iNOS deficiency aggravates DNFB-induced atopic dermatitis in mice.

Nitric oxide signaling in Alzheimer's disease: A double-edged sword.

Nitric oxide (NO) is a central signaling molecule that regulates vascular tone, neurotransmission, and immune function. NO production from L-arginine by nitric oxide synthase (NOS) must be tightly controlled, as excess NO contributes to oxidative and nitrosative stress. Asymmetric dimethylarginine (ADMA) and monomethylarginine (L-NMMA) are endogenous NOS inhibitors whose accumulation leads to cardiovascular, renal, and neurodegenerative diseases. Dimethylarginine dimethylaminohydrolase (DDAH) converts ADMA and NMMA to L-citrulline and dimethylamine or monomethylamine, respectively, thereby controlling NO bioavailability. Two DDAH isoforms are present in humans, namely, DDAH1 and DDAH2. DDAH1 has a demonstrated role in the catabolism of ADMA, while DDAH2 appears to be functionally divergent, playing potential regulatory and signaling roles. Structural analyses reveal that, despite a conserved α/β-propeller architecture, the different biochemical properties of the two isoforms depend on key amino acid substitutions within the active site. Dysregulation of DDAH1 leads to pathological ADMA accumulation, linking impaired enzyme function to endothelial dysfunction and oxidative stress. Consequently, DDAH1 represents an emerging therapeutic target, and several substrate analogues, small molecules, and natural ligands have been identified as inhibitors. On the other hand, the assessment of DDAH2 function is still to be defined. The present review summarizes current molecular, biochemical, and structural insights into DDAH isoforms and discusses their potential as pharmacological targets for diseases associated with altered NO signaling.

Sepiapterin: From sapropterin to next-generation therapy.

To investigate the effects of a 13-week Pilates Method (PM) program, combining mat and apparatus-based exercises, on ambulatory blood pressure (BP), autonomic reflex regulation, and endothelial function in women with hypertension receiving pharmacological treatment. Twenty-eight women with hypertension (39-59 years) were randomized to a control group (CG, n = 14) or a Pilates group (PG, n = 14). The PG completed supervised PM sessions twice weekly, while the CG maintained usual care. Outcomes included ambulatory BP monitoring (24-h, daytime, and nighttime), heart rate variability (HRV), autonomic reflex tests (Valsalva ratio, deep breathing, HR and BP response to standing, and isometric handgrip), flow-mediated dilation (FMD), and circulating nitric oxide (NO) and nitric oxide synthase (NOS). Analyses were adjusted for baseline body weight. Significant Group × Time interactions were observed for all ambulatory BP parameters (all P ≤ 0.022, η2p = 0.19-0.31), with greater reductions in PG (e.g., 24-h SBP -10.3 mmHg, P = 0.009). Among autonomic reflex tests, only the deep breathing test demonstrated a significant interaction (P < 0.001, η2p = 0.61), whereas HRV indices did not change. FMD showed no time or interaction effects. NO decreased in the CG (P = 0.002) but remained stable in the PG, while NOS decreased in the PG (P < 0.001). A 13-week PM program was associated with reductions in ambulatory BP and enhanced autonomic reflex responsiveness in women with hypertension. PM appears to be a feasible and safe low-to-moderate-intensity adjunct to pharmacological treatment, with favorable hemodynamic effects.

NOS2 and COX2 impact the spatial landscape of CD8+ T cells in ER-breast cancer, providing novel mechanistic insight that drives tumor progression and poor survival.

Distinct catalytic activity of Staphylococcus Aureus nitric oxide synthase compared to other bacterial NOS-like enzymes.

Endogenous nitric oxide production induced by pulsed electric field modulates postharvest quality of mango.

Mechanistic insights into ROS induction by Clostridium perfringens epsilon toxin in MDCK cells.

Targeting iNOS and associated proteins in neutrophils: An in-silico and ex-vivo approach for anti-sepsis therapy.

Clerodendrum japonicum (Thunb.) Sweet is a medicinal plant native to East Asia, including Korea, Japan, and China. Its leaves have traditionally been used to relieve respiratory symptoms and inflammatory conditions. However, no studies have systematically explored its anti-inflammatory activity and antioxidant capacity. This study aimed to investigate the anti-inflammatory effects of C. japonicum (Thunb.) Sweet extract (CJSE) in a lipopolysaccharide (LPS)-induced inflammatory model and determine its antioxidant capacity. Anti-inflammatory activity was investigated in LPS-stimulated RAW 264.7 macrophages by evaluating nitric oxide (NO) production, inflammatory gene expression, and related signaling pathways. Antioxidant capacity was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assays and by determining total phenolic and flavonoid contents. CJSE reduced LPS-induced NO production in a dose-dependent manner without detectable cytotoxicity. CJSE also decreased the expression of key inflammatory mediators, including inducible nitric oxide synthase and cyclooxygenase-2, and proinflammatory cytokine genes, such as tumor necrosis factor-α, interleukin-6, and interferon-β. Mechanistically, CJSE was associated with reduced phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) in LPS-stimulated cells. Moreover, CJSE demonstrated strong DPPH and ABTS radical scavenging activities and contained substantial levels of phenolic and flavonoid compounds, which supported its antioxidant potential. CJSE suppresses LPS-induced inflammatory responses in macrophages and exhibits remarkable antioxidant capacity, suggesting that it could serve as a potential natural source of bioactive compounds for managing inflammation and oxidative stress.

The antihypertensive and cardiovascular effects of lawsone methyl ether in high salt-induced hypertensive rats are mediated through multiple pathways.

Infection-driven bladder carcinogenesis: Molecular mechanisms of pathogen-urothelial cell interactions.

Linagliptin enhances coronary microvascular function and collateralization in a large animal model of cardiometabolic syndrome.

A hallmark of pulmonary hypertension (PH) is the progressive increase in pulmonary arterial resistance caused by impaired pulmonary artery (PA) relaxation and vascular remodeling. Salusin-α, a cardiovascular-active peptide, has been implicated in several cardiovascular diseases; however, its role in PH remains undefined. PAs were isolated from rats for isometric tension recording to assess relaxation. PA remodeling was quantified using histological morphometric analysis. Right ventricular pressure and hypertrophy were measured to evaluate PH severity. Salusin-α levels were significantly decreased in both plasma and PAs from PH rats compared with controls. Both acute and chronic salusin-α administration improved endothelium-dependent and -independent PA relaxation, increased endothelial nitric oxide synthase activity and nitric oxide levels in PA endothelial cells, enhanced Nrf2 (nuclear factor erythroid 2-related factor 2) and superoxide dismutase expression and activity in PA smooth muscle cells, and decreased NAD(P)H oxidase expression, activity, and reactive oxygen species levels. Salusin-α also inhibited PA smooth muscle cell proliferation and migration, attenuated pulmonary vascular remodeling, and decreased right ventricular pressure, hypertrophy, and mortality in PH rats. Neutralizing endogenous salusin-α exerted opposite effects. Pharmacological inhibition demonstrated that endothelial nitric oxide synthase and superoxide dismutase contributed to the protective actions of salusin-α, whereas NAD(P)H oxidase inhibition or reactive oxygen species scavenging prevented the effects of salusin-α neutralization. Salusin-α improves endothelium-dependent vasodilation via endothelial nitric oxide synthase mediated nitric oxide release in PA endothelial cells, and promotes endothelium-independent vasodilation while attenuating pulmonary vascular remodeling via inhibition of NAD(P)H oxidase-reactive oxygen species signaling and activation of the Nrf2/superoxide dismutase signaling. Restoring reduced salusin-α may present a novel therapeutic strategy for PH treatment.

The paraventricular nucleus (PVN) plays a central role in neuroendocrine and autonomic regulation, including male sexual behaviour. Dopaminergic and nitrergic signalling within the PVN are functionally linked, but their cellular relationship remains unclear. We examined the colocalization of dopamine D1 and D2 receptors with neuronal nitric oxide synthase (nNOS) in adult male rats using double-label immunohistochemistry. nNOS-immunoreactive neurons were widely distributed in PVN, with subsets co-expressing D1R or D2R. Approximately 45% of nNOS-positive neurons expressed dopaminergic receptors. These findings provide structural evidence for dopaminergic-nitrergic interaction in the PVN and support the possibility of direct dopaminergic modulation of nitrergic neurons.

The treatment of glioblastoma remains a major clinical challenge, largely due to intrinsic and acquired resistance to Temozolomide (TMZ). We aim to advance a novel therapeutic approach to overcome TMZ resistance in human glioblastoma by using the neuronal nitric oxide synthase inhibitor BA-101 as both a monotherapy and an adjuvant therapy. This approach leverages the additive anti-cancer activity of BA-101 to enhance the efficacy of TMZ and thereby improve treatment outcomes for glioblastoma patients. We used TMZ-resistant human glioblastoma LN-18 and LN-229 cells to study the therapeutic potential and additive anticancer activity of nNOS inhibitor BA-101 using invitro cancer functional assays, including cell proliferation, cell invasion, and migration assays, and biochemical assessment of biomarkers for nitrosative stress, and apoptosis using western blot analysis, flow cytometry and AnnexinV/PI staining. We further performed an invivo preclinical evaluationusing an LN-229 xenograft tumor model in SCID mice. Our findings demonstrate that BA-101 displays significant anti-cancer activity and sensitizes resistant glioblastoma cells to TMZ, reducing nitrosative stress, inhibiting clonogenic growth, invasion and migration, and promoting apoptotic cell death. It also demonstrates a significant decrease in tumor volume, suggesting that BA-101 exerts additive anti-tumor activity when used as an adjuvant to TMZ in SCID mice bearing LN 229 xenografts. Collectively, our findings strongly suggest that BA-101 has potential for further preclinical and translational development as an anticancer agent and a novel TMZ chemosensitizer for GBM therapy.

Nitric oxide redox signaling as a convergent mechanism in aging and fibrosis.

Anti-inflammatory ent-kaurane diterpenoids from the whole plants of Sphagneticola trilobata (L.) Pruski.

Amelioration of obesity-induced endothelial dysfunction by a synthetic ocean-derived peptide via regulating PPARα/γ pathway.