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Leptin plays a crucial role in blood pressure (BP) regulation, notably in the context of obesity through central sympatho-mediated pressor effects. Leptin also relaxes arteries via endothelial (EC) leptin receptor (LepREC)-mediated increases in nitric oxide (NO) bioavailability. Herein, we investigated whether leptin-mediated increases in NO bioavailability represent a buffering mechanism against leptin-induced sympatho-activation. We tested the direct contribution of LepREC to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepREC. LepREC deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepREC−/− mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepREC+/+:94.7 ± 1.6, LepREC−/−:95.1 ± 1.8 mmHg; HR:LepREC+/+:492.4 ± 11.7, LepREC−/−:509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepREC+/+:101.1 ± 1.7, LepREC−/−:101.7 ± 1.8 mmHg; HR, LepREC+/+:535.6 ± 11.1, LepREC−/−:539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepREC−/− mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepREC deficiency did not alter endothelium-dependent relaxation in resistance vessels, nor NO contribution to vasodilatation. Lastly, leptin induced similar increases in adrenergic contractility in mesenteric arteries from both LepREC+/+ and LepREC−/− mice. Collectively, these results demonstrate that the NO buffering effects of leptin are absent in resistance arteries and do not contribute to BP regulation. We provide further evidence that leptin-mediated hypertension involves increased vascular sympatho-activation and extend these findings by demonstrating for the first time that increased cardiac sympatho-activation and reduced vagal tone also contribute to leptin-mediated hypertension. [Display omitted] • Leptin-induced NO bioavailability is absent in resistance arteries. • Endothelial leptin signaling does not contributes to blood pressure regulation. • Leptin-induced endothelial NO bioavailability is specific to conductance arteries. • Endothelial NO does not buffer leptin-mediated sympatho-activation. • Leptin-induced hypertension involves cardiac sympatho-excitation and reduced vagal tone. [ABSTRACT FROM AUTHOR]

R2666 --> 849.6 --> Diabetes, whether insulin‐dependent or independent is a major cause of endothelial dysfunction and a leading risk factor for cardiovascular disease. While compelling evidence indicates that endothelial dysfunction is a precursor and contributor to cardiovascular disease, the etiology of diabetes‐induced endothelial dysfunction remains ill‐defined. Recently alteration in endothelial cell bioenergetics has emerged as a new contributor to vascular diseases. However, whether alterations in endothelial glycolysis, the main endothelial cell bioenergetic pathway contributes to endothelial dysfunction is unknown. Herein, we tested the hypothesis that diabetes‐associated endothelial dysfunction involved increases in endothelial cells glycolysis and upregulation of its primary regulator, 6‐phosphofructo‐2‐kinase/fructose‐2, 6‐bisphosphatase 3 (PFKFB3). Measurement of glycolytic activity via Seahorse analyzer in primary human aortic endothelial cells (HAEC) from control and diabetic patients revealed a significant increase in basal glycolysis in diabetic subjects (p<0.05). We also employed Akita mice, a mouse model of type 1 diabetes. Male Akita mice showed a diabetic phenotype with 3‐folds increase in blood glucose. Seahorse analysis in intact aortic explants revealed a 1.7‐fold increase in basal glycolysis and a 1.3‐fold increase in maximal glycolysis in Akita mice (P<0.05). The increase in glycolysis was endothelial‐derived as aortic denudation significantly decreased glycolysis in Akita mice and abolished the difference between groups. No significant difference in mitochondrial function was depicted in the mito‐stress test between Akita and WT aortic explants (p>0.05). Additionally, endothelial cells extracted from aortas of Akita mice exhibited a 2‐fold increase in PFKFB3 mRNA expression(P<0.05). Interestingly, inhibition of PFKFB3 using 3PO (20μM) restored endothelial function in Akita mice. Similarly, Non‐obese diabetic females (NOD), a model for type‐1 diabetes, showed 4‐fold increases in PFKFB3 mRNA expression in aortic endothelial cells and impaired EDR which was restored with 3PO (p<0.05). To further evaluate the role of PFKFB3 in vascular endothelial function we overexpressed PFKFB3 in WT aortas with adenovirus (Ad‐PFKFB3), and reported impaired aorta EDR(P<0.05). Transduction of HAEC with Ad‐PFKFB3 showed a significant increase in ROS producing enzyme (NOX1). Also, inhibition of NOX1 using the selective inhibitor GKT771 restored EDR in Akita and Ad‐PFKFB3‐transduced WT aortas. In Conclusion, our data identified for the first time a role for endothelial glycolysis in the control of vascular relaxation and showed a crucial role of PFKFB3‐mediated endothelial glycolysis in vascular endothelial dysfunction associated with Type‐1 diabetes in males and females. The underlying mechanism potentially involves NOX1 as a downstream target for PFKFB3. Thus, Inhibitors of PFKFB3 could be a potential therapeutic target for diabetes‐induced vascular endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Highlights: [•] Silymarin enhanced ER-β but decreased ER-α and androgen receptor expression. [•] Silymarin showed powerful antioxidant and pro-apoptotic properties. [•] Silymarin enhanced P21 expression, Bax/Bcl-xl ratio and caspase-3 activity. [•] Silymarin could be a promising candidate in the management of BPH. [Copyright &y& Elsevier]

Western diet-induced obesity is linked to the development of metabolic dysfunctions, including type 2 diabetes and complications that include retinopathy, a leading cause of blindness. Aberrant activation of the inflammasome cascade leads to the progression of obesity-induced pathologies. Our lab showed the critical role of arginase 2 (A2), the mitochondrial isoform of this ureahydrolase, in obesity-induced metabolic dysfunction and inflammation. A2 deletion also has been shown to be protective against retinal inflammation in models of ischemic retinopathy and multiple sclerosis. We investigated the effect of A2 deletion on western diet-induced retinopathy. Wild-type mice fed a high-fat, high-sucrose western diet for 16 weeks exhibited elevated retinal expression of A2, markers of the inflammasome pathway, oxidative stress, and activation of microglia/macrophages. Western diet feeding induced exaggerated retinal light responses without affecting visual acuity or retinal morphology. These effects were reduced or absent in mice with global A2 deletion. Exposure of retinal endothelial cells to palmitate and high glucose, a mimic of the obese state, increased expression of A2 and inflammatory mediators and induced cell death. These effects, except for A2, were prevented by pretreatment with an arginase inhibitor. Collectively, our study demonstrated a substantial role of A2 in early manifestations of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(−/−) or A1(+/−) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2−/−, but not A1+/−, mice. Additionally, A2−/− HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1α, PPAR-γ, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-α, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2−/− mice, but more prominently maintained in A1+/− mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction. [ABSTRACT FROM AUTHOR]

Sepsis is a major cause of mortality in intensive care units, which results from a severely dysregulated inflammatory response that ultimately leads to organ failure. While antibiotics can help in the early stages, effective strategies to curtail inflammation remain limited. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. While HMGB1 has been shown to play a role in sepsis, the role of other family members including HMGXB4 remains unknown. We found that expression of HMGXB4 is strongly induced in response to lipopolysaccharide (LPS)-elicited inflammation in murine peritoneal macrophages. Genetic deletion of Hmgxb4 protected against LPS-induced lung injury and lethality and cecal ligation and puncture (CLP)-induced lethality in mice, and attenuated LPSinduced proinflammatory gene expression in culturedmacrophages. By integrating genome-wide transcriptome profiling and a publicly available ChIP-seq dataset, we identified HMGXB4 as a transcriptional activator that regulates the expression of the proinflammatory gene, Nos2 (inducible nitric oxide synthase 2) by binding to its promoter region, leading to NOS2 induction and excessive NO production and tissue damage. Similar to Hmgxb4 ablation in mice, administration of a pharmacological inhibitor of NOS2 robustly decreased LPS-induced pulmonary vascular permeability and lethality in mice. Additionally, we identified the cell adhesion molecule, ICAM1, as a target of HMGXB4 in endothelial cells that facilitates inflammation by promoting monocyte attachment. In summary, our study reveals a critical role of HMGXB4 in exacerbating endotoxemia via transcriptional induction of Nos2 and Icam1 gene expression and thus targeting HMGXB4 may be an effective therapeutic strategy for the treatment of sepsis. [ABSTRACT FROM AUTHOR]

Gastric ulcer is a serious disease that affects millions of individuals worldwide. Alcohol consumption is a major contributor to the disease pathogenesis and ethanol-induced ulcer in rats closely recapitulates the clinical pathology of ulcer. In this study, rats were pretreated with carvacrol (CAR,50 and 100 mg/kg, orally) 1 h before absolute ethanol administration to induce gastric ulcer. CAR prevented ethanol-induced increases in gastric volume and acidity while restored mucin content. The gastro-protective activity of CAR, particularly the higher dose (100 mg/kg), was further supported by histopathological examination, as manifested by reduced gastric lesions. Interestingly, oxidative stress is linked to early stages of ulcer development and progression. In this study, ethanol administration upregulated the levels of ROS-producing enzymes, NADPH oxidase homologs 1 and 4 (Nox1 and Nox4) and lipid peroxides while depleting the antioxidant defense mechanisms, including GSH, Glutathione Peroxidase (GPX) and catalase. Interestingly, these alterations were significantly ameliorated by CAR pretreatment. Additionally, CAR possesses anti-inflammatory and anti-apoptotic activities. Pretreatment with CAR blunted ethanol-induced increases in inflammatory cytokines (NF-κB and TNF-α) and rectified the apoptosis regulator (Bax/Bcl2 ratio) in gastric tissue. Moreover, the docking simulation of CAR illustrated good fitting and interactions with GPX, Nox1 and TNF-α through the formation of hydrogen and hydrophobic (pi -H) bonds with conservative amino acids, thus, further supporting the anti-inflammatory and antioxidant effects underlying the gastroprotective effects of CAR. In conclusion, this study elucidates, using in silico and in vivo models, that the gastroprotective activity of CAR is attributed, at least in part, to its mucin-secretagogue, antioxidative, anti-inflammatory, and anti-apoptotic mechanisms. • Carvacrol (CAR) stimulated mucin-secretion and prevented ethanol-induced gastric ulcers in vivo. • CAR alleviated ethanol-induced oxidative stress and reduced Nox1 and Nox4 levels. • Ethanol-mediated inflammation and increases in NF-kB and TNF-α were restored by CAR. • CAR restored Bax/Bcl2 ratio and prevented ethanol-induced apoptosis in gastric tissues. • In silico docking showed good fitting and binding of CAR with GPx, Nox1 and TNF-α. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims Elevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology. Methods and results To test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)- amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelialdependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment. Conclusion Vascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome. [ABSTRACT FROM AUTHOR]