Association of folic acid dosage with circulating unmetabolized folic acid in Chinese adults with H-type hypertension: a multicenter, double-blind, randomized controlled trial.

Background: There is growing concern regarding elevated levels of circulating unmetabolized folic acid (UMFA) due to excessive intake of folic acid (FA). However, no randomized clinical trial has been conducted to examine the FA-UMFA dose-response relationship. Objective: This study aimed to investigate the FA-UMFA dose-response relationship in Chinese adults with hypertension and elevated homocysteine (H-type hypertension), a population with clear clinical indication for FA treatment. Methods: The data for this study were derived from a randomized, double-blind, multicenter clinical trial of 8 FA dosages on efficacy of homocysteine (Hcy) lowering. The parent trial had three 3 stages: screening period (2-10 days), run-in period (0-2 weeks, baseline visit), and double-blind treatment period (8 weeks) with follow-up visits at the end of the 2nd, 4th, 6th, and 8th weeks of treatment. Participants were randomly assigned to 8 treatment groups corresponding to FA dosages of 0, 0.4, 0.6, 0.8, 1.2, 1.6, 2.0 mg to 2.4 mg. Results: This study included 1,567 Chinese adults aged ≥45 years with H-type hypertension. There was a positive but non-linear association between FA supplementation and UMFA levels in the dosage range of 0 mg to 2.4 mg. In the regression analysis, the coefficients for the linear and quadratic terms of FA dosage were both statistically significant (P < 0.001). Notably, the slope for UMFA was greater for FA dosages >0.8 mg (ß = 11.21, 95% CI: 8.97, 13.45) compared to FA dosages ≤0.8 mg (ß = 2.94, 95% CI: 2.59, 3.29). Furthermore, FA dosages higher than 0.8 mg did not confer additional benefits in terms of increasing 5-methyl tetrahydrofolic acid (5-MTHF, active form of folate) or reducing homocysteine (Hcy). Conclusion: In Chinese adults with H-type hypertension, this study showed a positive, non-linear, dosage-response relationship between FA supplementation ranging from 0 to 2.4 mg and circulating UMFA levels. It revealed that 0.8 mg FA is an optimal dosage in terms of balancing efficacy (increasing 5-MTHF and lowering Hcy) while minimizing undesirable elevation of UMFA. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03472508?term=NCT03472508&draw=2&rank=1, identifier NCT03472508.

Deoxycholic Acid-Induced Gut Dysbiosis Disrupts Bile Acid Enterohepatic Circulation and Promotes Intestinal Inflammation.

BACKGROUND: A Western diet is a risk factor for the development of inflammatory bowel disease (IBD). High levels of fecal deoxycholic acid (DCA) in response to a Western diet contribute to bowel inflammatory injury. However, the mechanism of DCA in the natural course of IBD development remains unanswered. AIMS: The aim of this study is to investigate the effect of DCA on the induction of gut dysbiosis and its roles in the development of intestinal inflammation. METHODS: Wild-type C57BL/6J mice were fed an AIN-93G diet, either supplemented with or without 0.2% DCA, and killed at 24 weeks. Distal ileum and colon tissues were assessed by histopathological analysis. Hepatic and ileal gene expression was examined by qPCR, and the gut microbiota was analyzed by high-throughput 16S rRNA gene sequencing. HPLC-MS was used for fecal bile acid quantification. RESULTS: Mice fed the DCA-supplemented diet developed focal areas of ileal and colonic inflammation, accompanied by alteration of the composition of the intestinal microbiota and accumulation of fecal bile acids. DCA-induced dysbiosis decreased the deconjugation of bile acids, and this regulation was associated with the repressed expression of target genes in the enterohepatic farnesoid X receptor-fibroblast growth factor (FXR-FGF15) axis, leading to upregulation of hepatic de novo bile acid synthesis. CONCLUSIONS: These results suggest that DCA-induced gut dysbiosis may act as a key etiologic factor in intestinal inflammation, associated with bile acid metabolic disturbance and downregulation of the FXR-FGF15 axis.

Protective effects of luteolin-7-O-glucoside against starvation-induced injury through upregulation of autophagy in H9c2 Cells.

Cardiomyocyte nutrient deprivation is a common clinical event that mediates various cardiac ischemic processes and is associated with autophagy activation and cell survival or death. Luteolin-7-O-glucoside (LUTG) was one of the flavonoid glycosides isolated from Dracocephalum tanguticum. Previous research had showed that LUTG pretreatment had significant protective effects against doxorubicin-induced cardiotoxicity. However, whether LUTG could protect cardiomyocytes from starvation-induced injury was not clear. In this study, cardioprotection and mechanisms of LUTG against starvation-induced injury were investigated in vitro. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazolium bromide (MTT) assay showed starvation-induced autophagy is a homeostatic and protective response for H9c2 cell survival. LUTG could protect against injury induced by starvation in H9c2 cells. Acridine orange (AO) staining showed that pretreatment with LUTG enhanced lysosomal autophagy. Western blotting indicated that LUTG enhanced autophagy by down-regulating the expression of phospho-extracellular signal regulated kinase1/2 (p-ERK), phospho-protein kinase B (p-Akt) and phospho-mammalian target of rapamycin (p-mTOR). These results suggest that LUTG might act as a promising therapeutic agent for preventing starvation-induced cardiotoxicity by upregulation of autophagy through the Akt/mTOR and ERK signal pathway.

Determinants of hyperhomocysteinemia in healthy and hypertensive subjects: A population-based study and systematic review.

AIMS: Hyperhomocysteinemia (HHcy) is known to increase the risk of many diseases. Factors influencing HHcy in healthy and hypertensive subjects remain under-researched. METHODS: A large population-based study was conducted in 60 communities from Shenzhen, China. Responses to standardized questions on lifestyle factors and blood samples were collected from all participants after a 12-h overnight fast. Multiple linear and multivariate logistic regressions were used to explore risk factors for HHcy. Results were then compared to those from a systematic review of English-language articles listed in Pubmed, EBSCOhost, Web of Science, Embase and Cochrane libraries that investigated HHcy risk factors in healthy and hypertensive subjects. RESULTS: A total of 1586 healthy (Male/Female = 642/944) and 5935 hypertensive subjects (Male/Female = 2928/3007) participated in our population-based study. In logistic regression analyses, age, BMI and creatinine (Cr) were risk factors, while being female, fruit intake and physical activity were protective factors for HHcy in healthy subjects. In hypertensive subjects, seven [age, smoking, salt intake, systolic blood pressure (SBP), uric acid, triglycerides (TG), and Cr] and four [female, fruit intake, total cholesterol (TC), and glucose] factors were associated with higher and lower HHcy respectively. The review of 71 studies revealed that potential risk factors for Hcy included nutritional, physiologic, lifestyle habits, ethnicity, genetics, interactions between gene-environment, gene-gene, gene-nutritional, environment-environment, nutritional-nutritional. CONCLUSION: Our study indicates the potential importance of increasing folic acid and vitamin B supplementation, daily fruit and vegetable intake, regular exercise and refraining from tobacco smoking and alcohol consumption as preventive strategies for Hcy.

[Effects of different donor cells on the development of nuclear-transferred porcine embryos].

This study was undertaken to systematically examine the effects of different donor cells and numbers of passages on the development of nuclear-transferred porcine embryos, so as to establish a preliminary procedure for porcine cloning. Porcine oocytes obtained at slaughter were matured in vitro for 40-44 h and then enucleated in manipulation medium containing 5 micro g/mL cytochalasin B. Fibroblast cells (FC), oviduct epithelial cells (OEC), granulosa cells (GC) and cumulus cells (CC) after 3-9 passages in 10% FBS-supplemented culture medium were either treated by serum starvation (0.5% FBS for 2-9 days), 0.1 micro g/mL aphidiconlin (APD) for 1 day and 0.5% FBS for 2-9 days or left untreated in complete medium for 2-9 days. They were transferred into enucleated oocytes by microinjection or electric fusion (100 V/mm, 30 ms and 1 pulse). Reconstituted embryos were activated with a combination of calcium ionophore A23187 or electric pulse and 6-DMAP, and cultured for 6 days, to evaluate their cleavage and embryonic development. The cleavage rate of embryos reconstructed with FC and GC pretreated with 0.1 micro g/mL APD + 0.5% FBS were significantly higher than that of serum starvation group and control group (P<0.01). There was a significant difference in the cleavage rate and embryonic development among embryos derived from GC, CC and FC, OEC pretreated with 0.1 micro g/mL APD + 0.5% FBS. The cleavage rate of embryos reconstructed with GC by electrofusion was significantly higher than that by microinjection (P<0.05), but no difference was found in the proportion of embryos that developed to blastocysts. About 75% to 85% of GC at 3 and 6 passages, and FC at 6 and 10 passages had a normal karyotype, and resulted in similar cleavage rate and blastocyst development. These results indicate that: (1) FC and GC can be cultured up to 9 passages and maintain a relatively stable karyotype; (2) Treatment of donor cells with 0.1 micro g/mL APD prior to nuclear transfer can improve the efficiency of somatic cell nuclear transfer in buffalo but serum starvation is inefficient in our system; (3) Both FC and GC cells can be used as the donor karyoplasts for nuclear transfer, and their efficiency is not influenced by the culture passages. (4) The development of reconstructed embryos by electrofusion is higher than that by microinjection, but there is no difference in the overall efficiency between the two methods.