Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation.

Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD+/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.

Sennoside A restores colonic barrier function through protecting colon enterocytes from ROS-induced mitochondrial damage in diet-induced obese mice.

The intestinal barrier dysfunction is closely implicated in low-grade chronic inflammation for insulin resistance in diet-induced obesity (DIO). It is generally believed that degradation of colon enterocytes contributes to intestinal barrier dysfunction in the pathological process of obesity. Sennoside A (SA) is reported to improve metabolic disorders, but the effect and mechanism of SA on colonic barrier function of DIO remains unknown. In this study, SA was found to restore colonic barrier function by protecting the continuity and integrity of colon enterocytes in DIO mice. An increase in mRNA expression of tight junction proteins Occludin, Claudin-2 and ZO-1 provides another mechanism of restoring colonic barrier function in SA-treated group. In the research of mechanism, mitophagy was inhibited by SA via a protection of mitochondrial structure and function in colon. A reduction was found in production of reactive oxygen species (ROS) in the colon, and the benefical effect was attributed to an inhibition of activity in complex I and III with a reduction of protein expression and an increase of Mn-SOD activity. The results indicate that SA can restores colonic barrier function through protecting colon enterocytes from ROS-induced mitochondrial damage in DIO mice.

[Screening of anti-aging active ingredients and mechanism analysis based on molecular docking technology].

Dampness evil is the source of all diseases, which is easy to cause disease and promote aging, while aging could also promote the occurence and development of diseases. In this paper, the relationship between the dampness evil and aging would be discussed, to find the anti-aging active ingredients in traditional Chinese medicine (TCM), and analyze the anti-aging mechanism of dampness eliminating drug. Molecular docking technology was used, with aging-related mammalian target of rapamycin as the docking receptors, and chemical components of Fuling, Sangzhi, Mugua, Yiyiren and Houpo as the docking molecules, to preliminarily screen the anti-aging active ingredients in dampness eliminating drug. Through the comparison with active drugs already on the market (temsirolimus and everolimus), 12 kinds of potential anti-aging active ingredients were found, but their drug gability still needs further study. The docking results showed that various components in the dampness eliminating drug can play anti-aging activities by acting on mammalian target of rapamycin. This result provides a new thought and direction for the method of delaying aging by eliminating dampness.

[Study on mechanism for anti-hypertension efficacy of Eucommiae Cortex through assistant analysis systems for acting mechanisms of traditional Chinese medicine].

Elucidate the mechanism of Eucommiae Cortex in treatment of hypertension, to provide the basis for further research and development of Eucommiae Cortex. Our study using the entity grammar systems inference rules to analyse the interactions of chemical constituents of Eucommiae Cortex and disease target proteins at the molecular level, and got a biological network of Eucommiae Cortex anti-hypertension which inciude 602 nodes and 2 354 edges. We got 3 treatment of hypertension pathways of Eucommiae Cortex by analyzing biological network, that is, by inhibition of vascular remodeling to improve the deterioration of hypertension, reduce activity of polymorphism genetic genes related to essential hypertension, inhibition of carbonic anhydrase 1 to maintain the osmotic pressure, Eucommiae Cortex play the role of anti-hypertension.

[Study on mechanism for anti-depression efficacy of Sini San through auxiliary mechanism elucidation system for Chinese medicine].

As regulating the function of the liver and spleen of the famous traditional formula, Sini San is widely used in the treatment of various diseases caused by liver depression and Qi stagnation, and its efficacy is significant clinically. Recently it is discovered that Sini San is effective in the treatment of nervous system diseases such as depression. Furthermore, there is a lot of literature about the effect of Sini San on the molecular mechanism of antidepressant. However, the anti-depression mechanism of Sini San is not very clear, in our present study, based on the auxiliary mechanism elucidation system for Chinese medicine and network pharmacology system to construct the chemical ingredients of the target interactions and disease-related protein of the interaction network. Results show that there are 263 chemical ingredients and 19 corresponding targets of depression in Sini San network. Sini San can anti-depressant effect through G-protein coupled receptor protein signaling pathway, cAMP system, neurological system process and neurotransmitter secretion, inflammatory response, neuroendocrine, metal ion transport and so on. These studies provided valuable clues for the mechanism and treatment of anti-depressant.

[Discovering L-type calcium channels inhibitors of antihypertensive drugs based on drug repositioning].

This study was amid to construct the pharmacophore model of L-type calcium channel antagonist in the application of screening Drugbank and TCMD. This paper repositions the approved drugs resulting from virtual screening and discusses the relocation-based drug discovery methods, screening antihypertensive drugs with L-type calcium channel function from TCMD. Qualitative hypotheses wre generated by HipHop separately on the basis of 12 compounds with antagonistic action on L-type calcium channel expressed in rabbit cardiac muscle. Datebase searching method was used to evaluate the generated hypotheses. The optimum hypothesis was used to search Drugbank and TCMD. This paper repositions the approved drugs and evaluates the antihypertensive effect of the chemical constituent of traditional Chinese medicine resulting from virtual screening by the matching score and literature. The results showed that optimum qualitative hypothesis is with six features, which were two hydrogen-bond acceptors, four hydrophobic groups, and the CAI value of 2.78. Screening Drugbank achieves 93 approved drugs. Screening TCMD achieves 285 chemical constituents of traditional Chinese medicine. It was concluded that the hypothesis is reliable and can be used to screen datebase. The approved drugs resulting from virtual screening, such as pravastatin, are potentially L-type calcium channels inhibitors. The chemical constituents of traditional Chinese medicine, such as Arctigenin III and Arctigenin are potentially antihypertensive drugs. It indicates that Drug Repositioning based on hypothesis is possible.