Nitric Oxide Synthesis Research Articles

Endothelial dysfunction in combination of occupational pathology of the respiratory system and atherosclerosis in coal industry workers

Introduction. The increasing prevalence of cardiovascular pathology among industrial workers determines the importance of studying not only occupational diseases, but also their combination with diseases of the circulatory system. Endothelial dysfunction is a key link in the pathogenesis of atherosclerosis. Evaluation of endothelial function indicators in occupational respiratory diseases in combination with atherosclerosis in workers of the coal mining industry is an urgent task. The study aims to consider the indicators of endothelial function in miners with occupational respiratory diseases in combination with atherosclerosis. Materials and methods. The authors have examined 88 miners with previously diagnosed occupational respiratory diseases (chronic dust bronchitis, anthracosilicosis, chronic obstructive pulmonary disease), 45 of them showed signs of atherosclerosis. There were two comparison groups without signs of atherosclerosis: 44 miners who work long-term in harmful working conditions, without lung pathology (control group) and 42 residents of Novokuznetsk who have never worked in harmful working conditions, and without lung pathology (unexposed group). Results. We found that miners with occupational respiratory diseases in combination with atherosclerosis had several forms of endothelial dysfunction: vasomotor (decreased synthesis of nitric oxide, increased endothelin-1 levels), hemostatic (increased levels of Willebrand factor), adhesive (increased levels of endothelial adhesion molecules sVCAM-1). The development of respiratory insufficiency in miners with occupational respiratory diseases increases endothelial dysfunction: miners with respiratory insufficiency have lower levels of nitric oxide (NO), higher levels of endothelin-1 and endothelial adhesion molecules sVCAM-1 than miners without respiratory insufficiency. There are correlations between indicators of endothelial function and production factors: with work experience in harmful working conditions, the level of the average concentration of coal-rock dust in the workplace and the frequency of exceeding the maximum permissible concentration of coal-rock dust. Limitations. The study is limited to a sample of workers in the main professions of coal mines who were examined at the Research Institute of Complex Hygiene Problems and Occupational Diseases, aged 40 to 54 years, with more than 15 years of experience working in underground dust conditions. Conclusion. Miners with occupational respiratory diseases in combination with atherosclerosis develop several forms of endothelial dysfunction: vasomotor, hemostatic, adhesive. The development of respiratory failure increases endothelial dysfunction. Ethics. This medical study involving a human as a subject was carried out in compliance with the Ethical principles presented in the latest version of the Helsinki Declaration, developed by the World Medical Association.

Effect of S-Allyl-L-Cysteine on Nitric Oxide and Cadmium Processes in Rice (Oryza sativa L. sp. Zhongzao35) Seedlings

Nitric oxide (NO) is an important signaling molecule involved in regulating plant processes to cope with abiotic stress. S-allyl-L-cysteine (SAC) is known to induce NO synthesis in animals. However, it is unknown whether SAC can trigger NO biosynthesis, regulate Cd transport, or alleviate Cd stress in plants. After being sprayed with 0.2 mM SAC, rice seedlings had a NO content that was 1.8 times higher than that of the control (ctrl) group at the ninth hour, which then gradually decreased. The expressions of Cd uptake and transport genes in the roots (including OsNRAMP5, OsNRAMP1, and OsHMA2) were markedly downregulated by 27.2%, 24.8%, and 49.1%, respectively, 72 h after SAC spraying treatment. The Cd content in seedling roots’ cell wall (CW) components significantly increased by 43.5% compared to that of the ctrl group. The Cd content in the shoots and roots decreased by 49.0% and 29.8%, respectively. Cd stress in the seedlings was also substantially alleviated. In conclusion, spraying rice seedlings with SAC triggered an increase in NO synthesis, regulated the expression of genes related to Cd transport, increased Cd fixation in the root CW components, and reduced Cd accumulation in the roots and shoots.

β3-adrenergic agonist counters oxidative stress and Na+-K+ pump inhibitory S-glutathionylation of placental cells: Implications for preeclampsia.

Oxidative stress from placental ischemia/reperfusion and hypoxia/reoxygenation (H/R) in preeclampsia is accompanied by Na+-K+ pump inhibition and S-glutathionylation of its β1 subunit (GSS-β1), a modification that inhibits the pump. β3-adrenergic receptor (β3-AR) agonists can reverse GSS-β1. We examined effects of the agonist CL316,243 on GSS-β1 and sources of H/R-induced oxidative stress in immortalized first trimester human trophoblast (HTR-8/SVneo) and freshly isolated placental explants from normal term pregnancies. H/R increased GSS-β1 and, reflecting compromised α1/β1 subunit interaction, it reduced α1/β1 pump subunit co-immunoprecipitation. H/R increased p47phox/p22phox NADPH oxidase subunit co-immunoprecipitation reflecting membrane translocation of cytosolic p47phox that is needed to activate NADPH oxidase. Fluorescence of O2•--sensitive dihydroethidium increased in parallel. H/R increased S-glutathionylation of endothelial nitric oxide synthase (GSS-eNOS) that uncouples NO synthesis towards synthesis of O2•- and reduced trophoblast migration. Oxidative stress induced by tumor necrosis factor α (TNF-α) increased soluble fms-like tyrosine kinase receptor 1 (sFlt-1) trophoblast release, a marker of preeclampsia, and reduced trophoblast integration into endothelial cellular networks. CL316,243 eliminated H/R-induced GSS-β1 and decreases of α1/β1 subunit coimmunoprecipitation, eliminated NADPH oxidase activation and increases in GSS-eNOS, restored trophoblast migration, eliminated increased sFlt-1 release and restored trophoblast integration in endothelial cell networks. H/R induced GSS-β1, α1/β1 subunit co-immunoprecipitation and NADPH oxidase activation of placental explants reflected effects of H/R for trophoblasts and CL316,243 eliminated these changes. We conclude a β3-AR agonist counters key pathophysiological features of preeclampsia in vitro. β3 agonists already in human use for another purpose are potential candidates for re-purposing to treat preeclampsia.

Nitric oxide facilitates the S-nitrosylation and deubiquitination of Notch1 protein to maintain cancer stem cells in human NSCLC.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality, with tumour heterogeneity, fueled by cancer stem cells (CSCs), intricately linked to treatment resistance. Therefore, it is imperative to advance therapeutic strategies targeting CSCs in NSCLC. In this study, we utilized RNA sequencing to investigate metabolic pathway alterations in NSCLC CSCs and identified a crucial role of nitric oxide (NO) metabolism in governing CSC stemness, primarily through modulation of the Notch1 protein. Mechanistically, NO-induced S-nitrosylation of Notch1 facilitated its interaction with the deubiquitylase UCHL1, leading to increased Notch1 protein stability and enhanced CSC stemness. By inhibiting NO synthesis and downregulating UCHL1 expression, we validated the impact of NO on the Notch signalling pathway and CSC stemness. Importantly, targeting NO effectively reduced CSC populations within patient-derived organoids (PDOs) during radiotherapy. This mechanism presents a promising therapeutic target to surmount radiotherapy resistance in NSCLC treatment.

Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to prevent HER2+ breast cancer.

Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing SEP, the endogenous precursor of BH 4 (the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we report that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively prevented tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention. These findings suggest the possible roles of the SEP/BH 4 /NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.

L-Arginine and asymmetric dimethylarginine (ADMA) transport across the mouse blood-brain and blood-CSF barriers: Evidence of saturable transport at both interfaces and CNS to blood efflux

L-Arginine is the physiological substrate for the nitric oxide synthase (NOS) family, which synthesises nitric oxide (NO) in endothelial and neuronal cells. NO synthesis can be inhibited by endogenous asymmetric dimethylarginine (ADMA). NO has explicit roles in cellular signalling and vasodilation. Impaired NO bioavailability represents the central feature of endothelial dysfunction associated with vascular diseases. Interestingly, dietary supplementation with L-arginine has been shown to alleviate endothelial dysfunctions caused by impaired NO synthesis. In this study the transport kinetics of [3H]-arginine and [3H]-ADMA into the central nervous system (CNS) were investigated using physicochemical assessment and the in situ brain/choroid plexus perfusion technique in anesthetized mice. Results indicated that L-arginine and ADMA are tripolar cationic amino acids and have a gross charge at pH 7.4 of 0.981. L-Arginine (0.00149±0.00016) has a lower lipophilicity than ADMA (0.00226±0.00006) as measured using octanol-saline partition coefficients. The in situ perfusion studies revealed that [3H]-arginine and [3H]-ADMA can cross the blood-brain barrier (BBB) and the blood-CSF barrier. [3H]-Arginine (11.6nM) and [3H]-ADMA (62.5nM) having unidirectional transfer constants (Kin) into the frontal cortex of 5.84±0.86 and 2.49±0.35 μl.min-1.g-1, respectively, and into the CSF of 1.08±0.24 and 2.70±0.90 μl.min-1.g-1, respectively. In addition, multiple-time uptake studies revealed the presence of CNS-to-blood efflux of ADMA. Self- and cross-inhibition studies indicated the presence of transporters at the BBB and the blood-CSF barriers for both amino acids, which were shared to some degree. Importantly, these results are the first to demonstrate: (i) saturable transport of [3H]-ADMA at the blood-CSF barrier (choroid plexus) and (ii) a significant CNS to blood efflux of [3H]-ADMA. Our results suggest that the arginine paradox, in other words the clinical observation that NO-deficient patients respond well to oral supplementation with L-arginine even though the plasma concentration is sufficient to saturate endothelial NOS, could be related to altered ADMA transport (efflux).

Antioxidant and anti-glycation activities of Mandevilla velutina extract and effect on parasitemia levels in Trypanosoma cruzi experimental infection: In vivo, in vitro and in silico approaches

Ethnopharmacological relevanceMandevilla velutina (Mart. Ex Stadelm.) Woodson, known in Brazil as "infalível" and "jalapa", is a medicinal plant native from the Cerrado region (Brazilian Savannah). The underground organ (xylopodium) of this species is prepared as ethanolic extract or infusion and it is commonly used in traditional medicine to treat snake venom. Although, locals and indigenous populations from Cerrado have used M. velutina for the treatment of infection by Trypanosoma cruzi (Chagas’ disease). Aim of the studyThis study aimed to evaluate the in vitro antioxidant and anti-glycation activities of the crude hydroethanolic extract of M. velutina xylopodium. Besides, it aimed to evaluate its effect on parasitemia levels in vivo T. cruzi experimental infection. In addition, this study aimed to determine possible interactions between the main compound of the extract and molecular targets associated with survival and virulence of T. cruzi in silico approaches. Materials and methodsDetermination of total polyphenols, flavonoids and steroidal aglycones content were performed. In addition, high performance liquid chromatography (HPLC) was carried out to identify main compounds of the extract. Antioxidant activity was determined by DPPH radical scavenging, ferric ion reducing power (FRAP), Thiobarbituric acid reactive species (TBARS) and Oxygen Radical Absorbance Capacity (ORAC) methods. Anti-glycation activity was demonstrated through relative mobility in electrophoresis (RME), determination of free amino groups and inhibition of AGEs formation. Determination of the action of extract in parasitemia levels was performed by T. cruzi experimental infection of mice and nitrite levels were measured in the serum of animals evaluated in this study. Molecular docking analyses of the main compound (Velutinol A) with DNA and molecular targets associated with survival and virulence of T. cruzi. ResultsPhytoconstituents evaluation exhibited the presence polyphenols, flavonoids and steroidal aglycone, and HPLC identified the major presence of Velutinol A. Antioxidant and anti-glycation evaluations showed that the extract present significant activity in all methods evaluated. In addition, extract reduced the number of trypomastigotes and increased the survival of treated animals. The treatment using extract showed an interference in the synthesis of physiological nitric oxide as an immune response to infection. In silico assays demonstrated interaction between Velutinol A and DNA and molecular targets of T. cruzi. ConclusionsThe results showed that the hydroethanolic extract of M. velutina xylopodium contains bioactive compounds including polyphenols, flavonoids and steroidal aglycones (mainly Velutinol A) of which may be responsible for the antioxidant, anti-glycation and anti-parasitic activity against T. cruzi. Trypanocidal activity of M. velutina compounds may be linked to their influence on NO synthesis during infection and/or their capacity to bind and inhibit molecules associated to virulence and survival of T. cruzi.

L-arginine, aminoguanidine and mesenchymal stem cells reduce the level of endoplasmic reticulum stress markers and D-dimer in the lungs of mice with antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by damage to the intima of the microcirculatory blood vessels as a result of the formation of autoimmune antibodies to phospholipids of cell membranes. Recent data indicate a possible link between the occurrence of autoimmune diseases and endoplasmic reticulum stress, impaired nitric oxide availability, high plasma D-dimer level. The aim of the study was to estimate the effect of nitric oxide synthesis modulators L-arginine and aminoguanidine, and mesenchymal stem cells on the level of inositol-requiring enzyme-1a (IRE-1a), glucose-regulated protein 78 (GRP-78) as ER stress markers, and the level of D-dimer in the lung tissue of female BALB/c line mice with experimental APS induced with cardiolipin administration. 30 experimental animals were divided into five groups: 1 – control animals; 2 – mice with APS; 3 – mice with APS, injected intraperitoneally with L-arginine hydrochloride (25 mg/kg) and aminoguanidine (10 mg/kg); 4 – mice with APS, injected intraperitoneally with stem cells (5×106/kg); 5 – mice with APS, injected with L-arginine hydrochloride, aminoguanidine and stem cells in combination. After 10 days post APS formation animals were removed from the experiment, proteins were extracted from the lung tissue and their level was determined with Western blotting. It was established that in group with APS the levels of IRE-1, GRP-78 and D-dimer were substantially increased as compared to the control group. After separate administration of both arginine with aminoguanidine and MSC, as well as with their combined use, the level of IRE-1, GRP-78 and D-dimer decreased compared to the indices in animals with induced APS. The obtained data indicated that this effect is probably due to the reduction of ER stress through iNOS inhibition and the anti-inflammatory action of MSCs. Keywords: aminoguanidine, antiphospholipid syndrome, D-dimer, endoplasmic reticulume stress, GRP-78, IRE-1, L-arginine, lung, mesenchymal stem cells

Lack of AMP-activated protein kinase-α1 reduces nitric oxide synthesis in thoracic aorta perivascular adipose tissue

ObjectivePerivascular adipose tissue (PVAT) releases anti-contractile bioactive molecules including NO. PVAT anti-contractile activity is attenuated in mice lacking AMPKα1 (AMP-activated protein kinase-α1). As AMPK regulates endothelial NO synthase (eNOS) activity in cultured cells, NO synthesis was examined in PVAT from AMPKα1 knockout (KO) mice. Methods and resultsEndothelium-denuded thoracic or abdominal aortic rings were isolated from wild type (WT) and KO mice. NOS inhibition enhanced vasoconstriction in PVAT-intact thoracic aortic rings from mice of either genotype yet had no effect on abdominal rings as assessed by wire myography. Thoracic aorta PVAT exhibited increased NO production, NOS activity and levels of the brown adipose tissue marker uncoupling protein-1 (UCP1) compared to abdominal PVAT. In KO mice, NO production was significantly reduced in thoracic but not abdominal PVAT. Reduced NO production in KO thoracic PVAT was not due to altered levels or phosphorylation of eNOS but was associated with increased caveolin-1:eNOS association and caveolin-1 Tyr14 phosphorylation. A peptide that disrupts eNOS:caveolin-1 association increased NO synthesis and reduced vasoconstriction of PVAT-intact thoracic but not abdominal aortic rings. KO thoracic PVAT also exhibited reduced UCP1 levels. ConclusionsMurine thoracic aorta PVAT exhibits higher NO synthesis and UCP1 levels than abdominal aortic PVAT. Downregulation of AMPK suppresses NO synthesis which may contribute to the reduced anticontractile activity and reduced brown adipose tissue phenotype of KO thoracic PVAT. The mechanism underlying the effect of AMPK downregulation likely results from increased caveolin-1:eNOS association associated with caveolin-1 Tyr14 phosphorylation.

Nitric Oxide: Structure, Pathophysiology and Clinical Significance

Hypertension is the most important modifiable risk factor and, if treated, leads to a reduction in cardiovascular diseases and mortality. A recent perspective emphasizes the central role of nitric oxide bioavailability in the maintenance of healthy vasculature and the regulation of blood pressure. The molecule nitric oxide is very complex with far-reaching implications concerning cardiovascular well-being and pathology. Synthesis of nitric oxide as well as signaling cascades and their regulation thus stands as a critical process in acquiring an understanding regarding its involvement under physiological as well as pathological conditions. With the rapid pace at which NO research is evolving, there are significant gaps in our knowledge that must be filled in if we are ever to take full advantage of its therapeutic potential. Nitric oxide is also considered to be a very important molecule involved in the defense of hypertension through its effects on endothelial function and vascular homeostasis. This review will summarize the current state of knowledge regarding the relationship between NO and hypertension and will attempt to identify those areas where significant lacunae exist and where further research would be appropriate. In addition, focus is directed toward the structure and clinical relevance of NO, describing its functions in endothelial activity, cardiovascular health, and any possible clinical utility.

Neuro- and vasoprotective potential of neuropeptide Y Y2 receptor agonist, NPY13-36, against transient focal cerebral ischemia in spontaneously hypertensive rats

Numerous in vitro and in vivo experimental studies indicate that neuropeptide Y Y2 receptors (Y2R) are potential targets for neuroprotective therapy, including neuroprotection against ischemic stroke in healthy rats. Since stroke in humans is typically associated with comorbidities and long-term hypertension is the most common comorbidity leading to stroke, this study aimed to assess the neuroprotective potential of the Y2R agonist NPY13–36 in the rats with essential hypertension (SHR) subjected to 90 min middle cerebral artery suture occlusion with subsequent reperfusion (MCAOR). The cerebrocortical microflow in the ischemic focus and penumbra was continuously monitored with a Laser-Doppler flowmeter. NPY13–36 (10 μg/6 μl physiological saline solution) was administered intracerebroventricularly (i.c.v.) during ischemia or early reperfusion. The infarct area (triphenyltetrazolium chloride staining), behavioral tests (gait, mobility, and sensorimotor functions), and the response of the cerebrocortical microcirculation in the penumbra to hypercapnia and to the inhibition of the synthesis of nitric oxide were studied. Our results demonstrate that administration of NPY13-36 reduces the size of the infarct, improves motor functions, and restores microcirculatory response to the blockade of nitric oxide synthase when administered during reperfusion. The novelty of this study is a finding of the vasoprotective effect of NPY13-36 in brain ischemia/reperfusion. Moreover, this study provides evidence of the beneficial effects of NPY13-36 in animals with essential hypertension and indicates that Y2R ligands may be promising candidates for treating the ischemic brain in the case of this disease.

Transient changes in L-arginine, asymmetric and symmetric dimethyl arginine in triathletes following Norseman Xtreme Triathlon.

Arterial vasodilation is dependent on nitric oxide synthesized from L-arginine by endothelial nitric oxide synthase. Triathletes are reported to display altered serum concentrations of nitric oxide metabolites such as L-arginine, asymmetric dimethyl arginine (ADMA) and symmetric dimethyl arginine (SDMA) shortly after completing long-distance triathlon races. In other populations, similar changes to nitric oxide metabolites are established risk markers of cardiovascular disease. The objective of this study was to assess serum concentrations of metabolites for endothelial nitric oxide synthesis in triathletes one week following a long-distance triathlon race. In this prospective observational study, we used high-performance liquid chromatography to measure circulating concentrations of L-arginine, ADMA, and SDMA in triathletes. Venous blood samples were collected before, immediately after, day one, and one week following the triathlon race. Serum concentrations and L-arginine/ADMA ratio were determined for each time-point and compared to baseline. L-arginine/ADMA ratio was reduced on day one (147 ± 32 vs 163 ± 40, p < 0.02). ADMA was reduced immediately after and increased at day one and remained elevated at oneweek (0.29 ± 0.05μM, p < 0.001, 0.44 ± 0.08μM, p < 0.001 and 0.42 ± 0.07μM, p = 0.04, respectively vs 0.40 ± 0.05μM). SDMA was increased at all time-points when compared to baseline (0.48 ± 0.10μM, p < 0.001, 0.53 ± 0.11μM, p < 0.001 and 0.42 ± 0.08μM, p = 0.048 vs 0.38 ± 0.05μM). L-arginine was only decreased immediately after (46.0 ± 9.3μM vs. 64.6 ± 16.1μM, p < 0.001). Long-distance triathlon racing induces altered levels of metabolites for endothelial nitric oxide production that mostly normalizes within one week following racing. The clinical relevance of these transient changes has yet to be elucidated in the athletic population.

The Toxin Diversity, Cytotoxicity, and Enzymatic Activity of Cape Cobra (Naja nivea) Venom.

"True" cobras (genus Naja) are among the venomous snakes most frequently involved in snakebite accidents in Africa and Asia. The Cape cobra (Naja nivea) is one of the African cobras of highest medical importance, but much remains to be learned about its venom. Here, we used a shotgun proteomics approach to better understand the qualitative composition of N. nivea venom and tested its cytotoxicity and protease activity as well as its effect on intracellular Ca2+ release and NO synthesis. We identified 156 venom components representing 17 protein families, with the dominant ones being three-finger toxins, mostly of the short-chain type. Two-thirds of the three-finger toxin entries identified were assigned as cytotoxins, while the remainder were categorized as neurotoxins, including short-chain, long-chain, and ancestral three-finger toxins. We also identified snake venom metalloproteinases and members of CRISP, l-amino acid oxidase, and other families. Protease activity and its effect on intracellular Ca2+ release and NO synthesis were low. Phospholipase A2 activity was surprisingly high, despite this toxin family being marginally recovered in the analyzed venom. Cytotoxicity was relevant only at higher venom concentrations, with macrophage and neuroblastoma cell lines showing the lowest viability. These results are in line with the predominantly neurotoxic envenomation symptoms caused by Cape cobra bites. The present overview of the qualitatively complex and functionally intriguing venom of N. nivea may provide insights into the pathobiochemistry of this species' venom.

Dynamics of nitrergic system activation in the rat brain provoked by experimentally induced seizures

Epilepsy is a pathophysiological condition displaying a highly diverse phenotype. Consequently, comprehending the mechanisms underlying seizures necessitates moving beyond a simplistic model focused on the imbalance between the classical excitatory and inhibitory neurotransmitter systems. Nitric oxide (NO), a nonclassical and multifunctional gaseous neurotransmitter, has the potential to exert a profound influence on epileptic reactivity. Unfortunately, numerous studies have not provided clear answers about its involvement in the pathophysiology of epilepsy. The objective of our study was to delineate the temporal dynamics of alterations in nitrergic system activation after experimentally induced seizures. Seizures were induced in 2-month-old male Wistar rats by an administration of pilocarpine. Over a 6-hour observation period, seizure behaviour intensity was continuously evaluated using a modified Racine scale. At intervals of 6, 12, 24, 48, or 96 h post-chemoconvulsant administration, NO spin trapping was conducted with ferrous-diethyldithiocarbamate complexes (Fe(DETC)2). Electron paramagnetic resonance (EPR) spectroscopy was employed to quantify mononitrosyl iron complexes (NO-Fe(DETC)2) in the brain. The temporal kinetic of NO release after seizures revealed a rise in NO synthesis during the initial 12 h. Subsequently, a sharp decline occurred, returning to baseline 96 h after pilocarpine injection. Notably, our research suggests that the level of NO synthesis does not interfere with the severity of the epileptic seizures that occur. In light of this, we propose that the nitrergic system is quickly activated in the epileptic brain as a compensatory mechanism of the central nervous system. However, under usual conditions, this activation is insufficient to effectively attenuate seizures.

The Role of Inducible Nitric Oxide Synthase in Assessing the Functional Level of Coronary Artery Lesions in Chronic Coronary Syndrome.

Chronic coronary syndrome (CCS) is a long-term manifestation of coronary artery disease, marked by stable but recurring chest pain and myocardial ischemia due to the gradual buildup of atherosclerotic plaques in the coronary arteries. It is a metabolic disorder of coronary arteries characterized by oxidative stress, endothelial dysfunction, inflammation, and hyperlipidemia. The imbalance in oxidative-antioxidative status contributes to stable ischemic heart disease. Oxidative stress involves reactive oxygen and nitrogen species, leading to low-density lipoprotein (LDL) oxidation. Endothelial dysfunction, marked by reduced nitric oxide (NO) bioavailability, is an early onset of CCS, affecting vasodilation, cell proliferation, and inflammatory responses. Enzyme myeloperoxidase (MPO), traditionally considered protective, plays a dual role in initiating and progressing inflammatory diseases. MPO interacts with NO, modulating its catalytic activity. Elevated NO levels inhibit MPO through a reversible complex formation, preventing NO-induced inhibition by inducible nitric oxide synthase (iNOS). MPO also inactivates endothelial nitric oxide synthase (eNOS) and reacts with L-arginine, hindering NO synthesis. The interplay between MPO and NO significantly influences inflammation sites, impacting peroxidation rates and oxidation reactions. Peroxynitrite, a reactive species, contributes to nitration of tyrosine residues and lipid peroxidation. Mechanistic pathways suggest MPO enhances iNOS catalytic activity, influencing CCS development. iNOS, implicated in inflammation and atherosclerosis, is connected to NO regulation. This review analyzes the complex interplay of MPO, iNOS, and NO that affects plaque morphology, oxidative stress, and inflammation, contributing to atherosclerosis progression. Therefore, it is possible that the phenotypes of atherosclerotic plaques, focal and diffuse coronary artery disease, could be defined by the relationship between MPO and iNOS.

The role of L-arginine as a donor of nitric oxide and the prospects for its use: the review

The article discusses recent research on the effective and safe use of the amino acid L-arginine for medicinal purposes in various pathologies. The practical significance of using L-arginine as a source of nitric oxide is considered. The physiological role of nitric oxide, the main vasodilator, was shown, and its deficiency was found to be a key link in endothelial dysfunction. An analysis of modern studies confirming the effectiveness of L-arginine as a donor of nitric oxide was carried out. Ample evidence suggests that oral administration of L-arginine, within physiological limits, can benefit human health by increasing NO synthesis and hence tissue blood flow.

Mitochondrial abnormalities in septic cardiomyopathy.

Septic cardiomyopathy is a common complication in patients with sepsis, and is one of the indicators of poor prognosis. Its pathogenesis is complex, involving calcium ion imbalance in cardiomyocytes, nitric oxide (NO) synthesis disorder, mitochondrial abnormalities and immune inflammatory reaction, especially mitochondrial abnormalities. In this paper, the mechanism of mitochondrial abnormalities causing septic cardiomyopathy was discussed from the aspects of mitochondrial structure change, mitochondrial energy metabolism disorder, redox imbalance, mitochondrial calcium overload, mitochondrial biosynthesis and autophagy abnormalities.

A review of gut microbial metabolites and therapeutic approaches in hypertension

Abstract Background Hypertension is a prevalent and complex disease that is increasingly recognized to be influenced by the gut microbiome and its metabolites. Understanding the relationship between gut microbial metabolites and blood pressure regulation could provide new therapeutic avenues. Main body This review examines the role of key microbial metabolites—short-chain fatty acids, trimethylamine N-oxide, tryptophan derivatives, polyamines, bile acids, and phenylacetylglutamine—in blood pressure regulation. Short-chain fatty acids, produced through dietary fiber fermentation, can lower blood pressure by modulating immune responses and reducing inflammation. Elevated trimethylamine N-oxide levels are associated with increased cardiovascular risk and hypertension, influencing cholesterol metabolism and promoting atherosclerosis. Tryptophan derivatives interact with vascular and renal functions to modulate blood pressure. Polyamines affect blood pressure regulation through their impact on nitric oxide synthesis and vascular tone. Bile acids influence blood pressure via gut microbiota modulation and activation of metabolic receptors. Phenylacetylglutamine has been linked to hypertension through its effects on platelet hyperactivity and thrombosis. Therapeutic approaches targeting these metabolites, including probiotics, prebiotics, fecal microbiota transplantation, dietary interventions, and polyphenols, have shown varying degrees of success. Probiotics and prebiotics promote the growth of beneficial gut bacteria and may lower blood pressure. Dietary interventions, such as the Mediterranean diet, positively affect blood pressure and cardiovascular health by modulating the gut microbiota. Polyphenols, known for their antioxidant properties, are associated with blood pressure reductions and improved vascular function. Fecal microbiota transplantation shows promise in restoring gut microbial balance and improving metabolic health, potentially influencing blood pressure regulation. Conclusion The review highlights the significant role of gut microbial metabolites in regulating blood pressure, offering new avenues for hypertension management. Key metabolites, including short-chain fatty acids, trimethylamine N-oxide, and bile acids, play critical roles in blood pressure modulation. Therapeutic strategies targeting these metabolites, such as probiotics, prebiotics, and dietary interventions, hold promise, though further research is needed to fully understand their mechanisms and optimize their use. Advancing microbiota-based interventions through large-scale studies and exploring personalized therapies will be essential for developing effective treatments in hypertension management.

Accumulation of Cerebrospinal Fluid, Ventricular Enlargement, and Cerebral Folate Metabolic Errors Unify a Diverse Group of Neuropsychiatric Conditions Affecting Adult Neocortical Functions.

Cerebrospinal fluid (CSF) is a fluid critical to brain development, function, and health. It is actively secreted by the choroid plexus, and it emanates from brain tissue due to osmolar exchange and the constant contribution of brain metabolism and astroglial fluid output to interstitial fluid into the ventricles of the brain. CSF acts as a growth medium for the developing cerebral cortex and a source of nutrients and signalling throughout life. Together with perivascular glymphatic and interstitial fluid movement through the brain and into CSF, it also acts to remove toxins and maintain metabolic balance. In this study, we focused on cerebral folate status, measuring CSF concentrations of folate receptor alpha (FOLR1); aldehyde dehydrogenase 1L1, also known as 10-formyl tetrahydrofolate dehydrogenase (ALDH1L1 and FDH); and total folate. These demonstrate the transport of folate from blood across the blood-CSF barrier and into CSF (FOLR1 + folate), and the transport of folate through the primary FDH pathway from CSF into brain FDH + ve astrocytes. Based on our hypothesis that CSF flow, drainage issues, or osmotic forces, resulting in fluid accumulation, would have an associated cerebral folate imbalance, we investigated folate status in CSF from neurological conditions that have a severity association with enlarged ventricles. We found that all the conditions we examined had a folate imbalance, but these folate imbalances were not all the same. Given that folate is essential for key cellular processes, including DNA/RNA synthesis, methylation, nitric oxide, and neurotransmitter synthesis, we conclude that ageing or some form of trauma in life can lead to CSF accumulation and ventricular enlargement and result in a specific folate imbalance/deficiency associated with the specific neurological condition. We believe that addressing cerebral folate imbalance may therefore alleviate many of the underlying deficits and symptoms in these conditions.

Characterization of interferon-stimulated gene 15 from Bostrychus sinensis: Cloning, expression and functional analyses

In this study, the interferon-stimulated gene 15 (referred to as BsISG15) was sequenced and characterized in Bostrychus sinensis. BsISG15 encodes a 155-amino-acid protein weighing ∼17 kDa, featuring two conserved ubiquitin-like domains and an LRGG conjugation motif at the C-terminal. The real-time PCR assays revealed constitutive expression of the BsISG15 gene in all examined organs of healthy B. sinensis, with the peripheral blood showing the highest level of expression. The expression levels of the BsISG15 gene in the head kidney, liver, spleen, and peripheral blood of B. sinensis were significantly altered by both poly (I:C) stimulation and Vibrio parahaemolyticus infection. Western blot analyses showed that the expression of the BsISG15 protein was induced in both the liver and spleen of B. sinensis infected with either poly (I:C) or bacteria, with a concomitant increase in the levels of protein ISGylation, particularly evident in the bacterial-infected liver tissues. Besides, Western blot analyses have demonstrated that head kidney lymphocytes of B. sinensis are capable of secreting the free BsISG15 protein. The recombinant BsISG15 protein significantly increased the production of reactive oxygen species, synthesis of NO, and phagocytosis in macrophages from B. sinensis and also upregulated the expression of proinflammatory cytokine genes (IFNg, IL-1β, IL-6, and IL-8) in these cells. Knockdown of endogenous BsISG15 elevated the expression levels of proinflammatory cytokines IL-1β, IL-6, and IL-8, suggesting a negative regulation of BsISG15 on the inflammatory response in macrophages. The results indicate that BsISG15 plays a significant role in the innate antiviral and antibacterial immunity of B. sinensis.