Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3.

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.

TRPC5 deletion in the central amygdala antagonizes high-fat diet-induced obesity by increasing sympathetic innervation.

Transient receptor potential channel 5 (TRPC5) is predominantly distributed in the brain, especially in the central amygdala (CeA), which is closely associated with pain and addiction. Although mounting evidence indicates that the CeA is related to energy homeostasis, the possible regulatory effect of TRPC5 in the CeA on metabolism remains unclear. Here, we reported that the expression of TRPC5 in the CeA of mice was increased under a high-fat diet (HFD). Specifically, the deleted TRPC5 protein in the CeA of mice using adeno-associated virus resisted HFD-induced weight gain, accompanied by increased food intake. Furthermore, the energy expenditure of CeA-specific TRPC5 deletion mice (TRPC5 KO) was elevated due to augmented white adipose tissue (WAT) browning and brown adipose tissue (BAT) activity. Mechanistically, deficiency of TRPC5 in the CeA boosted nonshivering thermogenesis under cold stimulation by stimulating sympathetic nerves, as the ß3-adrenoceptor (Adrb3) antagonist SR59230A blocked the effect of TRPC5 KO on this process. In summary, TRPC5 deletion in the CeA alleviated the metabolic deterioration of mice fed a HFD, and these phenotypic improvements were correlated with the increased sympathetic distribution and activity of adipose tissue.

TRPC3 deficiency attenuates high salt-induced cardiac hypertrophy by alleviating cardiac mitochondrial dysfunction.

Long-term high salt intake leads to cardiac hypertrophy, but the mechanism remains elusive. Transient receptor potential channel, canonical 3(TRPC3), located in mitochondria, regulates mitochondrial calcium and reactive oxygen species(ROS) production. Herein, we investigated whether TRPC3 participates in high salt-induced cardiac hypertrophy by impairing cardiac mitochondrial function. High salt treatment increased the expression of mitochondrial TRPC3 in cardiomyocytes, accompanied by enhanced mitochondrial calcium uptake and elevated ROS production. Inhibition of TRPC3 significantly reduced high salt-induced ROS generation, promoted ATP production by stimulating oxidative phosphorylation, and increased enzyme activity in mitochondria in cardiomyocytes. Additionally, TRPC3 deficiency inhibited high salt-induced cardiac hypertrophy in vivo. A long-term high salt diet increased cardiac mitochondrial TRPC3 expression, elevated expression of cardiac hypertrophic markers atrial natriuretic peptide (ANP),brain natriuretic peptide (BNP) and ß-myosin heavy chain (ß-MHC) and decreased ATP production and mitochondrial complex I and II enzyme activity in a TRPC3-dependent manner. TRPC3 deficiency antagonises high salt diet-mediated cardiac hypertrophy by ameliorating TRPC3-mediated cardiac mitochondrial dysfunction. TRPC3 may therefore represent a novel target for preventing high salt-induced cardiac damage.

Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats.

BACKGROUND/AIMS: High salt consumption is a major risk factor for hypertension, and sodium homeostasis is regulated by both intestinal sodium absorption and urinary sodium excretion. Chronic caffeine intake has been reported to attenuate salt-sensitive hypertension by promoting urinary sodium excretion; however, its exact role in intestinal sodium absorption remains unknown. Here, we investigated whether and how chronic caffeine consumption antagonizes salt-sensitive hypertension by inhibiting intestinal sodium absorption. METHODS: Dahl salt-sensitive rats were fed 8% NaCl chow and 0.1% caffeine in their drinking water for 15 days. The blood pressure and fecal sodium content were measured. The effect of caffeine on the movement of Cl- in enterocyte cells was determined with the Ussing chamber assay. RESULTS: Rats that were treated with caffeine displayed significantly lower mean blood pressure and higher fecal sodium content than the controls. Consistent with these findings, caffeine intake decreased fluid absorption by the intestine in the fluid perfusion experiment. Further, the results from the Ussing chamber assay indicated that caffeine promoted Cl- secretion through enterocyte apical cystic fibrosis transmembrane conductance regulator (CFTR), and thus inhibited sodium absorption. Moreover, depletion of cAMP or inhibition of CFTR completely abolished the effect of caffeine on Cl- secretion. CONCLUSION: The results indicate that chronic caffeine consumption reduces sodium absorption by promoting CFTR-mediated Cl- secretion in the intestine, which contributes to the anti-hypertensive effect of caffeine in salt-sensitive rats.

Enhancement of Neural Salty Preference in Obesity.

BACKGROUND/AIMS: Obesity and high salt intake are major risk factors for hypertension and cardiometabolic diseases. Obese individuals often consume more dietary salt. We aim to examine the neurophysiologic effects underlying obesity-related high salt intake. METHODS: A multi-center, random-order, double-blind taste study, SATIETY-1, was conducted in the communities of four cities in China; and an interventional study was also performed in the local community of Chongqing, using brain positron emission tomography/computed tomography (PET/CT) scanning. RESULTS: We showed that overweight/obese individuals were prone to consume a higher daily salt intake (2.0 g/day higher compared with normal weight individuals after multivariable adjustment, 95% CI, 1.2-2.8 g/day, P < 0.001), furthermore they exhibited reduced salt sensitivity and a higher salt preference. The altered salty taste and salty preference in the overweight/obese individuals was related to increased activity in brain regions that included the orbitofrontal cortex (OFC, r = 0.44, P= 0.01), insula (r = 0.38, P= 0.03), and parahippocampus (r = 0.37, P= 0.04). CONCLUSION: Increased salt intake among overweight/obese individuals is associated with altered salt sensitivity and preference that related to the abnormal activity of gustatory cortex. This study provides insights for reducing salt intake by modifying neural processing of salty preference in obesity.

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.

Gastrointestinal Tract: a Promising Target for the Management of Hypertension.

The pathogenesis of hypertension remains elusive. Current treatments on hypertension have only achieved modest reductions. Facilitating theoretical research and looking for new therapeutic strategy are urgently needed. Besides food digestion and nutrients absorption, the gastrointestinal tract (GI) has been shown to influence the status of the central nervous system, immune system, metabolism, and cardiovascular homeostasis. Emerging findings demonstrate that endogenous factors derived from GI including gut hormones, autonomic nerve, and gut microbiota play important roles in the regulation of vascular function and/or blood pressure. Meanwhile, evidences from clinical practice and experimental study have found that intervention in GI through metabolic surgery, probiotics consumption, and dietary modification can efficiently ameliorate or even remit hypertension and related cardiometabolic diseases. Thus, we propose that GI might be an initiating organ of hypertension and a promising target for the management of hypertension. Further, illuminating this concept may aid to understand the pathogenesis and control of hypertension.

The Gastrointestinal Tract: an Initial Organ of Metabolic Hypertension?

Hypertension is an important global public-health challenge because of its high prevalence and concomitant risks for cardiovascular and kidney diseases. More than 60% of the risk factors for hypertension are associated with metabolic disorders. Furthermore, many metabolic risk factors can directly cause the vascular dysfunction and the elevated blood pressure. Metabolic disorders not only increase the risk for hypertension but also participate in the development of hypertension. Thus, some types of hypertension induced by metabolic disturbances can be defined as metabolic hypertension. However, the pathogenesis of metabolic hypertension remains largely unknown. The gastrointestinal tract is a unique gate through which external food, metabolites, and microbes enter the human body. Thus, metabolism-related risk factors may affect blood pressure through the gastrointestinal tract and alter processes such as taste perception, mucosal absorption, gut hormone homeostasis, GI nerve activity, and gut microbiota. Meanwhile, gastrointestinal intervention through dietary approaches, gut microbiota modification, and metabolic surgery could profoundly improve or remit the vascular dysfunction and metabolic hypertension. It suggests that the GI tract could be an initial organ of metabolic hypertension. However, more clinical and basic studies are necessary to further validate this novel concept.

Activation of TRPV1 channel by dietary capsaicin improves visceral fat remodeling through connexin43-mediated Ca2+ influx.

BACKGROUND: The prevalence of obesity has dramatically increased worldwide and has attracted rising attention, but the mechanism is still unclear. Previous studies revealed that transient receptor potential vanilloid 1 (TRPV1) channels take part in weight loss by enhancing intracellular Ca2+ levels. However, the potential mechanism of the effect of dietary capsaicin on obesity is not completely understood. Ca2+ transfer induced by connexin43 (Cx43) molecules between coupled cells takes part in adipocyte differentiation. Whether TRPV1-evoked alterations in Cx43-mediated adipocyte-to-adipocyte communication play a role in obesity is unknown. MATERIALS AND METHODS: We investigated whether Cx43 participated in TRPV1-mediated adipocyte lipolysis in cultured 3T3-L1 preadipocytes and visceral adipose tissues from humans and wild-type (WT) and TRPV1-deficient (TRPV1-/-) mice. RESULTS: TRPV1 and Cx43 co-expressed in mesenteric adipose tissue. TRPV1 activation by capsaicin increased the influx of Ca2+ in 3T3-L1 preadipocytes and promoted cell lipolysis, as shown by Oil-red O staining. These effects were deficient when capsazepine, a TRPV1 antagonist, and 18 alpha-glycyrrhetinic acid (18α-GA), a gap-junction inhibitor, were administered. Long-term chronic dietary capsaicin reduced the weights of perirenal, mesenteric and testicular adipose tissues in WT mice fed a high-fat diet. Capsaicin increased the expression levels of p-CaM, Cx43, CaMKII, PPARδ and HSL in mesenteric adipose tissues from WT mice fed a high-fat diet, db/db mice, as well as obese humans, but these effects of capsaicin were absent in TRPV1-/- mice. Long-term chronic dietary capsaicin decreased the body weights and serum lipids of WT mice, but not TRPV1-/- mice, fed a high-fat diet. CONCLUSION: This study demonstrated that capsaicin activation of TRPV1-evoked increased Ca2+ influx in Cx43-mediated adipocyte-to-adipocyte communication promotes lipolysis in both vitro and vivo. TRPV1 activation by dietary capsaicin improves visceral fat remodeling through the up-regulation of Cx43.

Diabetes mellitus is associated with early chronic venous disorder of the lower extremities in Chinese patients with cardiometabolic risk factors.

BACKGROUND: Metabolic syndrome has received great attention because it poses a potential cardiovascular hazard, which increases the risk of lower extremity atherosclerosis. However, the relationship between the components of metabolic syndrome and the onset of chronic venous disorder of the lower extremities remains unexplained. METHODS: This study investigated the characteristics of cardiometabolic risk factors of early chronic venous disorder of the lower extremities in subjects with cardiometabolic risk. The characteristics of risk factors and diabetes-related complications in diabetic patients with early chronic venous disorder of the lower extremities were also investigated. In addition, the association between early chronic venous disorder and atherosclerosis of the lower extremities was analysed. The study examined 782 subjects with cardiometabolic risk factors, including obesity, hypertension, diabetes mellitus and dyslipidaemia. Lower extremity venous function was measured by digital photoplethysmography. RESULTS: Women had a higher prevalence of early chronic venous disorder than did men (p < 0.01). Male subjects with early chronic venous disorder had a higher systolic blood pressure than those with normal venous function (p < 0.01), and female subjects with early chronic venous disorder had a higher fasting plasma glucose level than did controls (p < 0.05). The prevalence of diabetes mellitus is also significantly higher in female patients with early chronic venous disorder (p = 0.000). Diabetic patients with early chronic venous disorder not only had higher fasting plasma glucose and total cholesterol levels but also had more serious macrovascular complications than the control group. The independent risk factors of early chronic venous disorder in female subjects with cardiometabolic risks were age and fasting plasma glucose in men it was only age Women face a two times greater risk than men. The independent risk factors of early chronic venous disorder in diabetic patients were age, gender, HbA1c and triglyceride levels Women had an almost 12 times greater risk of early chronic venous disorder than men. Among the diabetic patients, the prevalence of early chronic venous disorder did not differ by ankle-brachial index. CONCLUSION: Female subjects with cardiometabolic risk factors or female diabetic patients face a greater risk of early chronic venous disorder than do male subjects. Diabetic patients with early chronic venous disorder had more serious macrovascular complications than did the controls, and the early venous function was found to be correlated with the blood glucose level and triglyceride status.

Inflammatory factor-specific sumoylation regulates NF-κB signalling in glomerular cells from diabetic rats.

OBJECTIVE: The activation of nuclear factor (NF)-κB by cytokines under hyperglycaemic conditions is a potential mechanism for complications in diabetes. We investigated whether small ubiquitin-like modifier 4 (SUMO4) regulates renal NF-κB signalling in diabetic rats. METHODS: Histological changes in kidney were analysed in diabetic GK rats. The expressions of tumour necrosis factor (TNF)-α, NF-κB (p65), IκBα and SUMO4 in renal tissues were examined by immunohistochemistry and Western blotting. Primary cultured glomerular endothelial cells from rats were stimulated by TNF-α or interleukin (IL)-2. RESULTS: The renal expression of TNF-α, NF-κB (p65), IκBα and SUMO4 was significantly higher in diabetic GK rats than in control rats. In control rats, no nuclear translocation was observed for IκBα or NF-κB (p65). However, in diabetic GK rats, translocation of NF-κB (p65) and IκBα into the nucleus was observed, and the expression of SUMO4 and IκBα was up-regulated in the glomerular endothelial cells. SUMO4 was localised in both the cytoplasm and nucleus, while IκBα was predominantly located in the nucleus after stimulation with TNF-α. In contrast, SUMO4 was localised in the nucleus, and increased cytoplasm SUMO4 localisation was found after stimulation with IL-2. CONCLUSIONS: SUMO4 plays a role in regulating NF-κB signalling in glomerular cells. Cytokines have a unique effect in regulating the sumoylation of NF-κB.

Dietary cinnamaldehyde activation of TRPA1 antagonizes high-salt induced hypertension through restoring renal tubular mitochondrial dysfunction.

BACKGROUND: Renal proximal tubule plays a pivotal role in regulating sodium reabsorption and thus blood pressure. Transient receptor potential ankyrin 1 (TRPA1) has been reported to protect against renal injury by modulating mitochondrial function. We hypothesize that the activation of TRPA1 by its agonist cinnamaldehyde may mitigates high salt intake induced hypertension by inhibiting urinary sodium reabsorption through restoration of renal tubular epithelial mitochondrial function. METHODS: Trpa1-deficient (Trpa1-/-) mice and wild-type (WT) mice were fed standard laboratory chow [normal diet (ND) group, 0.4% salt], standard laboratory chow with 8% salt [high-salt diet (HS) group] or standard laboratory chow with 8% salt plus 0.015% cinnamaldehyde [high-salt plus cinnamaldehyde diet (HSC) group] for six months. Urinary sodium excretion, ROS production, mitochondrial function and the expression of NHE3 and Na+/K+-ATPase of renal proximal tubules were determined. RESULTS: Chronic dietary cinnamaldehyde supplementation reduced tail systolic blood pressure and 24-hour ambulatory arterial pressure in HS-fed WT mice. Compared with the mice fed HS, cinnamaldehyde supplementation significantly increased urinary sodium excretion, inhibited excess ROS production and alleviated mitochondrial dysfunction of renal proximal tubules in WT mice. However, these effects of cinnamaldehyde were absent in Trpa1-/- mice. Furthermore, chronic dietary cinnamaldehyde supplementation blunted HS-induced upregulation of NHE3 and Na+/K+-ATPase in WT mice but not Trpa1-/- mice. CONCLUSION: The present study demonstrated that chronic activation of Trpa1 attenuates HS-induced hypertension by inhibiting urinary sodium reabsorption through restoring renal tubular epithelial mitochondrial function. Renal TRPA1 may be a potential target for the management of excessive dietary salt intake-associated hypertension.

Leptin receptor deficiency impedes metabolic surgery related-weight loss through inhibition of energy expenditure in db/db mice.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective metabolic surgery against diabetes and obesity. Clinical evidence indicates that patients with severe obesity have a poor curative effect in losing weight if they suffer from leptin or its receptor deficiency, but the underlying mechanism remains elusive. Here, we investigated the effect of leptin receptor deficiency on metabolic dysfunction in db/db mice treated by RYGB surgery. METHODS: The db/db mice and their heterozygote control db/m mice were subjected to RYGB or sham surgery. Body weight, blood glucose, food intake and glucose tolerance were evaluated. Micro-PET/CT and histological analysis were performed to examine the glucose uptake of tissues and the fat changes in mice. The key factors in glucose and fatty acid metabolism were detected by western blot analysis. RESULTS: Compared with the sham group, the db/db mice in the RYGB group showed more significant weight regain after surgical recovery and improvement in hyperinsulinemia and glucose tolerance. However, the total body fat and multiple organ lipid deposition of RYGB-treated db/db mice was increased. The underlying mechanism studies suggested that the activation of AMPK regulated GLUT4 to increase glucose uptake, but AMPK could not promote fatty acid oxidation through the JAK2/STAT3 pathway under leptin receptor deficiency in db/db mice. CONCLUSION: We conclude that leptin receptor deficiency impedes the AMPK activation-mediated fat catabolism but does not affect AMPK-related glucose utilization after metabolic surgery in db/db mice. This result helps select surgical indications for patients with obesity and diabetes.

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.

INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive. OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Dietary capsaicin prevents nonalcoholic fatty liver disease through transient receptor potential vanilloid 1-mediated peroxisome proliferator-activated receptor δ activation.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid deposition and coincides often with cardiometabolic diseases. Several dietary factors attenuate NAFLD. Here, we report beneficial effects of chronic dietary capsaicin intake on NAFLD which is mediated by the transient receptor potential vanilloid 1 (TRPV1) activation. The results showed that TRPV1 activation by capsaicin reduced free fatty acids (FFAs) induced the intracellular lipid droplets in HepG2 cells and prevented fatty liver in vivo. Chronic dietary capsaicin promoted lipolysis by increasing hepatic phosphorylated hormone-sensitive lipase (phospho-HSL), carnitine palmitoyltransferase 1 (CPT1), and peroxisome proliferator-activated receptor δ (PPARδ) in wild-type (WT) mice. This effect was absent in TRPV1(-/-) mice. Dietary capsaicin did not affect lipogenesis, as indicated by the detection of hepatic fatty acid synthase (FAS), sterol regulatory element-binding protein-1 (SREBP-1), PPARα, and liver X receptor (LXR) in mice. Importantly, TRPV1 causes PPARδ activation which significantly increased the expression of autophagy-related proteins, such as light chain 3 (LC3)II, Beclin1, Atg5, and Atg7 in HepG2 cells. In the in vivo study, TRPV1 activation by dietary capsaicin enhanced hepatic PPARδ and autophagy-related proteins and reduced hepatic enzymes and inflammatory factor in WT but not TRPV1(-/-) mice. TRPV1 activation by dietary capsaicin prevents NAFLD through PPARδ-dependent autophagy enhancement in mice. Dietary capsaicin may represent a beneficial intervention in populations at high risk for NAFLD.

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.

Transient receptor potential canonical type 3 channels--their evolving role in hypertension and its related complications.

: Recent studies indicate that transient receptor potential canonical type 3 (TRPC3) channels contribute to the regulation of blood pressure and vascular and renal function. Several studies show that TRPC3 dysfunction is associated with hypertension, atherosclerosis, cardiac hypertrophy, and cerebrovascular events. In this review, we summarize the role of TRPC3 channels in the cardiovascular system, and we focus on their pathophysiological role in hypertension and related target organ damages. We provide new insight into the involvement of TRPC3 channels in the development of hypertension and its related complications.

Life cycle energy consumption, environmental impact, and costing assessment of coal to ethylene glycol processes via dimethyl oxalate and formaldehyde.

The popularization of conventional dimethyl oxalate to ethylene glycol (DMOtEG) has kept ongoing in the past decade in China. Recently, a northern China factory in construction attracts attention using alternative formaldehyde to ethylene glycol (FtEG) route. Thus, a question arises about the individual comparative advantages of these two processes. So, this paper conducts a systematic modeling analysis of DMOtEG and FtEG, and the life cycle assessment is performed by SimaPro v9 to compare their impact. The results indicate the inferiority of life cycle energy consumption and life cycle cost of FtEG to those of DMOtEG due to the high energy consumption and pollutant emissions. Moreover, most impact categories of FtEG are worse than the DMOtEG as global warming, and photochemical oxidant formation potential. Despite this, FtEG still wins for better potentials in ozone formation, fine particulate matter formation, and terrestrial acidification because of less nitride emissions. In addition, the decrease in energy consumption and external cost will significantly decrease the life cycle cost under controllable catalyst costs of FtEG. These results describe the impact categories of DMOtEG and FtEG and provide a basis to help decision-makers develop coal to ethylene glycol processes.

Systematic analysis of lysine crotonylation in human macrophages responding to MRSA infection.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most commonly encountered bacteria found in healthcare clinics and has been ranked a priority 2 pathogen. Research is urgently needed to develop new therapeutic approaches to combat the pathogen. Variations in the pattern of protein posttranslational modifications (PTMs) of host cells affect physiological and pathological events, as well as therapeutic effectiveness. However, the role of crotonylation in MRSA-infected THP1 cells remains unknown. In this study, we found that crotonylation profiles of THP1 cells were altered after MRSA infection. It was then confirmed that lysine crotonylation profiles of THP1 cells and bacteria were different; MRSA infection inhibited global lysine crotonylation (Kcro) modification but partially elevated Kcro of host proteins. We obtained a proteome-wide crotonylation profile of THP1 cells infected by MRSA further treated by vancomycin, leading to the identification of 899 proteins, 1384 sites of which were down-regulated, and 160 proteins with 193 sites up-regulated. The crotonylated down-regulated proteins were mainly located in cytoplasm and were enriched in spliceosome, RNA degradation, protein posttranslational modification, and metabolism. However, the crotonylated up-regulated proteins were mainly located in nucleus and significantly involved in nuclear body, chromosome, ribonucleoprotein complex, and RNA processing. The domains of these proteins were significantly enriched on RNA recognition motif, and linker histone H1 and H5 families. Some proteins related to protecting against bacterial infection were also found to be targets of crotonylation. The present findings point to a comprehensive understanding of the biological functions of lysine crotonylation in human macrophages, thereby providing a certain research basis for the mechanism and targeted therapy on the immune response of host cells against MRSA infection.