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Li Zhang, XiaoXin Zhang, Xuejing Zhang, Yu Lu, Lei Li, and Sheng Cui

MicroRNAs (MiRNAs) play important regulatory roles in many cellular processes. MiR-143 is highly enriched in the mouse ovary, but its roles and underlying mechanisms are not well understood. In the current study, we show that miR-143 is located in granulosa cells of primary, secondary and antral follicles. To explore the specific functions of miR-143, we transfected miR-143 inhibitor into primary cultured granulosa cells to study the loss of function of miR-143 and the results showed that miR-143 silencing significantly increased estradiol production and steroidogenesis-related gene expression. Moreover, our in vivo and in vitro studies showed that follicular stimulating hormone (FSH) significantly decreased miR-143 expression. This function of miR-143 is accomplished by its binding to the 3’-UTR of KRAS mRNA. Furthermore, our results demonstrated that miR-143 acts as a negative regulating molecule mediating the signaling pathway of FSH and affecting estradiol production by targeting KRAS. MiR-143 also negatively acts in regulating granulosa cells proliferation and cell cycle-related genes expression. These findings indicate that miR-143 plays vital roles in FSH-induced estradiol production and granulosa cell proliferation, providing a novel mechanism that involves miRNA in regulating granulosa cell functions.

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Y. D. Li, Z. W. Zhang, and W. X. Li


The effect of transferrin on basal and FSH-stimulated aromatase activity of granulosa cells from immature female rats treated with diethylstilboestrol (DES) was examined in vitro by a radiometric method. The basal activity of the enzyme was very low after 3 days of incubation. Treatment with FSH (20 ng/ml) resulted in a 9·6-fold increase in activity, whereas coincubation with increasing doses of transferrin (3–300 μg/ml) produced a dose-dependent inhibition of FSH-stimulated aromatase activity with a projected minimal effective dose of < 2 μg/ml. A time-course study showed that the inhibitory effect of transferrin on aromatase activity has become significant at 48 h of incubation.

The inhibitory action of transferrin on the enzyme complex was further confirmed by showing that the FSH dose–response curve was significantly suppressed by concomitant treatment with 100 μg transferrin/ml with a maximum suppression of 54·1 % at a dose of 30 ng FSH/ml.

The possibility that transferrin may act through a non-specific inhibitory effect seems unlikely, as no changes in cell number and DNA content per well were observed. In fact, protein synthesis was enhanced after treatment with transferrin. Aromatase activity, stimulated by several promoters of cyclic AMP (cAMP), such as prostaglandin E2 (PGE2), forskolin and 8-bromo-cAMP, was significantly suppressed by 100 μg transferrin/ml (36·6, 47·4 and 23·4% inhibition respectively), suggesting that the effect of transferrin on FSH action may involve a site(s) distal to cAMP generation.

These findings indicated that transferrin, present in follicular fluid, may play an important role in the regulation of granulosa cell differentiation.

Journal of Endocrinology (1991) 131, 245–250

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Rong Wan, Chao Zhu, Rui Guo, Lai Jin, Yunxin Liu, Li Li, Hao Zhang, and Shengnan Li

Urocortin (UCN1) is a member of corticotrophin-releasing factor (CRF) family, which has been proven to participate in inflammation. Previous work showed that dihydrotestosterone (DHT) could promote the inflammatory process. Little is known about the effect of DHT on UCN1 expression. The aim of our study is to investigate the effects and underlying mechanisms of DHT on endothelial UCN1 expression in the absence and presence of induced inflammation. Therefore, we tested the alterations of endothelial UCN1 expression treated with DHT in the presence or absence of lipopolysaccharide (LPS). Our data showed that DHT alone decreased UCN1 levels, which were attenuated in the presence of the androgen receptor (AR) antagonist flutamide. Conversely, in the presence of LPS, DHT augmented the LPS-induced increase in UCN1 expression, which was, interestingly, not affected by flutamide. When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter. In the presence of LPS, DHT did not influence AR expression and location while it increased toll-like receptor 4 expression and activation, which was not altered by flutamide. DHT enhanced LPS-induced p38MAPK, ERK1/2, and nuclear factor κB pathway activation, which may contribute to the elevated expression of UCN1. These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively.

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Yuhui Liu, Le Zhang, Jing Li, Zhongyan Shan, and Weiping Teng

Marginal iodine deficiency is a major health problem in pregnant women, but its impact on nerve and intelligence development in offspring has been rarely reported. Our study aimed to investigate the effects of maternal marginal iodine deficiency on nerve and cognitive development in offspring and the related mechanisms. Marginal iodine-deficient rats were given 3 μg iodine per day, while normal control rats were given 4 μg iodine daily. Western blot was used to detect the amounts of brain-derived neurotropic factor (BDNF) and early growth response protein 1 (EGR1) in the hippocampus of each group. Immunohistochemistry was used to measure c-jun and c-fos expression in the hippocampal CA1 region. Finally, the water maze method was used to measure spatial performance. Free thyroxine (FT4) levels in marginal iodine-deficient rats decreased by about 30%. Seven days after birth, EGR1 and BDNF protein levels significantly decreased in the hippocampus of marginal iodine deficiency rats compared with the normal control group. In addition, c-jun and c-fos expression in the hippocampus of 40-day-old rats was decreased in marginal iodine-deficient rats, compared with control. The spatial learning and memory ability of 40-day-old marginal iodine-deficient rats had a downward trend compared with the normal control group. FT4 significantly decreased after pregnancy in rats with marginal iodine deficiency, affecting the expression of related proteins in the brain of offspring.

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G Li, Y Zhang, JT Wilsey, and PJ Scarpace

The effects of the chronic activation of the central melanocortin (MC) system by melanotan II (MTII) were assessed in chow-fed (CH) and high-fat (HF) diet-induced obese (DIO) Sprague-Dawley rats. Six-day central infusion of MTII (1 nmol/day) reduced body weight and visceral adiposity compared with ad libitum-fed control and pair-fed groups and markedly suppressed caloric intake in both CH and DIO rats. The anorexic response to MTII was similar in DIO relative to CH rats. MTII induced a sustained increase in oxygen consumption in DIO but a delayed response in CH rats. In both diet groups, MTII reduced serum insulin and cholesterol levels compared with controls. HF feeding increased brown adipose tissue (BAT) uncoupling protein 1 (UCP1) by over twofold, and UCP1 levels were further elevated in MTII-treated CH and DIO rats. MTII lowered acetyl-CoA carboxylase expression and prevented the reduction in muscle-type carnitine palmitoyltransferase I mRNA by pair-feeding in the muscle of DIO rats. Compared with CH controls, hypothalamic MC3 and MC4 receptor expression levels were reduced in DIO controls. This study has demonstrated that, despite reduced hypothalamic MC3/MC4 receptor expression, anorexic and thermogenic responses to MTII are unabated with an initial augmentation of energy expenditure in DIO versus CH rats. The HF-induced up-regulation of UCP1 in BAT may contribute to the immediate increase in MTII-stimulated thermogenesis in DIO rats. MTII also increased fat catabolism in the muscle of DIO rats and improved glucose and cholesterol metabolism in both groups.

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Zhongyang Lu, Xiaoming Zhang, Yanchun Li, Junfei Jin, and Yan Huang

Although it has been reported that deficiency of toll-like receptor 4 (TLR4) is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined whether treatment with a TLR4 antagonist reduces atherosclerosis in nondiabetic or diabetic mice that have TLR4 expression. In this study, we determined the effect of Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist, on early-stage atherosclerosis in nondiabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe −/−) mice. Analysis of atherosclerotic lesions of both en face aortas and cross sections of aortic roots showed that administration of Rs-LPS in 14-week-old diabetic Apoe −/− mice for 10 weeks significantly reduced atherosclerotic lesions. Although atherosclerotic lesions in nondiabetic Apoe −/− mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant. Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in nondiabetic mice but not in diabetic mice. Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin 6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques. Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic Apoe −/− mice and lowered serum cholesterol and triglyceride levels in nondiabetic Apoe −/− mice.

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Sihan Lv, Xinchen Qiu, Jian Li, Jinye Liang, Weida Li, Chao Zhang, Zhen-Ning Zhang, and Bing Luan

Hormonal signals help to maintain glucose and lipid homeostasis in the liver during the periods of fasting. Glucagon, a pancreas-derived hormone induced by fasting, promotes gluconeogenesis through induction of intracellular cAMP production. Glucagon also stimulates hepatic fatty acid oxidation but the underlying mechanism is poorly characterized. Here we report that following the acute induction of gluconeogenic genes Glucose 6 phosphatase (G6Pase) and Phosphoenolpyruvate carboxykinase (Pepck) expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genes Acyl-coenzyme A oxidase (Aox) and Carnitine palmitoyltransferase 1a (Cpt1a) expression via extracellular cAMP. Increase in extracellular cAMP promotes PPARα activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuates Aox and Cpt1a expression. Importantly, cAMP injection improves lipid homeostasis in fasted mice and obese mice, while inhibition of cAMP efflux deteriorates hepatic steatosis in fasted mice. Collectively, our results demonstrate the vital role of glucagon-stimulated extracellular cAMP in the regulation of hepatic lipid metabolism through AMPK-mediated PPARα activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.

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Chan-Juan Ma, Ai-Fang Nie, Zhi-Jian Zhang, Zhi-Guo Zhang, Li Du, Xiao-Ying Li, and Guang Ning

Genipin, a compound derived from Gardenia jasminoides Ellis fruits, has been used over the years in traditional Chinese medicine to treat symptoms of type 2 diabetes. However, the molecular basis for its antidiabetic effect has not been fully revealed. In this study, we investigated the effects of genipin on glucose uptake and signaling pathways in C2C12 myotubes. Our study demonstrates that genipin stimulated glucose uptake in a time- and dose-dependent manner. The maximal effect was achieved at 2 h with a concentration of 10 μM. In myotubes, genipin promoted glucose transporter 4 (GLUT4) translocation to the cell surface, which was observed by analyzing their distribution in subcellular membrane fraction, and increased the phosphorylation of insulin receptor substrate-1 (IRS-1), AKT, and GSK3β. Meanwhile, genipin increased ATP levels, closed KATP channels, and then increased the concentration of calcium in the cytoplasm in C2C12 myotubes. Genipin-stimulated glucose uptake could be blocked by both the PI3-K inhibitor wortmannin and calcium chelator EGTA. Moreover, genipin increases the level of reactive oxygen species and ATP in C2C12 myotubes. These results suggest that genipin activates IRS-1, PI3-K, and downstream signaling pathway and increases concentrations of calcium, resulting in GLUT4 translocation and glucose uptake increase in C2C12 myotubes.

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Zhenhua Li, Tao Zhang, Hongyan Dai, Guanghui Liu, Haibin Wang, Yingying Sun, Yun Zhang, and Zhiming Ge

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Zhenhua Li, Tao Zhang, Hongyan Dai, Guanghui Liu, Haibin Wang, Yingying Sun, Yun Zhang, and Zhiming Ge

Apoptosis plays a critical role in the diabetic cardiomyopathy, and endoplasmic reticulum stress (ERS) is one of the intrinsic apoptosis pathways. Previous studies have shown that the endoplasmic reticulum becomes swollen and dilated in diabetic myocardium, and ERS is involved in heart failure and diabetic kidney. This study is aimed to demonstrate whether ERS is induced in myocardium of streptozotocin (STZ)-induced diabetic rats. We established a type 1 diabetic rat model, used echocardiographic evaluation, hematoxylin–eosin staining, and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify the existence of diabetic cardiomyopathy and enhanced apoptosis in the diabetic heart. We performed immunohistochemistry, western blot, and real-time PCR to analyze the hallmarks of ERS that include glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase12. We found these hallmarks to have enhanced expression in protein and mRNA levels in diabetic myocardium. Also, another pathway that can lead to cell death of ERS, c-Jun NH2-terminal kinase-dependent pathway, was also activated in diabetic heart. Those results suggested that ERS was induced in STZ-induced diabetic rats' myocardium, and ERS-associated apoptosis occurred in the pathophysiology of diabetic cardiomyopathy.