Identification and immunological characterization of cuproptosis-related molecular clusters in ulcerative colitis.

BACKGROUND: Ulcerative colitis is one of the two main forms of inflammatory bowel disease. Cuproptosis is reported to be a novel mode of cell death. METHODS: We examined clusters of cuproptosis related genes and immune cell infiltration molecules in 86 ulcerative colitis samples from the GSE179285 dataset. We identified the differentially expressed genes according to the clustering method, and the performance of the SVM model, the random forest model, the generalized linear model, and the limit gradient enhancement model were compared, and then the optimal machine model was selected. To assess the accuracy of the learning predictions, the nomogram and the calibration curve and decision curve analyses showed that the subtypes of ulcerative colitis have been accurately predicted. RESULTS: Significant cuproptosis-related genes and immune response cells were detected between the ulcerative colitis and control groups. Two cuproptosis-associated molecular clusters were identified. Immune infiltration analysis indicated that different clusters exhibited significant heterogeneity. The immune scores for Cluster2 were elevated. Both the residual error and root mean square error of the random forest machine model had clinical significance. There was a clear correlation between the differentially expressed genes in cluster 2 and the response of immune cells. The nomogram and the calibration curve and decision curve analyses showed that the subtypes of ulcerative colitis had sufficient accuracy. CONCLUSION: We examined the complex relationship between cuproptosis and ulcerative colitis in a systematic manner. To estimate the likelihood that each subtype of cuproptosis will occur in ulcerative colitis patients and their disease outcome, we developed a promising prediction model.

Quantum-Memory-Enhanced Preparation of Nonlocal Graph States.

Graph states are an important class of multipartite entangled states. Previous experimental generation of graph states and in particular the Greenberger-Horne-Zeilinger (GHZ) states in linear optics quantum information schemes is subjected to an exponential decay in efficiency versus the system size, which limits its large-scale applications in quantum networks. Here, we demonstrate an efficient scheme to prepare graph states with only a polynomial overhead using long-lived atomic quantum memories. We generate atom-photon entangled states in two atomic ensembles asynchronously, retrieve the stored atomic excitations only when both sides succeed, and further project them into a four-photon GHZ state. We measure the fidelity of this GHZ state and further demonstrate its applications in the violation of Bell-type inequalities and in quantum cryptography. Our work demonstrates the prospect of efficient generation of multipartite entangled states in large-scale distributed systems with applications in quantum information processing and metrology.

Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)-salt-induced hypertension.

Hypertension-induced renal fibrosis contributes to the progression of chronic kidney disease, and apigenin, an anti-hypertensive flavone that is abundant in celery, acts as an agonist of transient receptor potential vanilloid 4 (TRPV4). However, whether apigenin reduces hypertension-induced renal fibrosis, as well as the underlying mechanism, remains elusive. In the present study, the deoxycorticosterone acetate (DOCA)-salt hypertension model was established in male Sprague-Dawley rats that were treated with apigenin or vehicle for 4 weeks. Apigenin significantly attenuated the DOCA-salt-induced structural and functional damage to the kidney, which was accompanied by reduced expression of transforming growth factor-ß1 (TGF-ß1)/Smad2/3 signaling pathway and extracellular matrix proteins. Immunochemistry, cell-attached patch clamp and fluorescent Ca2+ imaging results indicated that TRPV4 was expressed and activated by apigenin in both the kidney and renal cells. Importantly, knockout of TRPV4 in mice abolished the beneficial effects of apigenin that were observed in the DOCA-salt hypertensive rats. Additionally, apigenin directly inhibited activation of the TGF-ß1/Smad2/3 signaling pathway in different renal tissues through activation of TRPV4 regardless of the type of pro-fibrotic stimulus. Moreover, the TRPV4-mediated intracellular Ca2+ influx activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway, which inhibited the TGF-ß1/Smad2/3 signaling pathway. In summary, dietary apigenin has beneficial effects on hypertension-induced renal fibrosis through the TRPV4-mediated activation of AMPK/SIRT1 and inhibition of the TGF-ß1/Smad2/3 signaling pathway. This work suggests that dietary apigenin may represent a promising lifestyle modification for the prevention of hypertension-induced renal damage in populations that consume a high-sodium diet.

NXPH4 can be used as a biomarker for pan-cancer and promotes colon cancer progression.

NXPH4 promotes cancer proliferation and invasion. However, its specific role and mechanism in cancer remain unclear. Transcriptome and clinical data for pan-cancer were derived from the TCGA database. K-M survival curve and univariate Cox were used for prognostic analysis. CIBERSORT and TIMER algorithms were employed to calculate immune cell infiltration. Gene set enrichment analysis (GSEA) was employed for investigating the function of NXPH4. Western blot verified differential expression of NXPH4 in colon cancer. Functional assays (CCK-8, plate clonogenicity assay, wound healing assay, and Transwell assay) confirmed the impact of NXPH4 on proliferation, invasion, and migration of colon cancer cells. Dysregulation of NXPH4 in pan-cancer suggests its potential as a diagnostic and prognostic marker for certain cancers, including colon and liver cancer. High expression of NXPH4 in pan-cancer might be associated with the increase in copy number and hypomethylation. NXPH4 expression in pan-cancer is substantially linked to immune cell infiltration in the immune microenvironment. NXPH4 expression is associated with the susceptibility to immunotherapy and chemotherapy. Western blot further confirmed the higher expression of NXPH4 in colon cancer. Knockdown of NXPH4 significantly suppresses proliferation, invasion, and migration of colon cancer cell lines HT-29 and HCT116, as validated by functional assays.

Dietary curcumin ameliorates aging-related cerebrovascular dysfunction through the AMPK/uncoupling protein 2 pathway.

BACKGROUND/AIMS: Age-related cerebrovascular dysfunction contributes to stroke, cerebral amyloid angiopathy, cognitive decline and neurodegenerative diseases. One pathogenic mechanism underlying this effect is increased oxidative stress. Up-regulation of mitochondrial uncoupling protein 2 (UCP2) plays a crucial role in regulating reactive oxygen species (ROS) production. Dietary patterns are widely recognized as contributors to cardiovascular and cerebrovascular disease. In this study, we tested the hypothesis that dietary curcumin, which has an antioxidant effect, can improve aging-related cerebrovascular dysfunction via UCP2 up-regulation. METHODS: The 24-month-old male rodents used in this study, including male Sprague Dawley (SD) rats and UCP2 knockout (UCP2-/-) and matched wild type mice, were given dietary curcumin (0.2%). The young control rodents were 6-month-old. Rodent cerebral artery vasorelaxation was detected by wire myograph. The AMPK/UCP2 pathway and p-eNOS in cerebrovascular and endothelial cells were observed by immunoblotting. RESULTS: Dietary curcumin administration for one month remarkably restored the impaired cerebrovascular endothelium-dependent vasorelaxation in aging SD rats. In cerebral arteries from aging SD rats and cultured endothelial cells, curcumin promoted eNOS and AMPK phosphorylation, up-regulated UCP2 and reduced ROS production. These effects of curcumin were abolished by either AMPK or UCP2 inhibition. Chronic dietary curcumin significantly reduced ROS production and improved cerebrovascular endothelium-dependent relaxation in aging wild type mice but not in aging UCP2-/- mice. CONCLUSIONS: Curcumin improves aging-related cerebrovascular dysfunction via the AMPK/UCP2 pathway.

TRPV1-mediated UCP2 upregulation ameliorates hyperglycemia-induced endothelial dysfunction.

BACKGROUND: Diabetic cardiovascular complications are characterised by oxidative stress-induced endothelial dysfunction. Uncoupling protein 2 (UCP2) is a regulator of mitochondrial reactive oxygen species (ROS) generation and can antagonise oxidative stress, but approaches that enhance the activity of UCP2 to inhibit ROS are scarce. Our previous studies show that activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin can prevent cardiometabolic disorders. In this study, we conducted experiments in vitro and in vivo to investigate the effect of capsaicin treatment on endothelial UCP2 and oxidative stress. We hypothesised that TRPV1 activation by capsaicin attenuates hyperglycemia-induced endothelial dysfunction through a UCP2-mediated antioxidant effect. METHODS: TRPV1(-/-), UCP2(-/-) and db/db mice, as well as matched wild type (WT) control mice, were included in this study. Some mice were subjected to dietary capsaicin for 14 weeks. Arteries isolated from mice and endothelial cells were cultured. Endothelial function was examined, and immunohistological and molecular analyses were performed. RESULTS: Under high-glucose conditions, TRPV1 expression and protein kinase A (PKA) phosphorylation were found to be decreased in the cultured endothelial cells, and the effects of high-glucose on these molecules were reversed by the administration of capsaicin. Furthermore, high-glucose exposure increased ROS production and reduced nitric oxide (NO) levels both in endothelial cells and in arteries that were evaluated respectively by dihydroethidium (DHE) and DAF-2 DA fluorescence. Capsaicin administration decreased the production of ROS, restored high-glucose-induced endothelial dysfunction through the activation of TRPV1 and acted in a UCP2-dependent manner in vivo. Administration of dietary capsaicin for 14 weeks increased the levels of PKA phosphorylation and UCP2 expression, ameliorated the vascular oxidative stress and increased NO levels observed in diabetic mice. Prolonged dietary administration of capsaicin promoted endothelium-dependent relaxation in diabetic mice. However, the beneficial effect of capsaicin on vasorelaxation was absent in the aortas of UCP2(-/-) mice exposed to high-glucose levels. CONCLUSION: TRPV1 activation by capsaicin might protect against hyperglycemia-induced endothelial dysfunction through a mechanism involving the PKA/UCP2 pathway.

Identification and subtype analysis of biomarkers associated with the solute carrier family in acute myocardial infarction.

The dysregulation of some solute carrier (SLC) proteins has been linked to a variety of diseases, including diabetes and chronic kidney disease. However, SLC-related genes (SLCs) has not been extensively studied in acute myocardial infarction (AMI). The GSE66360 and GSE60993 datasets, and SLCs geneset were enrolled in this study. Differentially expressed SLCs (DE-SLCs) were screened by overlapping DEGs between the AMI and control groups and SLCs. Next, functional enrichment analysis was carried out to research the function of DE-SLCs. Consistent clustering of samples from the GSE66360 dataset was accomplished based on DE-SLCs selected. Next, the gene set enrichment analysis (GSEA) was performed on the DEGs-cluster (cluster 1 vs cluster 2). Three machine learning models were performed to obtain key genes. Subsequently, biomarkers were obtained through receiver operating characteristic (ROC) curves and expression analysis. Then, the immune infiltration analysis was performed. Afterwards, single-gene GSEA was carried out, and the biomarker-drug network was established. Finally, quantitative real-time fluorescence PCR (qRT-PCR) was performed to verify the expression levels of biomarkers. In this study, 13 DE-SLCs were filtered by overlapping 366 SLCs and 448 DEGs. The functional enrichment results indicated that the genes were implicated with amino acid transport and TNF signaling pathway. After the consistency clustering analysis, the samples were classified into cluster 1 and cluster 2 subtypes. The functional enrichment results showed that DEGs-cluster were implicated with chemokine signaling pathway and so on. Further, SLC11A1 and SLC2A3 were identified as SLC-related biomarkers, which had the strongest negative relationship with resting memory CD4 T cells and the strongest positive association with activated mast cells. In addition, the single-gene GSEA results showed that cytosolic ribosome was enriched by the biomarkers. Five drugs targeting SLC2A3 were predicted as well. Lastly, the experimental results showed that the biomarkers expression trends were consistent with public database. In this study, 2 SLC-related biomarkers (SLC11A1 and SLC2A3) were screened and drug predictions were carried out to explore the prediction and treatment of AMI.

Fabrication of Rechargeable Photoactive Silk Fibroin/Polyvinyl Alcohol Blend Nanofibrous Membranes for Killing Bacteria.

Antibacterial materials that prevent bacterial infections and mitigate bacterial virulence have attracted great scientific interest. In recent decades, bactericidal polymers have been presented as promising candidates to combat bacterial pathogens. However, the preparation of such materials has proven to be extremely challenging. Herein, photoactive silk fibroin/polyvinyl alcohol blended nanofibrous membranes grafted with 3,3',4,4'-benzophenone tetracarboxylic dianhydride (G-SF/PVA BNM) were fabricated by an electrospinning technique. The premise of this work is that the G-SF/PVA BNM can store photoactive activity under light irradiation and release reactive oxygen species for killing bacteria under dark conditions. The results showed that the resultant G-SF/PVA BNM exhibited the integrated properties of an ultrathin fiber diameter (298 nm), good mechanical properties, robust photoactive activity and photo-store capacity, and great photoinduced antibacterial activity against E. coli and S. aureus (99.999% bacterial reduction with 120 min). The successful construction of blended nanofibrous membranes gives a new possibility to the design of highly efficient antibacterial materials for public health protection.

[Evaluation of visceral adipose in abdominal obesity and its clinical application].

OBJECTIVE: To compare the values of measurements of obesity, including body mass index(BMI), waist circumference (WC), waist-to-hip ratio (WHR), bioelectrical impedance analyzer(BIA) (fat mass and FAT%), ultrasonography (US) (subcutaneous fat distance and intraabdominal fat distance), and computed tomography (CT) in predicting the quantification of visceral adipose in abdominal obesity, and to evaluate the best cut-off point, sensitivity and specificity of these methods. METHODS: 4,301 inpatients with hypertension, 2,155 males and 2,146 females, aged (56.4 +/- 13.8) (11 - 89), all with at least 1 risk factor of cardiovascular diseases, underwent simple body fat measurement. 3458 received BIA, 2,553 received B mode ultrasonography, 1039 underwent CT examination, and 659 received all kinds of examination. Abdominal visceral adipose area (VA) measured with CT >or= 100 cm(2) was the diagnostic criteria of visceral fat obesity (VFO). Receiver operating characteristic (ROC) curve was used to analyze the body fat indexes to determine the best cut-off point. RESULTS: (1) It was accurate for WC, fat mass, BMI, intraabdominal fat distance, FAT%, and WHR were all accurate in diagnosis of VFO with the values of area under ROC of 0.730 - 0.867. WC was the most effective measurement. (2) The best cut-off points of these methods in predicting abdominal visceral obesity in males and females were as follows: WC: 89.5 cm and 85.5 cm for WC. 25 kg/m(2) and 26 kg/m(2) for BMI, 0.97 and 0.95 for WHR, 29% and 38% for fat composition, 18.6 kg, and 20.4 kg for fat mass, and 38.5 mm and 34.7 mm for intraabdominal fat distance. CONCLUSIONS: WC, fat mass, BMI, intraabdominal fat distance, simple fat parameters, and WHR all can predict visceral adipose in abdominal obesity, in which WC is the best. For a given WC, the type of obesity can be determined by BIA and US.

[Relationship of different types of abdominal obesity to risk of metabolic syndrome].

OBJECTIVE: To explore the relationship of different types of abdominal obesity to risk of metabolic syndrome (MS). METHODS: Visceral fat area (VA) and substantial fat area (SA) were assessed by CT in 846 patients, 470 males and 376 females, aged 55 +/- 12, who suffered from at least one cardiometabolic risk factor and divided into 4 groups according to their VA and waist circumference (WC): non-obesity, masked visceral fat obesity (VFO), pseudo-VFO, and VFO groups. Blood pressure, fasting blood glucose, fasting serum insulin, and lipid profile were also measured. The MS risks of different types of abdominal obesity were compared. RESULTS: The prevalence rate of masked VFO of males was 10.9% (51/470), significantly higher than that of female (4.8%, 18/376). The prevalence rate of MS of the male patients with masked VFO was 43.1%, significantly higher than that of those in non-obesity group (25.0%), and lower than those of the males in the pseudo-VFO group (78.7%) and in the VFO group (88.6%), whereas the MS prevalence rate of the males in the pseudo-VFO group was significantly higher than those in the non-obesity and masked VFO groups. On the other hand, the MS prevalence rate of the female patients with masked VFO was 33.3%, not significantly different from that of the female patients in the non-obesity group (31.2%), but significantly lower than those of the pseudo-VFO and VFO groups (78.7% and 90.9% respectively). The MS prevalence rate of the female pseudo-VFO patients was also significantly higher than those in the non-obesity and masked VFO groups. Logistic regression analysis showed that WC and VA were independent risk factors for MS [OR (95% CI) = 1.13 (1.10-1.17), 1.01 (1.01-1.02), respectively, P < 0.01). CONCLUSION: Different types of abdominal obesity have important impacts on the risk of metabolic syndrome. Masked VFO, even though with normal WC, and pseudo-VFO have considerably higher cardiometabolic risks.

Experimental entanglement of 25 individually accessible atomic quantum interfaces.

A quantum interface links the stationary qubits in a quantum memory with flying photonic qubits in optical transmission channels and constitutes a critical element for the future quantum internet. Entanglement of quantum interfaces is an important step for the realization of quantum networks. Through heralded detection of photon interference, we generate multipartite entanglement between 25 (or 9) individually addressable quantum interfaces in a multiplexed atomic quantum memory array and confirm genuine 22-partite (or 9-partite) entanglement. This experimental entanglement of a record-high number of individually addressable quantum interfaces makes an important step toward the realization of quantum networks, long-distance quantum communication, and multipartite quantum information processing.

Non-insulin determinant pathways maintain glucose homeostasis upon metabolic surgery.

Insulin is critical for glucose homeostasis, and insulin deficiency or resistance leads to the development of diabetes. Recent evidence suggests that diabetes can be remitted independent of insulin. However, the underlying mechanism remains largely elusive. In this study, we utilized metabolic surgery as a tool to identify the non-insulin determinant mechanism. Here, we report that the most common metabolic surgery, Roux-en-Y gastric bypass (RYGB), reduced insulin production but persistently maintained euglycemia in healthy Sprague-Dawley (SD) rats and C57 mice. This reduction in insulin production was associated with RYGB-mediated inhibition of pancreatic preproinsulin and polypyrimidine tract-binding protein 1. In addition, RYGB also weakened insulin sensitivity that was evaluated by hyperinsulinemic-euglycemic clamp test and downregulated signaling pathways in insulin-sensitive tissues. The mechanistic evidence suggests that RYGB predominately shifted the metabolic profile from glucose utilization to fatty acid oxidation, enhanced the energy expenditure and activated multiple metabolic pathways through reducing gut energy uptake. Importantly, the unique effect of RYGB was extended to rats with islet disruption and patients with type 2 diabetes. These results demonstrate that compulsory rearrangement of the gastrointestinal tract can initiate non-insulin determinant pathways to maintain glucose homeostasis. Based on the principle of RYGB action, the development of a noninvasive intervention of the gastrointestinal tract is a promising therapeutic route to combat disorders characterized by energy metabolism dysregulation.

Everolimus (RAD001) inhibits the proliferation of rat vascular smooth muscle cells by up-regulating the activity of the p27/kip1 gene promoter.

OBJECTIVE: We investigated whether the inhibitory effect of the immunosuppressant everolimus (RAD001) on vascular smooth muscle cell (VSMC) proliferation is mediated by p27/kip1 gene promoter activity. METHODS: In this experimental study, cultured rat VSMCs were transiently transfected with a recombinant plasmid (pXp27) containing p27/kip1 gene promoter sequence and a chloramphenicol acetyltransferase (CAT) reporter gene. After stimulation with the mitogen platelet-derived growth factor (PDGF-BB, 10 ng/mL) in the presence or absence of RAD001 (10 nM), the promoter activity, mRNA expression, and protein expression of p27/kip1 were examined by CAT assay, RT-PCR, and immunoblotting, respectively. Cell cycle-related changes were detected by flow cytometry. DNA synthesis was determined using 3H-TdR incorporation. RESULTS: Compared with the non-stimulation group, PDGF-BB stimulation induced a significant proliferative response in the VSMCs as indicated by decreased p27/kip1 gene promoter activity, decreased p27/kip1 mRNA and protein expression, increased S-phase and G2/M-phase cells, and increased DNA synthesis. RAD001 intervention increased p27/kip1 gene promoter activity 3.5-fold, promoted p27/kip1 mRNA and protein expression, increased G0-phase cells, reduced DNA synthesis, and, overall, inhibited PDGF-BB-stimulated cell proliferation. CONCLUSION: RAD001 inhibits PDGF-BB-stimulated proliferation of cultured VSMCs by upregulating p27/kip1 gene promoter activity and increasing p27/kip1 mRNA and protein expression.

Activation of cold-sensing transient receptor potential melastatin subtype 8 antagonizes vasoconstriction and hypertension through attenuating RhoA/Rho kinase pathway.

Environmental cold is a nonmodifiable hypertension risk factor. Transient receptor potential melastatin subtype 8 (TRPM8) is a cold-sensing cation channel that can be activated by menthol, a compound with a naturally cold sensation in mint. Little is known about the effect of TRPM8 activation on vascular function and blood pressure. Here, we report that TRPM8 is abundantly expressed in the vasculature. TRPM8 activation by menthol attenuated vasoconstriction via RhoA/Rho kinase pathway inhibition in wild-type mice, but the effect was absent in TRPM8(-/-) mice. Chronic dietary menthol blunted mesenteric arterial constriction and lowered blood pressure in genetic hypertensive rats via inhibition of RhoA/Rho kinase expression and activity in the vivo study. TRPM8 effect was associated with inhibition of intracellular calcium release from the sarcoplasmic reticulum, RhoA/Rho kinase activity, and sustained arterial contraction in the vitro study. Importantly, 8-week chronic menthol capsule treatment moderately lowered systolic blood pressure and diastolic blood pressure in prehypertensive individuals compared with the placebo group. Furthermore, chronic menthol capsule administration also improved flow-mediated dilatation in prehypertensive individuals, but not in the placebo group. In conclusion, our study demonstrates that TRPM8 activation by menthol benefits vascular function and blood pressure by inhibiting calcium signaling-mediated RhoA/Rho kinase activation in the vasculature. These findings add to the evidence that long-term dietary menthol treatment had favorable effects on hypertension treatment.

Gastrointestinal intervention ameliorates high blood pressure through antagonizing overdrive of the sympathetic nerve in hypertensive patients and rats.

BACKGROUND: We investigated the hypothesis that the favorable effects of gastrointestinal (GI) intervention on hypertension (HTN) and cardiovascular (CV) disturbances are mediated by antagonizing overdrive of the sympathetic nervous system (SNS). METHODS AND RESULTS: Hypertensive patients with metabolic disturbances underwent laparoscopic Roux-en-Y gastric bypass surgery, and spontaneously hypertensive rats (SHRs) underwent RYGB or sham surgery. Blood pressure (BP), heart rate (HR), endothelium-dependent flow-mediated dilation, and anthropometric as well as laboratory parameters were measured at baseline and during follow-up. Changes of BP and HR in response to cold stress, renal sympathetic nervous activity (RSNA), vasoconstriction induced by electrical field stimulation, microinjection of nucleus of the solitary tract (NTS), and CV function and structure were examined in SHRs with or without surgery. Compared with baseline, BP and HR were significantly reduced in both hypertensive patients with type 2 diabetes and rats. Impaired endothelial-dependent vasodilatation and metabolic disturbances in hypertensive patients were also ameliorated after surgery. CV disturbances were reversed by surgery in SHRs. Under acute cold exposure, the variations in BP and HR were smaller in surgically treated SHRs, compared to sham SHRs. RSNA and vasoconstriction induced by perivascular nerve stimulation as well as NTS-mediated changes of BP were decreased in surgically treated SHRs, compared to sham SHR. Weight loss did not affect BP and RSNA in sham SHRs. CONCLUSIONS: GI intervention ameliorates HTN in both hypertensive patients and rats by inhibiting overdrive of the SNS. Therefore, targeting gastrointestine could be a novel strategy to treat HTN with metabolic disturbances.

Transient receptor potential vanilloid 1 activation by dietary capsaicin promotes urinary sodium excretion by inhibiting epithelial sodium channel α subunit-mediated sodium reabsorption.

High salt (HS) intake contributes to the development of hypertension. Epithelial sodium channels play crucial roles in regulating renal sodium reabsorption and blood pressure. The renal transient receptor potential vanilloid 1 (TRPV1) cation channel can be activated by its agonist capsaicin. However, it is unknown whether dietary factors can act on urinary sodium excretion and renal epithelial sodium channel (ENaC) function. Here, we report that TRPV1 activation by dietary capsaicin increased urinary sodium excretion through reducing sodium reabsorption in wild-type (WT) mice on a HS diet but not in TRPV1(-/-) mice. The effect of capsaicin on urinary sodium excretion was involved in inhibiting αENaC and its related with-no-lysine kinase 1/serum- and glucocorticoid-inducible protein kinase 1 pathway in renal cortical collecting ducts of WT mice. Dietary capsaicin further reduced the increased αENaC activity in WT mice attributed to the HS diet. In contrast, this capsaicin effect was absent in TRPV1(-/-) mice. Immunoprecipitation study indicated αENaC specifically coexpressed and functionally interact with TRPV1 in renal cortical collecting ducts of WT mice. Additionally, ENaC activity and expression were suppressed by capsaicin-mediated TRPV1 activation in cultured M1-cortical collecting duct cells. Long-term dietary capsaicin prevented the development of high blood pressure in WT mice on a HS diet. It concludes that TRPV1 activation in the cortical collecting ducts by capsaicin increases urinary sodium excretion and avoids HS diet-induced hypertension through antagonizing αENaC-mediated urinary sodium reabsorption. Dietary capsaicin may represent a promising lifestyle intervention in populations exposed to a high dietary salt intake.