FMO3-TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population / 医学前沿

The association among plasma trimethylamine-N-oxide (TMAO), FMO3 polymorphisms, and chronic heart failure (CHF) remains to be elucidated. TMAO is a microbiota-dependent metabolite from dietary choline and carnitine. A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction, with the longest follow-up of 7 years. The concentrations of plasma TMAO and its precursors, namely, choline and carnitine, were determined by liquid chromatography-mass spectrometry, and the FMO3 E158K polymorphisms (rs2266782) were genotyped. The top tertile of plasma TMAO was associated with a significant increment in hazard ratio (HR) for the composite outcome of cardiovascular death or heart transplantation (HR = 1.47, 95% CI = 1.13-1.91, P = 0.004) compared with the lowest tertile. After adjustments of the potential confounders, higher TMAO could still be used to predict the risk of the primary endpoint (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). This result was also obtained after further adjustment for carnitine (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). The FMO3 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort, and lower TMAO levels were found in the AA-genotype. Thus, higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders, and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.

Predictive value of plasma TMAO combined with NT-proBNP on the prognosis and length of hospitalization of patients with ischemic heart failure / 中华心血管病杂志

Objective: To explore the value of the assessment of plasma trimethylamine N-oxide (TMAO) combined with N-terminal pro-B-type natriuretic peptide (NT-proBNP) on predicting the all-cause mortality, length of hospitalization, and hospital cost in ischemic heart failure (IHF) patients. Methods: This prospective cohort study included 189 patients (157 males, mean age (64.0±10.5) years) with a left ventricular ejection fraction<45% caused by coronary artery disease, who hospitalized in our department from March 2016 to December 2020. Baseline data, including demographics, comorbid conditions and laboratory examination, were analyzed. The cumulative rate of all-cause mortality was evaluated using the Kaplan-Meier method and compared between the groups according to the log-rank test. Relative risks were reported as hazard ratios (HR) and 95% confidence interval (95%CI) calculated using the Cox proportional-hazards analysis, with stepwise adjustment for covariables. Spearman correlation analysis was then performed to determine the relationship between TMAO combined with NT-proBNP and length of hospitalization and hospital cost. Results: There were 50 patients in the low TMAO+low NT-proBNP group, 89 patients in high TMAO or high NT-proBNP group, 50 patients in high TMAO+high NT-proBNP group. The mean follow-up period was 3.0 years. Death occurred in 70 patients (37.0%), 27 patients (54.0%) in high TMAO+high NT-proBNP group, 29 patients (32.6%) in high TMAO or high NT-proBNP group and 14 patients (28.0%) in low TMAO+low NT-proBNP group. TMAO, in combination with NT-proBNP, improved all-cause mortality prediction in IHF patients when stratified as none, one or both biomarker(s) elevation, with the highest risk of all-cause mortality in high TMAO+high NT-proBNP group (HR=3.62, 95%CI 1.89-6.96, P<0.001). ROC curve analysis further confirmed that TMAO combined with NT-proBNP strengthened the prediction performance on the risk of all-cause death (AUC=0.727(95%CI 0.640-0.813), sensitivity 55.0%, characteristic 83.1%). Spearman correlation analysis showed that IHF patients with high TMAO and high NT-proBNP were positively associated with longer duration of hospitalization (r=0.191,P=0.009), but not associated with higher hospital cost (r=0.030, P=0.686). Conclusions: TMAO combined with NT-proBNP are valuable prediction tool on risk stratification of patients with IHF, and those with two biomarkers elevation face the highest risk of mortality during follow-up period, and are associated with the longer hospital stay.

Gut microbiota and its metabolite trimethylamine-N-oxide (TMAO): a novel regulator in coronary artery disease / 生物工程学报

Coronary artery disease (CAD) is a chronic disease but causes the highest mortality and morbidity among the cardiovascular diseases worldwide. Correlations between CAD and gut microbiota have been observed. This suggests that the gut microbiota could become a vital diagnostic marker of CAD, and restoring the gut habitat may become a promising strategy for CAD therapy. The elevated level of trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite, was found to be associated with the increased risk of cardiovascular disease and the all-cause mortality. Preclinical studies have shown that it has pro-arteriosclerosis properties. It is likely that regulating the production of TMAO by gut microbiota may become a promising strategy for anti-atherosclerosis therapy. This review summarizes the clinical and preclinical researches on the intervention of CAD by regulating the gut microbiota and the microbiota-derived metabolite TMAO, with the aim to provide new target for the therapy of CAD.

Trimethylamine-N-oxide and cardiovascular events in chronic kidney disease / 中南大学学报(医学版)

Trimethylamine-N-oxide (TMAO) is a biologically active molecule which is metabolized by intestinal microflora and excreted by the kidney. The incidence and mortality of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) are significantly increased, which seriously affects the prognosis of patients with CKD. Recent studies have shown that TMAO can cause myocardial fibrosis and cardiovascular damage. Plasma TMAO levels are elevated in CKD patients, and TMAO was an independent predictor for all-cause mortality in patients with CKD, including CVD events. As a "uremic toxin", TMAO can promote the progression and the occurrence of CVD in CKD patients through its toxic effects, such as inflammatory response and oxidative stress. Taken together, it may suggest that reducing TMAO production and plasma TMAO levels may decrease the occurrence of CVD events in CKD and that TMAO may be a therapeutic target for ameliorating the prognosis of CKD.

Biofiltration of trimethylamine in biotrickling filter inoculated with Aminobacter aminovorans

Background: Trimethylamine (TMA) is the main responsible for the odor associated with rotting fish and other annoying odors generated in many industrial activities. Biofiltration has proved to be efficient for treating odorous gaseous emissions. The main objective of this work was to determine the removal capacity of TMA of a biotrickling filter inoculated with Aminobacter aminovorans and to evaluate the effect of H2S on its performance. Results: The maximumspecific growth rate ofA. aminovorans in a liquid culture was 0.15 h -1 , witha TMAto biomass yield of 0.10 (g g -1) and a specific consumption rate of 0.062 g·g-1·h-1 . The initial specific consumption rate of TMA was highly influenced by the presence of H2S in liquid culture at concentrations of 20 and 69 ppm in heading space oftheflasks.ABTF inoculatedwithA. aminovorans showedremoval efficiencieshigher than98%ina range ofloading rate of 0.2 to 8 g·m-3·h-1 at empty bed residence time (EBRT) of 85 and 180 s. No effect on the elimination capacity and efficiency was detected when H2S was added at 20 and 50 ppm to the inlet gaseous emission, though the fraction of A. aminovorans measured by qPCR in the biofilm decreased. Conclusions:Abiotrickling filter inoculated with A. aminovorans can remove efficiently the TMA in a gaseous stream. The elimination capacity of TMA can be negatively affected by H2S, but its effect is not notorious when it is forming part of a biofilm, due to its high specific consumption rate of TMA.

H NMR-based metabolomics approach to investigating the renal protective effects of Genipin in diabetic rats / 中国天然药物

Diabetic nephropathy is one of the various complications of diabetes mellitus, affecting patients for lifetime. Earlier studies have revealed that genipin can not only improve diabetes, but also induce cytotoxicity. Therefore, it is not clear which effect of genipin on kidneys occurs, when it is used in the treatment of diabetes. In the present study, we performed nuclear magnetic resonance (NMR)-based metabolomics analysis of urine and kidney tissue samples obtained from diabetic rats to explore the change of endogenous metabolites associated with diabetes and concomitant kidney disease. Nine significant differential metabolites that were closely related to renal function were screened. They were mainly related to three metabolic pathways: synthesis and degradation of ketone bodies, glycine, serine and threonine metabolism, and butanoate metabolism, which are involved in methylamine metabolism, energy metabolism and amino acid metabolism. In addition, after the intervention of genipin, the metabolic levels of all the metabolites tended to be normal, indicating a protective effect of genipin on kidneys. Our results may be helpful for understanding the antidiabetic effect of genipin.

H NMR-based metabolomics approach to investigating the renal protective effects of Genipin in diabetic rats / 中国天然药物

Diabetic nephropathy is one of the various complications of diabetes mellitus, affecting patients for lifetime. Earlier studies have revealed that genipin can not only improve diabetes, but also induce cytotoxicity. Therefore, it is not clear which effect of genipin on kidneys occurs, when it is used in the treatment of diabetes. In the present study, we performed nuclear magnetic resonance (NMR)-based metabolomics analysis of urine and kidney tissue samples obtained from diabetic rats to explore the change of endogenous metabolites associated with diabetes and concomitant kidney disease. Nine significant differential metabolites that were closely related to renal function were screened. They were mainly related to three metabolic pathways: synthesis and degradation of ketone bodies, glycine, serine and threonine metabolism, and butanoate metabolism, which are involved in methylamine metabolism, energy metabolism and amino acid metabolism. In addition, after the intervention of genipin, the metabolic levels of all the metabolites tended to be normal, indicating a protective effect of genipin on kidneys. Our results may be helpful for understanding the antidiabetic effect of genipin.

Distribution characteristics of trimethylamine N-oxide and its association with gut microbiota / 南方医科大学学报

<p><b>OBJECTIVE</b>To analyze the distribution of trimethylamine N-oxide (TMAO) in healthy adults with different risk factors and explore its association with gut microbiota.</p><p><b>METHODS</b>We collected fasting blood samples and fresh fecal samples from 181 subjects without atherogenesis in the carotid arteries. Plasma TMAO levels of the subjects were determined using stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS). The fecal DNA was extracted, and the 16S rRNA V4 tags were amplified and sequenced by Illumina HiSeq 2000. The association between TMAO and classical cardiovascular risk factors were analyzed. Gut microbial community structure was analyzed with QIIME, and LEfSe was used to identify the biomarkers.</p><p><b>RESULTS</b>The median (IQR) TMAO level was 2.66 (1.96-4.91) µmol/L in the subjects. TMAO level was significantly correlated with body mass index and operational taxonomic units (OTU). Individuals with high TMAO levels were found to have abundant Clostridiales, Phascolarctobacterium, Oscillibacter, and Alistipes but less abundant Anaerosprobacter.</p><p><b>CONCLUSION</b>Chinese subjects have in general low levels of TMAO. TMAO levels are not significantly correlated with the classical cardiovascular risk factors or the gut microbial structures.</p>

Intestinal Microbiota Metabolism and Atherosclerosis / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>This review aimed to summarize the relationship between intestinal microbiota metabolism and cardiovascular disease (CVD) and to propose a novel CVD therapeutic target.</p><p><b>DATA SOURCES</b>This study was based on data obtained from PubMed and EMBASE up to June 30, 2015. Articles were selected using the following search terms: "Intestinal microbiota", "trimethylamine N-oxide (TMAO)", "trimethylamine (TMA)", "cardiovascular", and "atherosclerosis".</p><p><b>STUDY SELECTION</b>Studies were eligible if they present information on intestinal microbiota metabolism and atherosclerosis. Studies on TMA-containing nutrients were also included.</p><p><b>RESULTS</b>A new CVD risk factor, TMAO, was recently identified. It has been observed that several TMA-containing compounds may be catabolized by specific intestinal microbiota, resulting in TMA release. TMA is subsequently converted to TMAO in the liver. Several preliminary studies have linked TMAO to CVD, particularly atherosclerosis; however, the details of this relationship remain unclear.</p><p><b>CONCLUSIONS</b>Intestinal microbiota metabolism is associated with atherosclerosis and may represent a promising therapeutic target with respect to CVD management.</p>

Some current challenges in research on air pollution and health / Desafíos actuales de la investigación sobre contaminación del aire y salud

This commentary addresses some of the diverse questions of current interest with regard to the health effects of air pollution, including exposure-response relationships, toxicity of inhaled particles and risks to health, multipollutant mixtures, traffic-related pollution, accountability research, and issues with susceptibility and vulnerability. It considers the challenges posed to researchers as they attempt to provide useful evidence for policy-makers relevant to these issues. This commentary accompanies papers giving the results from the ESCALA project, a multi-city study in Latin America that has an overall goal of providing policy-relevant results. While progress has been made in improving air quality, driven by epidemiological evidence that air pollution is adversely affecting public health, the research questions have become more subtle and challenging as levels of air pollution dropped. More research is still needed, but also novel methods and approaches to address these new questions.

Este comentario aborda algunos de los temas de interés actual en relación con los efectos de la contaminación del aire sobre la salud, tales como las relaciones exposición-respuesta, la toxicidad y riesgos para la salud de las partículas inhaladas, las mezclas de contaminantes múltiples, la contaminación relacionada con el tráfico, la investigación sobre responsabilidad, y los problemas de susceptibilidad y vulnerabilidad. Considera los retos que se presentan a los investigadores que intentan proporcionar evidencia para los responsables políticos en estas cuestiones. Este texto acompaña otros trabajos con resultados del proyecto ESCALA, un estudio en varias ciudades de América Latina que tiene como objetivo general proporcionar resultados relevantes para la política pública. Aunque ha habido avances para mejorar la calidad del aire, gracias a la evidencia epidemiológica de que la contaminación aérea está afectando negativamente a la salud pública, las preguntas de investigación se han vuelto más sutiles y difíciles a medida que los niveles de contaminación se reducen. Se necesita más investigación, pero también nuevos métodos y enfoques capaces de enfrentar estas preguntas.

A simple and effective pressure culture system modified from a transwell cell culture system

Mechanical pressure plays an important role in many physiological and pathological processes. Mimicking the mechanical pressure present in vitro is necessary for related research, but usually requires expensive and complicated equipment. In this study we created a simple pressure culture system based on the transwell culture system. By cutting off the top rim of the transwell insert, the cells were compressed between the insert membrane and the well floor. The new pressure culture system was proven effective in that it induced cell morphological change, integrin β1 upregulation, actin polymerization and growth change in rat retinal ganglion cells, human nasopharyngeal carcinoma cells and mice embryonic fibroblasts. Though the pressure value is immeasurable and inhomogeneous, the easily available culture system still provides a choice for the laboratories that do not have access to the better, but much more expensive pressure culture equipment.

Study on influence of glucoside Tripterygium total tablets on metabolism in rats by NMR metabonomic technique / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the toxic effects of Glucoside Tripterygium total on rats with nuclear magnetic resonance (NMR)-based metabonomic method.</p><p><b>METHOD</b>The influence of intragastric administration of Glucoside Tripterygium total suspension at two different doses on endogenetic metabolites in normal rat urine was determined with bio-NMR method then analyzed by pattern recognition technique and partial least-squares discriminant analysis (PLS-DA). Histopathological analysis was carried out.</p><p><b>RESULT</b>Escalations of concentrations of urinary taurine, TMAO and glucose as well as reductions of concentrations of urinary citrate and 2-oxoglutarate were found by analysis of the 1H-NMR spectra, which was coincident with the result of histopathological analysis. The result of pathological examination indicated that pathologic change was not observed in nephridial tissue, but there were obvious changes in hepatic tissue.</p><p><b>CONCLUSION</b>The urinary metabomic spectra were closely associated with the hepatic toxicity, which manifested the mitochondrial dysfunctions, the abnormal energy metabolism in TCA cycle as well as the abnormal glucose metabolism.</p>

Off-flavors removal and storage improvement of mackerel viscera by supercritical carbon dioxide extraction.

The oil in mackerel viscera was extracted by supercritical carbon dioxide (SCO2) at a semi-batch flow extraction process and the fatty acids composition in the oil was identified. Also the off-flavors removal in mackerel viscera and the storage improvement of the oils were carried out. As results obtained, by increasing pressure and temperature, quantity was increased. The maximum yield of oils obtained from mackerel viscera by SCO, extraction was 118 mgg(-1) (base on dry weight of freeze-dried raw anchovy) at 50 degrees C, 350 bar And the extracted oil contained high concentration of EPA and DHA. Also it was found that the autoxidation of the oils using SCO2 extraction occurred very slowly compared to the oils by organic solvent extraction. The off-flavors in the powder after SCO2 extraction were significantly removed. Especially complete removal of the trimethylamine which influences a negative compound to the products showed. Also other significant off-flavors such as aldehydes, sulfur-containing compounds, ketones, acids or alcohols were removed by the extraction.

Spectrophotometric determination of trimethylamine-nitrogen in cadaver tissues for the estimation of late postmortem interval: a pilot study / 华中科技大学学报（医学）（英德文版）

To study the relationship between the late postmortem interval (PMI) and trimethylamine-nitrogen (TMA-N) in postmortem tissues of cadaver, TMA-N in muscles, livers and kidneys of rats was measured at different postmortem intervals (PMI) by using a modified spectrophotometric method. The results indicated that the detection sensitivity of TMA-N was 1 mg/L, and there was a good linear correlation between the value of absorbance (A value) and TMA-N at the concentration of 1-10 mg/L (R (2) = 0.9991). Although TMA variation in muscles was different from that in inner organs during the time since death, TMA-N changes in cadaver tissues was positively correlated with PMI. During 2 to 7 d since death, the best correlation between PMI and TMA-N concentration was found in muscles. With PMI as an independent variable, the cubic polynomial regression equation was y= -0.457x(3)+6.519x(2)-24.574x+27.207 (R (2)=0.969). During 3 to 8 days since death, PMI was best correlated with TMA-N concentration in inner organs. With PMI as the independent variable, the cubic polynomial regression equation was y=0.509x(3)-9.153x(2)+55.727x-95.819 (R (2)=0.953). It was concluded that TMA-N in tissues could be used as a new estimator for late PMI. The method used in this study offered advantages such as accuracy, sensitivity, little samples required and wide PMI estimation.

A Case of Stroke Associated with Isometheptene

No abstract available.

Efecto de tratamientos térmicos sobre las características químicas de carne de jaiba mora (Homalaspis plana) / Effect of thermal treatments on the chemical characteristics of mora crab meat (Homalaspis plana)

Marine species muscles present non-proteins nitrogenated compounds, used as quality index. They are total volatile basis (NBVT), trimethylamine oxide (TMAO) and trimethylamine (TMA). pH is considered too as a quality index. The aim of this work was to evaluate these parameters in a fresh and canned marine product from the V region, corresponding to mora crab (Homalaspis plana). Fresh pincer meat from mora crab was extracted and kept in ice until theits analysis and thermal process of the canned product. A 3(2) statistical design was applied, considering two variables with 3 levels: 15, 30 y 45 minutes time levels: 80 degrees, 100 degrees y 121 degrees C temperature levels. Nine conditions of time-temperature were obtained. The thermal treatment caused an increase in pH and BVT. The TMA was increased since reduction of TMAO.

Analogue-resistant mutants of Azotobacter chroococcum derepressed for nitrogenase activity and early ammonia excretion having potential as inoculants for cereal crops.

Spontaneous mutants resistant to methionine sulfoximine (Msx), methyl alanine (Mal) and methyl ammonium chloride (Mac) were derived from A. chroococcum strain A103. Msx and Mal-resistant mutants expressed 1.73 to 10.98% of the fully derepressed nitrogenase activity when grown in Burk's medium containing ammonium acetate. Mac-resistant mutants did not express nitrogenase activity in ammonium acetate supplemented medium. The mutants excreted ammonia even after 2 days of growth and some mutants excreted more ammonia as compared to the parent. Selected mutants were inoculated on wheat (Triticum aestivum) and barley (Hordeum vulgare) under field conditions. Majority of the derepressed mutants increased grain yield of wheat and barley varying from 1.2 to 33.3%. However, host-dependent effects on grain yield were observed with different mutants. Two mutants, Mal 27 and Mac 19 showed significant increase in grain yields of both the crops. The results suggest that metabolic analogue-resistant mutants of Azotobacter have potential for use as a biofertilizer for cereal crops.

Response of the portal vein of spontaneous hypertensive rats to intracellular pH.

The effect of intracellular pH perturbations on the portal vein preparations of spontaneously hypertensive rats and their control Wistar Kyoto rats was investigated. Intracellular alkalinity induced by application of 20 mM NH4Cl or 20 mM trimethylamine produced dilatation of both preparations. Intracellular acidity induced by washout of the previous ammonium and trimethylamine solutions or by application of 20 mM sodium propionate solution caused constriction of both preparations. These responses of the portal veins of both animals to intracellular pH variations were qualitatively the same in nonactivated preparations and in preparations precontracted with 26 mM K+ or 1 microM norepinephrine. Recovery from acidic constrictions induced by washout of ammonium and trimethylamine solutions was significantly slower in spontaneous hypertensive rats than in Wistar Kyoto rats preparations. Conceivably, a lower intracellular pH in the vascular smooth muscle of the resistance vessels of hypertensive patients, as compared to normotensive individuals, may partly account for the hypertensive phenomena.

Interactions of the regulatory ligands Mg2+ and MgATP2- with the renal plasma membrane Ca(2+)-ATPase: effects of osmolytes that stabilize or destabilize protein structure

In this report we analyze the kinetics of activation of the plasma membrane Ca(2+)-ATPase from kidney proximal tubules by the regulatory ligands Mg2+ and MgATP2-, and we examine modifications in the effects of these ligands that are promoted by organic solutes of natural occurrence that stabilize or destabilize protein structure and function. The solutes tested were trimethylamine-N-oxide (TMA-O), sucrose and urea. TMA-O and sucrose were chosen as representative of the different methylamines and polyols, respectively, that accumulate in living organisms. The results lead to the conclusion that free Mg2+ and the MgATP2- complex both activate the rate-determining E2-->E1 transition during the catalytic cycle of the enzyme, by binding to nonidentical and independent regulatory sites. They also indicate that TMA-O, sucrose and urea not only promote global modifications in the enzyme structure, but also modify specific interactions of the ligands Mg2+ and MgATP2- at their regulatory sites

Nucleophilic scission of thioester linkages and conformational changes in human plasma low density lipoproteins.

A comparison between conformations of native and methylamine modified human plasma low density lipoproteins (hydrated density 1.032-1.043 g/ml) has been presented. Near UV circular dichroism and difference absorption spectra of modified low density lipoprotein have suggested substantial differences in the local environments of several aromatic amino acid side chains. Relatively lower ellipticity at 222 nm of modified lipoprotein indicated alterations in the secondary structures of its protein moiety. Nucleophilic reaction of methylamine did not cause the peptide bond scission but it brought conformational transition such that some of the buried hydrophobic domains of the protein moiety got exposed to the aqueous environment.