tilarginine (L-NMMA) / Arginox Pharma, Houston Methodist Research Institute, Galera Therap - LARVOL DELTA

Methylarginine Levels and Their Impact on Vascular Aging: A Systematic Review. (PubMed, Vasc Biol) - "Among the factors involved in this process, methylarginines, such as asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and NG-monomethyl-L-arginine (L-NMMA), stand out...The in vitro study reinforced this evidence by demonstrating that increasing concentrations of ADMA accelerate endothelial cell senescence, reduce telomerase activity, and decrease NO production. Interpretation of the results should consider the methodological limitations of the included studies, but the findings reinforce the role of methylarginines as potential biomarkers of vascular aging and highlight the need for further investigations exploring therapeutic strategies to minimize their deleterious effects."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders

A novel tetranortirucallane-type alkaloid with potential anti-inflammatory activity from Aglaia lawii. (PubMed, Nat Prod Res) - "1 possessed potent anti-inflammatory activity against NO production with IC50 values of 9.65 μM compared with the positive control NG-monomethyl-L-arginine (L-NMMA, IC50 = 33.85 μM). In addition, 1 was evaluated for cytotoxicity against five human tumour cell lines (HL-60, A-549, SMMC-7721, MDA-MB-231, and SW480), but was found to be inactive."

Journal • Oncology

Passive Limb Movement: A Tool to Assess Vascular Health and Guide Rehabilitation (clinicaltrials.gov) - P=N/A | N=130 | Active, not recruiting | Sponsor: VA Office of Research and Development | Recruiting ➔ Active, not recruiting | Trial completion date: Oct 2025 ➔ Oct 2027 | Trial primary completion date: Oct 2025 ➔ Oct 2027

Enrollment closed • Trial completion date • Trial primary completion date • Cardiovascular

Structurally diverse sesquiterpenoid glycosides with anti-inflammatory activity from Cissampelopsis spelaeicola. (PubMed, Phytochemistry) - "Compounds 12 and 14-16 exhibited potent NO inhibitory effects (IC50 = 5.62-19.29 μM), outperforming the positive control L-NMMA (IC50 = 21.20 ± 0.57 μM). Further evaluation revealed that compound 15 (IC50 = 5.62 ± 0.37 μM) effectively attenuated LPS-stimulated overexpression of IL-1β, IL-6, iNOS, and TNF-α in BV-2 cells."

Journal • Inflammation • IL1B • IL6 • TNFA

Anti-Inflammatory Jatrophane Diterpenoids With Multiple Chiral Carbon Centers From Jatropha curcas. (PubMed, Chirality) - "The anti-inflammatory activity of these compounds was evaluated by inhibiting NO production in LPS-stimulated RAW264.7 macrophages, and compounds 5, 8-11, and 13 showed potent activity with IC50 values ranging from 16.86 to 32.49 μM, which were comparable with that of the positive control l-NMMA (IC50: 21.90 μM). The structure-activity relationships of jatrophane-type diterpenoids revealed that compounds 5 and 11 showed the most potent anti-inflammatory effects."

Journal

Endothelial and non-endothelial actions of estrogen receptor subtypes in male and female mouse aorta. (PubMed, Vascul Pharmacol) - "Some experiments were conducted in the presence of pharmacological inhibitors targeting endothelium-dependent relaxation pathways-L-NMMA, indomethacin, and apamin/charybdotoxin-as well as the PI3K pathway inhibitor LY294002 hydrochloride. However, subtle sex differences among ER subtypes were observed in the contribution of NOS and PI3K pathways. The PI3K pathway may attenuate vasorelaxant effect by promoting MLC phosphorylation in vascular smooth muscle, and its inhibition unmasks the vasorelaxant potential of estrogen."

Journal • Preclinical • Cardiovascular • ER

Mechanisms of Pilocarpine-Induced Nitric Oxide and Prostaglandin Production in Porcine Ciliary Muscle. (PubMed, FASEB Bioadv) - "Inhibitors of nitric oxide synthase (L-NMMA, L-NIO), phospholipase C (U-73122), cyclooxygenase (diclofenac), and calcium signaling (verapamil, TFP) all reduced mediator production, while calcium ionophore A23187 enhanced it. Pilocarpine activates M1 and M3 muscarinic receptors in the porcine ciliary muscle, stimulating NO and PGE 2 production via calcium-dependent PLC-NOS-COX signaling. These pathways may influence ciliary muscle function and lens physiology, offering potential therapeutic targets for glaucoma and presbyopia."

Journal • Preclinical • Glaucoma • Ophthalmology

A new verrucosane diterpenoid from the Vietnamese liverwort Plagiochila bantamensis. (PubMed, J Asian Nat Prod Res) - "Furthermore, all isolated compounds were evaluated for their ability to inhibit nitric oxide (NO) production. Compounds 1-3 and 6-7 demonstrated notable NO inhibitory activity, with IC50 values ranging from 12.85 to 51.37 µM, outperforming or comparable to that of the positive control L-NMMA (IC50 41.30 ± 6.60 µM)."

Journal

Effects of Combination Treatment on Renal Endothelial Function in Type 2 Diabetes Mellitus. (PubMed, Kidney Int Rep) - "Patients with T2DM were randomized to receive either E+L: (n = 34) or metformin and insulin glargine (M+I: n = 31), for 3 months...The NO activity in the renal circulation was assessed by analyzing change in RPF in response to i.v. administrated NG-monomethyl-l-arginine (L-NMMA), an NO inhibitor...Renal NO activity emerged as a determinant of the renal hemodynamic response in the combination therapy of E+L, but not in the combination therapy of M+I. Our study provides evidence that the treatment effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors may be contributed at least partly by the renal NO activity in patients with T2DM."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

: Vascular Function in Health and Disease (clinicaltrials.gov) - P1 | N=420 | Recruiting | Sponsor: Russell Richardson | Trial completion date: Aug 2025 ➔ Aug 2026 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Cardiovascular • Chronic Obstructive Pulmonary Disease • Heart Failure • Hypertension • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Cadmium Toxicity in Caenorhabditis elegans: Mechanisms and Interventions by Vitamin C and Fruit Juices. (PubMed, Foods) - "Conversely, the removal of NO by cPTIO [2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide] or L-NMMA (NG-Monomethyl-L-arginine) improved the vitality; however, it still did not affect ROS levels, indicating that ROS accumulation is a primary event in Cd-induced toxicity...In summary, our results elucidate that CdCl2 exposure leads to ROS accumulation in C. elegans, which in turn triggers NO production and ultimately reduces nematode activity. VC and VC-rich materials can effectively mitigate CdCl2 toxicity by scavenging ROS and NO, providing a potential strategy for alleviating Cd poisoning."

Journal

The diagnostic and prognostic significance of methylated arginine metabolites (ADMA, SDMA, L-NMMA) in patients with obstructive sleep apnea syndrome. (PubMed, Medicine (Baltimore)) - "The reduced arginine levels are likely due to increased utilization, while diminished synthesis of methylated arginine derivatives (ADMA, L-NMMA) may result from this metabolic shift. These findings imply that decreased arginine and methylated arginine levels may serve as potential diagnostic markers and could aid in identifying candidates for polysomnography (PSG), which is both costly and time-consuming, thereby contributing to more efficient patient selection and reducing the overall clinical burden."

Journal • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Differentiation between arginase 1 and 2 in regulating tolerance to cardiac ischemia-reperfusion via nitric oxide signaling by red blood cells (ESC-WCC 2025) - "At 15 min before ischemia, mice were given iv: saline, non-specific arginase inhibitor (nor-NOHA; 100 mg/kg), or the NOS inhibitor (L-NMMA; 10 mg/kg)... Arginase 1, but not arginase 2, plays an important role in cardiac ischemic tolerance. Arginase 1 in RBC is a critical determinant of cardiac protection against ischemia-reperfusion injury by regulating NO signaling."

Cardiovascular • Coronary Artery Disease • Myocardial Ischemia • Reperfusion Injury • ARG2

Alterisocoumarins A-M: Isocoumarins with anti-inflammatory and anti-tuberculosis activities from a mangrove endophytic fungus Alternaria sp. HN-17. (PubMed, Bioorg Chem) - "In bioassay, compounds 1, (-)-4, 10, and 18 displayed good anti-inflammatory activity with IC50 values ranging from 10.68 to 28.05 μM than positive control (L-NMMA: 32.83 μM)...In addition, compounds 21 and 22 showed notable anti-tuberculosis activities by inhibiting MptpA, MptpB and PTP1B. The molecular docking results showed that compound 22 binds deeply in the active cavity of PTP1B."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • PTPN1

Inhibition of iNOS Reduced Cerebral Vasoconstriction from Chronic Cocaine and Enhanced Angiogenesis in the Prefrontal Cortex. (PubMed, Brain Res Bull) - "In contrast, these effects were significantly attenuated in iNOS knockout (iNOS-KO) mice and in WT mice pretreated with the iNOS inhibitor L-NMMA (iNOS-Inh), thus indicating iNOS's involvement in the vascular changes triggered by cocaine...Together, these findings suggest that iNOS contribute significantly to cocaine-induced vasoconstriction and cerebral hypoperfusion. Thus, the inhibition of iNOS could be a potential therapeutic strategy to reduce the risk of cerebral ischemia in individuals with cocaine use disorder."

Journal • Cardiovascular

Targeting S-Nitrosylation to Overcome Therapeutic Resistance in NRAS-Driven Melanoma. (PubMed, Cancers (Basel)) - "Targeting this modification with nitric oxide synthase (NOS) inhibitors such as L-NAME, L-NMMA and 1400w restore sensitivity of MEK inhibitor, promotes dendritic cell activation, and enhances CD8+ T cell infiltration in preclinical models such as immunogenic mouse models and individual patient derived, primary melanoma cells. We also explore the emerging role of S-nitrosylation in regulating macrophage-mediated immune surveillance and propose translational strategies for combining redox modulation with targeted and immune therapies. These insights offer a compelling framework for overcoming therapeutic resistance and reprogramming the tumor immune microenvironment to activate the cytotoxic T-cells and enhance the responses to immunotherapy in NRAS-driven cancers."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • CD8 • NRAS

Clerodane Diterpenoids and Ecdysteroids From the Fruits of Tinospora sagittata (Oliv.) Gagnep. (PubMed, Chem Biodivers) - "Structurally, compound 8 is a rare ecdysteroid featuring a hexadienone unit, and 9 is an unprecedented ecdysteroid characterized by an oxygen bridge between C-2 and C-9. Additionally, compound 7 exhibited moderate inhibitory activity against nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells, with an IC50 value of 35.78 ± 0.37 µM, compared to the positive control, NG-monomethyl-L-arginine, which had an IC50 value of 40.28 ± 0.48 µM."

Journal

Phytochemicals from a Desert Crop, Sand Rice (Agriophyllum squarrosum), and Their Inflammatory Activity. (PubMed, ACS Omega) - "The new structures were determined by NMR, HRESIMS, and DFT calculations of their NMR and ECD data, which also led to the structural revision of suaeglaucin C. Anti-inflammatory assays revealed compounds 5 and 21 as potent inhibitors, outperforming L-NMMA, and the structure-activity relationship of the optically active dihydroisoflavones was briefly discussed. All compounds were isolated from this plant for the first time, except for compounds 11, 19, and 20."

Journal • Ophthalmology

Nitric oxide regulates spindle dynamics to modulate the maturation of goat oocytes. (PubMed, Theriogenology) - "In this study, the inhibition of NO synthase activity using L-NMMA was found to impair meiosis and inhibit the maturation of goat oocytes...These defects were partially rescued by supplementation with the NO donor sodium nitroprusside (SNP)...Our results further showed that reduced NO levels increased RhoA phosphorylation, which in turn suppressed KIF15 expression and disrupted MI spindle dynamics. In conclusion, this study provides new insights into the role of NO in goat oocyte maturation, revealing that it regulates spindle dynamics through the RhoA-ROCK-KIF15 signaling axis."

Journal • KIF15 • RHOA

Mechanisms of Vasovagal Syncope (clinicaltrials.gov) - P1 | N=90 | Completed | Sponsor: New York Medical College | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular

Combination of L-NMMA and sacituzumab govitecan as a novel targeted therapy for inflammatory breast cancer (AACR 2025) - "Treatment with the Combo significantly reduced tumor growth compared to single drugs and control group. There was no statistically significant difference between the L-NMMA group and sacituzumab govitecan-treated mice. Overall, our findings demonstrate the synergism between L-NMMA and sacituzumab govitecan, highlighting the potential use of these drugs in future clinical trials."

Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Targeting NOS2 and the tumor microenvironment in ovarian cancer: Switching the immune system from "cold" to "hot" (AACR 2025) - "By combining pan-NOS inhibitor L-NMMA with conventional Cisplatin administration, we want to convert the immune environment from "cold" or non-responsive to "hot" or responsive to chemotherapy. Our results showed the potential of the combination therapy to increase the infiltration of NK and NK/NKT cells and T lymphocytes into ascites together with the increase of effector markers in CD4+ T cells. The development of a second in vivo model based on the OVCAR8 NOS2 KO cell line will provide a better understanding of the role of NOS2 in the metastasis formation process and the impact of NOS2 on patients' survival."

Biomarker • Tumor microenvironment • Oncology • Ovarian Cancer • Solid Tumor • CD44 • NOS2 • VIM • ZEB1

iNOS inhibition reprograms the tumor microenvironment enhancing antitumor immunity in obesity associated triple negative breast cancer (TNBC) (AACR 2025) - "This study investigates whether combining the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) with docetaxel enhances antitumor efficacy in an obese TNBC model. L-NMMA effectively remodels the obesity-altered TME, reducing tumor growth and metastasis while promoting an immune-supportive environment. Targeting iNOS with L-NMMA in combination with chemotherapy emerges as a promising therapeutic strategy to enhance TNBC treatment, particularly for obese patients."

Biomarker • IO biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCL11 • CD24 • CD8 • CSF3 • IL17A • IL6 • MRC1 • TFRC • TNFA

Unraveling the microbiome-iNOS connection in obesity-driven triple-negative breast cancer (AACR 2025) - "- L-NMMA combined with docetaxel delayed tumor growth in both diet groups, though the untreated/treated tumor size ratio was higher in HFD mice (6.5) than ND mice (2.1). These findings suggest that HFD-induced gut microbiome alterations create a pro-inflammatory environment driving increased iNOS expression, promoting tumor aggressiveness and influencing therapeutic response. Targeting the gut microbiota, alongside iNOS inhibition, could provide novel strategies for managing obesity-associated TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • NOS2

Citrifuran E-I, Five Dimeric Polyketides with Potential Anti-inflammatory Activity from Aspergillus sp. AWG 1-15. (PubMed, Chem Biodivers) - "All compounds were assessed for anti-inflammatory activity by measuring their effects on nitric oxide (NO) production induced by LPS in RAW 264.7 cells. Compounds 1-4 exhibited inhibitory moderate activity, with the IC50 values ranging from 12.6 to 37.3 μM, compared to the positive control L-NMMA (IC50=40.6 μM)."

Journal