The aim of this study was to examine the effects of chlorogenic acid (CGA) on glucose and lipid metabolism in late diabetic db/db mice, as well as on adiponectin receptors and their signaling molecules, to provide evidence for CGA in the prevention of type 2 diabetes. We randomly divided 16 female db/db mice into db/db-CGA and db/db-control (CON) groups equally; db/m mice were used as control mice. The mice in both the db/db-CGA and db/m-CGA groups were administered 80 mg/kg/d CGA by lavage for 12 weeks, whereas the mice in both CON groups were given equal volumes of phosphate-buffered saline (PBS) by lavage. At the end of the intervention, we assessed body fat and the parameters of glucose and lipid metabolism in the plasma, liver and skeletal muscle tissues as well as the levels of aldose reductase (AR) and transforming growth factor-β1 (TGF-β1) in the kidneys and measured adiponectin receptors and the protein expression of their signaling molecules in liver and muscle tissues. After 12 weeks of intervention, compared with the db/db-CON group, the percentage of body fat, fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) in the db/db-CGA group were all significantly decreased; TGF-β1 protein expression and AR activity in the kidney were both decreased; and the adiponectin level in visceral adipose was increased. The protein expression of adiponectin receptors (ADPNRs), the phosphorylation of AMP-activated protein kinase (AMPK) in the liver and muscle, and the mRNA and protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) in the liver were all significantly greater. CGA could lower the levels of fasting plasma glucose and HbA1c during late diabetes and improve kidney fibrosis to some extent through the modulation of adiponectin receptor signaling pathways in db/db mice.
Copyright: Epis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT RNA-based therapeutics could represent a new avenue of cancer treatment. miRNA 331-3p (miR-331-3p) is implicated in prostate cancer (PCa) as a putative tumor suppressor, but its functional activity and synergy with other anti-tumor agents is largely unknown. We found miR-331-3p expression in PCa tumors was significantly decreased compared to non-malignant matched tissue. Analysis of publicly available PCa gene expression data sets showed miR-331-3p expression negatively correlated with Gleason Score, tumor stage, lymph node involvement and PSA value, and was significantly down regulated in tumor tissue relative to normal prostate tissue. Overexpression of miR-331-3p reduced PCa cell growth, migration and colony formation, as well as xenograft tumor initiation, proliferation and survival of mice. Microarray analysis identified seven novel targets of miR-331-3p in PCa. The 3'-untranslated regions of PLCγ1 and RALA were confirmed as targets of miR-331-3p, with mutation analyses confirming RALA as a direct target. Expression of miR-331-3p or RALA siRNA in PCa cells reduced RALA expression, proliferation, migration and colony formation in vitro. RALA expression positively correlated with Gleason grade in two separate studies, as well as in a PCa tissue microarray. Co-treatment using siRALA with an Aurora Kinase inhibitor (AKi-II) decreased colony formation of PCa cells while the combination of AKi-II with miR-331-3p resulted in significant reduction of PCa cell proliferation in vitro and PCa xenograft growth in vivo. Thus, miR-331-3p directly targets the RALA pathway and the addition of the AKi-II has a synergistic effect on tumor growth inhibition, suggesting a potential role as combination therapy in PCa.
Epidermal growth factor (EGF)-like growth factors, such as amphiregulin (AR) and EGF, have emerged as mediators to propagate Luteinizing hormone (LH) stimulus for the oocyte maturation throughout the preovulatory follicle, because cumulus cells and oocytes express few or no LH receptors. This study was to compare AR and EGF concentrations in follicular fluid (FF) among four controlled ovary stimulation (COS) protocols and to investigate the relationship between FF EGF-like growth factors and COS outcomes. Ninety-five patients who underwent in vitro fertilization-embryo transfer (IVF-ET) were treated by four different COS protocols, including gonadotropin-releasing hormone agonist (GnRH-a) long protocol, GnRH-a ultra-long protocol, GnRH-a short protocol, and GnRH antagonist protocol. FF was taken on oocyte retrieval day. FF AR and EGF concentrations were measured and their correlations with COS outcomes were analyzed. FF AR concentration was significantly different from each other among four COS protocol groups (GnRH-a ultra-long protocol group, 186.12 ng/ml; GnRH-a long protocol group, 128.35 ng/ml; GnRH antagonist protocol group, 108.23 ng/ml; GnRH-a short protocol group, 77.13 ng/ml, p < 0.05). FF AR concentrations were higher in GnRH-a ultra-long and long protocol groups, while number of oocytes retrieval, available embryos, and good quality embryos in these two groups were also significantly higher than GnRH-a short protocol group and GnRH antagonist protocol group. FF AR concentration was positively correlated with available embryos, but negatively correlated with serum LH level on hCG day. FF EGF concentration had no relationship with COS parameters. Different COS protocols might have variable effects on AR synthesis. FF AR might be a good indicator to predict the number of oocytes and embryos. FF AR elevation may result in increasing the number of oocyte retrieval and embryo generation, consequently increased cumulative pregnancy rate.
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