Comparison of the low-calorie DASH diet and a low-calorie diet on serum TMAO concentrations and gut microbiota composition of adults with overweight/obesity: a randomized control trial.

This study compares two diets, Dietary Approaches to Stop Hypertension (DASH) and a Low-Calorie Diet on Trimethylamine N-oxide (TMAO) levels and gut microbiota. 120 obese adults were randomly allocated to these three groups: a low-calorie DASH diet, a Low-Calorie diet, or a control group for 12 weeks. Outcomes included plasma TMAO, lipopolysaccharides (LPS), and gut microbiota profiles. After the intervention, the low-calorie DASH diet group demonstrated a greater decrease in TMAO levels (-20 ± 8.1 vs. -10.63 ± 4.6 µM) and a significant decrease in LPS concentration (-19.76 ± 4.2 vs. -5.68 ± 2.3) compared to the low-calorie diet group. Furthermore, the low-calorie DASH diet showed a higher decrease in the Firmicutes and Bactericides (F/B) ratio, which influenced TMAO levels, compared to the Low-Calorie diet (p = 0.028). The current study found the low-calorie DASH diet improves TMAO and LPS in comparison to a Low-Calorie diet.

Dose-dependent pharmacokinetics of midazolam in rats: influence of hepatic first-pass metabolism.

To characterise the dose-dependent pharmacokinetics of midazolam and evaluate the intestinal and hepatic first-pass effects on midazolam in Sprague-Dawley rats, the concentrations and area under the concentration-time curve (AUC) of midazolam in the portal and systemic plasma were simultaneously determined with a double cannulation method.It was found that about 75% of the dose was left in the portal blood with different oral administration doses, while the bioavailability in the liver was 37.86% at 20 mg/kg, significantly higher than 9.16% at 2 mg/kg.The disproportional increase in AUC of midazolam and significant decrease in exposure of metabolites were observed in systemic plasma after hepatic portal vein administration. And in the in vitro study, the formation rate of the metabolites of midazolam significantly decreased when midazolam was at 300 µM compared with 100 µM.These results indicated that not only the saturation of first-pass metabolism but also the inhibition of hepatic metabolism is responsible for the nonlinear PK of midazolam. Thus, a rational dose should be chosen when midazolam is used as a probe in the drug-drug interaction study, particularly for orally administered drugs that undergo hepatic first-pass metabolism.

Identification of the main flavonoids of Abelmoschus manihot (L.) medik and their metabolites in the treatment of diabetic nephropathy.

Introduction: Huangkui capsule (HKC) is made from the ethanol extract of Abelmoschus manihot (L.) Medik [Malvaceae; abelmoschi corolla] and received approval from the China Food and Drug Administration (Z19990040) in 1999. Currently, HKC is used for treatment of the patients with diabetic nephropathy (DN) in China. The bioactive chemical constituents in HKC are total flavonoids of A. manihot (L.) Medik (TFA). The present study aims to identify the primary flavonoid metabolites in HKC and TFA and their metabolism fates in db/db mice, the animal model for the study of type 2 diabetes and DN. Methods: HKC (0.84 g/kg/d) and TFA (0.076 g/kg/d) or vehicle were respectively administered daily via oral gavage in db/db mice for 4 weeks. The metabolism fate of the main metabolites of HKC in serum, liver, kidney, heart, jejunum, colon, jejunal contents, colonic contents, and urine of db/db mice were analyzed with a comprehensive metabolite identification strategy. Results and Discussion: In db/db mice administered with HKC and TFA, 7 flavonoid prototypes and 38 metabolites were identified. The related metabolic pathways at Phases I and II reactions included dehydroxylation, deglycosylation, hydrogenation, methylation, glucuronidation, sulphation, and corresponding recombined reactions. Quercetin, isorhamnetin, quercetin sulphate, quercetin monoglucuronide, and isorhamnetin monoglucuronide presented a high exposure in the serum and kidney of db/db mice. Thereby, the present study provides a pharmacodynamic substance basis for better understanding the mechanism of A. manihot (L.) Medik for medication of DN.

Qing-Zhi-Tiao-Gan-Tang (QZTGT) prevents nonalcoholic steatohepatitis (NASH) by expression pattern correction.

ETHNOPHARMACOLOGICAL RELEVANCE: Qing-Zhi-Tiao-Gan-Tang or Qing-Zhi-Tiao-Gan Decoction (QZTGT) is based on the compatibility theory of traditional Chinese medicine (TCM), that is a combination of three classical formulae for the treatment of nonalcoholic fatty liver disease (NAFLD). Its pharmacodynamic material basis is made up of quinones, flavanones, and terpenoids. AIM OF THE STUDY: This study aimed to look for a promising recipe for treating nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, and to use a transcriptome-based multi-scale network pharmacological platform (TMNP) to find its therapy targets. MATERIALS AND METHODS: A classical dietary model of NASH was established using MCD (Methionine- and choline-deficient) diet-fed mice. Liver coefficients like ALT, AST, serum TC, and TG levels were tested following QZTGT administration. A transcriptome-based multi-scale network pharmacological platform (TMNP) was used to further analyze the liver gene expression profile. RESULTS: The composition of QZTGT was analyzed by HPLC-Q-TOF/MS, a total of 89 compounds were separated and detected and 31 of them were found in rat plasma. QZTGT improved liver morphology, inflammation and fibrosis in a classical NASH model. Transcriptomic analysis of liver samples from NASH animal model revealed that QZTGT was able to correct gene expression. We used transcriptome-based multi-scale network pharmacological platform (TMNP) to predicted molecular pathways regulated by QZTGT to improve NASH. Further validation indicated that "fatty acid degradation", "bile secretion" and "steroid biosynthesis" pathways were involved in the improvement of NASH phenotype by QZTGT. CONCLUSIONS: Using HPLC-Q-TOF/MS, the compound composition of QZTGT, a Traditional Chinese prescription, was separated, analyzed and identified systematically. QZTGT mitigated NASH symptoms in a classical dietary model of NASH. Transcriptomic and network pharmacology analysis predicted the potential QZTGT regulated pathways. These pathways could be used as therapeutic targets for NASH.

Comprehensive Evaluation of Metabolism and the Contribution of the Hepatic First-Pass Effect in the Bioavailability of Glabridin in Rats.

Glabridin is a bioactive isoflavan, which has a wide range of biological properties and is widely used in the market of health products and dietary supplements. However, the transformation pathway of glabridin in vivo is unclear, and the bioavailability is controversial among different studies. Therefore, a new HPLC-Q-TOF method was developed to analyze and identify the prototype and metabolites of glabridin in rats. A total of 63 compounds were identified, including hydroxylation, demethylation, acetylation, demethylation to carboxylation, glucuronidation, and sulfate conjugation, and 43 of which were new metabolites that had not been reported. Additionally, our study verified that the oral bioavailability of glabridin was 6.63 ± 2.29% in rats. Furthermore, we found that the hepatic first-pass effect was 62.12 ± 15.7% for glabridin. These results indicated that a high hepatic first-pass effect and extensive metabolism of glabridin in vivo may lead to its limited oral bioavailability.