Search

Visual Abstract, Highlights • AAV9 vectors can upregulate Rxfp1 mRNA in murine heart after intravenous injection. • RXFP1 upregulation sensitizes the left ventricle to relaxin-induced inotropy. • RXFP1 overexpression protects heart from ischemia-reperfusion injury., Summary Relaxin is a pleiotropic hormone shown to confer cardioprotection in several preclinical models of cardiac ischemia-reperfusion injury. In the present study, the effects of up-regulating relaxin family peptide receptor 1 (RXFP1) via adeno-associated virus serotype 9 (AAV9) vectors were investigated in a mouse model of myocardial infarction. AAV9-RXFP1 vectors were generated and injected in adult male CD1 mice. Up-regulation of Rxfp1 was confirmed via quantitative polymerase chain reaction, and overexpressing animals showed increased sensitivity to relaxin-induced ventricular inotropic response. Overexpressing animals also demonstrated reduced infarct size and preserved cardiac function 24 hours after ischemia-reperfusion. Up-regulation of RXFP1 via AAV9 vectors has potential therapeutic utility in preventing adverse remodeling after myocardial infarction.

Graphical abstract, Highlights • Subchronic HCB-administration in male rats generates arterial hypertension. • AT1 activity is involved in HCB- induced hypertension. • AT1 activity is involved in arterial morphological changes caused by HCB. • AT1 activity is involved in HCB- produced alterations in arterial relaxation. • Losartan prevents HCB-produced alterations in TGF-β1, eNOS and AT1 expressions., Environmental hexachlorobenzene (HCB) increases blood pressure (BP) in female rats, causing alterations in arterial structure and function. Here we study the role of Angiotensin II receptor type 1 (AT1) in HCB-induced hypertension through the use of AT1 antagonist losartan. HCB-treated male rats showed a 22.7% increase in BP which was prevented by losartan. Losartan blocked HCB-induced changes in arterial morphology (decreased aorta cell number and increased wall thickness). Losartan also prevented HCB-induced alterations in artery relaxation by acetylcholine and nitroprusside but not the reduction in the maximum contraction by phenylephrine. Losartan rescued arterial molecular alterations caused by HCB (i.e. an increase in TGF-β1 and AT1 expression and a decrease in eNOS expression and nitrite levels) and reduced hydrogen sulfide plasma concentration. In conclusion: in this work we demonstrate that AT1 activity is involved in HCB effects on the vascular system leading to hypertension.

Graphical abstract, Highlights • Naringin inhibits and/or scavenge in vitro free radicals. • Exposure to cyclophosphamide (CYCP) invoked erythrocytotoxicity. • Erythrocytotoxicity was characterized by oxidative stress and dyslipidaemia. • LDH (a marker of anaerobic ATP generation) was also depleted. • Naringin pre-administered reversed the CYCP-induced erythrocytotoxicity., Earlier reports have shown that Cyclophosphamide (CYCP), an anti-malignant drug, elicited cytotoxicity; and that naringin has several beneficial potentials against oxidative stress and dyslipidaemias. We investigated the influence of naringin on free radical scavenging, cellular integrity, cellular ATP, antioxidants, oxidative stress, and lipid profiles in the CYCP-induced erythrocytotoxicity rat model. Rats were pretreated orally by gavage for fourteen consecutive days with three doses (50, 100, and 200 mg/kg) naringin before single CYCP (200 mg/kg, i.p.) administration. Afterwards, the rats were sacrificed. Naringin concentrations required for 50 % scavenging hydrogen peroxide and nitric oxide radical were 0.27 mg/mL and 0.28 mg/mL, respectively. Naringin pretreatment significantly (p < 0.05) protected erythrocytes plasma membrane architecture and integrity by abolishing CYCP-induced decrease in the activity of erythrocyte LDH (a marker of ATP). Pretreatment with naringin remarkably (p < 0.05) reversed CYCP-induced decreases in the erythrocytes glutathione levels, activities of glutathione-S-transferase, catalase, glutathione peroxidase, and glutathione reductase; attenuated CYCP-mediated increases in erythrocytes levels of malondialdehyde, nitric oxide, and major lipids (cholesterol, triacylglycerol, phospholipids, and non-esterified fatty acids). Taken together, different acute pretreatment doses of naringin might avert CYCP-mediated erythrocytes dysfunctions via its antioxidant, free-radical scavenging, and anti-dyslipidaemia properties.

Background & Aims Alcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD is mostly unexplored. Methods To decipher the role of hepatic sEH in ALD, we generated mice with liver-specific sEH disruption (Alb-Cre; Ephx2fl/fl). Alb-Cre; Ephx2fl/fl and control (Ephx2fl/fl) mice were subjected to an ethanol challenge using the chronic plus binge model of ALD and hepatic injury, inflammation, and steatosis were evaluated under pair-fed and ethanol-fed states. In addition, we investigated the capacity of pharmacologic inhibition of sEH in the chronic plus binge mouse model. Results We observed an increase of hepatic sEH in mice upon ethanol consumption, suggesting that dysregulated hepatic sEH expression might be involved in ALD. Alb-Cre; Ephx2fl/fl mice presented efficient deletion of hepatic sEH with corresponding attenuation in sEH activity and alteration in the lipid epoxide/diol ratio. Consistently, hepatic sEH deficiency ameliorated ethanol-induced hepatic injury, inflammation, and steatosis. In addition, targeted metabolomics identified lipid mediators that were impacted significantly by hepatic sEH deficiency. Moreover, hepatic sEH deficiency was associated with a significant attenuation of ethanol-induced hepatic endoplasmic reticulum and oxidative stress. Notably, pharmacologic inhibition of sEH recapitulated the effects of hepatic sEH deficiency and abrogated injury, inflammation, and steatosis caused by ethanol feeding. Conclusions These findings elucidated a role for sEH in ALD and validated a pharmacologic inhibitor of this enzyme in a preclinical mouse model as a potential therapeutic approach., Graphical abstract

Background and aim Renal ischemia-reperfusion is associated with inflammation and oxidative stress. As a major compound in black pepper, piperine has anti-inflammatory and anti-oxidative properties. In present study, the protective effects of oral administration of piperine in renal ischemia-reperfusion (IR) induced acute kidney injuries (AKI) were investigated. Experimental procedure Male Wistar rats received piperine (10 or 20 mg/kg.bw) or vehicle for 10 days. The artery and vein of both kidneys were then clamped for 30 min, followed by a 24-h reperfusion period. Concentrations of creatinine and urea-nitrogen in descending aorta blood were measured, and malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels were measured in kidney tissue to evaluate the oxidative stress. Inflammation was evaluated by measuring the TNF-α and ICAM-1 mRNA expression levels in renal cortical tissue using Real Time PCR method and counting leukocytes infiltration to interstitium. Further measured were tissue damages in H & E stained sections. Results Renal IR reduced FRAP, while increasing the plasma concentrations of creatinine and urea-nitrogen, tissue MDA level, TNF-α and ICAM-1 mRNA expressions, leukocyte infiltration and histopathologic injuries. Piperine administration significantly reduced the plasma concentrations of creatinine and urea-nitrogen, expression of pro-inflammatory factors, oxidative stress and renal histopathologic injuries. It is to be noted that 20 mg/kg dose was more effective. Conclusion Our results suggest piperine protects the kidney against ischemia-reperfusion induced acute kidney injuries by its anti-inflammatory and anti-oxidative properties., Graphical abstract Image 102975, Highlights • Renal ischemia-reperfusion increased the inflammation and oxidative stress parameters. • Ischemia-reperfusion increased histopathological damages and functional parameters. • Piperine pretreatment significantly reduced the inflammation and oxidative stress. • Piperine administration ameliorated renal function and histopathologic damages.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is accompanied by progressive joint damage and disability. The intolerability of conventional antirheumatic drugs by some patients necessitates the search for effective antirheumatic agents having better tolerability. In the current work, we aimed to investigate the efficacy of cinnamaldehyde, tadalafil, and aliskiren as potential antirheumatic candidates and to explore their modulatory effects on joint destruction, inflammatory response, and intracellular signaling. Arthritis was induced in female Wistar rats by complete Freund's adjuvant (CFA) 0.4 ml s.c. on days 1, 4, and 7. Treated groups received their respective drugs, starting from day 13, daily for 3 weeks. Methotrexate and prednisolone were the standard antirheumatic drugs, while cinnamaldehyde, tadalafil, and aliskiren were the test agents. Treatment with cinnamaldehyde, tadalafil, or aliskiren reduced serum levels of rheumatoid factor, and pro-inflammatory cytokines; tumor necrosis factor-alpha and interleukin-6 (IL-6), along with elevated level of IL-10 which is an anti-inflammatory cytokine. Besides, cartilage and bone destruction biomarkers; matrix metalloproteinase-3 (MMP-3) and receptor activator of nuclear factor-kappa B ligand (RANKL); were significantly reduced after treatment with the test agents, which was further confirmed by histopathological investigation. The elevated protein expressions of phosphorylated-Janus kinase 2 (p-JAK2), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), and inducible nitric oxide synthase (iNOS) in articular tissue were markedly attenuated after treatment with cinnamaldehyde, tadalafil, or aliskiren, while that of endothelial nitric oxide synthase (eNOS) was greatly enhanced. In addition, oxidative stress and inflammatory markers such as malondialdehyde, nitric oxide, and myeloperoxidase were reduced in joint tissue after treatment with the test agents, while glutathione content was elevated. Furthermore, the renin inhibitor aliskiren produced effects close to those of the normal and methotrexate, the gold standard antirheumatic drug, in most of the measured parameters. Collectively, these findings led to the assumption that the downregulation of IL-6/JAK2/STAT3 signaling by cinnamaldehyde, tadalafil, and aliskiren could alleviate joint destruction by MMP-3 and RANKL, reduce iNOS, and enhance eNOS expressions. Moreover, aliskiren could be a promising therapeutic agent for RA, because of its ability to normalize most of the measured parameters after CFA-induced arthritis.

Graphical abstract, Highlights • Methanol extract of Psiadia punctulata (MAPP) produced a significant vasodilation. • Chloroform fraction and its methylated flavonoids were responsible for this effect. • Vasodilation is referred to endothelial nitric oxide and, Ca2+ dependent eNOS. • Interference with calcium entrance is another possible mechanism of vasodilation., Vasodilators are important pharmacologic agents for managing and/or treating hypertension. Medicinal plants are considered as valuable source of bioactive compounds. We used a bioguided approach to isolate, identify, and investigate the possible vasodilation activities and mechanism(s) of the prepared methanol extract from aerial parts of Psiadia punctulata (MAPP), its bioactive fraction and active compounds. Vascular effects of MAPP were studied using isolated artery technique in the presence or absence of specific candidate pathways inhibitors, and found to produce a significant vasodilation of phenylephrine preconstricted rat aortae. The bioactive chloroform fraction yielded five methoxylated flavonoids: umuhengerin (1), gardenin A (2), gardenin B (3), luteolin-3′,4′ -dimethyl ether (4), and 5,3′-dihydroxy-6,7,4′,5′-tetramethoxyflavone (5). Metabolites 1, 4, and 5 produced a significant vasodilation. Removal of the endothelium significantly inhibited MAPP vasodilation. Nitric oxide synthase inhibition and not prostacycline inhibition or K+ channel blocking, was found to cause the observed vasodilation inhibition. Both guanylate cyclase and adenylate cyclase inhibitions markedly inhibited MAPP vasodilation. In conclusion MAPP possesses vasodilation activities that is mediated through endothelial nitric oxide pathway, calcium dependent endothelial nitric oxide synthase activation, and interference with the depolarization process through calcium channel blocking activity.

Cardiovascular diseases are a rapidly growing epidemic with high morbidity and mortality. There is an urgent need to develop nutraceutical-based therapy with minimum side effects to reduce cardiovascular risk. Panax ginseng occupies a prominent status in herbal medicine for its various therapeutic effects against inflammation, allergy, diabetes, cardiovascular diseases, and even cancer, with positive, beneficial, and restorative effects. The active components found in most P. ginseng varieties are known to include ginsenosides, polysaccharides, peptides, alkaloids, polyacetylene, and phenolic compounds, which are considered to be the main pharmacologically active constituents in ginseng. P. ginseng is an adaptogen. That is, it supports living organisms to maintain optimal homeostasis by exerting effects that counteract physiological changes caused by physical, chemical, or biological stressors. P. ginseng possesses immunomodulatory (including both immunostimulatory and immunosuppressive), neuromodulatory, and cardioprotective effects; suppresses anxiety; and balances vascular tone. P. ginseng has an antihypertensive effect that has been explained by its vasorelaxant action, and paradoxically, it is also known to increase blood pressure by vasoconstriction and help maintain cardiovascular health. Here, we discuss the potential adaptogenic effects of P. ginseng on the cardiovascular system and outline a future research perspective in this area.

Visual Abstract, Highlights • The role of ERα non-nuclear signaling in female heart failure was investigated, using a novel mouse line in which ERα non-nuclear signaling was selectively disrupted by inhibiting the interaction between ERα and striatin, a scaffold protein residing at caveolae. • ERα non-nuclear signaling was linked to myocardial PKG activity in female hearts and ameliorated cardiac maladaptive remodeling induced by pressure overload. • ERα non-nuclear signaling was indispensable to the therapeutic efficacy of cGMP-PDE5 inhibition in heart failure but not to that of sGC stimulation. • sGC stimulation potently ameliorated cardiac remodeling, regardless of estrogen conditions, in sharp contrast to PDE5 inhibition. • The study provided the first in vivo evidence for the role of ERα non-nuclear signaling in heart failure, linking it to cGMP-PKG pathways. The data also supported the advantage of sGC stimulation over PDE5 inhibition as a potential therapeutic strategy in treating heart failure in post-menopausal women, highlighting the need for female-specific therapeutic strategies., Summary Using genetically engineered mice lacking estrogen receptor-α non-nuclear signaling, this study demonstrated that estrogen receptor−α non-nuclear signaling activated myocardial cyclic guanosine monophosphate-dependent protein kinase G and conferred protection against cardiac remodeling induced by pressure overload. This pathway was indispensable to the therapeutic efficacy of cyclic guanosine monophosphate−phosphodiesterase 5 inhibition but not to that of soluble guanylate cyclase stimulation. These results might partially explain the equivocal results of phosphodiesterase 5 inhibitor efficacy and also provide the molecular basis for the advantage of using a soluble guanylate cyclase simulator as a new therapeutic option in post-menopausal women. This study also highlighted the need for female-specific therapeutic strategies for heart failure.

The current coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges to global health. Although the majority of COVID-19 patients exhibit mild-to-no symptoms, many patients develop severe disease and need immediate hospitalization, with most severe infections associated with a dysregulated immune response attributed to a cytokine storm. Epidemiological studies suggest that overall COVID-19 severity and morbidity correlate with underlying comorbidities, including diabetes, obesity, cardiovascular diseases, and immunosuppressive conditions. Patients with such comorbidities exhibit elevated levels of reactive oxygen species (ROS) and oxidative stress caused by an increased accumulation of angiotensin II and by activation of the NADPH oxidase pathway. Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis. In this review, we survey the mechanisms of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces oxidative stress and the consequences of this stress on patient health. We further shed light on aspects of the host immunity that are crucial to prevent the disease during the early phase of infection. A better understanding of the disease pathophysiology as well as preventive measures aimed at lowering ROS levels may pave the way to mitigate SARS-CoV-2-induced complications and decrease mortality., Graphical abstract

Highlights • Mechanotransduction through cell surface GAGs is a potential driver of metastasis. • SAHA, a histone deacetylase inhibitor, reduces tumor cell NDST1 and HS. • SAHA blocked metastasis of highly metastatic renal carcinoma cells in a mouse model. • Reduction of hyaluronic acid suppresses metastasis in a mouse kidney cancer model., Mammalian cells, including cancer cells, are covered by a surface layer containing cell bound proteoglycans, glycoproteins, associated glycosaminoglycans and bound proteins that is commonly referred to as the glycocalyx. Solid tumors also have a dynamic fluid microenvironment with elevated interstitial flow. In the present work we further investigate the hypothesis that interstitial flow is sensed by the tumor glycocalyx leading to activation of cell motility and metastasis. Using a highly metastatic renal carcinoma cell line (SN12L1) and its low metastatic counterpart (SN12C) we demonstrate in vitro that the small molecule Suberoylanilide Hydroxamic Acid (SAHA) inhibits the heparan sulfate synthesis enzyme N-deacetylase-N-sulfotransferase-1, reduces heparan sulfate in the glycocalyx and suppresses SN12L1 motility in response to interstitial flow. SN12L1 cells implanted in the kidney capsule of SCID mice formed large primary tumors and metastasized to distant organs, but when treated with SAHA metastases were not detected. In another set of experiments, the role of hyaluronic acid was investigated. Hyaluronan synthase 1, a critical enzyme in the synthetic pathway for hyaluronic acid, was knocked down in SN12L1 cells and in vitro experiments revealed inhibition of interstitial flow induced migration. Subsequently these cells were implanted in mouse kidneys and no distant metastases were detected. These findings suggest new therapeutic approaches to the treatment of kidney carcinoma metastasis.

Endothelial cells are sensitive to mechanical stress and respond differently to oscillatory flow versus unidirectional flow. This review highlights the mechanisms by which a wide range of unidirectional laminar shear stress induces activation of the redox sensitive antioxidant transcription factor nuclear factor-E2-related factor 2 (Nrf2) in cultured endothelial cells. We propose that fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor (BDNF) and 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) are potential Nrf2 activators induced by laminar shear stress. Shear stress-dependent secretion of FGF-2 and its receptor-mediated signaling is tightly controlled, requiring neutrophil elastase released by shear stress, αvβ3 integrin and the cell surface glycocalyx. We speculate that primary cilia respond to low laminar shear stress (15 dyn/cm2) induces vesicular exocytosis of BDNF from endothelial cells, and we propose that BDNF via the p75NTR receptor could induce CK2-mediated Nrf2 activation. Unidirectional laminar shear stress upregulates gene expression of FGF-2 and BDNF and generation of 15d-PGJ2, which cooperate in sustaining Nrf2 activation to protect endothelial cells against oxidative damage., Graphical abstract Image 1, Highlights • Primary cilia amplify low unidirectional shear stress signals in endothelial cells. • Low shear stress induces release of IGF-1 and neutrophil elastase. • IGF-1 and elastase cooperate in upregulating FGF-2 gene expression and secretion. • Glycocalyx facilitates FGF-2 secretion, trapping, expression and receptor signaling. • FGF-2, BDNF and 15d-PGJ2 are shear stress-related potential Nrf2 activators.

JHEP reports 3(4), 100316 (2021). doi:10.1016/j.jhepr.2021.100316, Published by Elsevier, Amsterdam

Identification of the links among flavonoid consumption, mitigation of oxidative stress and improvement of disease in humans has significantly advanced in the last decades. This review used (−)-epicatechin (EC) as an example of dietary flavonoids, and inflammation, endothelial dysfunction/hypertension and insulin resistance/diabetes as paradigms of human disease. In these pathologies, oxidative stress is part of their development and/or their perpetuation. Evidence from both, rodent studies and characterization of mechanisms in cell cultures are encouraging and mostly support indirect antioxidant actions of EC and EC metabolites in endothelial dysfunction and insulin resistance. Human studies also show beneficial effects of EC on these pathologies based on biomarkers of disease. However, there is limited available information on oxidative stress biomarkers and flavonoid consumption to allow establishing conclusive associations. The evolving discovery of metabolites that could serve as reliable markers of intake of specific flavonoids constitutes a powerful tool to link flavonoid consumption to disease and prevention of oxidative stress in human populations., Graphical abstract Image 1, Highlights • Flavonoid’s metabolism and concentration determine their antioxidant mechanisms. • Except for the GI tract, flavonoids are relevant indirect antioxidants in organs and tissues. • Flavonoid's health effects are not always linked to biomarkers of oxidative stress. • (‒)-Epicatechin mitigates the redox deregulation involved in hypertension/T2D pathogenesis. • More human studies will strength links among flavonoids, oxidative stress, and disease.

Visual Abstract, Highlights • CMECs exert a direct positive effect on cardiomyocyte contraction and relaxation, which is mainly mediated by endothelial-derived NO. • Pro-inflammatory stimulation of CMECs by pre-incubation with TNF-α or interleukin-1β abrogates the positive regulatory function of these cells on cardiomyocyte contractile property. • Mechanistically, pro-inflammatory activation of CMECs leads to mitochondrial and cytoplasmic ROS accumulation that results in the scavenging of NO. • Empagliflozin directly restores the beneficial effect of CMECs on cardiomyocyte contraction and relaxation by reducing TNF-α-induced mitochondrial and cytoplasmic ROS accumulation, which leads to reinstatement of CMEC-derived NO delivery., Summary The positive findings of the EMPA-REG OUTCOME trial (Randomized, Placebo-Controlled Cardiovascular Outcome Trial of Empagliflozin) on heart failure (HF) outcome in patients with type 2 diabetes mellitus suggest a direct effect of empagliflozin on the heart. These patients frequently have HF with preserved ejection fraction (HFpEF), in which a metabolic risk-related pro-inflammatory state induces cardiac microvascular endothelial cell (CMEC) dysfunction with subsequent cardiomyocyte (CM) contractility impairment. This study showed that CMECs confer a direct positive effect on contraction and relaxation of CMs, an effect that requires nitric oxide, is diminished after CMEC stimulation with tumor necrosis factor-α, and is restored by empagliflozin. Our findings on the effect of empagliflozin on CMEC-mediated preservation of CM function suggests that empagliflozin can be used to treat the cardiac mechanical implications of microvascular dysfunction in HFpEF.

Oxidative stress and inflammation interact in the development of diabetic atherosclerosis. Intracellular hyperglycemia promotes production of mitochondrial reactive oxygen species (ROS), increased formation of intracellular advanced glycation end-products, activation of protein kinase C, and increased polyol pathway flux. ROS directly increase the expression of inflammatory and adhesion factors, formation of oxidized-low density lipoprotein, and insulin resistance. They activate the ubiquitin pathway, inhibit the activation of AMP-protein kinase and adiponectin, decrease endothelial nitric oxide synthase activity, all of which accelerate atherosclerosis. Changes in the composition of the gut microbiota and changes in microRNA expression that influence the regulation of target genes that occur in diabetes interact with increased ROS and inflammation to promote atherosclerosis. This review highlights the consequences of the sustained increase of ROS production and inflammation that influence the acceleration of atherosclerosis by diabetes. The potential contributions of changes in the gut microbiota and microRNA expression are discussed. Keywords: Atherosclerosis, Diabetes mellitus, Reactive oxygen species, Gut microbiota, MicroRNA

Hemodialysis vascular access dysfunction is a common and intractable problem in clinical practice with no definitive therapy yet available. As a key mediator of vascular and cardiac maladaptive remodeling, mineralocorticoid receptor (MR) plays a pivotal role in vascular fibrosis and intimal hyperplasia (IH) and is potentiated locally in hemodialysis vascular access following diverse injuries, like barotrauma, cannulation and shear stress. MR-related genomic and non-genomic pathways are responsible for triggering vascular smooth muscle cell activation, proliferation, migration and extracellular matrix overproduction. In endothelial cells, MR signaling diminishes nitric oxide production and its bioavailability, but amplifies reactive oxygen species, leading to an inflammatory state. Moreover, MR favors macrophage polarization towards a pro-inflammatory phenotype. In clinical settings like post-angioplasty or stenting restenosis, the beneficial effect of MR antagonists on vascular fibrosis and IH has been validated. In aggregate, therapeutic targeting of MR may provide a new avenue to prevent hemodialysis vascular access dysfunction., Highlights • MR signaling is instrumental in both insufficient outward remodeling and exuberant inward remodeling of AVF. • The effects of MR in VSMC, endothelial cell, and macrophage act synergistically to promote IH and vascular fibrosis in AVF. • Pharmacological targeting of MR represents a novel therapeutic strategy to prevent hemodialysis vascular access dysfunction.

Graphical abstract, Highlights • The coexistence of diabetes and hypertension represents a major risk factor for the onset of cardiovascular problems. • The purinergic signaling pathway constitutes a ubiquitous system of cell–cell communication. • Purinergic system plays a pivotal role in physiopathological conditions. • Several alterations in purine metabolism have been demonstrated in diabetes and hypertension. • Purinergic system can be an important target related to therapeutic approaches in diabetes and hypertension., Diabetes mellitus (DM) and hypertension are highly prevalent worldwide health problems and frequently associated with severe clinical complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy, stroke, and cardiac arrhythmia, among others. Despite all existing research results and reasonable speculations, knowledge about the role of purinergic system in individuals with DM and hypertension remains restricted. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. The main components of this system that will be presented in this review are: P1 and P2 receptors and the enzymatic cascade composed by CD39 (NTPDase; with ATP and ADP as a substrate), CD73 (5′-nucleotidase; with AMP as a substrate), and adenosine deaminase (ADA; with adenosine as a substrate). The purinergic system has recently emerged as a central player in several physiopathological conditions, particularly those linked to inflammatory responses such as diabetes and hypertension. Therefore, the present review focuses on changes in both purinergic P1 and P2 receptor expression as well as the activities of CD39, CD73, and ADA in diabetes and hypertension conditions. It can be postulated that the manipulation of the purinergic axis at different levels can prevent or exacerbate the insurgency and evolution of diabetes and hypertension working as a compensatory mechanism.

Background Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown. Objectives The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes. Methods A screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints. Results Because ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects. Conclusions These results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183), Central Illustration

Visual Abstract, Highlights • In patients with STEMI treated with primary percutaneous coronary intervention, iron deficiency is associated with larger infarcts, more extensive microvascular obstruction, and a higher frequency of adverse left ventricular remodeling. • An iron-deficient diet reduces the tolerance to ischemia/reperfusion in mice at least in part by interfering with the cardioprotective pathway eNOS/soluble guanylate cyclase/protein kinase G. • An iron-deficient diet reduces eNOS activity by increasing oxidative/nitrosative stress and its proteasome-dependent degradation. • Not only iron excess but also iron deficiency may have deleterious effects in the context of acute myocardial ischemia., Summary In patients with a first anterior ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention, iron deficiency (ID) was associated with larger infarcts, more extensive microvascular obstruction, and higher frequency of adverse left ventricular remodeling as assessed by cardiac magnetic resonance imaging. In mice, an ID diet reduced the activity of the endothelial nitric oxide synthase/soluble guanylate cyclase/protein kinase G pathway in association with oxidative/nitrosative stress and increased infarct size after transient coronary occlusion. Iron supplementation or administration of an sGC activator before ischemia prevented the effects of the ID diet in mice. Not only iron excess, but also ID, may have deleterious effects in the setting of ischemia and reperfusion.

In smooth muscle, cytoglobin (Cygb) functions as a potent nitric oxide (NO) dioxygenase and regulates NO metabolism and vascular tone. Major questions remain regarding which cellular reducing systems regulate Cygb-mediated NO metabolism. To better define the Cygb-mediated NO dioxygenation process in vascular smooth muscle cells (SMCs), and the requisite reducing systems that regulate cellular NO decay, we assessed the intracellular concentrations of Cygb and its putative reducing systems and examined their roles in the process of NO decay. Cygb and the reducing systems, cytochrome b5 (B5)/cytochrome b5 reductase (B5R) and cytochrome P450 reductase (CPR) were measured in aortic SMCs. Intracellular Cygb concentration was estimated as 3.5 μM, while B5R, B5, and CPR were 0.88, 0.38, and 0.15 μM, respectively. NO decay in SMCs was measured following bolus addition of NO to air-equilibrated cells. siRNA-mediated knockdown experiments indicated that ∼78% of NO metabolism in SMCs is Cygb-dependent. Of this, ∼87% was B5R- and B5-dependent. CPR knockdown resulted in a small decrease in the NO dioxygenation rate (VNO), while depletion of ascorbate had no effect. Kinetic analysis of VNO for the B5/B5R/Cygb system with variation of B5 or B5R concentrations from their SMC levels showed that VNO exhibits apparent Michaelis–Menten behavior for B5 and B5R. In contrast, linear variation was seen with change in Cygb concentration. Overall, B5/B5R was demonstrated to be the major reducing system supporting Cygb-mediated NO metabolism in SMCs with changes in cellular B5/B5R levels modulating the process of NO decay.

Aldehydes are implicated in the development of hypertension. Trans, trans-2,4-decadienal (tt-DDE), a dietary α,β-unsaturated aldehyde, is widespread in many food products. However, the role of tt-DDE in the pathophysiology of hypertension remains unknown. This study was designed to investigate whether tt-DDE consumption evokes hypertension and to explore the mechanisms underlying such a role. Sprague-Dawley rats were administered different concentrations of tt-DDE. After 28 days, blood pressure and endothelial function of mesenteric arteries were measured. Results showed that tt-DDE treatment significantly increased blood pressure and impaired endothelial function based on endothelium-dependent vasorelaxation and p-VASP levels. Mechanistically, tt-DDE induced oxidative/nitrative stress in the arteries of rats as evidenced by overproductions of superoxide and peroxynitrite, accompanied with increased expressions of iNOS and gp91phox. To further investigate the effects of tt-DDE on endothelial cells and underlying mechanisms, human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of tt-DDE. tt-DDE induced oxidative/nitrative stress in HUVECs. Moreover, tt-DDE induced endothelial cells apoptosis through JNK-mediated signaling pathway. These results show, for the first time, that oral intake of tt-DDE elevates blood pressure and induces endothelial dysfunction in rats through oxidative/nitrative stress and JNK-mediated apoptosis signaling, indicating that excess ingestion of tt-DDE is a potential risk factor for endothelial dysfunction and hypertension., Graphical abstract Image 1, Highlights • Trans, trans-2,4-decadienal (tt-DDE) is a dietary α,β-unsaturated aldehyde. • tt-DDE raised blood pressure and impaired endothelial function in rats. • Oxidative/nitrative stress was induced by tt-DDE in both rats and HUVECs. • HUVEC apoptosis in response to tt-DDE exposure was mediated by JNK signaling. • tt-DDE may be a risk factor for hypertension and associated cardiovascular disease.

Background Coronary microvascular dysfunction (CMD) is defined by diminished flow reserve. Functional and structural CMD endotypes have recently been described, with normal and elevated minimal microvascular resistance, respectively. Objectives This study determined the mechanism of altered resting and maximal flow in CMD endotypes. Methods A total of 86 patients with angina but no obstructive coronary disease underwent coronary pressure and flow measurement during rest, exercise, and adenosine-mediated hyperemia and were classified as the reference group or as patients with CMD by a coronary flow reserve threshold of 2.5; functional or structural endotypes were distinguished by a hyperemic microvascular resistance threshold of 2.5 mm Hg/cm/s. Endothelial function was assessed by forearm blood flow (FBF) response to acetylcholine, and nitric oxide synthase (NOS) activity was defined as the inverse of FBF reserve to NG-monomethyl-L-arginine. Results Of the 86 patients, 46 had CMD (28 functional, 18 structural), and 40 patients formed the reference group. Resting coronary blood flow (CBF) (24.6 ± 2.0 cm/s vs. 16.6 ± 3.9 cm/s vs. 15.1 ± 4.7 cm/s; p, Central Illustration

Background & Aims Liver stiffness is increased in advanced chronic liver disease (ACLD) and accurately predicts prognosis in this population. Recent data suggest that extracellular matrix stiffness per se may modulate the phenotype of liver cells. We aimed at investigating the effect of matrix stiffness on the phenotype of liver cells of rats with cirrhosis, assessing its influence on their response to antifibrotic strategies and evaluating associated molecular mechanisms. Methods Hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells were isolated from healthy rats or rats with cirrhosis (carbon tetrachloride or thioacetamide), and cultured on polyacrylamide gels with different physiologically relevant stiffness for 72 h. Results All cell types of rats with cirrhosis cultured at low stiffness showed a significant phenotype amelioration vs. rigid matrix (assessed by quantitative morphology, mRNA expression, protein synthesis, and electron microscopy imaging). Additionally, stiffness modified the antifibrotic effects of liraglutide in stellate cells of rats with cirrhosis. Finally, evaluation of nuclear morphology revealed that high stiffness induced nuclei deformation in all cell types, an observation confirmed in cells from human livers. Disconnecting the nucleus from the cytoskeleton by cytoskeleton disruption or a defective form of nesprin 1 significantly recovered spherical nuclear shape and quiescent phenotype of cells. Conclusions The environment's stiffness per se modulates the phenotype of healthy rats and liver cells of rats with cirrhosis by altering the nuclear morphology through cytoskeleton-derived mechanical forces. The reversibility of this mechanism suggests that targeting the stiffness-mediated intracellular mechanical tensions may represent a novel therapeutic strategy for ACLD. Lay summary During cirrhosis, the liver becomes scarred, stiff, and unable to perform its normal functions efficiently. In this study, we demonstrated that cells from diseased (stiff) livers recovered their functionality when placed in a soft environment (as that of a healthy liver). Furthermore, treatments aimed at tricking liver cells into believing they are in a healthy, soft liver improved their function and could potentially contribute to treat cirrhosis., Graphical abstract, Highlights • Low stiffness directly improves the phenotype of hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells. • Stiffness modulates sinusoidal crosstalk in advanced chronic liver disease (ACLD). • Stiffness may determine the efficacy of antifibrotic strategies. • Mechanical forces applied to the nucleus through the LINC complex mediate the effects of stiffness on liver cell phenotype.

Graphical abstract, COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.

Background Dysfunction of liver sinusoidal endothelial cells (LSECs) is permissive for the progression of liver fibrosis and cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal vs cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using scRNA-seq technology. Approach & Results Cirrhosis was generated in endothelial specific green fluorescent protein (GFP) reporter mice through carbon tetrachloride inhalation for 12 weeks. GFP-positive liver EC populations were isolated from control and cirrhotic mice by FACS. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs and 1 cluster of lymphatic ECs. Based on previously reported LSEC-landmarks, we mapped the 3 clusters of LSECs in zones 1, 2, and 3, and determined phenotypic changes in each zone between control and cirrhotic mice. We found genes representing capillarization of LSECs (eg, CD34) as well as extracellular matrix genes were most upregulated in LSECs of zone 3 in cirrhotic mice, which may contribute to the development of basement membranes. LSECs in cirrhotic mice also demonstrated decreased expression of endocytic receptors, most remarkably in zone 3. Transcription factors (Klf2 [Kruppel-like factor-2], Klf4 [Kruppel-like factor-4], and AP-1) that induce nitric oxide production in response to shear stress were downregulated in LSECs of all zones in cirrhotic mice, implying increased intrahepatic vascular resistance. Conclusion This study deepens our knowledge of the pathogenesis of liver cirrhosis at a spatial, cell-specific level, which is indispensable for the development of novel therapeutic strategies to target the most dysfunctional liver ECs., Graphical abstract

International audience; Thermoregulation is a homeostatic mechanism that is disrupted in some neurological diseases. Patients with multiple sclerosis (MS) are susceptible to increases in body temperature, especially with more severe neurological signs. This condition can become intolerable when these patients suffer febrile infections such as coronavirus disease-2019 (COVID-19). We review the mechanisms of hyperthermia in patients with MS, and they may encounter when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Finally, the thermoregulatory role and relevant adaptation to regular physical exercise are summarized.

Rapid and efficient digestion and absorption of dietary triglycerides and other lipids by the intestine, the packaging of those lipids into lipoprotein chylomicron (CM) particles, and their secretion via the lymphatic duct into the blood circulation are essential in maintaining whole-body lipid and energy homeostasis. Biosynthesis and assembly of CMs in enterocytes is a complex multistep process that is subject to regulation by intracellular signaling pathways as well as by hormones, nutrients, and neural factors extrinsic to the enterocyte. Dysregulation of this process has implications for health and disease, contributing to dyslipidemia and a potentially increased risk of atherosclerotic cardiovascular disease. There is increasing recognition that, besides intracellular regulation of CM assembly and secretion, regulation of postassembly pathways also plays important roles in CM secretion. This review examines recent advances in our understanding of the regulation of CM secretion in relation to mobilization of intestinal lipid stores, drawing particular attention to post-assembly regulatory mechanisms, including intracellular trafficking of triglycerides in enterocytes, CM mobilization from the lamina propria, and regulated transport of CM by intestinal lymphatics. Keywords: Intestine, Chylomicron, Triglycerides, Lymphatics

Visual Abstract, Highlights • Autonomic imbalance has been documented in patients with PAH. • Electrical VNS is known to restore autonomic balance and improve heart failure. • This study aimed to elucidate the therapeutic effects of VNS on severe PAH in a rat model. • VNS significantly restored autonomic balance, decreased mean pulmonary arterial pressure, attenuated pulmonary vascular remodeling, and preserved right ventricular function. In addition, VNS markedly improved the survival of rats with PAH. • Our findings may contribute greatly to the development of device therapy for PAH and widen the clinical applicability of VNS., Summary This study aimed to elucidate the therapeutic effects of electrical vagal nerve stimulation (VNS) on severe pulmonary arterial hypertension in a rat model. In a pathophysiological study, VNS significantly restored autonomic balance, decreased mean pulmonary arterial pressure, attenuated pulmonary vascular remodeling, and preserved right ventricular function. In a survival study, VNS significantly improved the survival rate in both the prevention (VNS from 0 to 5 weeks after a SU5416 injection) and treatment (VNS from 5 to 10 weeks) protocols. Thus, VNS may serve as a novel therapeutic strategy for pulmonary arterial hypertension.

The role of NADPH oxidase (Nox)-derived reactive oxygen species in kidney vascular function has extensively been investigated in the harmful context of oxidative stress in diabetes and obesity-associated kidney disease. Since hydrogen peroxide (H2O2) has recently been involved in the non-nitric oxide (NO) non-prostanoid relaxations of intrarenal arteries, the present study was sought to investigate whether NADPH oxidases may be functional sources of vasodilator H2O2 in the kidney and to assess their role in the endothelium-dependent relaxations of human and rat intrarenal arteries. Renal interlobar arteries isolated from the kidney of renal tumor patients who underwent nephrectomy, and from the kidney of Wistar rats, were mounted in microvascular myographs to assess function. Superoxide (O2.-) and H2O2 production was measured by chemiluminescence and Amplex Red fluorescence, and Nox2 and Nox4 enzymes were detected by Western blotting and by double inmunolabeling along with eNOS. Nox2 and Nox4 proteins were expressed in the endothelium of renal arterioles and glomeruli co-localized with eNOS, levels of expression of both enzymes being higher in the cortex than in isolated arteries. Pharmacological inhibition of Nox with apocynin and of CYP 2C epoxygenases with sulfaphenazol, but not of the NO synthase (NOS), reduced renal NADPH-stimulated O2.- and H2O2 production. Under conditions of cyclooxygenase and NOS blockade, acetylcholine induced endothelium-dependent relaxations that were blunted by the non-selective Nox inhibitor apocynin and by the Nox2 or the Nox1/4 inhibitors gp91ds-tat and GKT136901, respectively. Acetylcholine stimulated H2O2 production that was reduced by gp91ds-tat and by GKT136901. These results suggest the specific involvement of Nox4 and Nox2 subunits as physiologically relevant endothelial sources of H2O2 generation that contribute to the endothelium-dependent vasodilatation of renal arteries and therefore have a protective role in kidney vasculature., Graphical abstract fx1

The accumulation of uremic toxins in chronic kidney disease (CKD) induces inflammation, oxidative stress and endothelial dysfunction, which is a key step in atherosclerosis. Accumulating evidence indicates increased mitochondrial fission is a contributing mechanism for impaired endothelial function. Hippurate, a uremic toxin, has been reported to be involved in cardiovascular diseases. Here, we assessed the endothelial toxicity of hippurate and the contribution of altered mitochondrial dynamics to hippurate-induced endothelial dysfunction. Treatment of human aortic endothelial cells with hippurate reduced the expression of endothelial nitric oxide synthase (eNOS) and increased the expression of intercellular cell adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF). The mechanisms of hippurate-induced endothelial dysfunction in vitro depended on the activation of Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and overproduction of mitochondrial reactive oxygen species (mitoROS). In a rat model in which CKD was induced by 5/6 nephrectomy (CKD rat), we observed increased oxidative stress, impaired endothelium-dependent vasodilation, and elevated soluble biomarkers of endothelial dysfunction (ICAM-1 and vWF). Similarly, endothelial dysfunction was identified in healthy rats treated with disease-relevant concentrations of hippurate. In aortas of CKD rats and hippurate-treated rats, we observed an increase in Drp1 protein levels and mitochondrial fission. Inhibition of Drp1 improved endothelial function in both rat models. These results indicate that hippurate, by itself, can cause endothelial dysfunction. Increased mitochondrial fission plays an active role in hippurate-induced endothelial dysfunction via an increase in mitoROS., Graphical abstract fx1, Highlights • Hippurate causes pro-atherogenic and pro-inflammatory effects on endothelium. • Mitochondrial fission contributes to HA-induced endothelial dysfunction via mitoROS. • Drp1 inhibition protects endothelium from HA-induced endothelial toxicity.

Disruption of endothelial monolayer integrity is the primary instigating factor for many cardiovascular diseases. High density lipoprotein (HDL) oxidized by heme enzyme myeloperoxidase (MPO) is dysfunctional in promoting endothelial repair. Apolipoprotein A-1 mimetic 4F with its pleiotropic benefits has been proven effective in many in vivo models. In this study we investigated whether 4F promotes endothelial repair and restores the impaired function of oxidized HDL (Cl/NO2-HDL) in promoting re-endothelialization. We demonstrate that 4F and Cl/NO2-HDL act on scavenger receptor type I (SR-B1) using human aorta endothelial cells (HAEC) and SR-B1 (-/-) mouse aortic endothelial cells. Wound healing, transwell migration, lamellipodia formation and single cell migration assay experiments show that 4F treatment is associated with a recovery of endothelial cell migration and associated with significantly increased endothelial nitric oxide synthase (eNOS) activity, Akt phosphorylation and SR-B1 expression. 4F increases NO generation and diminishes oxidative stress. In vivo, 4F can stimulate cell proliferation and re-endothelialization in the carotid artery after treatment with Cl/NO2-HDL in a carotid artery electric injury model but fails to do so in SR-B1(-/-) mice. These findings demonstrate that 4F promotes endothelial cell migration and has a potential therapeutic benefit against early endothelial injury in cardiovascular diseases., Highlights • 4F restores the decreased ability of Cl/NO2-HDL in promoting endothelial repair. • 4F increases NO generation and diminishes oxidative stress. • 4F increases eNOS activity, Akt phosphorylation and SR-B1 expression. • 4F can stimulate re-endothelialization in a carotid artery electric injury model.

Aims Endothelial cells (ECs) constitute the defensive barrier of vasculature, which maintains the vascular homeostasis. Mitochondrial oxidative stress (mitoOS) in ECs significantly affects the initiation and progression of vascular diseases. The higher serum thyroid stimulating hormone (TSH) level is being recognized as a nonconventional risk factor responsible for the increased risk of cardiovascular diseases in subclinical hypothyroidism (SCH). However, effects and underlying mechanisms of elevated TSH on ECs are still ambiguous. We sought to investigate whether cyclophilin D (CypD), emerging as a crucial mediator in mitoOS, regulates effects of TSH on ECs. Methods and results SCH patients with TSH > = 10 mIU/L showed a positive correlation between serum TSH and endothelin-1 levels. When TSH levels declined to normal in these subjects after levothyroxine therapy, serum endothelin-1 levels were significantly reduced. Supplemented with exogenous thyroxine to keep normal thyroid hormones, thyroid-specific TSH receptor (TSHR)-knockout mice with injection of exogenous TSH exhibited elevated serum TSH levels, significant endothelial oxidative injuries and disturbed endothelium-dependent vasodilation. However, Tshr-/- mice resisted to TSH-impaired vasotonia. We further confirmed that elevated TSH triggered excessive mitochondrial permeability transition pore (mPTP) opening and mitochondrial oxidative damages in mouse aorta, as well as in cultured ECs. Genetic or pharmacological inhibition of CypD (the key regulator for mPTP opening) attenuated TSH-induced mitochondrial oxidative damages and further rescued endothelial functions. Finally, we confirmed that elevated TSH could activate CypD by enhancing CypD acetylation via inhibiting adenosine monophosphate-activated protein kinase/sirtuin-3 signaling pathway in ECs. Conclusions These findings reveal that elevated TSH triggers mitochondrial perturbations in ECs and provide insights that blocking mitochondrial CypD enhances the defensive ability of ECs under TSH exposure., Graphical abstract fx1, Highlights • Elevated TSH impairs endothelium-dependent vasodilation via mPTP -induced mitoOS. • Blocking CypD attenuates TSH-induced mitoOS and endothelial dysfunction. • Elevated TSH enhances CypD acetylation via inhibiting AMPK/SIRT3 signaling pathway.

Reactive carbonyl species (RCS) formed by lipidperoxidation as free forms or as enzymatic and non-enzymatic conjugates are widely used as an index of oxidative stress. Besides general measurements based on derivatizing reactions, more selective and sensitive MS based analyses have been proposed in the last decade. Untargeted and targeted methods for the measurement of free RCS and adducts have been described and their applications to in vitro and ex vivo samples have permitted the identification of many biological targets, reaction mechanisms and adducted moieties with a particular relevance to RCS protein adducts. The growing interest in protein carbonylation can be explained by considering that protein adducts are now recognized as being involved in the damaging action of oxidative stress so that their measurement is performed not only to obtain an index of lipid peroxidation but also to gain a deeper insight into the molecular mechanisms of oxidative stress. The aim of the review is to discuss the most novel analytical approaches and their application for profiling reactive carbonyl species and their enzymatic and non-enzymatic metabolites as an index of lipid-oxidation and oxidative stress. Limits and perspectives will be discussed., Graphical abstract Image 1

Cumulus cells play a crucial role as essential mediators in the maturation of ova. Ginger contains 10-gingerol, which induces apoptosis in colon cancer cells. Based on this hypothesis, this study aimed to determine whether 10-gingerol is able to induce apoptosis in normal cells, namely, cumulus cells.This study used anTheThese findings indicate that further examination is warranted for 10-gingerol as a contraception agent.تلعب الخلايا المحيطة بالبويضة دورا حاسما كوسيط أساسي في نضج البويضات. ويحتوي الزنجبيل على ١٠-جينجيرول، الذي يمكن أن يحفز موت الخلايا المبرمج في خلايا سرطان القولون. واستنادا إلى هذه الفرضية، هدفت هذه الدراسة إلى تحديد ما إذا كان ١٠ جينجيرول قادرا على تحريض موت الخلايا المبرمج في خلايا طبيعية، وتحديدا الخلايا المحيطة بالبويضة.استخدمت هذه الدراسة التحليل المختبري للخلايا المحيطة بالبويضة المستزرعة في محلول م ١٩٩ والمحتوي على١٠ جينجيرول في تركيزات مختلفة (١٢، ١٦، و٢٠ ميكرومول) ومن ثم الكشف عن نشاط قاتل للخلايا مبكر باستخدام عدة أنيكسين - فلورسين أيسو ثايو سايانيت للكشف.تُظهر البيانات في التجارب المختبرية أن عدد خلايا الموت المبرمج زادت مع زيادة فترة الحضانة: ١٢ ميكرومول (٦٣.٧١٪ ± ٢.١٩٢٪)، ١٦ ميكرومول (٧٤.٥١٪ ± ٤.٥٩٦٪)، و ٢٠ ميكرومول (٧٨.٧٩٥٪ ± ١.٤٣٥٪). تستطيع المادة ١٠ جينجيرول أن تحفز الموت المبرمج للخلايا في الخلايا المحيطة بالبويضة، إلا أنها تثبط وظائف الجين المسؤول عن برمجة مستَقبِل 5- هيدروكسي تريبتامين وتبطل عمل كلا من جلايكوجين سنثايز كاينايز ٣ بيتا والجين المبرمج لـ ” أي كي تي - ١ “.تشير نتائج هذه الدراسة إلى أن هناك حاجة لمزيد من الفحص لـ ١٠-جينجيرول كعامل منع للحمل.

Vascular peroxidase 1 (VPO1) is a member of the peroxidase family which aggravates oxidative stress by producing hypochlorous acid (HOCl). Our previous study demonstrated that VPO1 plays a critical role in endothelial dysfunction through dimethylarginine dimethylaminohydrolase2 (DDAH2)/asymmetric Dimethylarginine (ADMA) pathway. Hereby we describe the regulatory role of VPO1 on endothelial nitric oxide synthase (eNOS) expression and activity in human umbilical vein endothelial cells (HUVECs). In HUVECs AngiotensinII (100 nM) treatment reduced Nitric Oxide (NO) production, decreased eNOS expression and activity, which were reversed by VPO1 siRNA. Knockdown of VPO1 also attenuated ADMA production and eNOS uncoupling while enhancing phosphorylated ser1177 eNOS expression level. Furthermore, HOCl stimulation was shown to directly induce ADMA production and eNOS uncoupling, decrease phosphorylated ser1177 eNOS expression. It also significantly suppressed eNOS expression and activity together with NO production. Therefore, VPO1 plays a vital role in regulating eNOS expression and activity via hydrogen peroxide (H2O2)-VPO1-HOCl pathway., Highlights • Angiotensin II decreased eNOS expression and activity in HUVECs. • VPO1 plays an important role in regulating eNOS expression and activity in HUVECs. • VPO1 regulates eNOS expression and activity through VPO1/H2O2/HOCl pathway.

Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions, increasing rigidity, fragility, calcium influx-mediated dehydration, and adhesivity of red blood cells. Increased red cell fragility results in hemolysis, which reduces nitric oxide (NO) bioavailability, and induces platelet activation and inflammation leading to adhesion of circulating blood cells. Nitric Oxide inhibits adhesion and platelet activation. Nitrite has emerged as an attractive therapeutic agent that targets delivery of NO activity to areas of hypoxia through bioactivation by deoxygenated red blood cell hemoglobin. In this study, we demonstrate anti-platelet activity of nitrite at doses achievable through dietary interventions with comparison to similar doses with other NO donating agents. Unlike other NO donating agents, nitrite activity is shown to be potentiated in the presence of red blood cells in hypoxic conditions. We also show that nitrite reduces calcium associated loss of phospholipid asymmetry that is associated with increased red cell adhesion, and that red cell deformability is also improved. We show that nitrite inhibits red cell adhesion in a microfluidic flow-channel assay after endothelial cell activation. In further investigations, we show that leukocyte and platelet adhesion is blunted in nitrite-fed wild type mice compared to control after either lipopolysaccharide- or hemolysis-induced inflammation. Moreover, we demonstrate that nitrite treatment results in a reduction in adhesion of circulating blood cells and reduced red blood cell hemolysis in humanized transgenic sickle cell mice subjected to local hypoxia. These data suggest that nitrite is an effective anti-platelet and anti-adhesion agent that is activated by red blood cells, with enhanced potency under physiological hypoxia and in venous blood that may be useful therapeutically., Graphical abstract fx1, Highlights • Nitrite is a unique inhibitor of platelet activation bioactivated by RBCs in hypoxia. • Nitrite improves RBC properties following calcium-influx induced damage. • Nitrite blunts hemolysis and inflammation induced adhesion of blood cells. • Nitrite blunts adhesion of circulating blood cells in a sickle cell mouse model. • Nitrite may be harnessed therapeutically in sickle cell disease.

Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models. In vitro, fenestrae of primary LSECs gradually shrank, along with the down-regulation of the NO-dependent pathway and the augment of the AMPK-dependent autophagy; these effects were aggravated by rapamycin (an autophagy activator) or aldosterone treatment. Additionally, aldosterone increased oxidation mediated by Cav1, reduced ATP generation, and subsequently induced the AMPK-dependent autophagy, leading to the down-regulation of the NO-dependent pathway and LSECs defenestration. These effects were reversed by MR antagonist spironolactone, antioxidants or autophagy inhibitors. Besides, aldosterone enhanced the co-immunoprecipitation of Cav1 with p62 and ubiquitin, and induced Cav1 co-immunofluorescence staining with LC3, ubiquitin, and F-actin in the perinuclear area of LSECs. Furthermore, aldosterone treatment increased the membrane protein level of Cav1, whereas decrease the cytoplasmic protein level of Cav1, indicating that aldosterone induced Cav1-related selective autophagy and F-actin remodeling to promote defenestration. Consequently, Cav1-related selective autophagy initiated by aldosterone-induced oxidation promotes LSECs defenestration via activating the AMPK-ULK1 pathway and inhibiting the NO-dependent pathway.