Sennoside A (SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet (HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR (homeostatic model assessment for insulin resistance) and glucose tolerance test (GTT). SA restored plasma level of glucagon-like peptide 1 (GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids (SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota–GLP1 axis to improve glucose metabolism in the obese mice.
Luteolin is a falvonoid compound derived from Lonicera japonica Thunb. Numerous reports have demonstrated that luteolin has anticancer effects on many kinds of tumors. This study investigated the effects of luteolin on prostate cancer (PCa), assessing the PC3 and LNCaP cells. The cell viability and apoptosis were assessed by performing Cell Counting Kit-8 assay and Annexin V–fluorescein isothiocyanate/propidium iodide double staining. Luteolin was found to inhibit androgen-sensitive and androgen-independent PCa cell lines’ growth and induced apoptosis. To uncover the exact mechanisms and molecular targets, microRNA (miR) array analysis was performed. miR-301 was found to be markedly downregulated. Then, the expression of miR-301 was retrospectively analyzed in the primary PCa tissues by quantitative reverse transcription polymerase chain reaction and in situ hybridization methods. According to the quantitative reverse transcription polymerase chain reaction results of miR-301, the 54 PCa patients were divided into two groups: high and low miR-301 groups. The division indicator is a relative expression ≥5. Compared to the low-expression group, high miR-301 expression was associated with a significantly shorter overall survival (P=0.029). The proapoptotic gene, DEDD2, was predicted to be the direct target of miR-301. It was clarified in accordance with bioinformatics and luciferase activity analyses. The overexpression of miR-301 by plasmid decreased the luteolin effect. Taken together, these results suggest that luteolin inhibits PCa cell proliferation through miR-301, the poor predictive factor of PCa.
ObjectiveL-cell dysfunction is reported for GLP-1 reduction in type 2 diabetes. However, the mechanism of dysfunction remains unknown. In this study, we examined mitochondrial function in the mechanistic study in diet-induced obese (DIO) mice.SubjectsC57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks to establish the DIO model for GLP-1 reduction. The mice were then treated with berberine (BBR) (100 mg/kg/day) for 8 weeks to test the impact on GLP-1 expression. Mitochondrial activities of the colon enterocytes were compared among three groups of mice (lean, DIO, and DIO + BBR) at the end of treatment. Gut microbiota and short-chain fatty acids (SCFAs) were examined to understand the mitochondrial responses. A cellular model treated with palmitic acid (PA) was used in the mechanism study.ResultsA reduction in GLP-1 expression was observed in DIO mice with mitochondrial stress responses in the colon enterocytes. The mitochondria exhibited cristae loss, membrane rupture, and mitochondrial swelling, which was observed with an increase in ATP abundance, complex I activity, and deficiency in the activities of complexes II and IV. Those changes were associated with dysbiosis and a reduction in SCFAs in the colon of DIO mice. In the cellular model, an increase in ATP abundance, loss of mitochondrial potential, and elevation of apoptosis were induced by PA. All of the alterations in DIO mice and the cellular model were attenuated by BBR.ConclusionThe mitochondrial stress responses were observed in the colon enterocytes of DIO mice for GLP-1 reduction. The stress was prevented by BBR in the restoration of GLP-1 expression, in which BBR may act through direct and indirect mechanisms.
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