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Open research questions in Nitric Oxide and Endothelin Effects

44 unresolved questions extracted from the limitations and future-work sections of 237 Nitric Oxide and Endothelin Effects papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Understanding the role of nitric oxide in the intestinal stem cell niche. Developing effective prevention and treatment strategies for CAC. Overcoming the limitations of current studies, including the lack of direct causal evidence in human colitic ISCs.

    Nitric Oxide in the Intestinal Stem Cell Niche: A Spatial Model of Nitrosative Stress and Clonal Evolution in Colitis-Associated Colorectal Cancer · 2026 · DOI

  • Prospective validation is required to confirm the model's predictions. Further studies are needed to understand the role of nitric oxide in the intestinal stem cell niche and its connection to CAC.

    Nitric Oxide in the Intestinal Stem Cell Niche: A Spatial Model of Nitrosative Stress and Clonal Evolution in Colitis-Associated Colorectal Cancer · 2026 · DOI

  • Oxidative stress contributes to CLTI progression via endothelial dysfunction, impaired nitric oxide bioavailability, and HIF stability. Comorbidities like diabetes influence results. There are few studies that explicitly look at the oxidative stress-NO-HIF tripartite interaction in human CLTI tissues.

    Unraveling the association between oxidative stress, nitric oxide signaling, and hypoxia inducible factor in chronic limb-threatening ischemia · 2026 · DOI

  • The underlying mechanisms of septic shock-induced cardiac dysfunction are incompletely understood. The specific roles of endothelin and nitric oxide in cardiac dysfunction during endotoxic shock are not well characterized.

    Endothelin-Dependent Myocardial Dysfunction in an Experimental Endotoxic Shock Model · 2026 · DOI

  • Human studies also associate menopause with altered blood pressure, arterial stiffness, sympathetic activity, and baroreflex regulation, although direct evidence for estrogen receptor and Nox signaling within the human RVLM remains lacking.

    Sex differences in neurogenic hypertension: estrogen modulation of NADPH oxidase signaling in the rostral ventrolateral medulla · 2026 · DOI

  • Further studies are needed to confirm the proposed hypothesis. Investigations into the mechanisms underlying the transmural gradient of phosphorylated MLC are required. Research into the therapeutic potential of targeting the spatial regulation of MLC phosphorylation is needed.

    Unresolved mechanisms: a hypothesized spatial regulation of myosin light chain phosphorylation within the walls of resistance arteries · 2026 · DOI

  • The spatial control of MLC phosphorylation within the vessel wall is less well understood. The mechanisms underlying the transmural gradient of phosphorylated MLC are not fully understood.

    Unresolved mechanisms: a hypothesized spatial regulation of myosin light chain phosphorylation within the walls of resistance arteries · 2026 · DOI

  • The need for rapid and effective therapeutic strategies for treatment-resistant depression. The lack of robust evidence on the use of óxido nitroso in psychiatry.

    ÓXIDO NITROSO COMO ESTRATÉGIA TERAPÊUTICA EM PSIQUIATRIA: EVIDÊNCIAS EM DEPRESSÃO RESISTENTE E IMPLICAÇÕES NEUROBIOLÓGICAS · 2026 · DOI

  • There is a need for a comprehensive review of the evidence on óxido nitroso in psychiatry. The current evidence is not yet robust enough to establish a definitive role for óxido nitroso.

    ÓXIDO NITROSO COMO ESTRATÉGIA TERAPÊUTICA EM PSIQUIATRIA: EVIDÊNCIAS EM DEPRESSÃO RESISTENTE E IMPLICAÇÕES NEUROBIOLÓGICAS · 2026 · DOI

  • These findings support the potential of iNOS-targeted nanomedicine as an adjuvant strategy for TNBC treatment and warrant further investigation using in vivo models to evaluate pharmacokinetics, tumor accumulation, and antitumor efficacy of the NPs.

    Controlled delivery of iNOS antagonist, 1400W, for synergistic breast cancer therapy · 2026 · DOI

  • Multivariate research is necessary to account for comorbidities like diabetes. Revascularization testing with NO donors, HIF stabilizers, or oxidative stress scavengers is needed. Incorporating advanced omics technologies and integrating cutting-edge experimental platforms can help create personalized disease profiles for each patient.

    Unraveling the association between oxidative stress, nitric oxide signaling, and hypoxia inducible factor in chronic limb-threatening ischemia · 2026 · DOI

  • The interactions among NO system components during neurodestruction are not fully elucidated. The effects of colchicine on the nitric oxide system in the basal magnocellular nucleus of rats are not well understood.

    Nitric oxide system parameters in the basal magnocellular nucleus of the rat brain following intracerebroventricular administration of colchicine · 2026 · DOI

  • There is a need to investigate the potential role of eNOS G894T and ACE I/D polymorphisms in the genetic background of the metabolic profile.

    eNOS G894T and ACE I/D gene polymorphisms and their association with anthropometric and biochemical parameters · 2026 · DOI

  • The widespread availability of nitrite preparations on the market and the underestimated prevalence of recreational nitrite use. The difficulty in diagnosing complications due to nonspecific symptoms.

    Analysis of adverse effects of nitrates and nitrites with particular emphasis on methemoglobinemia and maculopathy based on clinical cases and publicly available literature · 2026 · DOI

  • There is a growing number of reported neurologic complications due to increased recreational nitrous oxide use. Early recognition and treatment of nitrous oxide-related neurologic injury are essential to prevent permanent neurologic injury.

    Nitrous Oxide (“Whippets”)–Induced Subacute Combined Degeneration: A Case Report · 2026 · DOI

  • While many experimental studies have elucidated the mechanisms of ET-1 through its two receptors, ETA and ETB, the complexity of responses and sometimes conflicting data make it challenging to understand the effects of ET-1, as well as potential therapeutic antagonism of ET-1 receptors, on human physiology.

    Quantifying the integrated physiological effects of endothelin-1 on cardiovascular and renal function in healthy subjects: a mathematical modeling analysis · 2024 · DOI

  • Biomolecule nitration is a fascinating area of research, and further insights into the disease relevance of these species remains a significant challenge for the scientific community, primarily due to the lack of enabling technologies that allow us to put these transformations into physiologic context. As a result, there exist significant opportunities for chemical biology to improve the toolbox for studying RNS. For example, through the application of chemoproteomic techniques and activitybased proteomic profiling (Moellering and Cravatt, 2012), cellpermeable nitrolipid probes could be developed to report on biomolecular reactions in an unbiased sense in vivo. These methods would also drive a deeper understanding of the lipidome (Quehenberger and Dennis, 2011). Additionally, the growing knowledge of tyrosine nitration and immunogenicity will enable structure–activity relationships to be delineated that can be harnessed in the creation of new synthetic vaccines or to engineer safer protein therapeutics. Nitration biochemistry has significant implications for drug molecules, since a small molecule may trigger RNS generation through redox cycling or indirectly increase RNS leading to toxicological outcomes. For example, cisplatin-induced ototoxicity was recently shown to (cid:1)$ be mediated via NOX3 activation, leading to increases in O2 production, causing tyrosine nitration of the cochlear protein Lmo4 (Jamesdaniel et al., 2012). In drug design, researchers could elucidate the propensity for tyrosine residues to react with electrophilic species and then harness this to deliberately target the covalent inactivation of specific proteins, similar to the cysteine targeting of kinases. There is, of course, significant promise for anti-inflammatory drugs that can reduce RNS for a number of diseases and where the effectiveness of treatments can be assessed using PTNs or 3-NT as biomarkers. Opportunities also exist for repurposing existing drugs or molecules in clinical development that can modulate nitration signatures of disease. For example, PPAR-g agonists can reverse the tyrosine nitration of sarcoplasmic endoplasmic reticulum Ca2+-ATPase found in the platelets of Type 2 diabetes mellitus patients, so normalizing calcium homeostasis and highlighting potential benefits for cardiovascular diseases (Randriamboavonjy et al., 2008). Alternatively, drugs that trigger nitration may have therapeutic benefit also. For example, simvastatin was used to increase the cytotoxicity of doxorubicin in human colon cancer cells by upregulating NF-kB, increasing NO and nitrative stress (Riganti et al., 2008). This caused tyrosine nitration of multidrug resistance-related protein 3, so increasing the intracellular concentrations of doxorubicin. Future endeavors in this area could focus on furthering our understanding of nitration biochemistry of protein misfolding, epigenetic regulation and autoimmunity in particular.

    Chemistry and Biology of Biomolecule Nitration · 2012 · DOI

  • " Though not completely understood due to the incalculable number of pathways involved, the number of manuscripts that facilitate the understanding of the underlying effects of reactive radical species on the oxidative stress on lipids, proteins, and DNA and its contribution to the aging process increases nearly exponentially each year.

    Aging and the Role of Reactive Nitrogen Species · 2002 · DOI

  • The review is limited to studies that examined the effects of nitrate on exercise performance, and may not be generalizable to other populations or contexts. The heterogeneity of the studies included in the review may limit the ability to draw firm conclusions. More research is needed to fully understand the effects of nitrate on exercise performance.

    Nitrat Metabolizması ve Fiziksel Aktivite: Sistematik İnceleme · 2026 · DOI

  • Further research on larger and more homogeneous cohorts is necessary to elucidate the potential significance of the polymorphisms.

    eNOS G894T and ACE I/D gene polymorphisms and their association with anthropometric and biochemical parameters · 2026 · DOI

  • The paper identifies a gap in the current state of research on the effect of sleep deprivation on the cardiovascular system

    The Effect of Sleep Deprivation on the Cardiovascular System and Endothelial Function · 2026 · DOI

  • Although there are conflicting data, it appears that beetroot juice supply may be a cheap, natural, and promising nutritional strategy for improving sports performance in both endurance and intermittent high intensity (start-stop) exercise.

    Beetroot Juice - Legal Doping for Athletes? · 2021 · DOI

  • Immunohistological studies of related enzymes are few, and the morphological dynamics of these enzymes in dental pulp and odontoblasts remain to be elucidated.

    Expression Profiles of NOS Isoforms in Dental Pulp and Odontoblasts in nNOS Knockout Mice · 2019 · DOI

  • The excerpt indicates the study focuses on serum markers but does not discuss whether tissue-level or local vascular endothelial dysfunction measurements would provide additional insights.

    ASSESSMENT OF ENDOTHELIAL HEMOSTASIS; SERUM NITRIC OXIDE AND ENDOTHELIN-1 LEVELS IN ISCHEMIC CEREBROVASCULAR STROKE WITH OR WITHOUT TYPE 2 DIABETES. · 2017 · DOI

  • The paper lacks discussion of mechanistic pathways linking endothelial hemostasis markers to stroke outcomes in diabetic versus non-diabetic patients.

    ASSESSMENT OF ENDOTHELIAL HEMOSTASIS; SERUM NITRIC OXIDE AND ENDOTHELIN-1 LEVELS IN ISCHEMIC CEREBROVASCULAR STROKE WITH OR WITHOUT TYPE 2 DIABETES. · 2017 · DOI

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44 open questions have been extracted from the limitations and future-work passages of 237 Nitric Oxide and Endothelin Effects papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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