Cardiovascular-kidney-metabolic (CKM) syndrome is a complex interaction of cardiovascular diseases, chronic kidney disease (CKD), and metabolic disorders, with its global prevalence rising due to increasing obesity and metabolic risk factors. The convergence of these conditions significantly worsens patient outcomes, leading to higher morbidity and mortality rates. Key pathophysiological mechanisms underpinning CKM syndrome include insulin resistance, oxidative stress, inflammation, and vascular dysfunction, all of which are exacerbated by reduced nitric oxide (NO) bioavailability and associated signaling dysfunctions. In clinical practice, organic nitrate has been used as NO donors; however, issues such as tolerance, side effects, and endothelial damage limit their effectiveness. The inorganic nitrate-nitrite-NO pathway offers a promising alternative, as emerging evidence from animal and human studies suggests that enhancing this pathway can significantly improve the progression of metabolic disorders, cardiovascular diseases, and CKD. The potential mechanisms may lie in its ability to improve the core pathophysiological processes of CKM syndrome, including inflammation, oxidative stress, insulin resistance, and vascular dysfunction. This review synthesizes current preclinical and clinical studies, highlighting the effects of inorganic nitrate and nitrite in managing CKM syndrome and suggesting avenues for future exploration.

Adventitious rooting is a key step for the clonal propagation of many economically important horticultural and woody species. Accumulating evidence suggests that nitric oxide (NO) serves as a key signaling molecule with key roles in root organogenesis. However, the role of NO in adventitious root development and its underlying mechanism in sweetpotato cuttings remain to be clarified. In this study, a pot experiment was conducted using hydroponically cultured sweetpotato cuttings (Ipomoea batatas cv. ‘Jin Ganshu No. 9’) treated with different concentrations of sodium nitroprusside (SNP, an NO donor) solution (0, 10, 50, 100, 200, and 500 μmol·L−1). Three treatments were established: Control, SNP (the optimal concentration of SNP), and SNP + 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO, an NO scavenger). The results showed that NO promoted adventitious rooting in a dose-dependent manner, with the maximal biological response observed at 100 μM SNP. At this concentration, the root number and length of adventitious roots increased by 1.22 and 2.36 times, respectively, compared to the control. SNP treatment increased fresh root weight, dry root weight, the content of soluble sugar, soluble protein, chlorophyll a (Chl a), chlorophyll b (Chl b), and total chlorophyll (a + b) [Chl(a + b)], as well as the activities of peroxidase (POD), polyphenol oxidase (PPO), and indole acetic acid oxidase (IAAO). It also enhanced the levels of maximum fluorescence (Fm), maximum photochemical efficiency of photosystem II (Fv/Fm), absorbed light energy (ABS/RC), trapped energy flux (TRo/RC), and electron transport flux (ETo/RC), while decreasing starch content and initial fluorescence (Fo). On the 7th day, the SNP treatment significantly enhanced several biochemical parameters compared to the control. We observed an increase in many of the parameters: POD activity by 1.35 times, PPO activity by 0.55 times, chlorophyll content (Chl a by 0.66 times, Chl b by 0.22 times, and Chl a + b by 0.57 times), and photosynthesis parameters by 28–98%. Meanwhile, starch content and Fo in the SNP treatment decreased by 10.77% and 23.86%, respectively, compared to the control. Furthermore, the positive effects of NO on adventitious root development and associated biochemical parameters were reversed by the NO scavenger cPTIO. Additionally, significant and positive correlations were observed between morphological characteristics and most physiological indicators. Collectively, these results demonstrate that NO promotes adventitious root formation, which may be by enhancing rooting-related enzyme activities, improving photosynthetic performance in leaves, and accelerating the metabolism of soluble sugar, soluble protein, and starch.

The antioxidant/prooxidant effects of dinitrosyl iron complexes (DNICs), physiological donors of nitric oxide (NO•), are studied in reaction systems modeling processes with cytochrome c occurring in mitochondria under oxidative stress and leading to apoptosis. Using luminol-dependent chemiluminescence, DNICs with glutathione and phosphate ligands were shown to decrease the level of prooxidants in a reaction system containing ferricytochrome c and cumene hydroperoxide. Electron paramagnetic resonance (EPR) spectroscopy revealed that glutathione DNICs (DNICs-GS) intercepted the free radicals formed during the interaction between cytochrome c and tert-butyl hydroperoxide. DNICs-GS were also shown to prevent the formation of oligomeric forms of cytochrome c, which were induced by organic hydroperoxides. Reduced glutathione was less effective as an antioxidant than DNICs-GS or could even occasionally exhibit the prooxidant properties. Ferricytochrome c also catalyzed the formation of DNICs-GS with nitroxyl anion (NO−) taking part.

In left ventricular hypertrophy (LVH), the combined external administration of hydrogen sulfide (H2S) and nitric oxide (NO) has been shown to reverse LVH by activating the endothelial nitric oxide synthase pathway (eNOS/NO), independent of the cystathionine γ-lyase (CSE/H2S) pathway. Individually, both H2S and NO have also been reported to significantly improve RCBP, restore renal excretory performance, and enhance α-adrenergic receptor responsiveness in rats. The induction of LVH was performed over a period of two weeks using drinking water with caffeine and isoprenaline. Five weeks later, the rats were fed with L-arginine (1.25 g/L) as a nitrogen oxide donor. Vascular reactions to methoxamine, phenylephrine, and noradrenaline were assessed in presences and absence of 5-methylurapidil (5-MeU), BMY7378, and chloroethylclonidine (CeC) and α1-adrenoceptor antagonists. In both the Control WKY and LVH-WKY groups, combined H2S+NO therapy significantly (p < 0.05) upregulated the renal mRNA of CSE and eNOS when compared with untreated LVH rats. The treatment also markedly increased RCBP in LVH-H2S+NO rats relative to LVH controls. Furthermore, H2S+NO administration enhanced the activity of α1A, α1B, and α1D adrenergic receptors in mediating renal vasoconstriction. Even under receptor blockade with high doses (HDs) of 5-MeU, CeC, and BMY 7378, renal vasoconstriction responses to adrenergic agonists like NA, PE, and ME in the LVH-H2S+NO group remained comparable to those observed in the counterpart Control-H2S+NO group. The findings of current study suggest that simultaneous exogenous administration of H2S and NO donors improve renal cortical blood flow, support renal function, and augment α1A, α1B, and α1D adrenergic receptor responsiveness to adrenergic agonists like NA, PE, and ME in LVH rats. This effect appears to rely primarily on the eNOS/NO pathway, with partial contribution from the CSE/H2S pathway.

Cerebral vasospasm (CVS) following a subarachnoid hemorrhage (SAH) is a critical complication driven by imbalances between vasodilators and vasoconstrictors. This review explores the bidirectional interplay between nitric oxide (NO) and endothelin-1 (ET-1) in CVS pathogenesis. NO, a potent vasodilator mainly produced by endothelial and neuronal nitric oxide synthase (eNOS/nNOS) under normal physiological conditions, is scavenged early after SAH by hemoglobin derivatives, leading to microcirculatory dysfunction, pericyte constriction, and impaired neurovascular coupling. Conversely, ET-1 exacerbates vasoconstriction by suppressing NO synthesis via ROS-dependent eNOS uncoupling and Rho-kinase activation. The NO/ET-1 axis further influences delayed cerebral ischemia (DCI) through mechanisms like 20-HETE-mediated cGMP suppression and oxidative stress. Emerging therapies—including NO donors, NOS gene therapy, and ET-1 receptor antagonists—aim to restore this balance. Understanding these pathways offers translational potential for mitigating CVS and improving outcomes post-SAH.

Sonodynamic therapy (SDT) is a viable alternative to traditional photodynamic therapy owing to its ability to penetrate tissue. However, the therapeutic efficacy of a single SDT treatment is constrained by the prolonged hypoxia of the tumor, rendering SDT ineffective for treating disease. SDT was used in conjunction with nitric oxide (NO) gas in this study to induce apoptosis and ferroptosis in hepatocellular carcinoma (HCC) cells for treating cancer treatment. We synthesized 5,10,15,20-tetra (4-aminophenyl) porphyrin nanobubbles (TAPP@NBs) for the SDT treatment. S-nitroso glutathione (GSNO) was used as an NO gas donor. Thein vitroanticancer effect of the combined treatment was examined using HepG2 and HUH7 hepatoma cell lines. Reactive oxygen species and NO were examined using 2,7-dichlorodihydrofluorescein diacetate and 3-amino,4-aminomethyl-2',7'-difluorescein diacetate staining, respectively. Cell proliferation and apoptosis were analyzed using CCK-8 and flow cytometry, respectively. Ferroptosis was evidenced using glutathione and malondialdehyde assays. The cellular migratory capacity was assessed using a Transwell assay. TAPP@NBs can serve as a sonosensitizer for the SDT. GSNO serves as an NO donor under ultrasound and contributes to gas treatment, considerably increasing SDT efficacy. HCC cell proliferation and migration were considerably lower after combined SDT and NO gas therapy. Combined SDT and NO gas therapy induced apoptosis and ferroptosis in HCC cells. This paper describes a novel approach for optimizing tumor treatment.

Fetal Growth Restriction (FGR) affects up to 10% of pregnancies and is linked to perinatal morbidity and mortality. This review summarizes current and emerging therapies aimed at preventing and treating placental-mediated FGR. Low-dose aspirin initiated before 16 weeks shows the strongest evidence for benefit. Low-molecular-weight heparin and other interventions-including phosphodiesterase-5 inhibitors, statins, nitric oxide donors, VEGF gene therapy, melatonin, and IGF-based strategies-remain investigational. Given shared pathophysiology with preeclampsia, FGR presents an opportunity for early intervention. Future efforts must focus on risk stratification and development of targeted therapies to improve placental function and fetal outcomes.

Aging, one of the main factors associated with cardiovascular diseases, induces vascular modifications through nitric oxide (NO) release and oxidative stress. Based on the antioxidant properties of the non-enzymatic spirulina extract (non-Enz-Spir-E) and that degrading enzymes enhances the extract bioactivity, the aim of this study was to analyze the in vitro effect of an Alcalase-assisted Enz-Spir-E on the vasodilator function of conduit and resistance arteries (which differently contribute to blood pressure regulation) in aging. Therefore, thoracic aorta (TA) and mesenteric arteries (MA) from male Sprague–Dawley rats (20–22 months-old) were divided into two groups: non-incubated vessels and vessels exposed to Enz-Spir-E (0.1% w/v) for 3 h. The vasodilation to acetylcholine (ACh), sodium nitroprusside (SNP, a NO donor), carbon-monoxide-releasing molecule (CORM), and cromakalim (a potassium channel opener), as well as NO and superoxide anion production, were studied. Enz-Spir-E increased the ACh-, SNP-, and CORM-induced responses in both types of arteries, while the cromalakim-induced relaxation was increased only in MA. Enz-Spir-E increased NO release (TA: 5.69-fold; MA: 1.79-fold), while it reduced superoxide anion formation (TA: 0.52-fold; MA: 0.66-fold). These results indicate that Enz-Spir-E improves aging-associated vasodilation through increasing NO release/bioavailability in both types of arteries and hyperpolarizing mechanisms only in MA.

Background It is now known regulatory effect of gaseous mediators (NO and H 2 S) in many bodily functions. However, detailed data on the regulatory role of each of these gasotransmitters are still not sufficiently elucidated. Objective The aim of this study was to estimate RBC microrheological changes under the influence of H 2 S donor in normotensive and hypertensive (AH) persons and the signaling pathways associated with these effects. Methods RBCs were incubated with: NaHS (H 2 S donor), ODQ, methylene blue, L-NAME, and SNP (NO donor). RBC deformability (RBCD) and aggregation (RBCA) were evaluated and compared with the corresponding control cell suspension. Results There was a difference in RBCD and RBCA between healthy individuals and AH patients, 6 and 58%, respectively. NaHS increased RBCD in both groups of individuals and significantly reduced RBCA. These positive effects of NaHS were eliminated by inhibition NO signaling pathway. A greater microrheological effect was observed with the combined action of NO and NaHS. Conclusion NO and H 2 S donors demonstrated cross-talk and caused a greater change in microrheological characteristics than their separate effects. The obtained data indicate that hydrogen sulfide, in microrheological responses to its exposure, may use the elements of the NO-associated signaling pathway.

Sonodynamic therapy (SDT) emerges as a promising noninvasive modality for deep tumors but is hindered by the hypoxic tumor microenvironment and glutathione (GSH)-mediated reactive oxygen species (ROS) scavenging. Herein, we report a GSH-responsive nanoplatform fabricated from an mPEG-b-PMNC copolymer, enabling spatiotemporal codelivery of nitric oxide (NO) donors and the sonosensitizer chlorin e6 (Ce6) via self-assembled micelles. Upon exposure to elevated intracellular GSH, the micelles disintegrate to release NO and Ce6 selectively. The released NO attenuates hypoxia through downregulation of hypoxia-inducible factor-1α (HIF-1α) and synergizes with ultrasound-triggered Ce6-generated ROS to yield highly cytotoxic peroxynitrite (ONOO-). This integrated synergy substantially potentiates SDT outcomes, as evidenced by an IC50 of 1.935 μg/mL for mPEG-b-PMNC@Ce6 micelles under ultrasound, outperforming free Ce6 (4.808 μg/mL) and control mPEG-b-PCL@Ce6 (2.736 μg/mL). This polycarbonate-based strategy provides a novel approach for synergistic gas-sonosensitizer delivery, overcoming key limitations of conventional SDT for treating hypoxic tumors.

Chitosan encapsulated S-nitrosoglutathione is an efficient nanodonor in Brassica napus seedlings.

Overcoming radiation-induced PD-L1 and COX-2 upregulation by nitric oxide gas nanogenerator to sensitize radiotherapy of lung cancer.

T-cell acute lymphoblastic leukemia is a malignant cancer with high morbidity and mortality in children. However, due to its abnormal proliferation and lack of effective therapeutic drugs, clinical treatment faces significant challenges. A series of nitric oxide donor-aurovertin B hybrids were synthesized and used to test the antiproliferative activity against triple-negative breast cancer. Particularly, the structure of the preferred compound was optimized to synthesize a new compound, 4D, which was formed by coupling a nitric oxide donor with aurovertin B hybrids. In this study, we investigated the effect of compound 4D in acute T-cell lymphoblastic leukemia cells. The results demonstrated that 4D effectively suppressed T-cell acute lymphoblastic leukemia cell proliferation while concurrently inducing apoptosis via the caspase pathway and ferroptosis through lipid peroxidation. Notably, as a ferroptosis inducer, 4D inhibited GPX4 by covalently binding, thereby suppressing both enzymatic activity and gene transcription levels. SIGNIFICANCE STATEMENT: The implications of this study are that a small molecule of furazan nitrogen oxide of nitric oxide donor coupled with aurovertin B hybrids, 4D, inhibited GPX4 through covalently binding to GPX4 to induce ferroptosis in acute T lymphocytic leukemia cells. This study identified a promising drug candidate for the development of an anti-T-cell acute lymphoblastic leukemia agent in the future.

Potential role of brain nitric oxide in inhibiting α7 nicotinic acetylcholine receptor-mediated suppression of the micturition reflex in rats.

Nitric oxide tuning enhances cytotoxicity and reduces inflammation in prostate cancer nanotherapy.

Injectable nanosuspension based on orthoester for synergistic chemo-photothermal/gas therapy in localized cancer treatment.

Nitric oxide (NO) is a potent signaling molecule with great therapeutic potential. However, the clinical application of direct NO delivery is limited by its short half-life and high reactivity, which creates challenges for effective controlled delivery. To overcome these limitations, S-nitrosothiols (RSNOs) are commonly used as NO donors in therapeutic applications, as they stabilize the short-lived free radical and improve NO pharmacokinetics. Despite their widespread use, the stability and release kinetics of RSNOs under physiological conditions have not been thoroughly evaluated, which is crucial for determining their therapeutic efficacy and safety. This study provides a comprehensive evaluation of the stability and in vitro NO release profiles of two commonly used RSNOs, S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP), at physiologically relevant conditions. Using a range of analytical techniques, including electrospray ionization mass spectrometry, Griess assay, and electrochemical sensing, we assessed RSNO stability across various conditions, including different buffers, pH levels, temperatures, as well as exposure to UV light irradiation to simulate common sterilization practices. Additionally, we investigated RSNO stability in cell culture media with varying glucose levels and serum compositions to better mimic biological environments. Our findings provide critical insights into the factors affecting RSNO stability and NO release, advancing the development of more effective NO-based therapies and biomedical devices.

Nitric oxide regulates spindle dynamics to modulate the maturation of goat oocytes.

Injectable protein hydrogel microspheres with reactive oxygen species-responsive nitric oxide release for cardiac protection against ischemia/reperfusion injury.

Fibrin-targeted ROS-scavenging micelles with photothermal and NO delivery for thrombolysis and post-thrombotic vascular remodeling.