Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy.

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.

[Review and analysis of transplant biological research projects funded by National Natural Science Foundation of China].

OBJECTIVE: To study the funding and achievements in the field of organ transplantation support by the National Natural Science Foundation of China (NSFC). METHODS: A search of NSFC database was made by using the key word "transplantation" and excluding "bone marrow transplantation" for the projects funded between 1988 and 2013. SCI indexed publications that marked with NSFC project number were collected by searching each grant number in the database of the Web of Science. RESULTS: Six hundreds fifty-five projects were identified and received about 220 million yuan in grant funding. These funded research projects were distributed among 25 provinces and autonomous regions, however, which were mainly in the developed coastal areas; of them, 43 (6.56%) projects were granted in xenotransplantation and 17 projects (2.60%) were funded in the field of traditional Chinese medicine-related organ transplantation; Transplantation on blood vessels, heart, kidney, liver, lung, small intestine, pancreatic, cornea, trachea, skin, etc. were primarily performed in research. Nine hundreds and sixty-one SCI-indexed publications were achieved. CONCLUSIONS: Magnitude and intensity of NSFC funding, output of SCI publications have been increasing, suggesting that NSFC positively promotes the development of organ transplantation. Although a great progress of transplantation has been made, basic and translational studies should be vigorously strengthened.

[National Natural Science Foundation of China promotes the development of Chinese medicine in China--an analysis of Chinese medicine project funded by National Natural Science Foundation of China in the last decade].

In recent years, projects funded by the Division V III of Health Sciences of the National Natural Science Foundation of China (NSFC) increased steadily, which enhanced the process of modernization of Chinese medicine (CM). We analyzed CM projects funded by NSFC during 2003 -2012, which aimed to provide reference to experts in the CM field.

Ca2+ participates in alpha1B-adrenoceptor-mediated cAMP response in HEK293 cells.

AIM: To investigate the alpha1B-adrenoceptor (alpha1B-AR)-mediated cAMP response and underlying mechanisms in HEK293 cells. METHODS: Full-length cDNA encoding alpha1B-AR was transfected into HEK293 cells using the calcium phosphate precipitation method, and alpha1B-AR expression and cAMP accumulation were determined by using the saturation radioligand binding assay and ion-exchange chromatography, respectively. RESULTS: Under agonist stimulation, alpha1B-AR mediated cAMP synthesis in HEK293 cells, and blockade by PLC-PKC or tyrosine kinase did not reduce cAMP accumulation induced by NE. Pretreatment with pertussis toxin (PTX) had little effect on basal cAMP accumulation as well as norepinephrine (NE)-stimulated cAMP accumulation. In addition, pretreatment with cholera toxin (CTX) neither mimicked nor blocked the effect induced by NE. The extracellular Ca2+ chelator egtazic acid (EGTA), nonselective Ca2+ channel blocker CdCl2 and calmodulin (CaM) inhibitor W-7 significantly reduced NE-induced cAMP accumulation from 1.59%+/-0.47% to 1.00%+/-0.31%, 0.78%+/-0.23%, and 0.90%+/-0.40%, respectively. CONCLUSION: By coupling with a PTX-insensitive G protein, alpha1BAR promotes Ca2+ influx via receptor-dependent Ca2+ channels, then Ca2+ is linked to CaM to form a Ca2+-CaM complex, which stimulates adenylyl cyclase (AC), thereby increasing the cAMP production in HEK293 cell lines.

Characterization of cAMP accumulation mediated by three alpha1-adrenoceptor subtypes in HEK293 cells.

AIM: To investigate the characterization of cAMP response mediated by alpha1-adrenoceptor (alpha1-AR) subtypes in HEK293 cells. METHODS: (1) Full-length cDNA encoding three alpha1-AR subtypes were transfected into HEK293 cells by the calcium phosphate precipitation method, respectively. (2) The densities of alpha1-AR subtypes expressed in HEK293 cells were measured by radioligand binding assay. (3) cAMP accumulation was measured by [3H]adenine prelabeling method. RESULTS: (1) Activation of each of three subtypes resulted in an increase of cAMP accumulation in HEK293 cells in a dose-dependent manner, which was inhibited by selective alpha1-AR antagonist prazosin. (2) Comparing the pharmacological property, the maximal responses of alpha1A-AR to agonists were the most potent, while the sensitivity of alpha1-AR subtypes to norepinephrine (NE) was the highest. CONCLUSION: Each of three alpha1-AR subtypes can mediate cAMP accumulation in HEK293 cell line, and there are differences in pharmacological property.