Potential efficacy and mechanism of eight mild-natured and bitter-flavored TCMs based on gut microbiota: A review / 中草药·英文版

The mild-natured and bitter-flavored traditional Chinese medicines (MB-TCMs) are an important class of TCMs that have been widely used in clinical practice and recognized as safe long-term treatments for chronic diseases. However, as an important class of TCMs, the panorama of pharmacological effects and the mechanisms of MB-TCMs have not been systemically reviewed. Compelling studies have shown that gut microbiota can mediate the therapeutic activity of TCMs and help to elucidate the core principles of TCM medicinal theory. In this systematic review, we found that MB-TCMs commonly participated in the modulation of metabolic syndrome, intestinal inflammation, nervous system disease and cardiovascular system disease in association with promoting the growth of beneficial bacteria Bacteroides, Akkermansia, Lactobacillus, Bifidobacterium, Roseburia as well as inhibiting the proliferation of harmful bacteria Helicobacter, Enterococcus, Desulfovibrio and Escherichia-Shigella. These alterations, correspondingly, enhance the generation of protective metabolites, mainly including short-chain fatty acids (SCFAs), bile acid (BAs), 5-hydroxytryptamine (5-HT), indole and gamma-aminobutyric acid (GABA), and inhibit the generation of harmful metabolites, such as proinflammatory factors trimethylamine oxide (TAMO) and lipopolysaccharide (LPS), to further exert multiplicative effects for the maintenance of human health through several different signaling pathways. Altogether, this present review has attempted to comprehensively summarize the relationship between MB-TCMs and gut microbiota by establishing the TCMs-gut microbiota-metabolite-signaling pathway-diseases axis, which may provide new insight into the study of TCM medicinal theories and their clinical applications.

Research Advance in the Relationship Between Plasma Trimethylamine Oxide Level and Heart Failure / 医药导报

Intestinal microorganisms and their metabolites are involved in the pathogenesis and progression of various cardiovascular diseases,especially in the progression of heart failure.This paper mainly discussed the gut microbial metabolites trimethylamine oxide(TMAO)participated in the pathological process of heart failure,and application value of TMAO in heart failure patients.This paper introduced the change characteristics of intestinal flora and its metabolites in heart failure patients,illu-minated the TMAO-mediated inflammatory response,and the related signal pathways and mechanism of myocardial hypertrophy and heart failure.High levels of TMAO are associated with poor outcomes in patients with heart failure indicating a good predictive value for the prognosis of heart failure.Regulating TMAO levels through diet,probiotics and prebiotics,antibiotics,fecal transplan-tation,and other pathways is expected to be a potential treatment for heart failure.

Effects of Buyang Huanwu Decoction on Intestinal Barrier, Intestinal Flora, and Trimethylamine Oxide in Rats with Heart Failure / 中国结合医学杂志

OBJECTIVE@#To explore the mechanisms of Buyang Huanwu Decoction (BYHWD) modulating the gut microbiome and trimethylamine oxide (TAMO) to exert cardioprotective effects.@*METHODS@#Ligation of the left anterior descending coronary artery was performed in rats to induce heart failure (HF). Except for the sham-operation group (n=10), 36 operation-induced models were randomized into 3 groups using a random number table (n=12 in each group): the model group, the BYHWD group (15.02 g/kg BYHWD), and the positive group (4.99 g/kg metoprolol succinate). After 4-week treatment (once daily by gavage), echocardiography was applied to evaluate the cardiac function and the Tei index (the ratio of ventricular isovolumic contraction time (IVCT) and isovolumic diastolic time (IVRT) to ejection time (ET)) was calculated; hematoxylin-eosin (HE) staining was observed to characterize the pathology of the myocardium and small intestinal villi. D-lactic acid was detected by an enzyme-linked immunosorbent assay (ELISA). Expressions of occludin, claudin-1, and zonula occludens (ZO-1) were detected by Western blot. 16S ribosomal ribonucleic acid (16S rRNA) sequencing was used to explore the changes in the intestinal flora. TMAO was detected via liquid chromatography-tandem mass spectrometry (LC-MS/MS).@*RESULTS@#In the echocardiography, the Tei index was considerably lower in the positive and BYHWD groups compared with the model group (P<0.05). Besides, BYHWD improved the pathology of myocardium and small intestine of HF rats and lowered the D-lactic acid content in the serum, when compared with the model group (P<0.05). BYHWD also improved the expression of occludin and claudin-1 (P<0.05); in the gut microbiota analysis, BYHWD slowed down modifications in the structure distribution of gut microbiota and regulated the diversity of intestinal flora in HF rats. The content of TMAO in the serum was significantly lowered by BYWHT compared with the model group (P<0.05).@*CONCLUSION@#BYHWD may delay progression of HF by enhancing the intestinal barrier structure, and regulating intestinal flora and TAMO.

Relationship between preoperative plasma trimethylamine oxide concentrations and postoperative delirium in elderly patients / 中华麻醉学杂志

Objective:To evaluate the relationship between preoperative plasma trimethylamine oxide (TMAO) concentrations and postoperative delirium (POD) in elderly patients.Methods:One hundred and eighty patients, aged ≥65 yr, of American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ, with body mass index of 17-30 kg/m 2, scheduled for elective hip replacement, were enrolled in this study. Venous blood samples were collected at 1 day before surgery, and the plasma TMAO concentrations were measured by high throughput liquid chromatography-tandem mass spectrometry. The patients were divided into 3 groups according to the concentrations of TMAO: low-concentration TMAO group (group L, ≤1.2 μmol/L), moderate-concentration TMAO group (group M, 1.3-1.9 μmol/L), and high-concentration TMAO group (group H, ≥2.0 μmol/L). All patients received superior inguinal fascia iliaca compartment block combined with intravenous general anesthesia. POD was identified by the Confusion Assessment Method-Chinese Reversion scale at 1, 2, 3 and 7 days after operation. The patients were divided into POD group and non-POD group according to whether POD occurred. Binary logistic regression analysis was used to evaluate the relationship between different plasma TMAO concentrations and POD. The receiver operating characteristic curve was used to evaluate the efficacy of plasma TMAO concentrations in predicting the occurrence of POD. Results:There were 60 cases in L group, 67 cases in M group and 53 cases in H group, and the incidence of POD was 12%, 22% and 32% in L, M and H groups, respectively. The incidence of POD was significantly higher in group H than in group L ( P<0.05). The plasma TMAO concentration was significantly higher in POD group than in non-POD group ( P<0.05). Logistic regression analysis showed that the risk of POD was 3.91 times higher in group H than in group L ( P<0.05). The area under the receiver operating characteristic curve of preoperative plasma TMAO concentrations in predicting POD was 0.754 (95% confidence interval 0.671-0.838, P<0.05). When the Youden index was 0.426, the optimal cut-off value of plasma TMAO concentrations was 1.625 μmol/L, and the specificity and sensitivity were 0.795 and 0.631, respectively. Conclusions:Elevated preoperative plasma TMAO concentration is associated with an increased risk of POD in elderly patients, and it has a good predictive value for POD.

Trimethylamine oxide induces pyroptosis of vascular endothelial cells through ALDH2/ROS/NLRP3/GSDMD pathway / 中南大学学报(医学版)

Objective: Trimethylamine oxide (TMAO) is a metabolite of intestinal flora and is known to promote the progression of atherosclerotic plaques. However, how TMAO works, including its effect on vascular endothelial cells, is not fully understood. This study aims to explore the biological role of TMAO in human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. Methods: Cell pyroptosis and the loss of plasma membrane integrity were induced under TMAO stimulation in HUVECs. The plasma membrane integrity of the cells was measured by Hoechst 33342/propidium iodide (PI) staining and lactate dehydrogenase leakage assay, and the changes in cell morphology were observed by atomic force microscope. The expression of proteins related to pyroptosis was determined by Western blotting or immunofluorescence. Mitochondrial acetaldehyde dehydrogenase 2 (ALDH2) activity in HUVECs was measured by the ALDH2 activity assay kit, and the level of reactive oxygen species (ROS) was detected by fluorescent probe DCFH-DA. Results: TMAO induced pyroptotic cell death, manifesting by the presence of propidium iodide-positive cells, the leakage of lactate dehydrogenase, the production of N-terminal gasdermin D (GSDMD-N), and the formation of plasma membrane pores. Moreover, TMAO induced elevated expression of inflammasome components, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3),apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 in cells. TMAO significantly inhibited ALDH2 activity and increased intracellular ROS production. However, the activation of ALDH2 by pharmacological manipulation attenuated TMAO-induced inflammasome activation and GSDMD-N production.Conclusion: TMAO induces pyroptosis of vascular endothelial cells through the ALDH2/ROS/NLRP3/GSDMD signaling pathway, which may be a potential therapeutic target for improving the treatment of atherosclerosis.

Xintahua water extract improves the disease indexes of atherosclerosis model rats / 中国临床药理学与治疗学

AIM: To investigate the effect of water extract of Ziziphora clinopodioides Lam (WEZ) on improving atherosclerosis model rats. METHODS: Sixty SD rats were randomly selected and 50 rats of them were randomly selected for atherosclerosis model with high-fat emulsion and vitamin D3, and then randomly divided into atherosclerosis (AS) model group, low, medium, high WEZ group and the positive control group. After 8 weeks of drug intervention, the plasma of each group of rats was collected to detect total cholesterol (TC), triglyceride (TG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and trimethylamine oxide (TMAO) level. The correlation between plasma TMAO and TNF-α and IL-6 levels in AS rats was detected. The aortic tissue-embedded sections of rats in each group were taken out to compare the aortic plaque area/aortic lumen area (PA/LA) ratio. RESULTS: Compared with the blank control group, the serum TC and TG levels of the AS model group increased significantly, and the difference was statistically significant (P<0.01). Compared with the AS model group, the serum TC and TG levels of the middle and high dose WEZ group and the positive control group were significantly decreased, and the difference was statistically significant (P<0.05). Compared with the blank control group, the serum TNF-α and IL-6 levels in the AS model group increased significantly, and the difference was statistically significant (P<0.01). Compared with the AS model group, the serum TNF-α and IL-6 levels of the high-dose WEZ group and the positive control group were significantly decreased, and the difference was statistically significant (P<0.05). Compared with the blank control group, the plasma TMAO level of rats in the AS model group increased significantly, and the difference was statistically significant (P<0.01). Compared with the AS model group, the plasma TMAO levels of rats in the high-dose WEZ group and the positive control group decreased significantly, and the difference was statistically significant (P<0.05). The analysis of the correlation between TMAO level and TNF-α/IL-6 level showed that TMAO level was positively correlated with TNF-α level (P=0.001, r=0.673), and positively correlated with IL-6 level (P=0.002, r= 0.646). Compared with the blank control group, the PA/LA ratio of the AS model group increased significantly, and the difference was statistically significant (P<0.01). Compared with the AS model group, the PA/LA ratio of rats in the medium and high dose WEZ group and the positive control group decreased significantly, and the difference was statistically significant (P<0.05). CONCLUSION: WEZ may regulate TMAO levels, down-regulate TNF-α and IL-6 levels, and reduces TC and TG levels, thereby improving AS, but its mechanism still needs further study.

Recent advance in relation between trimethylamine oxide metabolized by intestinal microbes and ischemic cerebrovascular diseases / 中华神经医学杂志

Trimethylamine oxide (TMAO) is a product of the metabolism of nutrients such as choline by intestinal microbes and liver enzymes. Recent studies have revealed that TMAO may be essential for occurrence and development of cerebrovascular diseases by disturbing the reverse transport of cholesterol, upregulating expressions of macrophage receptors associated with development of atherosclerosis, synthesis of bile acids, vascular endothelial cell inflammation, platelet aggregation and thrombosis. In this paper, we review recent studies about the production of TMAO, and efficacy of TMAO in occurrence and development of ischemic cerebrovascular diseases. This review will help us to understand TMAO related pathogenesis and pathophysiological process of ischemic cerebrovascular diseases and to identify potential therapeutic targets to facilitate translational research in this field.

Effects of telmisartan on intestinal flora and its metabolite TMAO in atherosclerosis / 中国临床药理学与治疗学

AIM: To investigate the effect of telmisartan on intestinal flora and metabolite TMAO in atherosclerosis. METHODS: Seventeen ApoE