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To investigate the association between single nucleotide polymorphism (SNP) at the rs3918188, rs1799983 and rs1007311 loci of the endothelial nitric oxide synthase (eNOS) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in northeastern China. The base distribution of eNOS gene rs3918188, rs1799983 and rs1007311 in 1712 human peripheral blood samples from Northeast China was detected by SNaPshot sequencing technology. The correlation between genotype, allele and gene model of these loci of the eNOS gene and the genetic susceptibility to SLE was investigated by logistic regression analysis. The results of the differences in the frequency distribution of their gene models were visualised using R 4.3.2 software. Finally, HaploView 4.2 software was used to analyse the relationship between the haplotypes of the three loci mentioned above and the genetic susceptibility to SLE. A multifactor dimensionality reduction (MDR) analysis was used to determine the best SNP-SNP interaction model. The CC genotype and C allele at the rs3918188 locus may be a risk factor for SLE (CC vs AA: OR = 1.827, P < 0.05; C vs A: OR = 1.558, P < 0.001), and this locus increased the risk of SLE in the dominant model and the recessive model (AC + CC vs AA: OR = 1.542, P < 0.05; CC vs AA + AC: OR = 1.707, P < 0.001), while the risk of SLE was reduced in the overdominant model (AC vs AA + CC: OR = 0.628, P < 0.001). The GT genotype and T allele at locus rs1799983 may be a protective factor for SLE (GT vs GG: OR = 0.328, P < 0.001; T vs G: OR = 0.438, P < 0.001) and this locus reduced the risk of SLE in the overdominant model (GT vs GG + TT: OR = 0.385, P < 0.001). There is a strong linkage disequilibrium between the rs1007311 and rs1799983 loci of the eNOS gene. Among them, the formed haplotype AG increased the risk of SLE compared to GG. AT and GT decreased the risk of SLE compared to GG. In this study, the eNOS gene rs3918188 and rs1799983 loci were found to be associated with susceptibility to SLE. This helps to deeply explore the mechanism of eNOS gene and genetic susceptibility to SLE. It provides a certain research basis for the subsequent exploration of the molecular mechanism of these loci and SLE, as well as the early diagnosis, treatment and prognosis of SLE. [ABSTRACT FROM AUTHOR]

The population in the areas neighboring the Semipalatinsk Nuclear Test Site (SNTS) in the eastern region of Kazakhstan faces increased cardiovascular disease (CVD) risk. Previous research has not explored gene polymorphisms related to CVD in this population. Therefore, the present study examines the prevalence of six CVD-associated genotypes in three generations exposed to SNTS radiation. The genotyping of ApoE Leu28 → Pro, AGT Met174 → Thr, AGT Met235 → Thr, eNOS T786 → C, PON1 Gln192 → Arg, and EDN 1 Lys198 → Asn was performed using real-time polymerase chain reaction. The present study encompassed a cohort of 218 participants with a familial history of arterial hypertension and/or carotid artery disease spanning at least three generations. The analysis unveiled significant disparities in the prevalence of ApoE Leu28 → Pro, eNOS T786 → C, and PON1 Gln192 → Arg genotypes across different generations. Furthermore, a substantial variation in the distribution of the eNOS T786 → C genotype was observed between individuals of Kazakh and Russian ethnicities. Nevertheless, no significant discrepancies were detected in the frequencies of the investigated genotypes between genders. Further research in this area is warranted to enhance the understanding of the genetic factors contributing to CVD in the population exposed to radiation from the SNTS. Specifically, future studies should broaden the scope of genetic polymorphisms investigated and include representatives of healthy individuals who have not been exposed to radiation as controls. [ABSTRACT FROM AUTHOR]

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Endothelial dysfunction, prevalent in cardiovascular diseases (CVDs) and linked to conditions like diabetes, hypertension, obesity, renal failure, or hypercholesterolemia, is characterized by diminished nitric oxide (NO) bioavailability—a key signaling molecule for vascular homeostasis. Current two‐dimensional (2D) in vitro studies on NO synthesis by endothelial cells (ECs) lack the crucial laminar shear stress, a vital factor in modulating the NO‐generating enzyme, endothelial nitric oxide synthase (eNOS), under physiological conditions. Here we developed a tracer‐based metabolomics approach to measure NO‐specific metabolites with mass spectrometry (MS) and show the impact of fluid flow on metabolic parameters associated with NO synthesis using 2D and 3D platforms. Specifically, we tracked the conversion of stable‐isotope labeled NO substrate L‐Arginine to L‐Citrulline and L‐Ornithine to determine eNOS activity. We demonstrated clear responses in human coronary artery endothelial cells (HCAECs) cultured with 13C6, 15N4‐L‐Arginine, and treated with eNOS stimulator, eNOS inhibitor, and arginase inhibitor. Analysis of downstream metabolites, 13C6, 15N3 L‐Citrulline and 13C5, 15N2 L‐Ornithine, revealed distinct outcomes. Additionally, we evaluated the NO metabolic status in static 2D culture and 3D microvessel models with bidirectional and unidirectional fluid flow. Our 3D model exhibited significant effects, particularly in microvessels exposed to the eNOS stimulator, as indicated by the 13C6, 15N3 L‐Citrulline/13C5, 15N2 L‐Ornithine ratio, compared to the 2D culture. The obtained results indicate that the 2D static culture mimics an endothelial dysfunction status, while the 3D model with a unidirectional fluid flow provides a more representative physiological environment that provides a better model to study endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Background: The mechanism by which a state of low testosterone leads to erectile dysfunction (ED) has not been determined. Endocan is a novel marker of endothelial function. However, whether endocan is involved in the regulation of erectile function under low testosterone levels remains unclear. Aim: In this study we sought to determine whether a low-testosterone state inhibits erectile function by regulating endocan expression in the endothelial cells of the rat penile corpus cavernosum. Methods: Thirty-six male Sprague–Dawley rats aged 8 weeks were randomly assigned to 6 groups (n = 6 per group) as follows: (1) control, (2) castration, (3) castration + testosterone treatment (treated with 3 mg/kg testosterone propionate per 2 days), (4) control + transfection (4 weeks after castration, injected with lentiviral vector (1 × 108 transduction units/mL, 10 μL), (5) castration + transfection, or (6) castration + empty transfection. One week after the injection, we measured the maximal intracavernous pressure/mean arterial pressure (ICPmax/MAP), serum testosterone and nitric oxide (NO) levels, and the expression of endocan, phospho–endothelial NO synthase (p-eNOS), eNOS, phospho–protein kinase B (p-AKT), and AKT in the rat penile corpus cavernosum. Outcomes: Under a low-androgen state, the expression of endocan in the rat penile corpus cavernosum was significantly increased, which inhibited the AKT/eNOS/NO signaling pathway and resulted in ED. Results: In the castration group, the expression of endocan in the rat penile corpus cavernosum was significantly higher than that in the control group (P < .05). Additionally, the levels of p-AKT/AKT, p-eNOS/eNOS, and NO in the rat penile corpus cavernosum and ICPmax/MAP were significantly lower in the castration group than in the control group (P < .05). In the castration + transfection group compared with the castration group there was a significant decrease in the expression of endocan (P < .05) and an increase in the ratios of p-AKT/AKT, p-eNOS/eNOS, and ICPmax/MAP (P < .05) in the rat penile corpus cavernosum. Clinical implications: Downregulating the expression of endocan in the penile corpus cavernosum may be a feasible approach for treating ED caused by hypoandrogenism. Strengths and limitations: The results of this study indicte that endocan may affect NO levels and erectile function through multiple signaling pathways, but further experiments are needed to clarify the relationship between endocan and androgens. Conclusion: A low-testosterone state inhibits the AKT/eNOS/NO signaling pathway by increasing the expression of endocan in the rat penile corpus cavernosum and impairing erectile function in rats. Decreasing the expression of endocan in the penile corpus cavernosum can improve erectile function in rats with low testosterone levels. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a microvascular complication of diabetes, and glomerular endothelial cell (GEC) dysfunction is a key driver of DKD pathogenesis. Krüppel-like factor 2 (KLF2), a shear stress-induced transcription factor, is among the highly regulated genes in early DKD. In the kidney, KLF2 expression is mostly restricted to endothelial cells, but its expression is also found in immune cell subsets. KLF2 expression is upregulated in response to increased shear stress by the activation of mechanosensory receptors but suppressed by inflammatory cytokines, both of which characterize the early diabetic kidney milieu. KLF2 expression is reduced in progressive DKD and hypertensive nephropathy in humans and mice, likely due to high glucose and inflammatory cytokines such as TNF-α. However, KLF2 expression is increased in glomerular hyperfiltration-induced shear stress without metabolic dysregulation, such as in settings of unilateral nephrectomy. Lower KLF2 expression is associated with CKD progression in patients with unilateral nephrectomy, consistent with its endoprotective role. KLF2 confers endoprotection by inhibition of inflammation, thrombotic activation, and angiogenesis, and thus KLF2 is considered a protective factor for cardiovascular disease (CVD). Based on similar mechanisms, KLF2 also exhibits renoprotection, and its reduced expression in endothelial cells worsens glomerular injury and albuminuria in settings of diabetes or unilateral nephrectomy. Thus KLF2 confers endoprotective effects in both CVD and DKD, and its activators could potentially be developed as a novel class of drugs for cardiorenal protection in diabetic patients. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess the erectogenic properties of isoliquiritigenin taking sildenafil (SDF) as the standard. Methods: The binding affinity of isoliquiritigenin (ISL) with the erectile marker proteins (endothelial nitric oxide synthase [eNOS] and enzyme phosphodiesterase type 5 [PDE5]) was investigated using Autodock Vina, which was validated using molecular dynamics simulation. Furthermore, the effect of ISL on the eNOS and PDE5 messenger ribonucleic acid (mRNA) expression and the sexual behavior of mice was investigated, along with the assessment of the pharmacokinetics of ISL. Key findings: The results revealed that the binding affinity of ISL-eNOS/PDE5 and SDF-eNOS/PDE5 was in the range of −7.5 to −8.6 kcal/mol. The ISL-eNOS/PDE5 complexes remained stable throughout the 100 ns simulation period. Root mean square deviation, Rg, SASA, hydrogen, and hydrophobic interactions were similar between ISL-eNOS/PDE5 and SDF-eNOS/PDE5. Analysis of mRNA expressions in paroxetine (PRX)-induced ED mice showed that the co-administration of PRX with ISL reduced PDE5 and increased eNOS mRNA expression, similar to the co-administered group (PRX+SDF). The sexual behavior study revealed that the results of PRX+ISL were better than those of the PRX+SDF group. Pharmacokinetic evaluation further demonstrated that ISL possesses drug-like properties. Conclusions: The results showed that ISL is equally potent as SDF in terms of binding affinity, specific pharmacological properties, and modulating sexual behavior. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are a matter of concern worldwide, and mitochondrial dysfunction is one of the major contributing factors. Vascular endothelial dysfunction has a major role in the development of atherosclerosis because of the abnormal chemokine secretion, inflammatory mediators, enhancement of LDL oxidation, cytokine elevation, and smooth muscle cell proliferation. Endothelial cells transfer oxygen from the pulmonary circulatory system to the tissue surrounding the blood vessels, and a majority of oxygen is transferred to the myocardium by endothelial cells, which utilise a small amount of oxygen to generate ATP. Free radicals of oxide are produced by mitochondria, which are responsible for cellular oxygen uptake. Increased mitochondrial ROS generation and reduction in agonist-stimulated eNOS activation and nitric oxide bioavailability were directly linked to the observed change in mitochondrial dynamics, resulting in various CVDs and endothelial dysfunction. Presently, the manuscript mainly focuses on endothelial dysfunction, providing a deep understanding of the various features of mitochondrial mechanisms that are used to modulate endothelial dysfunction. We talk about recent findings and approaches that may make it possible to detect mitochondrial dysfunction as a potential biomarker for risk assessment and diagnosis of endothelial dysfunction. In the end, we cover several targets that may reduce mitochondrial dysfunction through both direct and indirect processes and assess the impact of several different classes of drugs in the context of endothelial dysfunction. [ABSTRACT FROM AUTHOR]

[Display omitted] • Adropin increases eNOS expression in experimental subarachnoid hemorrhage. • Adropin reduces neurobehavioral deficits in experimental subarachnoid hemorrhage. • Adropin reduces oxidative stress in experimental subarachnoid hemorrhage. • Adropin reduces apoptosis in experimental subarachnoid hemorrhage. Purpose: We aimed to investigate early effects of exogenously administered adropin (AD) on neurological function, endothelial nitric oxide synthase (eNOS) expression, nitrite/nitrate levels, oxidative stress, and apoptosis in subarachnoid hemorrhage (SAH). Methods: Following intracerebroventricular AD administration (10 µg/5 µl at a rate of 1 µl/min) SAH model was carried out in Sprague–Dawley rats by injection of autologous blood into the prechiasmatic cistern. The effects of AD were assessed 24 h following SAH. The modified Garcia score was employed to evaluate functional insufficiencies. Adropin and caspase-3 proteins were measured by ELISA, while nitrite/nitrate levels, total antioxidant capacity (TAC) and reactive oxygen/nitrogen species (ROS/RNS) were assayed by standard kits. eNOS expression and apoptotic neurons were detected by immunohistochemical analysis. Results: The SAH group performed notably lower on the modified Garcia score compared to sham and SAH + AD groups. Adropin administration increased brain eNOS expression, nitrite/nitrate and AD levels compared to SHAM and SAH groups. SAH produced enhanced ROS/RNS generation and reduced antioxidant capacity in the brain. Adropin boosted brain TAC and diminished ROS/RNS production in SAH rats and no considerable change amongst SHAM and SAH + AD groups were detected. Apoptotic cells were notably increased in intensity and number after SAH and were reduced by AD administration. Conclusions: Adropin increases eNOS expression and reduces neurobehavioral deficits, oxidative stress, and apoptotic cell death in SAH model. Presented results indicate that AD provides protection in early brain injury associated with SAH. [ABSTRACT FROM AUTHOR]

Background: Systemic inflammation causes several organ damage by activating the intracellular signaling mechanisms. Heart and aorta tissues are the structures mostly affected by this situation. By examining underlying processes, this study sought to determine whether cannabidiol (CBD) may have protective effects against the cardiovascular damage brought on by lipopolysaccharide (LPS). Materials and methods: A total of 32 female rats were randomly allocated to one of four groups: control, lipopolysaccharide (LPS) (5 mg/kg, i.p., single dose), LPS + CBD (5 mg/kg, i.p., single dose), and CBD groups. The rats were killed six hours after receiving LPS, and tissues from the heart and aorta were taken. Histopathological and immunohistochemical analyzes were performed. Oxidative stress was evaluated biochemically by spectrophotometric method. Expression levels of genes were studied by RT-qPCR method. Results: Histopathological analysis of the LPS group showed moderate hyperemia, hemorrhages, edema, inflammation, and myocardial cell damage. There was a slight to moderate increase in Cox-1, G-CSF, and IL-3 immunoexpressions, along with enhanced expressions of IL-6, Hif1α, and STAT3 genes, and decreased expressions of eNOS genes. Additionally, there were increased levels of TOS and decreased TAS levels observed biochemically. CBD treatment effectively reversed and improved all of these observed changes. Conclusions: CBD protects the heart and aorta against systemic inflammation through its antioxidant and anti-inflammatory activity via regulating IL-6, Hif1α, STAT3, and eNOS intracellular pathways. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to comparatively assess the impact of single and repeated whole body vibration training (WBVT) and training without vibration on changes in the concentration of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and high-sensitivity C-reactive protein (hsCRP) in healthy, young, non-training women. Methods: The study involved 46 women (age 20.48 ± 1.72 years), who were divided into three groups: the experimental group participating in WBVT (EVG, n = 17); the comparison group performing the same exercises but without the vibration factor (EXG, n = 12); and the control group, which did not participate in any training (CON, n = 17). The program included participation in 36 training sessions conducted over 12 weeks, with a frequency of 3 times per week. In the EVG and EXG groups, venous blood was collected before and after the first and last training sessions, while in the CON group, blood was collected twice at a 3-month interval. Results: No significant changes were observed in the concentrations of the studied markers either after a single or repeated training session in both experimental groups (p > 0.05). Conclusions: The proposed WBVT protocol appears to be a safe form of exercise that does not induce negative inflammatory reactions. The applied vibration stimulus combined with physical exercises did not initiate pro-angiogenic processes or stimulate eNOS activity in healthy women, suggesting that similar studies should be conducted in individuals with circulatory problems or chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Diabetic cardiomyopathy is a serious complication of obesity with type 2 diabetes and is a major cause of mortality. Metabolic surgery, such as duodenal‐jejunal bypass (DJB), can effectively improve diabetic cardiomyopathy; however, the underlying mechanisms remain elusive. Oxidative stress is one of the pivotal mechanisms of diabetic cardiomyopathy. Our objective was to investigate the effect and potential mechanisms of DJB on oxidative stress in the heart of diabetic cardiomyopathy rats. Methods: High‐fat diet combined with intraperitoneal injection of streptozotocin was used to establish diabetic cardiomyopathy rats. DJB was performed on diabetic cardiomyopathy rats, and high glucose and palmitate were used to simulate diabetic cardiomyopathy in H9C2 cells in vitro. Sera from different groups of rats were used for experiments in vivo and in vitro. Results: DJB effectively improved oxidative stress and activated the adenosine monophosphate (AMP)‐activated protein kinase (AMPK) pathway to increase endothelial nitric oxide synthase (eNOS) phosphorylation level and the expression of antioxidative system‐related proteins and genes in the heart of diabetic cardiomyopathy rats. AMPK agonists and serum from DJB rats activated the AMPK pathway to increase eNOS phosphorylation level and the expression of antioxidative system‐related proteins and genes and decreased the content of reactive oxygen species in H9C2 cells, but this improvement was almost eliminated by the addition of AMPK inhibitors. Conclusions: DJB activates eNOS and enhances the antioxidant system by activating the AMPK pathway—and not solely by improving blood glucose—to improve oxidative stress in the heart of diabetic cardiomyopathy rats. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Remote ischaemic preconditioning (rIPC) for cardioprotection is severely impaired in diabetes, and therapeutic options to restore it are lacking. The vascular endothelium plays a key role in rIPC. Given that the activity of endothelial nitric oxide synthase (eNOS) is inhibited by proline‐rich tyrosine kinase 2 (Pyk2), we hypothesized that pharmacological Pyk2 inhibition could restore eNOS activity and thus restore remote cardioprotection in diabetes.New Zealand obese (NZO) mice that demonstrated key features of diabetes were studied. The consequence of Pyk2 inhibition on endothelial function, rIPC and infarct size after myocardial infarction were evaluated. The impact of plasma from mice and humans with or without diabetes was assessed in isolated buffer perfused murine hearts and aortic rings.Plasma from nondiabetic mice and humans, both subjected to rIPC, caused remote tissue protection. Similar to diabetic humans, NZO mice demonstrated endothelial dysfunction. NZO mice had reduced circulating nitrite levels, elevated arterial blood pressure and a larger infarct size after ischaemia and reperfusion than BL6 mice. Pyk2 increased the phosphorylation of eNOS at its inhibitory site (Tyr656), limiting its activity in diabetes. The cardioprotective effects of rIPC were abolished in diabetic NZO mice. Pharmacological Pyk2 inhibition restored endothelial function and rescued cardioprotective effects of rIPC.Endothelial function and remote tissue protection are impaired in diabetes. Pyk2 is a novel target for treating endothelial dysfunction and restoring cardioprotection through rIPC in diabetes. [ABSTRACT FROM AUTHOR]

Abstract To investigate the association between single nucleotide polymorphism (SNP) at the rs3918188, rs1799983 and rs1007311 loci of the endothelial nitric oxide synthase (eNOS) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in northeastern China. The base distribution of eNOS gene rs3918188, rs1799983 and rs1007311 in 1712 human peripheral blood samples from Northeast China was detected by SNaPshot sequencing technology. The correlation between genotype, allele and gene model of these loci of the eNOS gene and the genetic susceptibility to SLE was investigated by logistic regression analysis. The results of the differences in the frequency distribution of their gene models were visualised using R 4.3.2 software. Finally, HaploView 4.2 software was used to analyse the relationship between the haplotypes of the three loci mentioned above and the genetic susceptibility to SLE. A multifactor dimensionality reduction (MDR) analysis was used to determine the best SNP-SNP interaction model. The CC genotype and C allele at the rs3918188 locus may be a risk factor for SLE (CC vs AA: OR = 1.827, P

Renin–angiotensin system plays a critical role in blood pressure control, and the abnormal activation of the AT1 receptor contributes to the development of renovascular hypertension. This study aimed to evaluate the underlying cellular signaling for AT1 receptor activation by Ang II and to compare this mechanism between aortas from 2K-1C and 2K rats. Effects of antagonists and inhibitors were investigated on Ang II-induced contractions in denuded or intact-endothelium aortas. The AT1 receptor antagonist abolished Ang II-induced contraction in 2K-1C and 2K rat aortas, while AT2 and Mas receptors antagonists had no effect. Endothelial nitric oxide synthase inhibition increased the maximal effect (Emax) of Ang II in 2K, which was not changed in 2K-1C aortas. It was associated with lower eNOS mRNA levels in 2K-1C. Endothelium removal increased the Emax of Ang II in 2K-1C and mainly in 2K rat aortas. Nox and COX inhibition did not alter Ang II-induced contraction in 2K and 2K-1C rat aortas. However, AT1 expression was higher in 2K-1C compared to 2K rat aortic rings, whereas expression of phosphorylated (active) IP3 receptors was lower in 2K-1C than in 2K rats. These results demonstrate that endothelium removal impairs Ang II-stimulated contraction in the aorta of 2K-1C rats, which is associated with the reduction of IP3 receptor phosphorylation and activation. In addition, eNOS plays a critical role in Ang II-induced contraction in 2K rat aortas. It is possible that the high Ang II plasma levels could desensitize AT1 receptor in 2K-1C rats, leading to impaired IP3 receptors activation.

This study aimed to investigate the effects of focal brain cooling (FBC) on spreading depolarization (SD), which is associated with several neurological disorders. Although it has been studied from various aspects, no medication has been developed that can effectively control SD. As FBC can reduce neuronal damage and promote functional recovery in pathological conditions such as epilepsy, cerebral ischemia, and traumatic brain injury, it may also potentially suppress the onset and progression of SD. We created an experimental rat model of SD by administering 1 M potassium chloride (KCl) to the cortical surface. Changes in neuronal and vascular modalities were evaluated using multimodal recording, which simultaneously recorded brain temperature (BrT), wide range electrocorticogram, and two-dimensional cerebral blood flow. The rats were divided into two groups (cooling [CL] and non-cooling [NC]). Warm or cold saline was perfused on the surface of one hemisphere to maintain BrT at 37°C or 15°C in the NC and CL groups, respectively. Western blot analysis was performed to determine the effects of FBC on endothelial nitric oxide synthase (eNOS) expression. In the NC group, KCl administration triggered repetitive SDs (mean frequency = 11.57/h). In the CL group, FBC increased the duration of all KCl-induced events and gradually reduced their frequency. Additionally, eNOS expression decreased in the cooled brain regions compared to the non-cooled contralateral hemisphere. The results obtained by multimodal recording suggest that FBC suppresses SD and decreases eNOS expression. This study may contribute to developing new treatments for SD and related neurological disorders.

Abstract Background Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. Methods The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. Results Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. Conclusions NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

The hepatic content of amyloid beta (Aβ) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of Aβ deficiency in the liver. This is especially relevant in view of recent advances in anti‐Aβ therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of Aβ in transgenic AD mice immunized with Aβ antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP‐KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha‐actin, and collagen type I. Aβ absence in APP‐KO and deficiency in immunized mice lead to strong activation of transforming growth factor‐β (TGFβ), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial‐mesenchymal transition. Inversely, increased systemic and intrahepatic levels of Aβ42 in transgenic AD mice and neprilysin inhibitor LBQ657‐treated wild‐type mice protect the liver against carbon tetrachloride (CCl4)‐induced injury. Transcriptomic analysis of CCl4‐treated transgenic AD mouse livers uncovers the regulatory effects of Aβ42 on mitochondrial function, lipid metabolism, and its onco‐suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal Aβ as an indispensable regulator of cell–cell interactions in healthy liver and a powerful protector against liver fibrosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recurrent spontaneous abortion affects approximately 1–2% of reproductive-age women, with roughly half of RSA cases classified as unexplained recurrent spontaneous abortion (URSA). Genetic polymorphisms in eNOS gene have been shown to have significant implications across various disease processes. Nevertheless, the potential impact of eNOS gene polymorphisms on the susceptibility to URSA in Yunnan population has yet to be explored or documented. OBJECTIVE: This study aims to investigate the potential association between specific variations in the eNOS gene (VNTR 4b/a, - 786T > C, and + 894G > T) and the risk of URSA in Yunnan population. METHODS: A total of 243 URSA patients and 241 healthy females are involved in this study. We conducted amplification of the eNOS gene fragment and performed sanger sequencing to detect the specific eNOS gene polymorphisms, including VNTR 4b/a, - 786T > C, and + 894G > T. Using a multivariate logistic regression model, we evaluate the potential association between eNOS gene polymorphisms (VNTR 4b/a, - 786T > C, and + 894G > T) and the risk of URSA. Furthermore, serum NO levels were measured in URSA patients. RESULTS: The presence of VNTR 4a, - 786C, and + 894T alleles was found to be associated with an increased risk of URSA. Additionally, our study revealed a significant association between the G-C-4b haplotype of the investigated eNOS gene polymorphisms and a predisposition to URSA. Notably, these eNOS polymorphisms were shown to reduce serum NO levels in URSA patients. CONCLUSION: This study provides evidence supporting the association between eNOS gene polymorphisms, VNTR 4b/a, - 786T > C, and + 894G > T, and the occurrence of URSA in Yunnan Province, China. [ABSTRACT FROM AUTHOR]

Despite the significant progress in the fields of biology, physiology, molecular medicine, and pharmacology; the designation of the properties of nitrogen monoxide in the regulation of life-supporting functions of the organism; and numerous works devoted to this molecule, there are still many open questions in this field. It is widely accepted that nitric oxide (•NO) is a unique molecule that, despite its extremely simple structure, has a wide range of functions in the body, including the cardiovascular system, the central nervous system (CNS), reproduction, the endocrine system, respiration, digestion, etc. Here, we systematize the properties of •NO, contributing in conditions of physiological norms, as well as in various pathological processes, to the mechanisms of cytoprotection and cytodestruction. Current experimental and clinical studies are contradictory in describing the role of •NO in the pathogenesis of many diseases of the cardiovascular system and CNS. We describe the mechanisms of cytoprotective action of •NO associated with the regulation of the expression of antiapoptotic and chaperone proteins and the regulation of mitochondrial function. The most prominent mechanisms of cytodestruction—the initiation of nitrosative and oxidative stresses, the production of reactive oxygen and nitrogen species, and participation in apoptosis and mitosis. The role of •NO in the formation of endothelial and mitochondrial dysfunction is also considered. Moreover, we focus on the various ways of pharmacological modulation in the nitroxidergic system that allow for a decrease in the cytodestructive mechanisms of •NO and increase cytoprotective ones. [ABSTRACT FROM AUTHOR]

Background: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. Methods: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. Results: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. Conclusions: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is one of the leading causes of death worldwide. Danlou tablet (Dan) is an effective traditional Chinese medicine for cardiac protection, although the underlying mechanism was not fully understood. In this study, we used a murine MI model and demonstrated that Dan administration effectively attenuated myocardial apoptosis, cardiac remodeling, and heart failure post MI. Dan increased CD31-positive capillaries in MI hearts, and reduced the apoptosis and oxidative stress in human umbilical vein endothelial cells after oxygen–glucose deprivation stress, simultaneously with the activated HIF-1α/VEGFA/eNOS signaling. Moreover, inhibition of eNOS by L-NAME attenuated Dan-induced protection against MI, and abolished its effect in promoting angiogenesis and reducing endothelial apoptosis and oxidative stress. Collectively, Dan is beneficial to promote eNOS-dependent endothelial protection and angiogenesis thus protecting against MI. A deep understanding of Dan-induced protection might help promote clinical usage of Dan in MI treatment. [ABSTRACT FROM AUTHOR]

Nitric Oxide (NO) regulates important physiological functions. Garlic (Allium sativum) is an important food component consumed fresh and processed for thousands of years. It has high L-arginine, which contributes to the NO system in the body. Both garlic and NO impact important physiological processes. Here we produced brown garlic, with significantly higher nutritional and therapeutic value compared to fresh and black garlic. Lower exhaled NO was recorded in asthmatic mice fed with brown garlic but with higher blood SNOs and no change in eNOS and iNOS expression. Lung biopsy showed reduced eosinophil accumulation in asthmatic mice fed with brown garlic. Real-time PCR and Western blot analyses indicated high expression of antioxidant genes but reduced interleukin genes, IL-4, IL-5, IL-6, IL-13, IL1β, and TNF-α brown garlic-fed asthmatic mice as compared to that in fresh and black garlic-fed asthmatic mice. This study provides the first comprehensive and conclusive insight into the nutritional benefits of brown garlic and its therapeutic value for the treatment of asthma in animals.

Abstract Background Diabetic cardiomyopathy is a serious complication of obesity with type 2 diabetes and is a major cause of mortality. Metabolic surgery, such as duodenal‐jejunal bypass (DJB), can effectively improve diabetic cardiomyopathy; however, the underlying mechanisms remain elusive. Oxidative stress is one of the pivotal mechanisms of diabetic cardiomyopathy. Our objective was to investigate the effect and potential mechanisms of DJB on oxidative stress in the heart of diabetic cardiomyopathy rats. Methods High‐fat diet combined with intraperitoneal injection of streptozotocin was used to establish diabetic cardiomyopathy rats. DJB was performed on diabetic cardiomyopathy rats, and high glucose and palmitate were used to simulate diabetic cardiomyopathy in H9C2 cells in vitro. Sera from different groups of rats were used for experiments in vivo and in vitro. Results DJB effectively improved oxidative stress and activated the adenosine monophosphate (AMP)‐activated protein kinase (AMPK) pathway to increase endothelial nitric oxide synthase (eNOS) phosphorylation level and the expression of antioxidative system‐related proteins and genes in the heart of diabetic cardiomyopathy rats. AMPK agonists and serum from DJB rats activated the AMPK pathway to increase eNOS phosphorylation level and the expression of antioxidative system‐related proteins and genes and decreased the content of reactive oxygen species in H9C2 cells, but this improvement was almost eliminated by the addition of AMPK inhibitors. Conclusions DJB activates eNOS and enhances the antioxidant system by activating the AMPK pathway—and not solely by improving blood glucose—to improve oxidative stress in the heart of diabetic cardiomyopathy rats.

Abstract Background The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD). Aim To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD. Methods A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient. Results In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD. Conclusion In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD.

Background: The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD). Aim: To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD. Methods: A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient. Results: In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD. Conclusion: In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD. [ABSTRACT FROM AUTHOR]

Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This study sought to determine whether these effects could be translated in vivo and to determine the molecular mechanisms involved. CRISPR/Cas9-generated Trim2−/− mice that underwent a periarterial collar model of inflammation-induced angiogenesis exhibited significantly less adventitial macrophage infiltration relative to wildtype (WT) littermates, concomitant with decreased mRNA expression of macrophage marker Cd68 and reduced adventitial proliferating neovessels. Mechanistically, TRIM2 knockdown in endothelial cells in vitro attenuated inflammation-driven induction of critical angiogenic mediators, including nuclear HIF-1α, and curbed the phosphorylation of downstream effector eNOS. Conversely, in a hindlimb ischemia model of hypoxia-mediated angiogenesis, there were no differences in blood flow reperfusion to the ischemic hindlimbs of Trim2−/− and WT mice despite a decrease in proliferating neovessels and arterioles. TRIM2 knockdown in vitro attenuated hypoxia-driven induction of nuclear HIF-1α but had no further downstream effects on other angiogenic proteins. Our study has implications for understanding the role of TRIM2 in the regulation of angiogenesis in both pathophysiological contexts. [ABSTRACT FROM AUTHOR]

Globally, breast cancer is the common malignancy affecting women and understanding its associated molecular events could help in disease prevention and management strategies. The present study was set to investigate an association between total antioxidant capacity (TAC) and endothelial nitric oxide synthase (eNOS) polymorphisms with breast cancer. For this purpose, 100 subjects were participated in this work, including 50 female patients diagnosed with breast cancer recruited from Oncology hospital, Baghdad - Iraq and 50 healthy women as a control group. The concentration of antioxidants was measured in the serums collected from blood samples of breast cancer patients and healthy controls. While eNOS SNPs (rs1799983, G894T and rs2070744, T 786C) were assessed using TaqMan SNP genotyping and utilising genomic DNA extracted from the participants. The results showed that the antioxidants levels were significantly (P˂0.0001) reduced in blood samples of breast cancer patients in comparison to that of that healthy controls (0.144± 0.097 and 0.587±0.239 respectively). Additionally, the homozygous GG genotype G894T (rs1799983) could retain beneficial impact for the protection from breast cancer potential. While SNP genotyping results showed that both of the homozygous CC and heterozygous TC genotypes (rs2070744 T >C SNP) seem to contribute to the susceptibility of breast cancer development in the investigated set of patients. Overall, the present study findings suggest an association between reduced antioxidant capacity and eNOS gene polymorphisms in breast carcinogenesis. [ABSTRACT FROM AUTHOR]

The amount of evidence indicates that hyperphosphataemia (HP) can induce endothelial damage and significantly impair endothelial nitric oxide synthase (eNOS) expression. There are no clinical studies that have assessed HP and its correlation with circulating eNOS concentration in patients with end-stage renal disease (ESRD). Our preliminary study aimed to evaluate the relationship between plasma inorganic phosphorus (P) levels and circulating plasma eNOS concentration in patients on haemodialysis (HD). A total of 50 patients on HD were enrolled to the study. They were divided into groups according to the tertiles of P. The examined HD group was also analysed and compared with controls as a whole group; then, the group was divided into patients with and without dyslipidaemia (D) as well as into those with and without type 2 diabetes mellitus (type 2 DM). A total of 26 age-matched healthy volunteers were included in the study as the control group. The plasma levels of eNOS in HD patients are reduced in comparison to those in healthy subjects. There was no difference in plasma eNOS concentrations between HD patients with type 2 DM and those without DM as well as between those with D and without D. In the entire group of HD patients, there were positive correlations between circulating levels of eNOS and plasma P concentrations. In HD patients with D, higher systolic and diastolic blood pressure were accompanied by decreased plasma eNOS concentrations. In conclusion, HP and high blood pressure appear to decrease the circulating eNOS levels. These findings demonstrate an additional negative impact of HP on eNOS activity. [ABSTRACT FROM AUTHOR]

The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer's disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD. [ABSTRACT FROM AUTHOR]

Background: We aimed to elucidate the mechanism of change in mitochondrial fusion- and fission-related mediators for maintaining cell function through the effects of acupuncture treatment and apply findings to a liver disease model. We focused on the optic atrophy-1 (OPA1) and fission protein 1 (Fis1) genes of rat liver cells. Methods: Sprague Dawley rats were divided into a control group (no treatment) and LR2, LR3, LR4 and LR8 groups (acupuncture treatment to those points). Acupuncture was performed on each point for 10 minutes once daily for 4 days. Changes in the mRNA expression of Peroxisome proliferator-activated receptor-gamma coactivator 1-a (PGC-1a) and Fis1 were observed via quantitative real-time polymerase chain reaction (qRT-PCR); changes in OPA1, mitofusin-2 (MFN2), mitofusin-1 (MFN1), dynamin-related protein 1 (DRP1) and adenosine monophosphate-activated protein kinase (AMPK) proteins were observed through western blotting and endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) expressions were observed through immunohistochemistry. Result: OPA1 decreased in the LR3 and LR8 groups and Fis1 increased in the LR2 and LR4 groups. AMPK and PGC-1a decreased significantly in all acupuncture groups. eNOS and nNOS expression reduced in all acupuncture groups. Therefore, acupuncture can regulate mitochondrial fusion/fission by influencing the following mediators: AMPK, PGC-1a, OPA1, Fis1, eNOS and nNOS. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), plays a critical role in blood pressure regulation. Genome-wide association studies have identified genetic susceptibility loci for hypertension in human lymphocyte-specific protein 1 (LSP1) gene. LSP1 is recognized as modulator of leukocyte extravasation, and endothelial permeability, however, the role of LSP1 in regulation of NO signaling within endothelial cells (ECs) remains unknown. The present study investigated the role of LSP1 in the regulation of eNOS expression and activity utilizing human macrovascular ECs in vitro and LSP1 knockout (KO) mice. In ECs, specific CRISPR-Cas9 genomic editing deleted LSP1 and caused downregulation of eNOS expression. LSP1 gain-of-function through adenovirus-mediated gene transfer was associated with enhanced expression of eNOS. Co-immunoprecipitation and confocal fluorescence microscopy revealed that eNOS and LSP1 formed a protein complex under basal conditions in ECs. Furthermore, LSP1 deficiency in mice promoted significant upregulation and instability of eNOS. Utilizing a mass-spectrometry-based bottom-up proteomics approach, we identified novel truncated forms of eNOS in immunoprecipitates from LSP1 KO aortae. Our experimental data suggest an important role of endothelial LSP1 in regulation of eNOS expression and activity within human ECs and murine vascular tissues. [ABSTRACT FROM AUTHOR]

Climate variability is one of the main challenges faced by mankind, and understanding its relationship with water quality will generate knowledge that will enable the development of early adaptation strategies and the integral management of water resources. This study assessed the impact of the different intensities of the "El Niño-Southern Oscillation" (ENSO) climate phenomenon on Dissolved Oxygen (DO) from 1985 to 2015, at two monitoring stations on Cauca River. Spatial-temporal variation analysis of DO was performed using descriptive and inferential statistical techniques under different ENSO phases. The correlation between DO and the intensities of the ENSO phases was assessed using the Spearman correlation coefficient. No statistical differences were found in DO concentration at the two studied stations (p = 0.1164). Statical differences of DO were found depending on the ENSO phases at the Mediacanoa station (p = 0.002556); it was also found that the highest median concentrations of DO took place when La Niña was present. No correlation was found at the studied stations between the intensities of the ENSO phases and DO. The water quality of the Cauca River, at the Yotoco and Mediacanoa stations, showed very poor conditions, which has produced negative social, economic and environmental effects. [ABSTRACT FROM AUTHOR]

Background: It has been shown that methylation in the promoter region of eNOS can downregulate eNOS expression resulting in the endothelial dysfunction. However, it is unclear whether low androgen levels and type 1 diabetes cause ED by methylating the promoter region of eNOS in the penile corpus cavernosum. Objective: To clarify the effects of type 1 diabetes and hypo‐androgen status on the methylation level of the promoter region of the eNOS gene in penile cavernous tissue and their relationship with the erectile function. Methods: Fifty‐eight eight‐week‐old male Sprague–Dawley rats were randomly divided into six groups (n = 6): sham operation group, castration group, castration+testosterone (cast+T) group, normoglycemia group, diabetic group, and diabetic+methyltransferase inhibitor (5‐aza‐dc, 1.5 mg/kg) group. The ICPmax/MAP, serum T, the concentration of nitric oxide (NO), the expression of DNMT1, DNMT3a, DNMT3b, and eNOS, and the methylation level of the eNOS promoter region in penile corpus cavernosum of rat were examined 4 weeks after surgery in the sham‐operated group, the castration group, and the castration + testosterone replacement group. Those tests were examined after 6 weeks using of methylation inhibitors in the normoglycemic group, the diabetic group, and the diabetic + methylation inhibitor group. Results: ICPmax/MAP, DNMT1, DNMT3a, DNMT3b, eNOS, and NO levels were significantly lower in castrated rats than in sham and cast+T rats (P < 0.05). ICPmax/MAP, eNOS, and NO levels were lower, and DNMT1, DNMT3a, and DNMT3b expression levels were significantly increased in the diabetic group compared with the normoglycemic and diabetic+methyltransferase inhibitor groups (P < 0.05). There was no significant difference in the methylation level of the promoter region of eNOS in penile cavernous tissue of castrated rats compared with the sham group or the testosterone replacement group. The methylation level of the promoter region of eNOS in penile cavernous tissue was significantly higher in the diabetic group than in the normoglycemic group and diabetic+methyltransferase inhibitor group (P < 0.05). Conclusion: Although low androgen status inhibited the level of methyltransferase in rat penile cavernous tissue, did not affect the level of methylation in the promoter region of eNOS. Hyperglycemia inhibits the NO level in the penile cavernous tissue and the erectile function of rats by upregulating the methyltransferase level in the penile cavernous tissue and the methylation level in the promoter region of eNOS. Methylation inhibitors can partly improve the erectile function in type 1 diabetic rats. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (ED) is commonly considered a crucial initiating step in the pathogenesis of numerous cardiovascular diseases. The coupling of endothelial nitric oxide synthase (eNOS) is important in maintaining normal endothelial functions. However, it still remains elusive whether and how eNOS SUMOylation affects the eNOS coupling. In the study, we investigate the roles and possible action mechanisms of protein inhibitor of activated STAT 1 (PIAS1) in ED. Human umbilical vein endothelial cells (HUVECs) treated with palmitate acid (PA) in vitro and ApoE−/− mice fed with high‐fat diet (HFD) in vivo were constructed as the ED models. Our in vivo data show that PIAS1 alleviates the dysfunction of vascular endothelium by increasing nitric oxide (NO) level, reducing malondialdehyde (MDA) level, and activating the phosphatidylinositol 3‐kinase‐protein kinase B‐endothelial nitric oxide synthase (PI3K‐AKT‐eNOS) signaling in ApoE−/− mice. Our in vitro data also show that PIAS1 can SUMOylate eNOS under endogenous conditions; moreover, it antagonizes the eNOS uncoupling induced by PA. The findings demonstrate that PIAS1 alleviates the dysfunction of vascular endothelium by promoting the SUMOylation and inhibiting the uncoupling of eNOS, suggesting that PIAS1 would become an early predictor of atherosclerosis and a new potential target of the hyperlipidemia‐related cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Myoendothelial feedback (MEF), the endothelium-dependent vasodilation following sympathetic vasoconstriction (mediated by smooth muscle to endothelium gap junction communication), has been well studied in resistance arteries of males, but not females. We hypothesized that MEF responses would be similar between the sexes, but different in the relative contribution of the underlying nitric oxide and hyperpolarization mechanisms, given that these mechanisms differ between the sexes in agonistinduced endothelium-dependent dilation. We measured MEF responses (diameter changes) of male and female first- to secondorder mouse mesenteric arteries to phenylephrine (10 lM) over 30 min using isolated pressure myography ± blinded inhibition of nitric oxide synthase (NOS) using Nx-nitro-L-arginine methyl ester (L-NAME; 0.1-1.0 mM), hyperpolarization using 35 mM KCl, or transient receptor potential vanilloid 4 (TRPV4) channels using GSK219 (0.1-1.0 lM) or RN-1734 (30 lM). MEF was similar [%dilation (means ± SE): males = 26.7 ± 2.0 and females = 26.1 ± 1.9 at 15 min] and significantly inhibited by L-NAME (1.0 mM) at 15 min [%dilation (means ± SE): males = 8.2 ± 3.3, P < 0.01; females = 6.8 ± 1.9, P < 0.001] and over time (P < 0.01) in both sexes. LNAME (0.1 mM) þ 35 mM KCl nearly eliminated MEF in both sexes (P < 0.001-0.0001). Activation of TRPV4 with GSK101 (0.1-10 lM) induced similar dilation between the sexes. Inhibition of TRPV4, which is reportedly involved in the hyperpolarization mechanism, did not inhibit MEF in either sex. Similar expression of eNOS was found between the sexes with Western blot. Thus, MEF is prominent and similar in murine first- and second-order mesenteric resistance arteries of both sexes, and reliant primarily on NOS and secondarily on hyperpolarization, but not TRPV4. [ABSTRACT FROM AUTHOR]

Empagliflozin, a sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, are commonly recognized for their cardiovascular benefits in individuals with type 2 diabetes (T2D). In prior studies, we have demonstrated that both drugs, alone or in combination, were able to protect cardiomyocytes from injury induced by diabetes. Mechanistic investigations also suggested that the cardioprotective effect may be independent of diabetes In this study, we utilized a hypoxia-reoxygenation (H/R) model to investigate the cardiovascular benefits of SGLT2 inhibitor empagliflozin and GLP-1 receptor (GLP-1R) agonist liraglutide, both alone and in combination, in the absence of T2D. Our hypothesis was that empagliflozin and liraglutide, either individually or in combination, would demonstrate cardioprotective properties against H/R-induced injury, with an additive and/or synergistic effect anticipated from combination therapy. In this study, the cardiac muscle cell line, HL-1 cells, were treated with vehicle, empagliflozin, liraglutide, or a combination of the two drugs. The cells were then subjected to a hypoxia-reoxygenation (H/R) protocol, consisting of 1 h of hypoxia followed by 24 h of reoxygenation. The effects of the treatments on cytotoxicity, oxidative stress, endothelial nitric oxide synthase (eNOS) activity, phospho-protein kinase C (PKC) beta and phospho-eNOS (Thr495) expression were subsequently evaluated at the end of the treatments. We found that H/R increased cytotoxicity and reduces eNOS activity, empagliflozin, liraglutide or combination treatment attenuated some or all of these effects with the combination therapy showing the greatest improvement. Empagliflozin, liraglutide or combination of these two have cardioprotective effect regardless of diabetes. Cardioprotective effects of SGLT2 inhibitor and GLP-1R agonist is additive and synergistic. [ABSTRACT FROM AUTHOR]

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Background: Preclinical animal studies and clinical studies indicate that both maternal as well as paternal genetic alterations/gene defects might affect the phenotype of the next-generation without transmissions of the affected gene. Currently, the question of whether the same genetic defect present in the mother or father leads to a similar phenotype in the offspring remains insufficiently elucidated. Methods: In this head-to-head study, we crossbred female and male mice with heterozygous endothelial eNOS knockout (eNOS+/−) with male and female wildtype (wt) mice, respectively. Subsequently, we compared the phenotype of the resulting wt offspring with that of wt offspring born to parents with no eNOS deficiency. Results: Wt female offspring of mothers with heterozygous eNOS showed elevated liver fat accumulation, while wt male offspring of fathers with heterozygous eNOS exhibited increased fasting insulin, heightened insulin levels after a glucose load, and elevated liver glycogen content. By quantitative mass-spectrometry it was shown that concentrations of six serum metabolites (lysoPhosphatidylcholine acyl C20:3, phosphatidylcholine diacyl C36:2, phosphatidylcholine diacyl C38:1, phosphatidylcholine acyl-alkyl C34:1, phosphatidylcholine acyl-alkyl C36:3, and phosphatidylcholine acyl-alkyl C42:5 (PC ae C42:5) as well as four liver carbon metabolites (fructose 6-phosphate, fructose 1,6-bisphosphate, glucose 6-phosphate and fumarate) were different between wt offspring with eNOS+/− mothers and wt offspring with eNOS+/− fathers. Importantly, fumarate was inversely correlated with the liver fat accumulation in female offspring with eNOS+/− mothers and increased liver glycogen in offspring of both sexes with eNOS+/− fathers. The qRT-PCR results revealed that the gene expression patterns were different between wt offspring with eNOS+/− mothers and those offspring with eNOS+/− fathers. Different gene expression patterns were correlated with different observed phenotypic changes in male/female offspring born to mothers or fathers with a heterozygous eNOS genotype. Conclusion: The identical parental genetic alteration (heterozygous eNOS deficiency), without being passed on to the offspring, results in distinct metabolic, liver phenotype, and gene expression pattern variations depending on whether the genetic alteration originated from the father or the mother. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a severe pregnancy disorder posing significant health risks to both the mother and the fetus without available preventive measures or treatments. More specifically, the main pathological feature of early-onset PE (EO-PE) is the incomplete transformation of the spiral artery. Meanwhile, aspirin has proven effective for the treatment and prevention of PE. Previous studies indicated a relationship between the phytochemical compound of kopyor coconut water (KCW) and nutritional treatment for PE. Therefore, the objective of this study was to determine the efficacy of KCW as a potential preventive treatment for PE. An experimental laboratory method was used with pre-test and post-test control group designs. The samples comprised 35 pregnant Wistar rats, divided into five groups with seven members each. Rats were then randomized into control and groups exposed to L-NAME, L-NAME and aspirin, L-NAME and KCW 2 ml/200 gBW, as well as L-Name and KCW 2 ml/200 gBW for GD4 to 19. The results showed that after administering L-NAME to induce EO-PE, mean arterial pressure (MAP), proteinuria, placental hypoxia, oxidative stress, and endothelial dysfunction decreased due to KCW nutritional treatment. Specifically, KCW nutrition prevented the uterine spiral artery from expanding and reduced the number of neutrophils. The decreased survival rate caused by L-NAME-induced PE was reversed by providing KCW nutrition. Moreover, results indicated that KCW was a potential alternative for the prevention and treatment of EO-PE even at doses of 2 or 3 ml/200 gBW, offering insights for the community and clinical practitioners in treating PE as a therapeutic option. [ABSTRACT FROM AUTHOR]

Objective: To explore the effects and possible mechanisms of the drug pair Cornus officinalis and Radix achyranthis bidentatae (SYR-NX) on improving hypertensive kidney damage. Method: SYR-NX, a formulation of Cornus officinalis and Radix Achyranthis Bidentatae with a dose ratio 1:2.5, was used in this experiment. We investigated the effects of SYR-NX on spontaneously hypertensive rats (SHR) fed with a high-salt diet and Human Kidney-2 (HK2) cells exposed to hypoxia. After 8 weeks of treatment with SYR-NX, blood pressure was tested, and β 2-Microglobulin(β2-MG), blood creatinine (S-cr), endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate (NADPH), M2 pyruvate kinase (PKM2), adenosine triphosphate (ATP), pyruvate, lactate, connective tissue growth factor (CTGF) and tumor necrosis factor-α (TNF-α)were measured. HK2 cells pre-treated with SYR-NX were cultured in a three-gas hypoxic incubator chamber (5 % CO2, 1 % O2, 94 % N2) for 12 h, and then eNOS, PKM2, NADPH, ATP, pyruvate, lactate, CTGF and TNF-α were assessed. Results: SYR-NX significantly reduced SBP, DBP, β2-MG, S-cr, PKM2, pyruvate, lactate, CTGF and TNF-α, and increased eNOS, NADPH, and ATP. Conclusion: SYR-NX can regulate metabolic reprogramming through eNOS and improves hypertensive kidney injury.

Background. The pathological process underlying myocardial infarction is atherosclerotic thrombosis that causes endothelial dysfunction. In the AMI-STE process, eNOS has functions as the body's defense mechanism to prevent more severe damage to the endothelium. Decreased eNOS levels were found in modifiable AMI risk factors. This study aimed to determine the association of eNOS levels based on modifiable risk factors for AMI-STE patients. Method. This study was an analytical observational study with a historical cohort design. The samples were patients with AMI-STE diagnosis who had undergone PPCI at M. Djamil Hospital Padang from March to June 2022. The eNOS levels were taken from the blood samples. Modifiable AMI risk factors were taken from patient’s medical record. The T test was carried out to determine statistical analysis. Results. The average age of the 38 subjects was 62.53 ± 8.2 years, and 92.1% among them were male, and 52.6% subjects were diagnosed with anterior AMI-STE. The average eNOS level in subjects was 47.47 ± 23.88 (normal level is 48.16 pg/mL). More than half (73.5%) of the subjects in low eNOS group had diabetes mellitus as risk factor (P

Abstract The hepatic content of amyloid beta (Aβ) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of Aβ deficiency in the liver. This is especially relevant in view of recent advances in anti‐Aβ therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of Aβ in transgenic AD mice immunized with Aβ antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP‐KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha‐actin, and collagen type I. Aβ absence in APP‐KO and deficiency in immunized mice lead to strong activation of transforming growth factor‐β (TGFβ), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial‐mesenchymal transition. Inversely, increased systemic and intrahepatic levels of Aβ42 in transgenic AD mice and neprilysin inhibitor LBQ657‐treated wild‐type mice protect the liver against carbon tetrachloride (CCl4)‐induced injury. Transcriptomic analysis of CCl4‐treated transgenic AD mouse livers uncovers the regulatory effects of Aβ42 on mitochondrial function, lipid metabolism, and its onco‐suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal Aβ as an indispensable regulator of cell–cell interactions in healthy liver and a powerful protector against liver fibrosis.

RESUMO O objetivo deste trabalho foi avaliar a série de dados pluviométricos, sob o aspecto da homogeneidade, no cálculo do Índice de Precipitação Padronizado (IPP) e sua relação com os eventos de El Niño - Oscilação Sul (ENOS), para as regiões fisiográficas do Estado de Alagoas. Para tanto, foram avaliadas séries pluviométricas mensais utilizadas na determinação do IPP obtidas nas estações da Rede Hidrometeorológica da Superintendência do Desenvolvimento do Nordeste, disponíveis nas bases de dados Food and Agriculture Organization (FAOClim Net) e na Agência Nacional de Águas. Nas avaliações, foram adotados dois critérios para a seleção das séries: i) séries superiores ou iguais a 20 anos e ii) início e fim das séries, a partir de 1960 até 1990. Baseando-se nesses critérios, foram selecionadas 36 estações no Estado de Alagoas, distribuídas nas regiões fisiográficas da Zona da Mata, do Litoral, do Sertão, do Sertão do São Francisco, do Baixo São Francisco e do Agreste. Nas séries selecionadas, foi realizado o preenchimento de falhas por regressão linear e aplicou-se o método do resíduo acumulado para análise de homogeneidade. O IPP foi determinado para as séries não homogeneizadas e homogeneizadas, e posteriormente foi usado para caracterização da severidade da seca nas regiões fisiográficas do Estado de Alagoas. Eventos fortes de ENOS, juntamente com IPP homogeneizados, definem padrões mais realísticos dos períodos úmidos e secos do estado, em comparação aos eventos moderados de ENOS, associados com IPP não homogeneizados.

AbstractContext Gualou Guizhi decoction (GLGZD) is an ancient Chinese classical prescription widely used to treat ischemic stroke. However, the molecular mechanisms of GLGZD promoting angiogenesis are unavailable.Objective This study investigates the angiogenesis effect of GLGZD as well as its mechanism.Materials and methods Ischemic stroke was established by middle cerebral artery occlusion/reperfusion (MCAO/R) in male Sprague-Dawley (SD) rats. The GLGZD groups received GLGZD (3.6, 7.2 and 14.4 g/kg) orally. Oxygen-glucose deprivation/reoxygenation (OGD/R) model was constructed in HUVECs receiving GLGZD medicated serum (MS). MRI, H&E staining, qRT-PCR, western blot and immunofluorescence methods were employed. miRNA210 inhibitor was employed to confirm the effects of GLGZD on promoting angiogenesis. Dual luciferase assay was used to verify the binding of miRNA210 with HIF mRNA.Results GLGZD treatment improved neurological function (by 27%), alleviated neuronal injury (by 76%), reduced infarct volume (by 74%) and increased microvessel density (by fourfold) in vivo. In vitro data had also shown that GLGZD caused proliferation of the cells (by 58%), their migration, and eventual formation of tubes (by threefold). Simultaneously, GLGZD enhanced the levels of angiogenesis-related molecules and activated the HIF/VEGF signalling pathway. Surprisingly, the beneficial effects of GLGZD on post-stroke angiogenesis and neurological recovery were weakened by miRNA210 inhibitor, and also abolished the mediation of proangiogenic factors. miRNA210 directly targeted HIF mRNA.Discussion and conclusions GLGZD enhances angiogenesis via activation of the miRNA210/HIF/VEGF signalling pathway, suggesting it can be a novel application as an effective angiogenic formula for stroke recovery.

Background: Patients with treatment-resistant hypertension have a worse cardiovascular prognosis compared to those who achieve their target levels of blood pressure (BP). One of biochemical and clinical markers of a decreased response to antihypertensive therapy can be asymmetric dimethylarginine (ADMA), a molecule that reduces formation of nitric oxide and promotes endothelial dysfunction and vasoconstriction. Aim: To assess the status of the nitrogen oxide synthesis system and clinical and laboratory profile in patients, depending on the hypertensive disease stage, who achieved or not achieved their target BP levels during hospitalization. Materials and methods: We performed аn observational retrospective uncontrolled study in a consecutive sample of 192 patients aged 45–65 years who were admitted to the City Clinical Hospital No. 25 (city of Novosibirsk) with a diagnosis of uncomplicated hypertensive crisis. On the day of discharge, the patients were retrospectively divided into 2 groups. Group 1 included patients who achieved their target BP during hospitalization (target BP group, n = 116). Group 2 included patients with uncontrolled hypertension, in whom the administration of three antihypertensive drugs including a diuretic in optimal or maximal tolerated doses did not result in the achievement of the target BP below 140 and/or 90 mm Hg during hospitalization (non-target BP group, n = 76). The following parameters were measured: ADMA, symmetrical dimethylarginine (SDMA), N-monomethyl-L-arginine (NMMA), and total nitric oxide. Results: Serum ADMA concentrations (Me [Q25%; Q75%] were increasing with the stage of hypertension: stage I, 0.75 µmol/L [0.66; 0.78], stage II, 1.14 µmol/L [0.87; 1.39], stage III, 1.38 µmol/L [1.22; 1.49] (p 0.0001, Kruskal-Wallis test). In the pairwise comparison, the difference between all these subgroups was significant at p 0.01. In the patients with uncontrolled arterial hypertension ADMA levels were increased compared to those in the target BP group: 1.2 µmol/L [0.99; 1.47] vs 1.07 [0.79; 1.34] µmol/L (p = 0.002). The proportion of patients with type 2 diabetes mellitus among those with uncontrolled arterial hypertension was 31.2% (24/76), while in the target BP group there were only 3.5% of such patients (4/116) (odds ratio 12.57, 95% confidence interval 4.15–38.05; p = 0.00001). Conclusion: ADMA measurement may help identify patients with a potential poor response to antihypertensive therapy. This should be taken into account when choosing a treatment regimen and BP monitoring. In addition, ADMA seems to be a promising target for the development of new drug classes.

Background: The aim of the study was to comparatively assess the impact of single and repeated whole body vibration training (WBVT) and training without vibration on changes in the concentration of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and high-sensitivity C-reactive protein (hsCRP) in healthy, young, non-training women. Methods: The study involved 46 women (age 20.48 ± 1.72 years), who were divided into three groups: the experimental group participating in WBVT (EVG, n = 17); the comparison group performing the same exercises but without the vibration factor (EXG, n = 12); and the control group, which did not participate in any training (CON, n = 17). The program included participation in 36 training sessions conducted over 12 weeks, with a frequency of 3 times per week. In the EVG and EXG groups, venous blood was collected before and after the first and last training sessions, while in the CON group, blood was collected twice at a 3-month interval. Results: No significant changes were observed in the concentrations of the studied markers either after a single or repeated training session in both experimental groups (p > 0.05). Conclusions: The proposed WBVT protocol appears to be a safe form of exercise that does not induce negative inflammatory reactions. The applied vibration stimulus combined with physical exercises did not initiate pro-angiogenic processes or stimulate eNOS activity in healthy women, suggesting that similar studies should be conducted in individuals with circulatory problems or chronic inflammatory diseases.