90% and final pregnancy rates of 13–88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of “toxic” follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the “hypothalamus–pituitary–ovary” axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.

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Background/Aims: In dairy cows, β-hydroxybutyrate (BHBA) is utilized as precursors of de novo synthesized fatty acids in mammary gland. Ketotic cows are characterized by excessive negative energy balance (NEB), which can further increase the blood BHBA concentration. Sterol regulatory element-binding protein1 (SREBP1) and cell death-inducing DNA fragmentation factor-alpha-like effector α (Cidea) play crucial roles in lipid synthesis. Therefore, we hypothesized that BHBA could stimulate SREBP1/Cidea pathway to increase milk fat synthesis in bovine mammary epithelial cells. Methods: Bovine mammary epithelial cells were treated with different concentrations of BHBA and transfected with adenovirus to silence SREBP1 expression. The effects of BHBA on the lipid synthesis in bovine mammary epithelial cells were investigated. Results: The results showed that BHBA could significantly increase the expression of SREBP1, fatty acid synthase (FAS), acetyl-CoA carboxylase α (ACC-α), Cidea and diacylglycerol transferase-1 (DGAT-1), as well as the triglycerides (TG) content in bovine mammary epithelial cells. BHBA treatment also increased the transfer of mature SREBP1 to nucleus compared with control group. However, SREBP1 silencing could significantly down-regulate the overexpression of FAS, ACC-α, Cidea and DGAT-1, as well as TG content induced by BHBA. Conclusion: The present data indicate that BHBA can significantly increase TG secretion mediated by SREBP1 in bovine mammary epithelial cells.

The contributions of altered post-transcriptional gene silencing to the development of metabolic disorders remain poorly understood thus far. The objective of this study was to evaluate the roles of miR-181a in the regulation of hepatic glucose and lipid metabolism. MiR-181a is abundantly expressed in the liver, and we found that blood and hepatic miR-181a levels were significantly increased in patients and dairy cows with non-alcoholic fatty liver disease, as well as in high-fat diet and ob/ob mice. We determined that sirtuin1 is a target of miR-181a. Moreover, we found that hepatic sirtuin1 and peroxisome proliferator-activated receptor-γ coactivator-1α expression levels are downregulated, and acetylated peroxisome proliferator-activated receptor-γ coactivator-1α expression levels are upregulated in patients and dairy cows with non-alcoholic fatty liver disease, as well as in high-fat diet and ob/ob mice. MiR-181a overexpression inhibits the sirtuin1-peroxisome proliferator-activated receptor-γ coactivator-1α pathway, reduces insulin sensitivity, and increases gluconeogenesis and lipid synthesis in dairy cow hepatocytes and HepG2 cells. Conversely, silencing of miR-181a over-activates the sirtuin1-peroxisome proliferator-activated receptor-γ coactivator-1α pathway, increases insulin sensitivity and glycogen content, and decreases gluconeogenesis and lipid synthesis in hepatocytes, even under nonesterified fatty acids treatment conditions. Furthermore, miR-181a overexpression or sirtuin1 knockdown in mice increases lipid accumulation and decreases insulin sensitivity and glycogen content in the liver. Taken together, these findings indicate that increased hepatic miR-181a impairs glucose and lipid homeostasis by silencing sirtuin1 in non-alcoholic fatty liver disease.