Neo-clerodane Diterpenoids with Hypoglycemic Effects in Vivo from the Aerial Parts of Salvia hispanica L.

A new neo-clerodane diterpenoid, salvihispin H (1), and six known ones (2-7) were identified from the aerial parts of Salvia hispanica L. The structure and absolute configuration of 1 were elucidated by extensive analysis of spectroscopic (1 H, 13 C, and 2D NMR, and HR-ESI-MS) and single-crystal X-ray diffraction data. The anti-diabetic effects of salvihispin H (1) and salvifaricin (2) were evaluated in diabetic db/db mice. The data showed that 1 and 2 could significantly reduce fasting blood glucose level and improve insulin resistance, and compound 1 exerted glucose-lowering effect more quickly than metformin. In addition, 1 and 2 could also reduce serum TG level in db/db mice. These results demonstrated that compounds 1 and 2 could be considered as potent candidates for the therapy of type 2 diabetes mellitus (T2DM).

Combined treatment with FABP4 inhibitor ameliorates rosiglitazone-induced liver steatosis in obese diabetic db/db mice.

Rosiglitazone has been reported to exert dual effects on liver steatosis, and it could exacerbate liver steatosis in obese animal models, which was suggested to be closely related to the elevated hepatic expression of FABP4. This study aimed to investigate whether combined treatment with FABP4 inhibitor I-9 could alleviate rosiglitazone-induced liver steatosis in obese diabetic db/db mice. Male C57BL/KsJ-db/db mice were orally treated with rosiglitazone, rosiglitazone combined with I-9 daily for 8 weeks. The liver steatosis was evaluated by triglyceride content and H&E staining. The expression of hepatic lipogenic genes or proteins in liver tissue or in FFA-treated hepatocytes and PMA-stimulated macrophages were determined by real-time quantitative polymerase chain reaction (RT-qPCR) or western blotting. Results showed that combined treatment with I-9 decreased rosiglitazone-induced increase in serum FABP4 level and expression of lipogenic genes in liver, especially FABP4, and ameliorated liver steatosis in db/db mice. Rosiglitazone-induced intracellular TG accumulation and increased expression of FABP4 in the cultured hepatocytes and macrophages were also suppressed by combined treatment. We concluded that combined treatment with FABP4 inhibitor I-9 could ameliorate rosiglitazone-exacerbated elevated serum FABP4 level and ectopic liver fat accumulation in obese diabetic db/db mice without affecting its anti-diabetic efficacy.

A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism.

Diacylglycerol acyltransferase 1 (DGAT1) plays a pivotal role in lipid metabolism by catalyzing the committed step in triglyceride (TG) synthesis and has been considered as a potential therapeutic target of multiple metabolic diseases, including dyslipidemia, obesity and type 2 diabetes. Here we report a novel DGAT1 inhibitor, Yhhu2407, which showed a stronger DGAT1 inhibitory activity (IC50 = 18.24 ± 4.72 nM) than LCQ908 (IC50 = 78.24 ± 8.16 nM) in an enzymatic assay and led to a significant reduction in plasma TG after an acute lipid challenge in mice. Pharmacokinetic studies illustrated that Yhhu2407 displayed a low systemic, liver- and intestine-targeted distribution pattern, which is consistent with the preferential tissue expression pattern of DGAT1 and therefore might help to maximize the beneficial pharmacological effects and prevent the occurrence of side effects. Cell-based investigations demonstrated that Yhhu2407 inhibited free fatty acid (FFA)-induced TG accumulation and apolipoprotein B (ApoB)-100 secretion in HepG2 cells. In vivo study also disclosed that Yhhu2407 exerted a beneficial effect on regulating plasma TG and lipoprotein levels in rats, and effectively ameliorated high-fat diet (HFD)-induced dyslipidemia in hamsters. In conclusion, we identified Yhhu2407 as a novel DGAT1 inhibitor with potent efficacy on improving lipid metabolism in rats and HFD-fed hamsters without causing obvious adverse effects.

DGAT1 inhibitors protect pancreatic ß-cells from palmitic acid-induced apoptosis.

Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids (FFA), especially saturated fatty acids, could lead to pancreatic ß-cell apoptosis, which plays an important role in the progression of type 2 diabetes (T2D). Diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) synthesis, has been reported as a novel target for the treatment of multiple metabolic diseases. In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic ß-cells, and further verified their antidiabetic effects in db/db mice. We showed that DGAT1 inhibitors (4a and LCQ908) at the concentration of 1 µM significantly ameliorated palmitic acid (PA)-induced apoptosis in MIN6 pancreatic ß-cells and primary cultured mouse islets; oral administration of a DGAT1 inhibitor (4a) (100 mg/kg) for 4 weeks significantly reduced the apoptosis of pancreatic islets in db/db mice. Meanwhile, 4a administration significantly decreased fasting blood glucose and TG levels, and improved glucose tolerance and insulin tolerance in db/db mice. Furthermore, we revealed that pretreatment with 4a (1 µM) significantly alleviated PA-induced intracellular lipid accumulation, endoplasmic reticulum (ER) stress, and proinflammatory responses in MIN6 cells, which might contribute to the protective effects of DGAT1 inhibitors on pancreatic ß-cells. These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.

Tiaobu Xinshen Recipe () Improved Mild Cognitive Impairment of Alzheimer's Disease Patients with Xin (Heart) and Shen (Kidney) Deficiency.

OBJECTIVE: To observe the intervention effects of Tiaobu Xinshen Recipe (, TXR) on patients with mild cognitive impairment caused by Alzheimer's disease (MCI-AD). METHODS: Totally 88 MCI-AD patients with syndrome of Xin (Heart) and Shen (Kidney) deficiency were assigned to the experimental group (47 cases, treated with TXR) and the control group (41 cases, treated with donepezil hydrochloride) using a random number table. Final recruited qualified patients were 44 cases in the experimental group and 39 cases in the control group. The therapeutic course was 12 weeks. Neuropsychological scales [mini mental state examination (MMSE) and Montreal cognitive assessment (MoCA)], and Chinese medicine (CM) dementia syndromes scales were performed in all patients, and results were compared between groups or intra-group before and after treatment. RESULTS: MMSE and MoCA scores of the two groups were increased after treatment compared with those before treatment (P<0.05). But there was no statistical difference in MMSE or MOCA scores after treatment between the two groups (P>0.05). CM dementia syndrome score was significantly decreased after treatment in the experimental group compared with the control group (P<0.01). Visual spatial and executive function scores and delayed recall scores of the two groups were increased compared with those before treatment (P<0.01). CONCLUSION: TXR could effectively improve cognitive impairment of MCI-AD patients with syndrome of Xin and Shen deficiency.

Sanggenol F exerts anti-diabetic effects via promoting adipocyte differentiation and modifying adipokines expression.

Adipose tissue is not only a lipid storage site, but also a well-known endocrine organ. Dysfunction of adipose tissue is associated with irregular lipid metabolism, ectopic lipid accumulation and insulin resistance. It is proposed that modulating on adipose tissue is a reasonable way to ameliorate glucose and lipid metabolism. (±)-sanggenol F (SGF, purity >98.5%) was synthesized as a racemic mixture of natural (+)-sanggenol F. In this study, SGF was found to promote adipocyte differentiation, enhance insulin sensitivity, and upregulate beneficial adipokines expression in 3T3-L1 cells. Furthermore, in vivo study showed that treatment with SGF for 4 weeks improved glucose metabolism, by decreasing fasting blood glucose and enhancing insulin sensitivity. It also improved lipid metabolism, with reduced serum lipid level and ameliorated hepatic steatosis in db/db mice. During the process of target finding, we found that SGF had multiple activities of protein tyrosine phosphatase 1B inhibition, peroxisome proliferator-activated receptor γ and peroxisome proliferator-activated receptor α agonism. These results showed the potential of SGF as a candidate for the therapy of type 2 diabetes.