As a highly addictive and neurotoxic stimulant, methamphetamine poses a severe threat to public psychological well-being and social security. Dysbiosis of gut flora is presumed to be a potential mechanism for methamphetamine habituation. To test this hypothesis, we conducted a cross-species study to analyze the enduring effects of methamphetamine administration on the gut microbiome. Either in an abstinent cohort or sensitized mice, the microbial community remained distinct from controls even after a long-term methamphetamine withdrawal, establishing an emerging homeostasis through extensive interactions of symbionts. The dysbiosis was correlated to the duration of MA abuse. Within the discriminant genera, those in the order Clostridiales exhibited coordinated changes across hosts and functionally reshaped the gut flora, potentially contributing to recurring relapse of drug usage. These findings help comprehend the long-term detriment caused by methamphetamine and underscore the translational implications of leveraging gut microbiome analysis to combat MA-related criminal activities.

BACKGROUND:Developing countries face an "obesity epidemic," particularly affecting children and younger adults. While obesity is a known risk factor for 12 types of cancer, primarily affecting older populations, its impact on younger generations is understudied. METHODS:This study analyzed data from a population-based cancer registry covering 14.14 million individuals in China (2007-2021). We compared the incidence of obesity- and non-obesity-related cancers and applied an age-period-cohort model to estimate their impacts. FINDINGS:Among 651,342 cancer cases, 48.47% were obesity related. The age-standardized incidence rates (ASRs) of the 12 obesity-related cancers increased annually by 3.6% (p < 0.001), while ASRs for non-obesity-related cancers remained stable. Obesity-related cancers surged among younger adults, with rates rising across successive generations. The annual percentage of change decreased with age, from 15.28% for ages 25-29 years to 1.55% for ages 60-64 years. The incidence rate ratio for obesity-related cancer was higher in younger generations compared to those born in 1962-1966. We predict that the ASR for obesity-related cancers will nearly double in the next decade. CONCLUSIONS:The rising incidence of obesity-related cancers among young adults poses a significant public health concern. The increasing cancer burden underscores the need for targeted interventions to address the obesity epidemic. FUNDING:This work was supported by the National Natural Science Foundation of China (81930019, 82341076) to J.-K.Y.

BACKGROUND: Dilated cardiomyopathy is characterized by left ventricular dilation and continuous systolic dysfunction. Mitochondrial impairment is critical in dilated cardiomyopathy; however, the underlying mechanisms remain unclear. Here, we explored the cardioprotective role of a heart-enriched long noncoding RNA, the dilated cardiomyopathy repressive transcript (DCRT), in maintaining mitochondrial function. METHODS: The DCRT knockout (DCRT −/− ) mice and DCRT knockout cells were developed using CRISPR-Cas9 technology. Cardiac-specific DCRT transgenic mice were generated using α-myosin heavy chain promoter. Chromatin coimmunoprecipitation, RNA immunoprecipitation, Western blot, and isoform sequencing were performed to investigate the underlying mechanisms. RESULTS: We found that the long noncoding RNA DCRT was highly enriched in the normal heart tissues and that its expression was significantly downregulated in the myocardium of patients with dilated cardiomyopathy. DCRT −/− mice spontaneously developed cardiac dysfunction and enlargement with mitochondrial impairment. DCRT transgene or overexpression with the recombinant adeno-associated virus system in mice attenuated cardiac dysfunction induced by transverse aortic constriction treatment. Mechanistically, DCRT inhibited the third exon skipping of NDUFS2 (NADH dehydrogenase ubiquinone iron-sulfur protein 2) by directly binding to PTBP1 (polypyrimidine tract binding protein 1) in the nucleus of cardiomyocytes. Skipping of the third exon of NDUFS2 induced mitochondrial dysfunction by competitively inhibiting mitochondrial complex I activity and binding to PRDX5 (peroxiredoxin 5) and suppressing its antioxidant activity. Furthermore, coenzyme Q10 partially alleviated mitochondrial dysfunction in cardiomyocytes caused by DCRT reduction. CONCLUSIONS: Our study revealed that the loss of DCRT contributed to PTBP1-mediated exon skipping of NDUFS2, thereby inducing cardiac mitochondrial dysfunction during dilated cardiomyopathy development, which could be partially treated with coenzyme Q10 supplementation.

Diabetic cardiomyopathy (DCM) is defined as abnormalities in myocardial structure and function in the setting of diabetes and in the absence of cardiovascular diseases, such as coronary artery disease, hypertension, and valvular heart disease. DCM is one of the leading causes of mortality in patients with diabetes. However, the underlying pathogenesis of DCM has not been fully elucidated. Recent studies have revealed that non-coding RNAs (ncRNAs) in small extracellular vesicles (sEVs) are closely associated with DCM and may act as poten-tial diagnostic and therapeutic targets. Here, we introduced the role of sEV-ncRNAs in DCM, summarized the current therapeutic advancements and limitations of sEV-related ncRNAs against DCM, and discussed their potential improvement.

细胞外囊泡(EV)是由各种活细胞分泌的纳米级大小的双层脂质囊状物.细胞外囊泡可以在细胞之间转运DNA、RNA和蛋白,是细胞间信息传递的重要部分.microRNA是一类小的非编码RNA,其通过与靶向mRNA 3'UTR区域结合,促进mRNA的降解或抑制蛋白的合成.文章着重讨论了 microRNA产生的过程、细胞外囊泡作为microRNA的载体在细胞之间传递信息,以及EV-miRNA在心血管相关疾病中的重要作用.

Intensive glycemic control is insufficient for reducing the risk of heart failure among patients with diabetes mellitus (DM). While the "hyperglycemic memory" phenomenon is well documented, little is known about its underlying mechanisms. In this study, a type 1 DM model was established in C57BL/6 mice using streptozotocin (STZ). Leptin receptor-deficient (db/db) mice were used as a model of type 2 DM. A type 9 adeno-associated virus was used to overexpress or knock down miR-320 in vivo. Diastolic dysfunction was observed in the type 1 DM mice with elevated miR-320 expression. However, glycemic control using insulin failed to reverse diastolic dysfunction. miR-320 knockdown protected against STZ-induced diastolic dysfunction. Similar results were observed in the type 2 DM mice. In vitro, we found that miR-320 promoted CD36 expression, which in turn induced further miR-320 expression. CD36 was rapidly induced by hyperglycemia at protein level compared with the much slower induction of miR-320, suggesting a positive feedback loop of CD36/miR-320 with CD36 protein induction as the initial triggering event. In conclusion, in DM-induced cardiac injury, miR-320 and CD36 mutually enhance each other's expression, leading to a positive feedback loop and a sustained hyperlipidemic state in the heart.

Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation. By microRNA (miRNA) array, a Kaposi’s sarcoma-associated herpes virus (KSHV)-encoded miRNA, kshv-miR-K12-1-5p, was detected in patients with DCM. The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up. Increased KSHV seropositivity and quantitative titers were found in the patients with DCM compared with the non-DCM group (22.0% versus 9.1%, p < 0.05; 168 versus 14 copies/mL plasma, p < 0.05). The risk of the individual end point of death from cardiovascular causes or heart transplantation was increased among DCM patients with the KSHV DNA seropositivity during follow-up (adjusted hazard ratio 1.38, 95% confidence interval 1.01–1.90; p < 0.05). In heart tissues, the KSHV DNA load was also increased in the heart from patients with DCM in comparison with healthy donors (1016 versus 29 copies/10 5 cells, p < 0.05). The KSHV and kshv-miR-K12-1-5p in DCM hearts were detected using immunofluorescence and fluorescence staining in situ hybridization. KSHV itself was exclusively detectable in CD31-positive endothelium, while kshv-miR-K12-1-5p could be detected in both endothelium and cardiomyocytes. Moreover, kshv-miR-K12-1-5p released by KSHV-infected cardiac endothelium could disrupt the type I interferon signaling pathway in cardiomyocytes. Two models of kshv-miR-K12-1-5p overexpression (agomiR and recombinant adeno-associated virus) were used to explore the roles of KSHV-encoded miRNA in vivo. The kshv-miR-K12-1-5p aggravated known cardiotropic viruses-induced cardiac dysfunction and inflammatory infiltration. In conclusion, KSHV infection was a risk factor for DCM, providing developmental insights of DCM involving virus and its miRNA ( https://clinicaltrials.gov . Unique identifier: NCT03461107).

Klebsiella pneumoniae (K. pneumoniae) is an important pathogen that can cause severe hospital- and community-acquired infections. To systematically investigate its methylation features, we determined the whole-genome sequences of 14 K. pneumoniae strains covering varying serotypes, multilocus sequence types, clonal groups, viscosity/virulence, and drug resistance. Their methylomes were further characterized using Pacific Biosciences single-molecule real-time and bisulfite technologies. We identified 15 methylation motifs [13 N6-methyladenine (6mA) and two 5-methylcytosine (5mC) motifs], among which eight were novel. Their corresponding DNA methyltransferases were also validated. Additionally, we analyzed the genomic distribution of GATC and CCWGG methylation motifs shared by all strains, and identified differential distribution patterns of some hemi-/un-methylated GATC motifs, which tend to be located within intergenic regions (IGRs). Specifically, we characterized the in vivo methylation kinetics at single-base resolution on a genome-wide scale by simulating the dynamic processes of replication-mediated passive demethylation and MTase-catalyzed re-methylation. The slow methylation of the GATC motifs in the replication origin (oriC) regions and IGRs implicates the epigenetic regulation of replication initiation and transcription. Our findings illustrate the first comprehensive dynamic methylome map of K. pneumoniae at single-base resolution, and provide a useful reference to better understand epigenetic regulation in this and other bacterial species.