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With the increasing prevalence of metabolic disorders, hyperglycemia has become a common risk factor that endangers people's lives and the need for new drug solutions is burgeoning. Trans-2, 4-dimethoxystilbene (TDMS), a synthetic stilbene, has been found as a novel hypoglycemic small molecule from glucose consumption test. Normal C57BL/6 J mice, mouse models of type 1 diabetes mellitus and diet-induced obesity subjected to TDMS gavage were found with lower glycemic levels and better glycemic control. TDMS significantly improved the symptoms of polydipsia and wasting in type 1 diabetic mice, and could rise their body temperature at the same time. It was found that TDMS could promote the expression of key genes of glucose metabolism in HepG2, as do in TDMS-treated liver, while it could improve the intestinal flora and relieve intestinal metabolic dysbiosis in hyperglycemic models, which in turn affected its function in the liver, forming the gut-liver axis. We further fished PPARγ by virtual screening that could be promoted by TDMS both in-vitro and in-vivo, which was regulated by upstream signaling of AMPKα phosphorylation. As a novel hypoglycemic small molecule, TDMS was proven to be promising with its glycemic improvements and amelioration of diabetes symptoms. It promoted glucose absorption and utilization by the liver and improved the intestinal flora of diabetic mice. Therefore, TDMS is expected to become a new hypoglycemic drug that acts through gut-liver axis via AMPKα-PPARγ signaling pathway in improving glycemic metabolism, bringing new hope to patients with diabetes and glucose metabolism disorders.

Salvianolic acid A (SAA) is a traditional Chinese medicine that has a good therapeutic effect on cardiovascular disease. However, the underlying mechanisms by which SAA improves mitochondrial respiration and cardiac function in diabetic cardiomyopathy (DCM) remain unknown. This study aims to elucidate whether SAA had any cardiovascular protection on the pathophysiology of DCM and explored the potential mechanisms. Diabetes was induced in rats by 30 mg/kg of streptozotocin (STZ) treatment. After a week of stability, 5 mg/kg isoprenaline (ISO) was injected into the rats subcutaneously. 3 mg/kg SAA was orally administered for six weeks and 150 mg/kg Metformin was selected as a positive group. At the end of this period, cardiac function was assessed by ultrasound, electrocardiogram, and relevant cardiac injury biomarkers testing. Treatment with SAA improved cardiac function, glucose, and lipid levels, mitochondrial respiration, and suppressed myocardial inflammation and apoptosis. Furthermore, SAA treatment inhibits the apoptosis pathway through CRYAB in diabetic cardiomyopathy rats. As a result, this study not only provides new insights into the mechanism of SAA against DCM but also provides new therapeutic ideas for the discovery of anti-DCM compounds in the clinic.

Hypertension crisis is a severe disease and needs emergency treatment in clinic. It is an important task to discover novel drugs which could lower the blood pressure steadily and quickly. However, animal models for screening anti-hypertensive crisis agents are unsatisfactory. The present study aimed to establish a new hypertensive crisis rat model and then explore the therapeutic effects of three Rho-kinase inhibitors including Fasudil, DL0805-1 and DL0805-2 on such a disease model. The hypertensive crisis symptoms were developed on male Wistar rats by subcutaneously injecting small doses of norepinephrine (NE) for 10 days in the initial stage. A sudden increase in blood pressure (BP) was then induced by excessive NE infusion. Compounds to be tested were intravenously injected into the rats immediately when the rapidly increased systolic blood pressure appeared. The results have shown that after small dose administration with NE, the rats could obtain acute BP increase to a high level without sudden death when a large dose of NE was injected. Fasudil, DL0805-1 and DL0805-2 could lower the blood pressure quickly in a dose dependent manner and improve the survival rate. The compounds also prevent the animals from organ damage. In conclusion, we established a novel hypertensive crisis animal model which could evaluate agents within a short time. In this model, we found that three Rho-kinase inhibitors have potential therapeutic effects on hypertensive crisis. This work might contribute to the discovery and development of new anti-hypertensive crisis drugs.

Chemotherapy-induced intestinal mucositis (CIM) is a principal reason for reduced living quality of patients undergoing chemotherapy. Growing evidence showed gut microbiota played an important role in the development of intestinal mucositis. Dihydrotanshinone I (DHTS) is a liposoluble extract of Salvia miltiorrhiza Bunge with many bioactivities. Here we investigated the effect of DHTS on intestinal mucositis induced by 5-fluorouracil and irinotecan in mice. We detected the degree of intestinal mucosal damage and inflammatory response in CIM mice with or without DHTS administration. The body weight and disease activity index (DAI) of mice were monitored each day. H&E staining was used to evaluate pathological damage. The contents of interleukin 6 (IL-6), tumor necrosis factor (TNFα), diacylglycerol (DAO) and triglyceride (TG) in serum were determined by commercial kits. We also investigated the changes of fecal microbiota by 16S rRNA high-throughput sequencing. Spearman correlation analysis was used to evaluate the correlation between fecal microbiota and inflammatory factors. Tax4Funwas performed to infer the potential function of the microbial community. Results showed DHTS significantly reduced DAI, intestinal mucosal damage and inflammatory response in CIM mice by decreasing serum IL-6 and TNFα. In addition, there is an intense correlation between fecal microbiota and inflammatory factors. DHTS efficiently reversed disordered fecal microflora close to normal and increased the abundance of g__Akkermansia. DHTS also enriched bacterial species which promote butyric acid metabolism or negatively correlated with inflammatory factors. Besides, species enriched by DHTS in fecal microbiota were probably involved in glutamine production and ammonia oxidation. In conclusion, our study provides evidence that DHTS effectively attenuates CIM induced by 5-fluorouracil and irinotecan in mice. Regulation of the composition and function of fecal microbiota probably plays a critical role in the therapeutic effect of DHTS in CIM mice.