Sympathetic hyperinnervation drives abdominal aortic aneurysm development by promoting vascular smooth muscle cell phenotypic switching.

INTRODUCTION: Sympathetic hyperinnervation plays an important role in modulating the vascular smooth muscle cell (VSMC) phenotype and vascular diseases, but its role in abdominal aortic aneurysm (AAA) is still unknown. OBJECTIVES: This study aimed to investigate the role of sympathetic hyperinnervation in promoting AAA development and the underlying mechanism involved. METHODS: Western blotting and immunochemical staining were used to detect sympathetic hyperinnervation. We performed sympathetic denervation through coeliac ganglionectomy (CGX) and 6-OHDA administration to understand the role of sympathetic hyperinnervation in AAA and investigated the underlying mechanisms through transcriptome and functional studies. Sema4D knockout (Sema4D-/-) mice were utilized to determine the involvement of Sema4D in inducing sympathetic hyperinnervation and AAA development. RESULTS: We observed sympathetic hyperinnervation, the most important form of sympathetic neural remodeling, in both mouse AAA models and AAA patients. Elimination of sympathetic hyperinnervation by CGX or 6-OHDA significantly inhibited AAA development and progression. We further revealed that sympathetic hyperinnervation promoted VSMC phenotypic switching in AAA by releasing extracellular ATP (eATP) and activating eATP-P2rx4-p38 signaling. Moreover, single-cell RNA sequencing revealed that Sema4D secreted by osteoclast-like cells induces sympathetic nerve diffusion and hyperinnervation through binding to Plxnb1. We consistently observed that AAA progression was significantly ameliorated in Sema4D-deficient mice. CONCLUSIONS: Sympathetic hyperinnervation driven by osteoclast-like cell-derived Sema4D promotes VSMC phenotypic switching and accelerates pathological aneurysm progression by activating the eATP/P2rx4/p38 pathway. Inhibition of sympathetic hyperinnervation emerges as a potential novel therapeutic strategy for preventing and treating AAA.

Photoluminescence Quenching of Hydrophobic Ag29 Nanoclusters Caused by Molecular Decoupling during Aqueous Phase Transfer and EmissionRecovery through Supramolecular Recoupling.

Exploiting emissive hydrophobic nanoclusters for hydrophilic applications remains a challenge because of photoluminescence (PL) quenching during phase transfer. In addition, the mechanism underlying PL quenching remains unclear. In this study, the PL-quenching mechanism was examined by analyzing the atomically precise structures and optical properties of a surface-engineered Ag29 nanocluster with an all-around-carboxyl-functionalized surface. Specifically, phase-transfer-triggered PL quenching was justified as molecular decoupling, which directed an unfixed cluster surface and weakened the radiative transition. Furthermore, emission recovery of the quenched nanoclusters was accomplished by using a supramolecular recoupling approach through the glutathione-addition-induced aggregation of cluster molecules, wherein the restriction of intracluster motion and intercluster rotation strengthened the radiative transition of the clusters. The results of this work offer a new perspective on structure-emission correlations for atomically precise nanoclusters and hopefully provide insight into the fabrication of highly emissive cluster-based nanomaterials for downstream hydrophilic applications.

Association Between Solid Fuel Use and the Risk of Hypertension in China.

OBJECTIVE: The aim of the study is to assess the association between solid fuel use for cooking or heating and the risk of hypertension among individuals older than 45 years. METHODS: Baseline questionnaires were used to collect self-reported primary cooking and heating fuel usage. Outcomes were defined as the time of first diagnosis of hypertension. Data were analyzed using Cox proportional hazards models. RESULTS: Solid fuel use for cooking was associated with a higher risk of hypertension. The association between solid fuel for cooking and hypertension remained significant among residents in north China, individuals aged 45 to 65 years, urban residents, and nonsmokers. Solid fuel for heating was associated with a higher risk of hypertension only in South China. CONCLUSIONS: Solid fuel use may result in an increased risk of hypertension. Our findings further emphasize the health hazards of solid fuel for cooking and heating.

DeepFundus: A flow-cytometry-like image quality classifier for boosting the whole life cycle of medical artificial intelligence.

Medical artificial intelligence (AI) has been moving from the research phase to clinical implementation. However, most AI-based models are mainly built using high-quality images preprocessed in the laboratory, which is not representative of real-world settings. This dataset bias proves a major driver of AI system dysfunction. Inspired by the design of flow cytometry, DeepFundus, a deep-learning-based fundus image classifier, is developed to provide automated and multidimensional image sorting to address this data quality gap. DeepFundus achieves areas under the receiver operating characteristic curves (AUCs) over 0.9 in image classification concerning overall quality, clinical quality factors, and structural quality analysis on both the internal test and national validation datasets. Additionally, DeepFundus can be integrated into both model development and clinical application of AI diagnostics to significantly enhance model performance for detecting multiple retinopathies. DeepFundus can be used to construct a data-driven paradigm for improving the entire life cycle of medical AI practice.

Mutagenesis of the cleavage site of (pro)renin receptor abrogates aldosterone-salt-induced hypertension and renal injury in mice.

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (ANG II)-induced hypertension. Relatively, less is known for the function of sPRR in ANG II-independent hypertension such as mineralocorticoid excess. In the present study, we used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRRR279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na+ channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury.NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na+-retaining action of aldosterone in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na+ balance and blood pressure.

Na+-Retaining Action of COX-2 (Cyclooxygenase-2)/EP1 Pathway in the Collecting Duct via Activation of Intrarenal Renin-Angiotensin-Aldosterone System and Epithelial Sodium Channel.

BACKGROUND: The collecting duct (CD) is a major site of both biosynthesis and action of prostaglandin E2 as highlighted by the predominant expression of COX-2 (cyclooxygenase-2) and some E-prostanoid (EP) subtypes at this nephron site. The purpose of this study was to determine the relevance and mechanism of CD COX-2/prostaglandin E2/EP1 signaling for the regulation of Na+ hemostasis during Na+ depletion. METHODS: Mice with Aqp2Cre-driven deletion of COX-2 (COX-2fl/flAqp2Cre+) or the EP1 subtype (EP1fl/flAqp2Cre+) were generated and the Na+-wasting phenotype of these mice during low-salt (LS) intake was examined. EP subtypes responsible for prostaglandin E2-induced local renin response were analyzed in primary cultured mouse inner medullary CD cells. RESULTS: Following 28-day LS intake, COX-2fl/flAqp2Cre+ mice exhibited a higher urinary Na+ excretion and lower cumulative Na+ balance, accompanied with suppressed intrarenal renin, AngII (angiotensin II), and aldosterone, expression of CYP11B2 (cytochrome P450 family 11 subfamily B member 2), and blunted expression of epithelial sodium channel subunits compared to floxed controls (COX-2fl/flAqp2Cre-), whereas no differences were observed for indices of systemic renin-angiotensin-aldosterone system. In cultured CD cells, exposure to prostaglandin E2 stimulated release of soluble (pro)renin receptor, prorenin/renin and aldosterone and the stimulation was more sensitive to antagonism of EP1 as compared other EP subtypes. Subsequently, EP1fl/flAqp2Cre+ mice largely recapitulated Na+-wasting phenotype seen in COX-2fl/flAqp2Cre+ mice. CONCLUSIONS: The study for the first time reports that CD COX-2/EP1 pathway might play a key role in maintenance of Na+ homeostasis in the face of Na+ depletion, at least in part, through activation of intrarenal renin-angiotensin-aldosterone-system and epithelial sodium channel.

The role of enteric dysbacteriosis and modulation of gut microbiota in the treatment of inflammatory bowel disease.

The incidence of inflammatory bowel disease (IBD) is globally increasing. This disorder seriously affects the quality of life in patients. Interestingly, studies have detected that the intestinal flora imbalance is a critical factor in the progression of IBD. One potential treatment strategy for IBD involves regulating the composition and function of the intestinal flora. To date, a multitude of experiments have confirmed the relationship between intestinal flora, immune regulation, and anti-inflammation. The intestinal flora can reduce intestinal inflammation by regulating immunity and increasing the secretion of metabolic short-chain fatty acids. In this review, we discuss the composition and function of the intestinal flora, the relationship between the intestinal flora and the host, the role of intestinal flora disorders in IBD, and the progress in IBD treatment. Combining the regulation of the intestinal flora with probiotics treatment is considered a promising strategy for substantially improving the treatment of IBD.

Effects of molecular weight of chitosan on anti-inflammatory activity and modulation of intestinal microflora in an ulcerative colitis model.

This study investigated the therapeutic effects and mechanisms of chitosans (CSs) with different molecular weights on ulcerative colitis (UC). Three size classes of CSs (Mw ≤ 3, 50, and 200 kDa) were used in this study. The effect of large CSs (Mw ≤ 200 kDa) on UC was the best, followed by that of medium CSs (Mw ≤ 50 kDa), and that of small CSs (Mw ≤ 3 kDa) was the least in the LPS-induced Raw 264.7 cell model and DSS-induced UC mice model. The therapeutic mechanisms of three CSs are related to anti-oxidation, anti-inflammation, and regulation of immunoglobulin and intestinal flora by attenuating body weight loss, decreasing the disease activity index (DAI) and MPO activity, suppressing proinflammatory cytokines and IgG levels, down-regulating the level of oxidative stress, increasing anti-inflammatory cytokines, SOD activity and Prevotellaceae_UCG-001 levels, and reducing the abundance of Proteobacteria, Actinobacteria, and Escherichia-Shigella. In general, the molecular weight of CSs influences their efficacy against UC. CSs with an optimal molecular weight demonstrate good development prospects for ameliorating UC.

Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor.

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II)-dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.

Preparation of multi-functional magnetic-plasmonic nanocomposite for adsorption and detection of thiram using SERS.

Magnetic materials have been widely used for constructing substrate in surface enhanced Raman scattering (SERS) sensing due to the magnetic responsibility. Here, we reported a facile and effective approach to construct multi-functional SERS substrate based on assembling Ag nanoparticles (NPs) on porous Fe microspheres. The porous Fe microspheres were prepared through hydrogen reduction of Fe2O3 NPs with porous structure, in which the size and morphology of Fe could be well controlled. The surface of Fe was grafted with amino group, and then decorated with Ag NPs. The surface area and pore size of Fe microsphere were characterized by nitrogen adsorption and desorption. The Fe@Ag nanocomposite illustrated a good SERS activity. Furthermore, this substrate could be used for pesticide monitoring by portable Raman spectrometer. Especially, the porous Fe microsphere could adsorb analyte from target sample and the Fe@Ag could be concentrated by magnetic force to amplify the SERS signal for thiram detection.

(Pro)renin receptor contributes to pregnancy-induced sodium-water retention in rats via activation of intrarenal RAAS and α-ENaC.

The (pro)renin receptor (PRR) is a new component of the renin-angiotensin-aldosterone system (RAAS) and regulates renin activity. The objective of the present study was to test potential roles of the renal PRR and intrarenal RAAS in the physiological status of late pregnancy. Late pregnant Sprague-Dawley rats were studied 19-21 days after sperm was observed in vaginal smears. Experiments were performed using age-matched virgin rats and late pregnant rats treated with the specific PRR inhibitor PRO20 (700 µg·kg-1·day-1 sc for 14 days, 3 times/day for every 8 h) or vehicle. The indices of RAAS, including PRR, renin, angiotensin II, and aldosterone levels, were examined by immunoblotting, qRT-PCR, or ELISA. Further analyses of renal epithelial sodium channel (ENaC) expression, sodium-water retention, and plasma volume were performed. We first present evidence for the activation of intrarenal RAAS in late pregnant rats, including increases in urinary renin activity, active and total renin content, and prorenin content, angiotensin II and aldosterone excretion, in parallel with increased renal PRR expression and urinary soluble PRR excretion. Functional evidence demonstrated that PRR antagonism with PRO20 effectively suppressed the indices of intrarenal RAAS in late pregnant rats. In addition, our results revealed that renal α-ENaC expression, sodium-water retention, and plasma volume were elevated during late pregnancy, which were all attenuated by PRO20. In summary, the present study examined the renal mechanism of sodium-water retention and plasma volume expansion in late pregnant rats and identified a novel role of PRR in regulation of intrarenal RAAS and α-ENaC and thus sodium and fluid retention associated with pregnancy.

Aspirin prevents bone loss with little mechanical improvement in high-fat-fed ovariectomized rats.

Obesity and osteoporosis are often concurrently happened in the menopausal women. Obesity in menopausal women is not only related to a high risk of cardiovascular disease, but also results in a detrimental effect on bone health. This study aimed to investigate the effects of aspirin, a popular anti-thrombosis drug, on bone quantity and quality in the high-fat-fed animal model. Adult female rats were subjected to either sham operations or ovariectomized operations. The ovariectomized rats were orally administered with deionized water or standardized high fat emulsion with or without aspirin. All rats were injected with calcein before killed for the purpose of double in vivo labeling. Biochemistry, histomorphometry, micro-computed tomography analysis, mechanical test, and component analysis were performed after 12 weeks. In vitro cell culture was also performed to observe the effect of aspirin in osteogenesis. We found that high fat remarkably impaired bone formation and bone biomechanics. Aspirin treatment significantly prevented bone loss by increasing bone formation. In vitro studies also validated the enhancement of osteogenic differentiation. However, aspirin presented no significant improvement in bone mechanical properties. Component analysis shown aspirin could significantly increase the content of mineral, but had limited effect on the content of collagen. In conclusion, aspirin is beneficial for the prevention of bone loss; meanwhile, it may cause an imbalance in the components of bone which may weaken the mechanical properties. The current study provided further evidence that aspirin might not be powerful for the prevention of fracture in osteoporotic patients.

The effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in the high-fat-fed ovariectomized rats.

Previous studies reported that statins showed positive effects on bone in both human and animal models. This study aimed to investigate the effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in ovariectomized rats fed with high-fat emulsion. The 3-month-old female rats were subjected to either sham operations (n = 8) or ovariectomized operations (OVX, n = 24). The OVX rats were orally administered deionized water (n = 8) or standardized high-fat emulsion without (n = 8) or with atorvastatin (n = 8). All rats were injected twice with calcein before sacrificed for the purpose of double in vivo labeling. After 12 weeks, all rats were sacrificed under anesthesia. Biochemistry, histomorphometry, mechanical test, micro-computed tomography analysis, mechanical test, histology, and component analysis were performed. We found that high-fat emulsion significantly decreased body weight, bone formation, collagen content of bone, and bone biomechanics, while increased blood, liver, and bone marrow lipids. Atorvastatin treatment prevented dyslipidemia, reversed hepatic steatosis, optimized composition of bone, and improved bone mechanical properties. The current study provided further evidence that atorvastatin might be useful for the treatment of osteoporotic patients with dyslipidemia.