Aims
Aging is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-related diseases. However, whether the aged-associated dysbiosis contributes to age-related AF is still unknown. Direct demonstration that the aged gut microbiota is sufficient to transmit the enhanced AF susceptibility in a young host via microbiota-intestinal barrier-atria axis has not yet been reported. This study aimed to determine whether gut microbiota dysbiosis affects age-related AF.
Methods and Results
Herein, by using a fecal microbiota transplantation (FMT) rat model, we demonstrated that the high AF susceptibility of aged rats could be transmitted to a young host. Specially, we found the dramatically increased levels of circulating lipopolysaccharide (LPS) and glucose led to the up-regulated expression of NLR family pyrin domain containing 3 (NLRP3)-inflammasome, promoting the development of AF which depended on the enhanced atrial fibrosis in recipient host. Inhibition of inflammasome by a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, resulted in a lower atrial fibrosis and AF susceptibility. Then we conducted cross-sectional clinical studies to explore the effect of aging on the altering trends with glucose levels and circulating LPS among clinical individuals in two China hospitals. We found that both of serum LPS and glucose levels were progressively increased in elderly patients as compared with those young. Furthermore, the aging phenotype of circulating LPS and glucose levels, intestinal structure and atrial NLRP3-inflammasome of rats were also confirmed in clinical AF patients. Finally, aged rats colonized with youthful microbiota restored intestinal structure and atrial NLRP3-inflammasome activity, which suppressed the development of aged-related AF.
Conclusions
Collectively, these studies described a novel causal role of aberrant gut microbiota in the pathogenesis of age-related AF, which indicates that the microbiota-intestinal barrier-atrial NLRP3 inflammasome axis may be a rational molecular target for the treatment of aged-related arrhythmia disease.
Translational Perspective
The current study demonstrates that aged-associated microbiota dysbiosis promotes AF in part through a microbiota–gut–atria axis. Increased AF susceptibility due to enhanced atrial NLRP3-inflammasome activity by LPS and high glucose was found in an aged FMT rat model, and also confirmed within elderly clinical individuals. In a long-term FMT rat study, the AF susceptibility was ameliorated by treatment with youthful microbiota. The present findings can further increase our understanding of aged-related AF and address a promising therapeutic strategy that involves modulation of gut microbiota composition.
High-quality vinegars are traditionally produced by aging them in barrels or bottles. However, these processes are very time-consuming. To accelerate of Zhenjiang vinegar maturation, the ultrasound was used to treat the steeped vinegar. Results showed that, the optimum ultrasonic power, time and ethanol addition for aging vinegar were determined to be 50W/100mL, 75min and 0.75% (V/V), respectively. Under the optimum experimental conditions, the total amino acid of fresh vinegar decreased from 1082.259mg/100mL to 871.045mg/100mL. Several volatile components increased significantly, such as the total esters, aldehydes and heterocyclic. Total non-volatile organic acids increased from 202.59mg/10mL to 233.87mg/10mL. The changes of above-mentioned components develop towards the direction of mature vinegar. Coupling the HS-SPME/GC-MS analysis data with Principal Components Analysis, ultrasonic treatment vinegar was determined to be equivalent to 2-3years of natural aged Zhenjiang vinegar. This study has showed that ultrasound is promising not only in shortening the aging time and lowering costs for the vinegar-making industry, but also in producing fine vinegar.
Diabetic nephropathy (DN) is a frequently occurred microvascular complication associated with type I and type II diabetes mellitus. The participation of long noncoding RNAs (lncRNAs) in diabetes-related microvascular complications has been reported extensively. We attempted to unveil the possible regulatory mechanism of lncRNA growth arrest-specific transcript 5 (GAS5) and matrix metalloproteinase 9 (MMP9), an important inflammatory protein, in the progression of DN. A rat DN model was induced by streptozocin (STZ). The low expression of GAS5 and high expression of MMP9 in DN rats with DN was then determined by RT-qPCR and western blot analysis, and lentivirus-mediated GAS5 overexpression was shown to ameliorate STZinduced renal interstitial fibrosis (RIF) and inflammatory reaction in the kidney of DN rats. Moreover, MMP9 was found to be upregulated in STZ-induced DN, while MMP9 silencing induced by lentivirus expressing shRNA against MMP9 reduced RIF and suppressed inflammation in the kidney of DN rats. RIP, RNA pull-down, and ChIP assays demonstrated that GAS5 downregulated MMP9 via recruiting enhancer of zeste homolog 2 (EZH2) in the promoter region of MMP9. Overall, our study reveals that GAS5 downregulates MMP9 expression through recruiting EZH2 to MMP9 promoter region and alleviates the progression of renal fibrosis in DN rats, which sheds new light on the therapeutic potential of GAS5-targeted therapies in combating that disease.
K E Y W O R D Sdiabetic nephropathy, enhancer of zeste homolog 2, histone H3 methylated Lys27, long noncoding RNA growth arrest-specific transcript 5, matrix metalloproteinase 9, renal fibrosis
We observed a high incidence of PAH in ESRD patients undergoing CAPD. Logistic regression analysis revealed that DBP, NT-proBNP, LAD, RVID, RVOTD, LVEF, TAPSE and E/E' are high-risk factors for PAH in ESRD patients undergoing CAPD.
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