新型生物标志物TMAO与心血管疾病关系的研究进展

肠道菌群及其代谢产物与心血管疾病的关系是心血管领域研究的热点,有关探索肠道菌群在调节心血管生理和疾病进展中作用的基础与临床研究已取得了较大进展。国内外一些研究表明肠道微生物源代谢物三甲胺-N-氧化物（TMAO）已经成为影响心血管疾病发生发展的一个关键因素。近年来TMAO与心血管疾病的发生发展及预后关系的临床研究也取得了一些成果,血浆TMAO水平未来可作为心血管疾病危险分层、诊断及预后的新型生物标志物,对心血管疾病的发生和主要心血管事件（MACE）进行预测。本文就TMAO作为心血管疾病新型生物标志物及潜在治疗靶点的研究进展进行综述。     

Metabonomic study on the toxicity of Hei-Shun-Pian, the processed lateral root of Aconitum carmichaelii Debx. (Ranunculaceae)

The purpose of this paper was to study the effects of Hei-Shun-Pian, the processed lateral root of Aconitum carmichaelii Debx. (Ranunculaceae), on the metabolic profile of rats, to discuss the mechanism of toxicology and to find out the potential biomarkers of the toxic effects. Twenty male Wistar rats were divided into four groups (n=5) and each group were administered orally with the decoction of Hei-Shun-Pian (88.1g/kg per day, 35.6g/kg per day, 17.6g/kg per day) or equal volume of drinking water respectively for 14 days. Urine of every 24-h and the plasma of the last day were collected for NMR experiments, and then analyzed by multivariate analysis methods. Decreases in urinary excretion of taurine and trimethylamine-N-oxide (TMAO) and increases in urinary levels of citrate, 2-oxoglutarate (2-OG), succinate and hippurate were observed in the high and medium dosed groups at the early stage of the dosing period. Taurine level increased at the later stage of the dosing period to the normal value, and then even to a value higher than that of the control group at the end of the experiment. No metabolic differences were observed between low dosed and control groups until the later stage of the dosing period when a slight increase in urinary taurine level was observed, suggesting a cumulative effect. These results suggest the toxic effect of Hei-Shun-Pian on rat heart in a dose dependent manner.     

The unfolded protein response in retinal vascular diseases: Implications and therapeutic potential beyond protein folding

Angiogenesis is a complex, step-wise process of new vessel formation that is involved in both normal embryonic development as well as postnatal pathological processes, such as cancer, cardiovascular disease, and diabetes. Aberrant blood vessel growth, also known as neovascularization, in the retina and the choroid is a major cause of vision loss in severe eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and central and branch retinal vein occlusion. Yet, retinal neovascularization is causally and dynamically associated with vasodegeneration, ischemia, and vascular remodeling in retinal tissues. Understanding the mechanisms of retinal neovascularization is an urgent unmet need for developing new treatments for these devastating diseases. Accumulating evidence suggests a vital role for the unfolded protein response (UPR) in regulation of angiogenesis, in part through coordinating the secretion of pro-angiogenic growth factors, such as VEGF, and modulating endothelial cell survival and activity. Herein, we summarize current research in the context of endoplasmic reticulum (ER) stress and UPR signaling in retinal angiogenesis and vascular remodeling, highlighting potential implications of targeting these stress response pathways in the prevention and treatment of retinal vascular diseases that result in visual deficits and blindness.     

Changes of metabolic profiles in urine after oral administration of quercetin in rats

Quercetin has been studied extensively. However, its actions in vivo are not well understood. We investigated the overall metabolic changes in urine after oral quercetin administration in rats and try to provide useful information on the actions of quercetin in vivo. Rats were orally administered a single dose of quercetin aglycon (40 mg/kg body weight). Urine samples were collected and subjected to ¹H nuclear magnetic resonance (NMR)-based metabolomic analysis and high performance liquid chromatography–mass spectrometry (HPLC–MS). Significant changes of metabolic profiles were observed in urine after quercetin administration. Relative increase in the concentrations of choline, creatinine, dimethylglycine, hippurate, taurine, trimethylamine N-oxide and reduction in acetate, alanine, lactate were observed. The concentrations of citrate, 2-oxoglutarate and succinate increased in the 0–24 h period after treatment and decreased thereafter. Some peaks assignable to quercetin metabolites were found in the aromatic regions of ¹H NMR spectra. HPLC–MS analysis identified quercetin, methyl quercetin, quercetin sulfate, quercetin monoglucuronide, and methyl quercetin monoglucuronide in urine after administration of quercetin. Our current findings indicate that quercetin behaves not only as an antioxidant, but also a modulator for some metabolic processes in vivo. The active forms of quercetin present in the biofluids must be investigated further.     

Differential effect of short-term popular diets on TMAO and other cardio-metabolic risk markers

Background

Dietary nutrient intake and its metabolism by the gut microbiome have recently been implicated in cardiovascular disease (CVD) risk. In particular, trimethylamine N-oxide (TMAO), a metabolite of the gut microbiota, has been shown to be a predictor of incident CVD events. Elevated levels of branched-chain amino acids (BCAA) have also been associated with an increased propensity for insulin resistance.

A comparative study of the sub-chronic toxic effects of three organic arsenical compounds on the urothelium in F344 rats; gender-based differences in response

Epidemiological studies indicated that human arsenic exposure can induce urinary bladder cancer. Methylation of inorganic arsenic can generate more reactive and toxic organic arsenical species. In this regard, it was recently reported that the methylated arsenical metabolite, dimethylarsinic acid [DMA(V)], induced urinary bladder tumors in rats. However, other methylated metabolites, like monomethylarsonic acid [MMA(V)] and trimethylarsine oxide (TMAO) were not carcinogenic to the urinary bladder. In order to compare the early effects of DMA(V), MMA(V), and TMAO on the urinary bladder transitional cell epithelium at the scanning electron microscope (SEM) level, we investigated the sub-chronic (13 weeks) toxicological effects of MMA(V) (187 ppm), DMA(V) (184 ppm), TMAO (182 ppm) given in the drinking water to male and female F344 rats with a focus on the urinary bladder in this study. Obvious pathological changes, including ropy microridges, pitting, increased separation of epithelial cells, exfoliation, and necrosis, were found in the urinary bladders of both sexes, but particularly in females receiving carcinogenic doses of DMA(V). Urine arsenical metabolic differences were found between males and females, with levels of MMA(III), a potential genotoxic form, higher in females treated with DMA(V) than in males. Thus, this study provides clear evidence that DMA(V) is more toxic to the female urinary bladder, in accord with sensitivity to carcinogenesis. Important gender-related metabolic differences including enhanced presentation of MMA(III) to the urothelial cells might possibly account for heightened sensitivity in females. However, the potential carcinogenic effects of MMA(III) need to be further elucidated.     

Toxicological effects of cinnabar in rats by NMR-based metabolic profiling of urine and serum

Cinnabar, an important traditional Chinese mineral medicine, has been widely used as a Chinese patent medicine ingredient for sedative therapy. However, the pharmaceutical and toxicological effects of cinnabar, especially in the whole organism, were subjected to few investigations. In this study, an NMR-based metabolomics approach has been applied to investigate the toxicological effects of cinnabar after intragastrical administration (dosed at 0.5, 2 and 5 g/kg body weight) on male Wistar rats. Liver and kidney histopathology examinations and serum clinical chemistry analyses were also performed. The 1H NMR spectra were analyzed using multivariate pattern recognition techniques to show the time- and dose-dependent biochemical variations induced by cinnabar. The metabolic signature of urinalysis from cinnabar-treated animals exhibited an increase in the levels of creatinine, acetate, acetoacetate, taurine, hippurate and phenylacetylglycine, together with a decrease in the levels of trimethyl-N-oxide, dimethylglycine and Kreb's cycle intermediates (citrate, 2-oxoglutarate and succinate). The metabolomics analyses of serum showed elevated concentrations of ketone bodies (3-d-hydroxybutyrate and acetoacetate), branched-chain amino acids (valine, leucine and isoleucine), choline and creatine as well as decreased glucose, lipids and lipoproteins from cinnabar-treated animals. These findings indicated cinnabar induced disturbance in energy metabolism, amino acid metabolism and gut microflora environment as well as slight injury in liver and kidney, which might indirectly result from cinnabar induced oxidative stress. This work illustrated the high reliability of NMR-based metabolomic approach on the study of the biochemical effects induced by traditional Chinese medicine.