The present work reports the functional modeling chemistry of YtfE, which features a nonheme diiron active site and mediates the direct reduction of NO2- to NO. The model complex, [Fe2(HPTP)Cl2]1+ (1), reduces NO2- to NO in a 100% yield within 12 h and generates [Fe4(HPTP)2(μ-O)3(μ-OH)]3+ (2). Similar to YtfE, the reaction involves stepwise oxidation of two Fe(II) centers and product (NO) inhibition, of which the latter produces [Fe2(HPTP)(NO)2Cl2]1+ (3). Complex 3 could also be synthesized by the reaction of [Fe2(HPTP)(NO)2(ClO4)]2+ (4) and chloride. Complex 1 catalyzes the reduction of NO2- to NO in the presence of PhS-, albeit with a low TON of 5, due to the formation of an insoluble product, [Fe2(HPTP)(μ-SPh)Cl2] (5). Another model complex [Fe2(HPTP)(OPr)]1+ (6), reduced NO2- to NO in an 80% yield after 24 h, generated [Fe2(HPTP)(OPr)(NO)2]1+ (7), and offered a TON of 19. The third model complex, [Fe2(HPTP)(ClO4)2]1+ (8), could reduce NO2- to NO in a 100% yield but only after 48 h. A comparison of these results establishes that easy oxidation of the Fe(II) centers, easy accessibility of the Fe(II) centers for the coordination of NO2-, and easy release of NO from the in situ generated dinitrosyl diiron complex increase the efficiency of the functional model complexes of YtfE.

Vascular endothelium is integral to the regulation of vascular homeostasis and maintenance of normal arterial function in healthy individuals. Endothelial dysfunction is a significant contributor to the advancement of atherosclerosis, which can precipitate cardiovascular complications. A notable correlation exists between diabetes and endothelial dysfunction, wherein chronic hyperglycemia and acute fluctuations in glucose levels exacerbate oxidative stress. This results in diminished nitric oxide synthesis and heightened production of endothelin-1, ultimately leading to endothelial impairment. In clinical settings, it is imperative to implement appropriate therapeutic strategies aimed at enhancing endothelial function to prevent and manage diabetes-associated vascular complications. Various antidiabetic agents, including insulin, GLP-1 receptor agonists, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, thiazolidinediones (TZDs), and metformin, are effective in mitigating blood glucose variability and improving insulin sensitivity by lowering postprandial glucose levels. Additionally, traditional Chinese medicinal compounds, such as turmeric extract, resveratrol, matrine alkaloids, tanshinone, puerarin, tanshinol, paeonol, astragaloside, berberine, and quercetin, exhibit hypoglycemic properties and enhance vascular function through diverse mechanisms. Consequently, larger randomized controlled trials involving both pharmacological and herbal interventions are essential to elucidate their impact on endothelial dysfunction in patients with diabetes. This article aims to explore a comprehensive approach to the treatment of diabetic endothelial dysfunction based on an understanding of its pathophysiology.

This narrative review provides an analysis of the role of nitric oxide (NO) and its precursors, particularly L-arginine, in vascular regulation and health, with an emphasis on findings from our experimental research in animal models. NO serves as a critical mediator of vascular function, contributing to vasodilation, the regulation of blood flow, and the prevention of thrombosis. As a primary precursor of NO, L-arginine is essential for maintaining endothelial integrity, modulating mitochondrial function, and reducing oxidative damage. This review synthesises the data and contextualises these findings within the physiological challenges faced by blood donors, such as repeated blood donation and associated oxidative stress. It examines the effects of L-arginine supplementation on mitochondrial respiration, lipid peroxidation, and microsomal oxidation in different conditions, including differences in age, gender, and dietary interventions. The mechanisms by which L-arginine enhances NO production, improves vascular elasticity, and alleviates endothelial dysfunction caused by reduced NO bioavailability are also investigated. By integrating experimental findings with insights from the existing literature, this review provides a perspective on the potential of L-arginine supplementation to address the specific physiological needs of blood donors. It highlights the importance of personalised nutritional approaches in enhancing donor recovery and vascular resilience. In addition, this review assesses the wider implications of L-arginine supplementation in mitigating oxidative stress and preserving vascular function. The interplay between NO bioavailability, dietary factors, and physiological adaptation in blood donors is highlighted, along with the identification of current knowledge gaps and recommendations for future research. By presenting both original experimental evidence and a critical synthesis of the literature, this article highlights the therapeutic potential of NO precursors, particularly L-arginine, in promoting vascular health in the context of blood donation.

Emergency intravascular interventional therapy is the most effective approach to rapidly restore blood flow and manage occlusion of major blood vessels during the initial phase of acute ischemic stroke. Nevertheless, several patients continue to experience ineffective reperfusion or cerebral no-reflow phenomenon, that is, hypoperfusion of cerebral blood supply after treatment. This is primarily attributed to downstream microcirculation disturbance. As integral components of the cerebral microvascular structure, endothelial cells (ECs) attach importance to regulating microcirculatory blood flow. Unlike neurons and microglia, ECs harbor a relatively low abundance of mitochondria, acting as key sensors of environmental and cellular stress in regulating the viability, structural integrity, and function of ECs rather than generating energy. Mitochondria dysfunction including increased mitochondrial reactive oxygen species levels and disturbed mitochondrial dynamics causes endothelial injury, further causing microcirculation disturbance involved in the cerebral no-reflow phenomenon. Therefore, this review aims to discuss the role of mitochondrial changes in regulating the role of ECs and cerebral microcirculation blood flow during I/R injury. The outcomes of the review will provide promising potential therapeutic targets for future prevention and effective improvement of the cerebral no-reflow phenomenon.

Reaction of an Fe(II) complex, [Fe(6-COO--tpa)]1+ (1), with PhE- and NO2- produced [Fe(6-COO--tpa)(EPh)] (E = S, 2a; Se, 3) and [Fe(6-COO--tpa)(κ2-O,O'-NO2)] (4), respectively (6-COOH-tpa is bis(2-pyridylmethyl)(6-carboxyl-2-pyridylmethyl)amine). Treatment of 4 with 2 equiv of PhEH (E = S, Se) produced NO in ∼40% yields, respectively, along with 1 and the DNICs, [Fe(EPh)2(NO)2]1- (E = S, Se). Treatment of 4 with excess PhEH produced NO in similar yields, while 4 was converted to the same DNICs and 2a/3 (instead of 1). The DNICs have been proposed to be generated via the reaction of PhE- with an in situ generated, unstable {FeNO}7 intermediate, [Fe(6-COO--tpa)(NO)]1+ (6), which has also been synthesized separately. Compound 6 reacts with PhS- to generate [Fe(SPh)2(NO)2]1-, thus supporting the proposed reaction pathway. Finally, while the treatment of two unique compounds, featuring inbuilt proton sources, [Fe(6-COO--tpa)(S-C6H4-p-COOH)] (7) and [Fe(6-COO--tpa)(S-C6H4-o-OH)] (8), with 0.5 and 1 equiv of NO2- could produce NO only in 8-26% yields, treatment of 4 with HS-C6H4-p-COOH and HS-C6H4-o-OH produced NO in much higher yields (65-77%). The combined results delineated the importance of coordination of NO2- for the proton-assisted reduction of NO2- to generate NO.

Endothelial dysfunction (ED) is the in the background of multiple metabolic diseases and a key process in liver disease progression and cirrhosis decompensation. ED affects liver sinusoidal endothelial cells (LSECs) in response to different damaging agents, causing their progressive dedifferentiation, unavoidably associated with an increase in intrahepatic resistance that leads to portal hypertension and hyperdynamic circulation with increased cardiac output and low peripheral artery resistance. These changes are driven by a continuous interplay between different hepatic cell types, invariably leading to increased reactive oxygen species (ROS) formation, increased release of pro-inflammatory cytokines and chemokines, and reduced nitric oxide (NO) bioavailability, with a subsequent loss of proper vascular tone regulation and fibrosis development. ED evaluation is often accomplished by serum markers and the flow-mediated dilation (FMD) measurement of the brachial artery to assess its NO-dependent response to shear stress, which usually decreases in ED. In the context of liver cirrhosis, the ED assessment could help understand the complex hemodynamic changes occurring in the early and late stages of the disease. However, the instauration of a hyperdynamic state and the different NO bioavailability in intrahepatic and systemic circulation-often defined as the NO paradox-must be considered confounding factors during FMD analysis. The primary purpose of this review is to describe the main features of ED and highlight the key findings of the dynamic and intriguing relationship between ED and liver disease. We will also focus on the significance of FMD evaluation in this setting, pointing out its key role as a therapeutic target in the never-ending battle against liver cirrhosis progression.

Infections and thrombosis remain unsolved problems for implanted cardiovascular devices, such as left ventricular assist devices. Hence, the development of surfaces with improved blood compatibility and antimicrobial properties is imperative to reduce complications after artificial heart implantation. In this work, we report a novel approach to fabricate multifunctional surfaces for left ventricular transplanted ventricular assist devices (LVADs) by immobilizing nitric oxide (NO) generation catalysts and heparin and reducing silver nanoparticles in situ. The general view, structure, and chemical compositions of the pure/modified surfaces were characterized using digital imaging, scanning electron microscope (SEM), atomic force microscope (AFM), water contact angle (WCA), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma (ICP). All of the results demonstrated that the AgNPs and heparin were successfully immobilized on the surface. The Cu ions and NO release experimental results showed that the immobilized copper ions could catalyze the production of NO from S-nitrosothiols within the biological system. Meanwhile, due to the synergistic anticoagulant effect of NO and surface-immobilized heparin, the fabricated modified surfaces exhibited antiplatelet adhesion activities and good hemocompatibility. Finally, the antimicrobial activity of the samples was evaluated by Escherichia coli and Staphylococcus aureus, and cytocompatibility was measured using human umbilical vein endothelial cells (HUVECs). The results demonstrated that silver nanoparticles (AgNPs) immobilized by surface reduction reaction did not cause any significant inhibition of cell proliferation while providing stable and effective antimicrobial properties. We envision that this simple surface modification strategy with bifunctional activities of antimicrobial and anticoagulant will find widespread use in clinically used indwelling left ventricular assist devices.

The achievement of materials that are able to release therapeutic agents under the control of light stimuli to improve therapeutic efficacy is a significant challenge in health care. Nitric oxide (NO) is one of the most studied molecules in the fascinating realm of biomedical sciences, not only for its crucial role as a gaseous signaling molecule in the human body but also for its great potential as an unconventional therapeutic in a variety of diseases including cancer, bacterial and viral infections, and neurodegeneration. Handling difficulties due to its gaseous nature, reduced region of action due to its short half-life, and strict dependence of the biological effects on its concentration and generation site are critical questions to be solved for appropriate therapeutic uses of NO. Light-activatable NO precursors, namely, NO photodonors (NOPDs), address the above issues since they are stable in the dark and permit in a noninvasive fashion the remote-controlled delivery of NO on demand with great spatiotemporal precision. Engineering biocompatible materials with NOPDs and their combination with additional imaging, therapeutic, and phototherapeutic components leads to intriguing light-responsive multifunctional constructs exhibiting promising potential for biomedical applications. This contribution illustrates the most significant progress made over the last five years in achieving engineered materials including nanoparticles, gels, and thin films, sharing the common feature to deliver NO under the exclusive control of the biocompatible visible/near infrared light inputs. We will highlight the logical design behind the fabrication of these systems, illustrating the potential therapeutic applications with particular emphasis on cancer and bacterial infections.

This study aims to explore the role of estrogen in providing cardioprotective benefits to premenopausal women, examining how hormonal differences between sexes influence the prevalence of cardiovascular diseases (CVDs) in women.

Eighteen female Wistar rats were equally distributed into three treatment groups. Animals in Group I (sham-operated) and Group II (ovariectomized [OVX]) received oral saline solution at a dose of 2 mL/kg. Group III (OVX+E2) received oral E2 2 µg/mL/kg after ovariectomy. Hemodynamic parameters and baroreflex sensitivity were determined in all groups. Plasma levels of malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) were measured, along with those of the inflammatory markers tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high mobility group box-1 (HMGB-1).

The OVX group, compared with the sham-operated group, displayed significantly altered hemodynamic parameters and baroreflex sensitivity, along with elevated MDA levels and decreased SOD and NO levels. This group also had higher levels of inflammatory cytokines than the sham-operated group. In the absence of estrogen, these factors led to the advancement of cardiovascular abnormalities. In the OVX+E2 group, estrogen treatment considerably improved baroreflex sensitivity and hemodynamic profile while reducing the expression of inflammatory cytokines compared with the OVX group, demonstrating anti-inflammatory actions of estrogen.

Estrogen mediates cardioprotection by improving baroreflex sensitivity in ovariectomized Wistar rats through modulation of the NO pathway.

The multifaceted role nitric oxide (NO) plays in human physiology and pathophysiology has opened new scenarios in biomedicine by exploiting this free radical as an unconventional therapeutic against important diseases. The difficulties in handling gaseous NO and the strict dependence of the biological effects on its doses and location have made the light-activated NO precursors, namely NO photodonors (NOPDs), very appealing by virtue of their precise spatiotemporal control of NO delivery. The covalent integration of NOPDs and additional functional components within the same molecular skeleton through suitable linkers can lead to an intriguing class of multifunctional photoactivatable molecular hybrids. In this Perspective, we provide an overview of the recent advances in these molecular constructs, emphasizing those merging NO photorelease with targeting, fluorescent reporting, and phototherapeutic functionalities. We will highlight the rational design behind synthesizing these molecular hybrids and critically describe the advantages, drawbacks, and opportunities they offer in biomedical research.

As angiogenesis was recognized as a core hallmark of cancer growth and survival, several strategies have been implemented to target the tumour vasculature. Yet to date, attempts have rarely been so diverse, ranging from vessel growth inhibition and destruction to vessel normalization, reprogramming and vessel growth promotion. Some of these strategies, combined with standard of care, have translated into improved cancer therapies, but their successes are constrained to certain cancer types. This Review provides an overview of these vascular targeting approaches and puts them into context based on our subsequent improved understanding of the tumour vasculature as an integral part of the tumour microenvironment with which it is functionally interlinked. This new knowledge has already led to dual targeting of the vascular and immune cell compartments and sets the scene for future investigations of possible alternative approaches that consider the vascular link with other tumour microenvironment components for improved cancer therapy.

Obesity among adolescents have become a global public health problem. Exercises can effectively improve the bio-physiological factors of obese adolescents. High-intensive interval training (HIIT) has been applied to obese adolescents. Studies have reported that the Aquatic environment may bring the same or more positive exercise effects as the land environment. Therefore, the purpose of this study was to examine the effects of aquatic and land interventions on selected bio-and physiological variables among obese adolescences.

Twenty-eight obese adolescents who met the requirements participated in and completed this study. The participants were randomly assigned to Aquatic HIIT group (n=17) or Land HIIT group (n=11) for a four-week exercise intervention, 3 time/week. Each Intervention program was one-hour long, including 20 minutes of warm-up, 30 minutes of HIIT and 10 minutes of stretching and relaxation. Bio- and physiological variables including Anthropometry and body composition, Physical Function and blood pressure, and Lipid metabolism indexes were collected before and after the Aquatic and Land interventions.

After four weeks of exercise interventions, the body mass, BMI, body fat rate, waist circumference, hip circumference and body water content were significantly reduced (p<0.05), and the lean body mass were significantly increased (p<0.05) in both groups. Both group exhibited significant effects in decreasing, systolic blood pressure (p<0.05), diastolic blood pressure (p<0.01), and increasing vital capacity and total energy consumption (p<0.05). The Aquatic HIIT group showed significant effects on reducing Rest heart rate (p<0.05), but no significant changes in Rest heart rate in Land HIIT group (p=0.364). The low-density lipoprotein cholesterol in both groups was significantly decreased (p<0.05). Moreover, the Aquatic HIIT group had significant better improvements (p<0.05) in lean body mass, waist circumference, waist-to-hip ratio, vital capacity and total energy consumption than Land HIIT group did.

The results of the present study demonstrated that in a short-term (4 weeks) both Aquatic and Land HIIT interventions may improve the body composition, physical function, blood pressure and low-density lipoprotein cholesterol (LDL-C) of overweight and obese adolescents. Furthermore, the Aquatic HIIT may be superior than the Land HIIT in weight control among the obese adolescents.

Necrotic enteritis (NE) is an enteric disease of poultry that alters the structure of the gut microbial community causing dysbiosis. This 28 day experiment investigated the effects of 125% and 135% arginine diets on the gut microbial diversity and composition of broilers during a subclinical NE challenge. One hundred and twenty one-day-old chicks were randomly allocated to 4 treatments with six replicates each- Uninfected + Basal, NE + Basal, NE + Arg 125%, and NE + Arg 135% diet groups. NE was induced by inoculating 1 × 104 E. maxima sporulated oocysts on day 14 and 1 × 108 CFU C. perfringens on days 19, 20, and 21 of age. The NE challenge significantly decreased the number of observed amplicon sequence variants (p = 0.03), the abundance of the phylum Firmicutes (p < 0.01), and the species Mediterraneibacter cottocaccae (p = 0.01) in the ceca of birds on day 21. The NE challenge significantly increased the Bray-Curtis index (p < 0.01), and the abundance of the phylum Bacteroidota (p < 0.01), family Odoribacteraceae (p < 0.01), genus Odoribacter (p < 0.01), and species O. splanchnicus (p = 0.01) on day 21. During NE, the 125% arginine diet restored the abundance of the phylum Bacteroidota (p = 0.03), family Odoribacteraceae (p = 0.03) and Oscillospiraceae (p = 0.03), genus Odoribacter (p = 0.03), and species O. splanchnicus (p = 0.03) and M. cottocaccae (p < 0.01) on day 21. The 135% arginine diet effectively restored the loss in alpha diversity (p = 0.01) caused by NE, the abundance of the phylum Firmicutes (p = 0.01) and Bacteroidota (p < 0.01), family Oscillospiraceae (p = 0.03) and Odoribacteraceae (p < 0.01), genus Odoribacter (p < 0.01), and species O. splanchnicus (p < 0.01) and M. cottocaccae (p < 0.01) on day 21. On day 28, the treatments had a significant effect on the cecal propionate (p = 0.01), butyrate (p = 0.04), and total SCFA (p = 0.04) concentrations. In conclusion, the 125% and 135% arginine diets restored gut microbial composition during a subclinical NE challenge, but not the cecal SCFA profile. Hence, arginine in combination with other feed additives could be used in restoring gut microbial homeostasis during NE in poultry.

Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon.

Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an in vivo mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (Ntotal = 312).

Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase.

Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved.

Nitric oxide (NO) has been defined as the "miracle molecule" due to its essential pleiotropic role in living systems. Besides its implications in physiologic functions, it is also involved in the development of several disease states, and understanding this ambivalence is crucial for medicinal chemists to develop therapeutic strategies that regulate NO production without compromising its beneficial functions in cell physiology. Although nitric oxide synthase (NOS), i.e., the enzyme deputed to the NO biosynthesis, is a well-recognized druggable target to regulate NO bioavailability, some issues have emerged during the past decades, limiting the progress of NOS modulators in clinical trials. In the present review, we discuss the most promising advancements in the research of small molecules that are able to regulate NOS activity with improved pharmacodynamic and pharmacokinetic profiles, providing an updated framework of this research field that could be useful for the design and development of new NOS modulators.

Objective: To investigate the effects of 8-week aquatic and land high intensity interval training (HIIT) on hemodynamics and vascular function in middle-aged men. Methods: Thirty middle-aged men with low physical activity were selected and divided into 15 men (52.43 ± 4.11) in aquatic group and 15 men (52.74 ± 5.62) in land group by random number table. They performed HIIT exercise in aquatic and land 3 times a week for 8 weeks. Pre-test, inter-test and post-test respectively measure hemodynamics and blood vessel function. Results: (1) Body composition: After 8 weeks of exercise, weight, body mass index (BMI) and body fat rate (BF) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of BF in the aquatic group was better than that in the land group (p < 0.05); (2) Cardiac function: After 8 weeks of exercise, stroke volume (SV), left ventricular end-diastolic volume (EDV), cardiac output (CO), and left ventricular fractional shortening (FS), were higher than before exercise (aquatic group: p < 0.01, land group: p < 0.05), heart rate (HR) and left ventricular end-systolic volume (ESV) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of SV, HR, EDV, ESV, CO and FS in the aquatic group was better than that in the land group (p < 0.05); (3) Hemodynamics: After 8 weeks of exercise, systolic blood pressure (SBP), diastolic blood pressure (DBP) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05), wall shear stress (WSS) and peak systolic velocity (PSV) were higher than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of SBP, WSS and PSV in the aquatic group was better than that in the land group (p < 0.05); (4) Vascular function: basal diameter and brachial artery flow-mediated dilatation (FMD) level in aquatic group and land group was higher than before exercise, pulse wave velocity (PWV) level was lower than before exercise (aquatic and land group: p < 0.05). The improvement of FMD in the aquatic group was better than that in the land group. Conclusion: The body composition, hemodynamics and vascular function of middle-aged men were improved by 8-week aquatic and land HIIT. Aquatic HIIT has better effect on body fat rate, hemodynamics and vascular endothelial function in middle-aged men due to the effect of aquatic pressure and temperature.

Observed and recorded in various forms since ancient times, 'syncope' is often popularly called 'fainting', such that the two terms are used synonymously. Syncope/fainting can be caused by a variety of conditions, including but not limited to head injuries, vertigo, and oxygen deficiency. Here, we draw on a large body of literature on syncope, including the role of a recently discovered set of specialized mammalian neurons. Although the etiology of syncope still remains a mystery, we have attempted to provide a comprehensive account of what is known and what still needs to be performed. Much of our understanding of syncope is owing to studies in the laboratory mouse, whereas evidence from human patients remains scarce. Interestingly, the cardioinhibitory Bezold-Jarisch reflex, recognized in the early 1900s, has an intriguing similarity to-and forms the basis of-syncope. In this review, we have integrated this minimal model into the modern view of the brain-neuron-heart signaling loop of syncope, to which several signaling events contribute. Molecular signaling is our major focus here, presented in terms of a normal heart, and thus, syncope due to abnormal or weak heart activity is not discussed in detail. In addition, we have offered possible directions for clinical intervention based on this model. Overall, this article is expected to generate interest in chronic vertigo and syncope/fainting, an enigmatic condition that affects most humans at some point in life; it is also hoped that this may lead to a mechanism-based clinical intervention in the future.

Thrombosis, a coagulation disorder, occurs due to altered levels of coagulation, fibrinolytic and immune factors, which are otherwise known to maintain hemostasis in normal physiological conditions. Here, we review the direct and indirect participation of a multifunctional nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP1) in the expression of key genes and cellular processes involved in thrombotic pathogenesis. PARP1 biological activities range from maintenance of genomic integrity, chromatin remodeling, base excision DNA repair, stress responses to cell death, angiogenesis and cell cycle pathways. However, under homeostatic imbalances, PARP1 activities are linked with the pathogenesis of diseases, including cancer, aging, neurological disorders, and cardiovascular diseases. Disease-associated distressed cells employ a variety of PARP-1 functions such as oxidative damage exacerbations, cellular energetics and apoptosis pathways, regulation of inflammatory mediators, promotion of endothelial dysfunction, and ERK-mediated signaling in pathogenesis. Thrombosis is one such pathogenesis that comprises exacerbation of coagulation cascade due to biochemical alterations in endothelial cells, platelet activation, overexpression of adhesion molecules, cytokines release, and leukocyte adherence. Thus, the activation of endothelial and inflammatory cells in thrombosis implicates a potential role of PARP1 activation in thrombogenesis. This review article explores the direct impact of PARP1 activation in the etiology of thrombosis and discusses PARP1-mediated endothelial dysfunction, inflammation, and epigenetic regulations in the disease manifestation. Understanding PARP1 functions associated with thrombosis may elucidate novel pathogenetic mechanisms and help in better disease management through newer therapeutic interventions targeting PARP1 activity.

Metabolites in exercise have traditionally been viewed as a fuel source, waste product, or anabolic components required for exercise-induced biosynthetic processes. However, it is now recognised that metabolites and lipids may act as mediators of interorgan crosstalk to coordinate the local and systemic physiological adaptations required to meet the complex system-wide challenge of exercise. These bioactive metabolite and lipid signals have been termed metabokines and lipokines, respectively. There is emerging evidence that metabokines and lipokines contribute to the health benefits of exercise. This review highlights several of the key recent discoveries related to metabokine and lipokine signalling during exercise. The discovery of these metabokines and lipokines, and their signalling targets, may provide the basis of future therapies for human disease.

Synthesis, characterization, electronic structure, and redox reactions of a mononuclear {FeNO}7 complex with a very high N-O stretching frequency in solution are presented. Nitrosylation of [(LKP)Fe(DMF)]2+ (1) (LKP = tris((1-methyl-4,5-diphenyl-1H-imidazol-2-yl)methyl)amine) produced a five-coordinate {FeNO}7 complex, [(LKP)Fe(NO)]2+ (2). While complex 2 could accommodate an additional water molecule to generate a six-coordinate {FeNO}7 complex, [(LKP)Fe(NO)(H2O)]2+ (3), the coordinated H2O in 3 dissociates to generate 2 in solution. The molecular structure of 2 features a nearly linear Fe-N-O unit with an Fe-N distance of 1.744(4) Å, N-O distance of 1.162(5) Å, and Collapse

Cardiovascular aging is a progressive remodeling process constituting a variety of cellular and molecular alterations that are closely linked to mitochondrial dysfunction. Therefore, gaining a deeper understanding of the changes in mitochondrial function during cardiovascular aging is crucial for preventing cardiovascular diseases. Cardiac aging is accompanied by fibrosis, cardiomyocyte hypertrophy, metabolic changes, and infiltration of immune cells, collectively contributing to the overall remodeling of the heart. Similarly, during vascular aging, there is a profound remodeling of blood vessel structure. These remodeling present damage to endothelial cells, increased vascular stiffness, impaired formation of new blood vessels (angiogenesis), the development of arteriosclerosis, and chronic vascular inflammation. This review underscores the role of mitochondrial dysfunction in cardiac aging, exploring its impact on fibrosis and myocardial alterations, metabolic remodeling, immune response remodeling, as well as in vascular aging in the heart. Additionally, we emphasize the significance of mitochondria-targeted therapies in preventing cardiovascular diseases in the elderly.

The intriguing chemistry of chalcogen (S, Se)-containing ligands and their capability to bridge multiple metal centres have resulted in a plethora of reports on transition metal complexes featuring hydrosulfide (HS-) and polychalcogenides (En2-, E = S, Se). While a large number of such molecules are strictly organometallic complexes, examples of non-organometallic complexes featuring HS- and En2- with N-/O-donor ligands are relatively rare. The general synthetic procedure for the transition metal-hydrosulfido complexes involves the reaction of the corresponding metal salts with HS-/H2S and this is prone to generate sulfido bridged oligomers in the absence of sterically demanding ligands. On the other hand, the synthetic methods for the preparation of transition metal-polychalcogenido complexes include the reaction of the corresponding metal salts with En2- or the two electron oxidation of low-valent metals with elemental chalcogen, often at an elevated temperature and/or for a long time. Recently, we have developed new synthetic methods for the preparation of two new classes of binuclear transition metal complexes featuring either HS-, or Sn2- and Sen2- ligands. The new method for the synthesis of transition metal-hydrosulfido complexes involved transition metal-mediated hydrolysis of thiolates at room temperature (RT), while the method for the synthesis of transition metal-polychalcogenido complexes involved redox reaction of coordinated thiolates and exogenous elemental chalcogens at RT. An overview of the synthetic aspects, structural properties and intriguing reactivity of these two new classes of transition metal complexes is presented.

When exposed to high-altitude environments, the cardiovascular system undergoes various changes, the performance and mechanisms of which remain controversial.

To summarize the latest research advancements and hot research points in the cardiovascular system at high altitude by conducting a bibliometric and visualization analysis.

The literature was systematically retrieved and filtered using the Web of Science Core Collection of Science Citation Index Expanded. A visualization analysis of the identified publications was conducted employing CiteSpace and VOSviewer.

A total of 1674 publications were included in the study, with an observed annual increase in the number of publications spanning from 1990 to 2022. The United States of America emerged as the predominant contributor, while Universidad Peruana Cayetano Heredia stood out as the institution with the highest publication output. Notably, Jean-Paul Richalet demonstrated the highest productivity among researchers focusing on the cardiovascular system at high altitude. Furthermore, Peter Bärtsch emerged as the author with the highest number of cited articles. Keyword analysis identified hypoxia, exercise, acclimatization, acute and chronic mountain sickness, pulmonary hypertension, metabolism, and echocardiography as the primary research hot research points and emerging directions in the study of the cardiovascular system at high altitude.

Over the past 32 years, research on the cardiovascular system in high-altitude regions has been steadily increasing. Future research in this field may focus on areas such as hypoxia adaptation, metabolism, and cardiopulmonary exercise. Strengthening interdisciplinary and multi-team collaborations will facilitate further exploration of the pathophysiological mechanisms underlying cardiovascular changes in high-altitude environments and provide a theoretical basis for standardized disease diagnosis and treatment.

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.

Calmodulin (CaM) binds to a linker between the oxygenase and reductase domains of nitric oxide synthase (NOS) to regulate the functional conformational dynamics. Specific residues on the interdomain interface guide the domain-domain docking to facilitate the electron transfer in NOS. Notably, the docking interface between CaM and the heme-containing oxygenase domain of NOS is isoform specific, which is only beginning to be investigated. Toward advancing understanding of the distinct CaM-NOS docking interactions by infrared spectroscopy, we introduced a cyano-group as frequency-resolved vibrational probe into CaM individually and when associated with full-length and a bi-domain oxygenase/FMN construct of the inducible NOS isoform (iNOS). Site-specific, selective labeling with p-cyano-L-phenylalanine (CNF) by amber suppression of CaM bound to the iNOS has been accomplished by protein coexpression due to the instability of recombinant iNOS protein alone. We introduced CNF at residue 108, which is at the putative CaM-heme (NOS) docking interface. CNF was also introduced at residue 29, which is distant from the docking interface. FT IR data show that the 108 site is sensitive to CaM-NOS complex formation, while insensitivity to its association with the iNOS protein or peptide was observed for the 29 site. Moreover, narrowing of the IR bands at residue 108 suggests the C≡N probe experiences a more limited distribution of environments, indicating side chain restriction apparent for the complex with iNOS. This initial work sets the stage for residue-specific characterizations of structural dynamics of the docked states of NOS proteins.

Impaired nitric oxide (NO) formation may be associated with endothelial dysfunction and increased cardiovascular disease risk in preeclampsia (PE). Functional single-nucleotide polymorphisms (SNPs) of nitric oxide synthase 3 (NOS3) (rs3918226) and guanylate cyclase 1, soluble, alpha 3 (GUCY1A3) (rs7692387) increase susceptibility to the adverse consequences due to inadequate generation of NO by the endothelium. However, no previous study has examined whether these SNPs affect NO formation in healthy pregnancy and in gestational hypertension (GH) and PE. Here, we compared the alleles and genotypes of NOS3 (rs3918226) and GUCY1A3 (rs7692387) SNPs in normotensive pregnant women (NP, n = 153), in GH (n = 96) and PE (n = 163), and examined whether these SNPs affect plasma nitrite concentrations (a marker of NO formation) in these groups. We further examined whether the interaction among SNP genotypes is associated with GH and PE. Genotypes were determined using TaqMan allele discrimination assays, and plasma nitrite concentrations were determined by an ozone-based chemiluminescence assay. Multifactor dimensionality reduction was used to examine the interactions among SNP genotypes. Regarding NOS3 rs3918226, the CT genotype (p = 0.046) and T allele (p = 0.020) were more frequent in NP than in GH, and GH patients carrying the CT+TT genotypes showed lower nitrite concentrations than NP carrying the CT+TT genotypes (p < 0.05). Regarding GUCY1A3 rs7692387, the GA genotype (p = 0.013) and A allele (p = 0.016) were more frequent in PE than in NP, and NP women carrying the GG genotype showed higher nitrite concentrations than GH or PE patients carrying the GG genotype (p < 0.05). However, we found no significant interactions among genotypes for these functional SNPs to be associated with GH or PE. Our novel findings suggest that NOS3 rs3918226 and GUCY1A3 rs7692387 may affect NO formation and association with hypertensive disorders of pregnancy.

Acetic acid is a bioactive short-chain fatty acid produced in large quantities from ethanol metabolism. In this review, we describe how acetic acid/acetate generates oxidative stress, alters the function of pre-sympathetic neurons, and can potentially influence cardiovascular function in both humans and rodents after ethanol consumption. Our recent findings from in vivo and in vitro studies support the notion that administration of acetic acid/acetate generates oxidative stress and increases sympathetic outflow, leading to alterations in arterial blood pressure. Real-time investigation of how ethanol and acetic acid/acetate modulate neural control of cardiovascular function can be conducted by microinjecting compounds into autonomic control centers of the brain and measuring changes in peripheral sympathetic nerve activity and blood pressure in response to these compounds.

Comparative reactivity of a series of new Zn(II) and Fe(II) compounds, [(Py2ald)M(ER)] (E = S, R = Ph: M = Zn, 1aZn; M = Fe, 1aFe; E = S, R = 2,6-Me2-C6H3: M = Zn, 1bZn; M = Fe, 1bFe; E = Se, R = Ph: M = Zn, 2Zn; M = Fe, 2Fe), and [(Py2ald)M]22+ (M = Zn, 5Zn; M = Fe, 5Fe) is presented. Compound 1aZn could react with nitrite (NO2-) to produce [(Py2ald)Zn(ONO)] (3Zn), which, upon treatment with thiols and PhSeH (proton source), could regenerate either 1aZn/5Zn and 2Zn respectively, along with the production of nitric oxide (NO) where the yield of NO increases in the order tBuSH ≪ PhCH2SH < PhSH < PhSeH. In contrast to this, 1aFe, 2Fe and 5Fe could affect the direct reduction of NO2- in the absence of protons to generate NO and [{(Py2ald)(ONO)Fe}2-μ2-O] (8Fe). Moreover, 8Fe could regenerate 5Fe and 1aFe/2Fe upon treatment with 4 and 6 equiv. of PhEH (E = S/Se), respectively, along with the generation of NO. Finally, a comparative study of the mononuclear Zn(II) and Fe(II) compounds for the transfer of the coordinated thiolate/selenolate and the generation and transfer of reactive sulfur/selenium species (RES-, E = Se, S) to a series of organic substrates has been provided.

We hypothesized that perinatal manipulations of the nitrergic system would affect adult animal behaviors.

We tested this hypothesis by perinatally administering N(G)-Nitro-L-arginine methyl ester (L-NAME), a non-specific antagonist of nitric oxide synthase for 15 days and assessed anxiety- and depression-like behaviors in adult mice. At 70 days of age, the mice were subjected to a battery of tests consisting of the open-field, light/dark box, forced swim, and tail-flick tests. The tests were performed at two-day intervals, and the order of the tests within the battery was determined according to the progressive invasiveness degree.

L-NAME-treated animals exhibited decreased anxiety-like behavior in the light/dark box and open field tests, with no change in locomotor activity. Additionally, they demonstrated decreased depression-like behavior in the forced swim test and no change in pain perception in the tail-flick test.

The nitrergic system is possibly involved in neural circuitry development that regulates behaviors since blocking perinatal nitric oxide production decreases anxiety- and depression-like behaviors in adult mice.

To investigate serum biomarkers of inflammation 2 years following non-surgical root canal re-treatment (Re-RCT) and peri-apical surgery (PS). The results were correlated with signs and symptoms, treatment outcome, metabolic syndrome factors, infection with severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 (COVID-19) infection and COVID-19 vaccination.

Subjects from our previous study were recalled for 2 years post-treatment follow-up. Changes to the patient's history (medical, dental, social) were noted. Periapical health of the treated teeth was examined both clinically and radiographically. Blood pressure, fasting HbA1C and low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides and total cholesterol (TC) levels were measured. Serum inflammatory marker levels were assayed using a Bio-Rad Bio-Plex 200 analyser and values at different time points within the same group were compared using a Wilcoxon signed-rank test and differences between groups with a Mann-Whitney test. Linear associations were tested using Pearson's correlations.

The recall percentage at 2 years was 56.9% (n = 37), with a 100% radiographic success rate using periapical radiographs. In total, 21 cases (56.8%) were completely healed, and 16 cases (43.2%) were healing. Higher matrix metalloprotease 2 (MMP2) levels were present in the healing group compared to the healed group. Serum levels of high-sensitivity C-reactive protein (hs-CRP), asymmetric dimethylarginine (ADMA) and MMP-2 were significantly reduced (p ≤ .001) whereas other biomarkers showed significant increases at 2 year compared to pre-operative levels, while FGF-23 and ICAM-1 were not significantly increased. HbA1C (p = .015), TC (p = .003), LDL (p = .003) and HDL (p = .003) reduced significantly at 2 years post-treatment compared to their preoperative levels. COVID infection showed a significant association with MMP-9 (p = .048).

hs-CRP, ADMA and MMP-2 can be regarded as prognostic biomarkers of successful Re-RCT and PS as they reduced at 2 year recall in cases which showed evidence of clinical and radiographic success. The successful treatment of chronic apical periodontitis is correlated with improvements in metabolic syndrome indicators, better glycemic control, and reduction at 2 year of some systemic inflammatory markers which are related to risks of cardiovascular disease events.

The biological function of radicals is a broad continuum from signaling to killing. Yet, biomedical exploitation of radicals is largely restricted to the theme of healing-by-killing. To explore their potential in healing-by-signaling, robust radical generation methods are warranted. Acyl radicals are endogenous, exhibit facile chemistry and elicit matrix-dependent biological outcomes. Their implications in health and disease remain untapped, primarily due to the lack of a robust generation method with spatiotemporal specificity. Fusing the Norrish chemistry into the xanthene scaffold, we developed a novel general and modular molecular design strategy for photo-triggered generation of acyl radicals, i.e., acyl-caged rhodamine (ACR). A notable feature of ACR is the simultaneous release of a fluorescent probe for cell redox homeostasis allowing real-time monitoring of the biological outcome of acyl radicals. With a donor of the endogenous acetyl radical (ACR575a), we showcased its capability in precise and continuous modulation of the cell redox homeostasis from signaling to stress, and induction of a local oxidative burst to promote differentiation of neural stem cells (NSCs). Upon intracerebral-injection of ACR575a and subsequent fiber-optical activation, early AD mice exhibited enhanced differentiation of NSCs toward neurons, reduced formation of Aβ plaques, and significantly improved cognitive abilities, including learning and memory.

Ultraviolet (UV) radiation has both harmful and beneficial effects on human skin and health. It causes skin damage, aging, and cancer; however, it is also a primary source of vitamin D. Additionally, UV radiation can impact energy metabolism and has protective effects on several cardiovascular and metabolic disorders in mice and humans. However, the mechanisms of UV protection against these diseases have not been clearly identified.

This review summarizes the systemic effects of UV radiation on hypertension and several metabolic diseases such as obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) in mice, and we also consider the mechanisms of action of the related regulators nitric oxide (NO) and vitamin D.

UV exposure can lower blood pressure and prevent the development of cardiovascular diseases and metabolic disorders, such as metabolic syndrome, obesity, and type 2 diabetes, primarily through mechanisms that depend on UV-induced NO. UV radiation may also effectively delay the onset of type 1 diabetes through mechanisms that rely on UV-induced vitamin D. UV-induced NO and vitamin D play roles in preventing and slowing the progression of NAFLD.

UV exposure is a promising nonpharmacological intervention for cardiovascular and metabolic disorders. NO and vitamin D may play a crucial role in mediating these effects. However, further investigations are required to elucidate the exact mechanisms and determine the optimal dosage and exposure duration of UV radiation.

Amino acids which are essential nutrients for all cell types' survival are also recognised to serve as opportunistic/alternative fuels in cancers auxotrophic for specific amino acids. Accordingly, restriction of amino acids has been utilised as a therapeutic strategy in these cancers. Contrastingly, amino acid deficiencies in cancer are found to greatly impair immune functions, increasing mortality and morbidity rates. Dietary and supplemental amino acids in such conditions have revealed their importance as 'immunonutrients' by modulating cellular homeostasis processes and halting malignant progression. L-arginine specifically has attracted interest as an immunonutrient by acting as a nodal regulator of immune responses linked to carcinogenesis processes through its versatile signalling molecule, nitric oxide (NO). The quantum of NO generated directly influences the cytotoxic and cytostatic processes of cell cycle arrest, apoptosis, and senescence. However, L-lysine, a CAT transporter competitor for arginine effectively limits arginine input at high L-lysine concentrations by limiting arginine-mediated effects. The phenomenon of arginine-lysine antagonism can, therefore, be hypothesised to influence the immunonutritional effects exerted by arginine. The review highlights aspects of lysine's interference with arginine-mediated NO generation and its consequences on immunonutritional and anti-cancer effects, and discusses possible alternatives to manage the condition. However, further research that considers monitoring lysine levels in arginine immunonutritional therapy is essential to conclude the hypothesis.

The study was initiated in 2020 to test the efficacy of a nitric oxide-generating lozenge (NOL) in outpatients with newly diagnosed COVID-19 to mitigate disease severity. The study enrolled high-risk patients, African American and Latino.

This was a randomized, double-blinded, prospective, placebo-controlled trial. The primary endpoint was hospitalization, intensive care unit admission, intubation, dialysis, and death. The secondary endpoints were time to symptom resolution and the effect on oxygen saturation. Patients ages 50-85 years with recent COVID-19 diagnosis with at least one risk factor were recruited. Patients were randomized to either active treatment or placebo using block randomization. Blood pressure and oxygen saturation (SpO2) was measured prior to and after the first dose and each morning thereafter.

A total of 840 patients was planned, half in each of the lozenge and placebo groups. An interim review of data was prespecified. Of 524 patients, the composite endpoint occurred in 6 patients, 3 (1.1%) in each group. The time to symptom resolution was 1 day shorter on active treatment (8.7 ± 6.6 vs 9.8 ± 6.8 days) (P = .3). There was no change in SpO2 on placebo (0.0 ± 2.0%) and no significant change on treatment (0.14 ± 0.9%), P = .3. All events occurred in the first year (2020).

This study did not find a benefit of NOL therapy in COVID-19 patients and was terminated for futility. NOL treatment did not reduce mortality, hospitalization, intubation, or a reduction in symptoms duration. The study did find the NO lozenges were well tolerated in high-risk patients, without reported side effects.

Through nitrosylation of [Fe-S] proteins, or the chelatable iron pool, a dinitrosyl iron unit (DNIU) [Fe(NO)2] embedded in the form of low-molecular-weight/protein-bound dinitrosyl iron complexes (DNICs) was discovered as a metallocofactor assembled under inflammatory conditions with elevated levels of nitric oxide (NO) and superoxide (O2-). In an attempt to gain biomimetic insights into the unexplored transformations of the DNIU under inflammation, we investigated the reactivity toward O2- by a series of DNICs [(NO)2Fe(μ-MePyr)2Fe(NO)2] (1) and [(NO)2Fe(μ-SEt)2Fe(NO)2] (3). During the superoxide-induced conversion of DNIC 1 into DNIC [(K-18-crown-6-ether)2(NO2)][Fe(μ-MePyr)4(μ-O)2(Fe(NO)2)4] (2-K-crown) and a [Fe3+(MePyr)x(NO2)y(O)z]n adduct, stoichiometric NO monooxygenation yielding NO2- occurs without the transient formation of peroxynitrite-derived •OH/•NO2 species. To study the isoelectronic reaction of O2(g) and one-electron-reduced DNIC 1, a DNIC featuring an electronically localized {Fe(NO)2}9-{Fe(NO)2}10 electronic structure, [K-18-crown-6-ether][(NO)2Fe(μ-MePyr)2Fe(NO)2] (1-red), was successfully synthesized and characterized. Oxygenation of DNIC 1-red leads to the similar assembly of DNIC 2-K-crown, of which the electronic structure is best described as paramagnetic with weak antiferromagnetic coupling among the four S = 1/2 {FeIII(NO-)2}9 units and S = 5/2 Fe3+ center. In contrast to DNICs 1 and 1-red, DNICs 3 and [K-18-crown-6-ether][(NO)2Fe(μ-SEt)2Fe(NO)2] (3-red) display a reversible equilibrium of "3 + O2- ⇋ 3-red + O2(g)", which is ascribed to the covalent [Fe(μ-SEt)2Fe] core and redox-active [Fe(NO)2] unit. Based on this study, the supporting/bridging ligands in dinuclear DNIC 1/3 (or 1-red/3-red) control the selective monooxygenation of NO and redox interconversion between O2- and O2 during reaction with O2- (or O2).

Dietary nitrate (NO3-) supplementation can enhance nitric oxide (NO) bioavailability and lower blood pressure (BP) in humans. The nitrite concentration ([NO2-]) in the plasma is the most commonly used biomarker of increased NO availability. However, it is unknown to what extent changes in other NO congeners, such as S-nitrosothiols (RSNOs), and in other blood components, such as red blood cells (RBC), also contribute to the BP lowering effects of dietary NO3-. We investigated the correlations between changes in NO biomarkers in different blood compartments and changes in BP variables following acute NO3- ingestion. Resting BP was measured and blood samples were collected at baseline, and at 1, 2, 3, 4 and 24 h following acute beetroot juice (∼12.8 mmol NO3-, ∼11 mg NO3-/kg) ingestion in 20 healthy volunteers. Spearman rank correlation coefficients were determined between the peak individual increases in NO biomarkers (NO3-, NO2-, RSNOs) in plasma, RBC and whole blood, and corresponding decreases in resting BP variables. No significant correlation was observed between increased plasma [NO2-] and reduced BP, but increased RBC [NO2-] was correlated with decreased systolic BP (rs = -0.50, P = 0.03). Notably, increased RBC [RSNOs] was significantly correlated with decreases in systolic (rs = -0.68, P = 0.001), diastolic (rs = -0.59, P = 0.008) and mean arterial pressure (rs = -0.64, P = 0.003). Fisher's z transformation indicated no difference in the strength of the correlations between increases in RBC [NO2-] or [RSNOs] and decreased systolic blood pressure. In conclusion, increased RBC [RSNOs] may be an important mediator of the reduction in resting BP observed following dietary NO3- supplementation.

As one of the triumvirate of recognized gasotransmitter molecules, namely NO, H2S, and CO, the physiological effects of CO and its potential as a biomarker have been widely investigated, garnering particular attention due to its reported hypotensive, anti-inflammatory, and cytoprotective properties, making it a promising therapeutic agent. However, the development of CO molecular probes has remained relatively stagnant in comparison with the fluorescent probes for NO and H2S, owing to its inert molecular state under physiological conditions. In this review, starting from elucidating the definition and significance of CO as a gasotransmitter, the imperative for the advancement of CO probes, especially fluorescent probes, is expounded. Subsequently, the current state of development of CO probe methodologies is comprehensively reviewed, with an overview of the challenges and prospects in this burgeoning field of research.

Successful pregnancy for optimal fetal growth requires adequate early angiogenesis and remodeling of decidual spiral arterioles during placentation. Prior to the initiation of invasion and endothelial replacement by trophoblasts, interactions between decidual stromal cells and maternal leukocytes, such as uterine natural killer cells and macrophages, play crucial roles in the processes of early maternal vascularization, such as proliferation, apoptosis, migration, differentiation, and matrix and vessel remodeling. These placental angiogenic events are highly dependent on the coordination of several mechanisms at the early maternal-fetal interface, and one of them is the expression and activity of matrix metalloproteinases (MMPs) and endothelial nitric oxide synthases (NOSs). Inadequate balances of MMPs and nitric oxide (NO) are involved in several placentopathies and pregnancy complications. Since alcohol consumption during gestation can affect fetal growth associated with abnormal placental development, recently, we showed, in a mouse model, that perigestational alcohol consumption up to organogenesis induces fetal malformations related to deficient growth and vascular morphogenesis of the placenta at term. In this review, we summarize the current knowledge of the early processes of maternal vascularization that lead to the formation of the definitive placenta and the roles of angiogenic MMP and NOS/NO mechanisms during normal and altered early gestation in mice. Then, we propose hypothetical defective decidual cellular and MMP and NOS/NO mechanisms involved in abnormal decidual vascularization induced by perigestational alcohol consumption in an experimental mouse model. This review highlights the important roles of decidual cells and their MMP and NOS balances in the physiological and pathophysiological early maternal angiogenesis-vascularization during placentation in mice.

Hospital mortality in sepsis varies between 30-45%. It has been shown that administration of inhaled nitric oxide (iNO) and intravenous corticosteroid in a porcine endotoxemia model attenuated the systemic inflammatory response. We explored the anti-inflammatory effect of a double-treatment strategy (iNO + low-dose steroid) on the lungs in a long-term porcine endotoxic shock model. As metalloproteinases (MMPs) are involved in the initiation of multiple organ dysfunction in septic shock, we evaluated the influence of this combination therapy on MMP2 and MMP9 activity and proIL-1β maturation. A shock-like condition was established in 23 animals by continuous infusion of E. coli lipopolysaccharide (LPS) for 10 h. Then the animals were observed for 10 h. Twelve pigs received iNO and hydrocortisone (iNO treatment started 3 h after the initial LPS infusion and continued until the end of the experiment). Eleven pigs were controls. Pigs treated with iNO and hydrocortisone displayed less inflammatory infiltrates in the lungs than the controls and a lower level of IL-1β. The proMMP2 was significantly decreased in the iNO and hydrocortisone group. The amount of an active MMP9 (~ 60 kDa) was decreased in the iNO and hydrocortisone group. Total gelatinolytic activity was lower in the iNO and hydrocortisone group. Reduced MMP activity was accompanied by a 2.5-fold decrease of the active IL-1β form (17 kDa) in the pulmonary tissue of iNO combined with hydrocortisone exposed pigs. We demonstrated that in a porcine endotoxemia model the NO inhalation combined with intravenous hydrocortisone led to the attenuation of the inflammatory cascade induced by bacterial LPS. The decrease in pulmonary MMPs activities was accompanied by reduced proIL-1β processing.

Nitric oxide (NO) exerts diverse effects on the cardiovascular system. Impairment of NO production plays a key role in cerebral and coronary artery spasm. We aimed to explore the predicting factors of radial artery spasm (RAS) and the association of eNOS gene polymorphism (Glu298Asp) with RAS during cardiac catheterization.

200 patients underwent elective coronary angiography through a trans-radial approach. The subjects were genotyped to the Glu298Asp polymorphism (rs1799983) on the eNOS gene by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our results showed that the subjects with the TT genotype and T allele were significantly more likely to develop radial artery spasms (OR = 12.5, 4.6, P < 0.001 respectively). TT genotype of eNOS Glu298Asp polymorphism, number of punctures, size of the radial sheath, radial tortuosity, and right radial access are independent predictors of radial spasm.

The eNOS (Glu298Asp) gene polymorphism is associated with RAS during cardiac catheterization in Egyptians. TT genotype of eNOS Glu298Asp polymorphism, number of punctures, size of the radial sheath, right radial access, and tortuosity are independent predictors of RAS during cardiac catheterization.

There have been significant advances in the treatment of migraine. In response to the clinical success of monoclonal antibodies targeting calcitonin gene-related peptide, there is interest in the clinical trial outcomes of alternative emerging drugs that act on novel targets associated with migraine pathophysiology. As approximately 50% of patients do not respond to CGRP therapies, there is significant value in future drug innovation. Emerging drugs in clinical trials for the treatment of migraine aim to fill this need.

The emerging drugs that will be discussed in this review include zavegepant, lasmiditan, delta opioid receptor agonists, neuronal nitric oxide synthase inhibitors, monoclonal antibodies targeting pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor, dual orexin receptor antagonists, metabotropic glutamate receptor 5 antagonists, and inducers of ketosis.

When considering the preclinical and clinical research related to the emerging drug classes discussed in this review, most therapies are derived from highly supported targets of migraine pathogenesis. Although the individual drugs discussed in this review may be of dubious clinical value, the importance of the therapeutic targets on which they act cannot be understated. Future research is necessary to appropriately target the pathways elucidated by preclinical studies.

Vascular system is a complex network in which different cell types and vascular segments must work in concert to regulate blood flow distribution and arterial blood pressure. Although paracrine/autocrine signaling is involved in the regulation of vasomotor tone, direct intercellular communication via gap junctions plays a central role in the control and coordination of vascular function in the microvascular network. Gap junctions are made up by connexin (Cx) proteins, and among the four Cxs expressed in the cardiovascular system (Cx37, Cx40, Cx43, and Cx45), Cx40 has emerged as a critical signaling pathway in the vessel wall. This Cx is predominantly found in the endothelium, but it is involved in the development of the cardiovascular system and in the coordination of endothelial and smooth muscle cell function along the length of the vessels. In addition, Cx40 participates in the control of vasomotor tone through the transmission of electrical signals from the endothelium to the underlying smooth muscle and in the regulation of arterial blood pressure by renin-angiotensin system in afferent arterioles. In this review, we discuss the participation of Cx40-formed channels in the development of cardiovascular system, control and coordination of vascular function, and regulation of arterial blood pressure.

Objective: The positive impact of aerobic exercise on blood oxidative stress parameters is well documented. However, the effect of core exercises on these parameters in amputee football players (AF) remains unclear. Therefore, this study aims to investigate the impact of core exercises on blood oxidative stress parameters in this population. Methods: Experimental method was adopted in the study. Eleven elite AF players participated in the study. The participants were divided randomly into two groups a core exercise group (CEG) and a control group (CG). Blood measurements were taken before and after the 8-week core exercise program. Blood measurements included erythrocyte Total Oxidant Status (eTOS), erythrocyte Total Antioxidant Status (eTAS), erythrocyte oxidative stress index (eOSI), serum nitric oxide (sNO), serum Total Oxidant Status (sTOS), serum Total Antioxidant Status (sTAS), serum oxidative stress index (sOSI), serum total thiol (sTT), serum native thiol (sNT), and serum disulfide (sDS) parameters were studied. Results: According to the results of the study, a significant difference was found between the 0th and eighth week pre-aerobic training load (ATL) sTOS (p = .028) values of CEG values. A significant difference was found in sTOS (p = .028) and sOSI (p = .028) values after the 0th and eighth-week pre-ATL. A significant difference was found in the sTOS (p = .043) and sOSI values (p = .043) of CG at week 0th and eighth-week pre-ATL. Conclusion: Overall, the results suggest that core exercises had a positive effect on blood oxidative stress parameters in AF players by reducing blood total oxidant levels.

Preeclampsia (PE) is a multisystem obstetric disorder that affects 2-10% of pregnancies worldwide and it is a leading cause of maternal and fetal morbidity and mortality. The etiology of PE development is not clearly delineated, but since delivery of the fetus and placenta often leads to symptom resolution in the most cases of PE, it is hypothesized that the placenta is the inciting factor of the disease. Current management strategies for PE focus on treating the maternal symptoms to stabilize the mother in an attempt to prolong the pregnancy. However, the efficacy of this management strategy is limited. Therefore, identification of novel therapeutic targets and strategies is needed. Here, we provide a comprehensive overview of the current state of knowledge regarding mechanisms of vascular and renal pathophysiology during PE and discuss potential therapeutic targets directed at improving maternal vascular and renal function.

Metabolic syndrome is a cluster of conditions associated with the risk of diabetes mellitus type 2 and cardiovascular diseases (CVDs). Metabolic syndrome is closely related to obesity. Increased adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving metabolic syndrome components, namely insulin resistance, hypertension, and hyperlipidemia. An increasing number of studies confirm the importance of oxidative stress and chronic inflammation in the etiology of metabolic syndrome. However, few studies have reviewed the mechanisms underlying the role of oxidative stress in contributing to metabolic syndrome. In this review, we highlight mechanisms by which reactive oxygen species (ROS) increase mitochondrial dysfunction, protein damage, lipid peroxidation, and impair antioxidant function in metabolic syndrome. Biomarkers of oxidative stress can be used in disease diagnosis and evaluation of severity.

Nitric oxide, a ubiquitous molecule found throughout the natural world, is a key molecule implicated in many central and benefic molecular pathways and has a well-established role in the function of the central nervous system, as numerous studies have previously shown. Dysregulation of its metabolism, mainly the upregulation of nitric oxide production, has been proposed as a trigger and/or aggravator for many neurological affections. Increasing evidence supports the implication of this molecule in prevalent neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis. The mechanisms proposed for its neurotoxicity mainly center around the increased quantities of nitric oxide that are produced in the brain, their cause, and, most importantly, the pathological metabolic cascades created. These cascades lead to the formation of neuronal toxic substances that impair the neurons' function and structure on multiple levels. The purpose of this review is to present the main causes of increased pathological production, as well as the most important pathophysiological mechanisms triggered by nitric oxide, mechanisms that could help explain a part of the complex picture of neurodegenerative diseases and help develop targeted therapies.

We have synthesized cis-[Ru(bpy)₂(NO₂-κN)L^n-]^(n-1) and cis-[Ru(bpy)₂(NO₂-κO)L ^n-]^(n-1) (bpy = 2,2'-bipyridine; k = indication of the coordinated center to Ruthenium; L = pyridine type ligand) by reacting cis-[Ru(bpy)₂(H₂O)L^n-]^(n-2) with sodium nitrite or conducting basic cis-[Ru(bpy)₂NO(L^n-)]^(n-3) hydrolysis. Photolysis at the metal-ligand charge transfer band (MLCT) of the isomers yielded nitric oxide (NO) as determined by NO measurement. The NO photorelease rates obtained upon 447 nm laser irradiation of the ruthenium complexes showed that cis-[Ru(bpy)₂(NO₂-κO)L^n-]^(n-1) released NO three times faster than cis-[Ru(bpy)₂(NO₂-κN)L^n-]^(n-1). We investigated endothelium-dependent vasodilation induced by cis-[Ru(bpy)₂(4-pic)(NO₂-κN)]⁺ and cis-[Ru(bpy)₂(4-pic)(NO₂-κO)]⁺ (4-pic = 4-picoline) in isolated 3 mm aortic rings precontracted with L-phenylephrine. Maximum vasodilation was achieved under 447 nm laser irradiation of 0.5 μMol.L^-1 ruthenium complexes for 100 s.