Background: High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases. Methods: Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet–fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase). Results: Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression. Conclusions: This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt–induced cardiovascular damage in clinical practice.

A novel HA@ceria nanoquantum dots (HA@CQDs) exhibit efficient protective effects against damage induced by ROS. More importantly, aided by H2O2, the HA@CQDs-Ce6/H2O2 significantly enhanced PDT efficacy for the tumor therapy.

Background Altered adipokine secretion in dysfunctional adipose tissue facilitates the development of atherosclerotic diseases including lower extremity peripheral artery disease (PAD). Asprosin is a recently identified adipokine and displays potent regulatory role in metabolism, but the relationship between asprosin and lower extremity PAD remains uninvestigated. Methods 33 type 2 diabetes mellitus (T2DM) patients (DM), 51 T2DM patients with PAD (DM + PAD) and 30 healthy normal control (NC) volunteers were recruited and the blood samples were collected for detecting the circulatory asprosin level and metabolomic screening. RNA sequencing was performed using the aorta tissues from the type 2 diabetic db/db mice and human umbilical vein endothelial cells (HUVECs) were treated with asprosin to determine its impact on the endothelial-to-mesenchymal transition (EndMT). Results The circulating levels of asprosin in DM + PAD group were significantly higher than that of NC group and the DM group. Circulating asprosin level was remarkably negatively correlated with ankle-brachial index (ABI), even after adjusting for age, sex, body mass index (BMI) and other traditional risk factors of PAD. Logistic regression analysis revealed that asprosin is an independent risk factor for PAD and receiver-operator characteristic (ROC) curve determined a good sensitivity (74.5%) and specificity (74.6%) of asprosin to distinguish PAD. Data from metabolomics displayed a typical characteristics of de novo amino acid synthesis in collagen protein production by myofibroblasts in patients with PAD and activation of TGF-β signaling pathway appeared in the aortic tissue of db/db mice. Asprosin directly induces EndMT in HUVECs in a TGF-β-dependent manner as TGF-β signaling pathway inhibitor SB431542 erased the promotional effect of asprosin on EndMT. Conclusions Elevated circulatory asprosin level is an independent risk factor of lower extremity PAD and might serve as a diagnostic marker. Mechanistically, asprosin directly induces EndMT that participates in vascular injury via activation of TGF-β signaling pathway. Trial registration This trial was registered at clinicaltrials.gov as NCT05068895

Intracardiac ectopic thyroid tissue is a rare lesion. We present a case of successful excision of an ectopic thyroid adenoma originated from the right ventricular aspect of the interventricular septum and extending to the right ventricular outflow tract. The 12-month follow-up shows normal thyroid function and good clinical status of the patient. In our estimation, there was no case with an intracardiac ectopic thyroid adenoma reported before in China.

Motivation RNA-sequencing (RNA-seq) enables global identification of RNA-editing sites in biological systems and disease. A salient step in many studies is to identify editing sites that statistically associate with treatment (e.g. case versus control) or covary with biological factors, such as age. However, RNA-seq has technical features that incumbent tests (e.g. t-test and linear regression) do not consider, which can lead to false positives and false negatives. Results In this study, we demonstrate the limitations of currently used tests and introduce the method, RNA-editing tests (REDITs), a suite of tests that employ beta-binomial models to identify differential RNA editing. The tests in REDITs have higher sensitivity than other tests, while also maintaining the type I error (false positive) rate at the nominal level. Applied to the GTEx dataset, we unveil RNA-editing changes associated with age and gender, and differential recoding profiles between brain regions. Availability and implementation REDITs are implemented as functions in R and freely available for download at https://github.com/gxiaolab/REDITs. The repository also provides a code example for leveraging parallelization using multiple cores.

Tissue bacterial infections are a major pathological factor in many diseases. Effects on this aspect are in focus for the development of coordinated therapeutic strategies for bacterial killing and anti‐inflammation. Here, inspired by the biodetoxification capacity of immune cells, multifunctional biomimetic nanovesicles (MϕM‐LPs) that are co‐assembled by macrophage membranes and artificial lipids to deliver antibiotics for treating bacterial infections, are presented. The macrophage membrane endows the MϕM‐LPs with the capacity of lipopolysaccharide and inflammatory cytokine neutralization, while the artificial lipid membrane can be further engineered to increase the fluidity and anchor to bacteria. In addition, the MϕM‐LPs can deliver sufficient ciprofloxacin with controllable release to accomplish an excellent antibacterial activity and biodetoxification capacity in vitro. Based on these advantages, it is demonstrated in a mouse model of Staphylococcus aureus (S. aureus) focal infection, that a single injection of the biomimetic nanovesicles can effectively anchor to and eliminate S. aureus in the infected tissue and reduce inflammatory cytokine levels. Thus, the tissue regeneration and collagen deposition can be accelerated. These results indicate the potential values of integrating natural and artificial membrane materials as a multifunctional biomimetic drug delivery system to treat bacterial infections.

The combination of obesity and hypertension is associated with high morbidity and mortality; however, the mechanism underlying obesity-induced hypertension remains unclear. In this study, we detected the possible effects of TRPV1, a previously identified antihypertensive calcium (Ca2+) channel in adipose tissue, on the occurrence of obesity and hypertension in mice lacking UCP1, a spontaneously genetically manipulated obesity model, by generating TRPV1 and UCP1 double knockout mice. In these mice, obesity and hypertension appeared earlier and were more severe than in mice with the knockout of UCP1 or TRPV1 alone. The knockout of TRPV1 in UCP1 knockout mice further reduced functional brown adipose tissue (BAT) generation; decreased resting oxygen consumption, heat production, and locomotor activities; and was accompanied by severe mitochondrial respiratory dysfunction in BAT. Mechanistically, TRPV1, UCP1, and LETM1 acted as a complex to maintain an appropriate mitochondrial Ca2+ level, and TRPV1 knockout caused a compensatory increase in mitochondrial Ca2+ uptake via LETM1 activation. However, the compensatory response was blocked in UCP1−/− mice, resulting in dramatically reduced mitochondrial Ca2+ uptake and higher production of ATP and oxidative stress. This study provides in vivo evidence for the critical role of BAT mitochondrial Ca2+ homeostasis in obesity-associated hypertension and indicates that the TRPV1/UCP1/LETM1 complex may be an alternative intervention target.

Background Several genomic loci of type 2 diabetes (T2D) nominated in genome‐wide association studies (GWAS) have been suggested to regulate metabolism in muscle. However, a large portion of the genetic risk and the underlying regulation remain unexplained. The present study aimed to localize the potentially functional regions or genes at juxtaposed with another zinc finger protein 1 (JAZF1) locus and interpret their possible biological mechanisms in the muscle of T2D. Methods Seven GWAS datasets including 21,897 T2D patients and 32,710 healthy controls of 772 SNPs within JAZF1 locus were meta‐analysed using unconditional logistic regression. The Sherlock and GTEx protal online algorithms were implemented to show the significant colocalizations. Multiple omics data were integrated to predict the potential biological functions of JAZF1‐AS1 in muscle. The cis regulation of JAZF1‐AS1 was analysed using in vitro cloning in Human skeletal muscle cells (HSkMC). Results With a cross‐population meta‐analysis of seven GWAS, we identified a linkage disequilibrium (LD) block within intron 1 of JAZF1 that was significantly associated with T2D (false discovery rate < 0.05). The colocalization analysis showed a significant association between genetically determined expression of JAZF1 in skeletal muscle and T2D with a strong probability of colocalization (PP4 = 75.09%). This region also encodes the upstream regulatory region of the antisense non‐coding RNA JAZF1‐AS1. Expression‐quantitative trait loci analysis detected a regulatory SNP within this LD block, rs864745, which is associated with the expression of JAZF1‐AS1 and JAZF1. With in vitro cloning, we further reported the role of JAZF1‐AS1 in cis‐regulating JAZF1 by directly forming RNA double strands. Downregulation of JAZF1, caused by JAZF1‐AS1 depletion, inhibited the glucose uptake and lipid oxidation in skeletal muscle. Conclusions The present study proposes a strategy for identifying a novel T2D gene at the reported locus and generating a model in which polymorphisms at JAZF1 influence T2D risk through antisense‐mediated gene regulation.