Drought and heat stress: insights into tolerance mechanisms and breeding strategies for pigeonpea improvement.

MAIN CONCLUSION: Pigeonpea has potential to foster sustainable agriculture and resilience in evolving climate change; understanding bio-physiological and molecular mechanisms of heat and drought stress tolerance is imperative to developing resilience cultivars. Pigeonpea is an important legume crop that has potential resilience in the face of evolving climate scenarios. However, compared to other legumes, there has been limited research on abiotic stress tolerance in pigeonpea, particularly towards drought stress (DS) and heat stress (HS). To address this gap, this review delves into the genetic, physiological, and molecular mechanisms that govern pigeonpea's response to DS and HS. It emphasizes the need to understand how this crop combats these stresses and exhibits different types of tolerance and adaptation mechanisms through component traits. The current article provides a comprehensive overview of the complex interplay of factors contributing to the resilience of pigeonpea under adverse environmental conditions. Furthermore, the review synthesizes information on major breeding techniques, encompassing both conventional methods and modern molecular omics-assisted tools and techniques. It highlights the potential of genomics and phenomics tools and their pivotal role in enhancing adaptability and resilience in pigeonpea. Despite the progress made in genomics, phenomics and big data analytics, the complexity of drought and heat tolerance in pigeonpea necessitate continuous exploration at multi-omic levels. High-throughput phenotyping (HTP) is crucial for gaining insights into perplexed interactions among genotype, environment, and management practices (GxExM). Thus, integration of advanced technologies in breeding programs is critical for developing pigeonpea varieties that can withstand the challenges posed by climate change. This review is expected to serve as a valuable resource for researchers, providing a deeper understanding of the mechanisms underlying abiotic stress tolerance in pigeonpea and offering insights into modern breeding strategies that can contribute to the development of resilient varieties suited for changing environmental conditions.

Right Ventricular Pressure Waveform Analysis-Clinical Relevance and Future Directions.

Continuous measurement of pressure in the right atrium and pulmonary artery has commonly been used to monitor right ventricular function in critically ill and surgical patients. This approach is largely based upon the assumption that right atrial and pulmonary arterial pressures provide accurate surrogates for diastolic filling and peak right ventricular pressures, respectively. However, due to both technical and physiologic factors, this assumption is not always true. Accordingly, recent studies have begun to emphasize the potential clinical value of also measuring right ventricular pressure at the bedside. This has highlighted both past and emerging research demonstrating the utility of analyzing not only the amplitude of right ventricular pressure but also the shape of the pressure waveform. This brief review summarizes data demonstrating that combining conventional measurements of right ventricular pressure with variables derived from waveform shape allows for more comprehensive and ideally continuous bedside assessment of right ventricular function, particularly when combined with stroke volume measurement or 3D echocardiography, and discusses the potential use of right ventricular pressure analysis in computational models for evaluating cardiac function.

High-Risk Pulmonary Embolism: Management for the Intensivist.

High-risk pulmonary embolism (PE) also known as massive PE carries a high rate of morbidity and mortality. The incidence of high-risk PE continues to increase, yet the outcomes of high-risk PE continue to remain poor. Patients with high-risk PE are often critically ill, with complex underlying physiology, and treatment for the high-risk PE patient almost always requires care and management from an intensivist. Treatment options for high-risk PE continue to evolve rapidly with multiple options for definitive reperfusion therapy and supportive care. A thorough understanding of the physiology, risk stratification, treatment, and support options for the high-risk PE patient is necessary for all intensivists in order to improve outcomes. This article aims to provide a review from an intensivist's perspective highlighting the physiological consequences, risk stratification, and treatment options for these patients as well as providing a proposed algorithm to the risk stratification and acute management of high-risk PE.

Right Heart Failure in the Intensive Care Unit: Etiology, Pathogenesis, Diagnosis, and Treatment.

Right heart (RH) failure carries a high rate of morbidity and mortality. Patients who present with RH failure often exhibit complex aberrant cardio-pulmonary physiology with varying presentations. The treatment of RH failure almost always requires care and management from an intensivist. Treatment options for RH failure patients continue to evolve rapidly with multiple options available, including different pharmacotherapies and mechanical circulatory support devices that target various components of the RH circulatory system. An understanding of the normal RH circulatory physiology, treatment, and support options for the RH failure patients is necessary for all intensivists to improve outcomes. The purpose of this review is to provide clinical guidance on the diagnosis and management of RH failure within the intensive care unit setting, and to highlight the different pathophysiological manifestations of RH failure, its hemodynamics, and treatment options available at the disposal of the intensivist.

Integrating Right Ventricular Pressure Waveform Analysis With Two-Point Volume Measurement for Quantification of Systolic and Diastolic Function: Experimental Validation and Clinical Application.

OBJECTIVE: To define in an experimental model the variance, accuracy, precision, and concordance of single-beat measures of right ventricular (RV) contractility and diastolic capacitance relative to conventional reference standards, and apply the methods to a clinical data set. DESIGN: A retrospective, observational analysis of recorded pressure waveforms and RV volume measurements. SETTING: At a university laboratory. PARTICIPANTS: Archived data from previous studies of anesthetized swine and awake patients undergoing clinically-indicated right-heart catheterization. INTERVENTIONS: Recording of RV pressure with simultaneous measurement of RV volume by conductance (swine) or 3-dimensional (3D) echocardiography (humans) during changes in contractility and/or loading conditions. MEASUREMENTS AND MAIN RESULTS: Using experimental data, single-beat measures of RV contractility quantified as end-systolic elastance, and diastolic capacitance quantified as the predicted volume at an end-diastolic pressure of 15 mmHg (V15), were compared to multi-beat, preload- variant, reference standards using correlation, Bland-Altman analysis, and 4-quadrant concordance testing. This analysis indicated that the methods were not directly interchangeable with reference standards, but were sufficiently robust to suggest potential clinical utility. Clinical application supported this potential by demonstrating enhanced assessment of the response to inhaled nitric oxide in patients undergoing diagnostic right-heart catheterization. CONCLUSIONS: Study results supported the possibility of integrating automated RV pressure analysis with RV volume measured by 3D echocardiography to create a comprehensive assessment of RV systolic and diastolic function at the bedside.

Drought priming induces chilling tolerance and improves reproductive functioning in chickpea (Cicer arietinum L.).

KEY MESSAGE: Priming alleviates membrane damage, chlorophyll degradation along with cryoprotectants accumulation during chilling stress that leads to improved reproductive functioning and increased seed yield. Chilling temperatures below 15 °C have severe implications on the reproductive growth and development of chickpea. The abnormal reproductive development and subsequent reproductive failure lead to substantial yield loss. We exposed five chickpea cultivars (PBG1, GPF2, PDG3, PDG4, and PBG5) to drought stress (Priming) during the vegetative stage and analyzed for chilling tolerance during the reproductive stage. These varieties were raised in the fields in two sets: one set of plants were subjected to drought stress at the vegetative stage for 30 days (priming) and the second set of plants were irrigated regularly (non-primed). The leaf samples were harvested at the flowering, podding, and seed filling stage and analyzed for membrane damage, water status, chlorophyll content, cellular respiration, and certain cryoprotective solutes. The reproductive development was analyzed by accessing pollen viability, in vivo and in vitro germination, pollen load, and in vivo pollen tube growth. Principal component analysis (PCA) revealed that priming improved membrane damage, chlorophyll b degradation, and accumulation of cryoprotectants in GPF2, PDG3, and PBG5 at the flowering stage (< 15 °C). Pearson's correlation analysis showed a negative correlation with the accumulation of proline and carbohydrates with flower, pod, and seed abortion. Only, PBG5 responded best to priming while PBG1 was worst. In PBG5, priming resulted in reduced membrane damage and lipid peroxidation, improved water content, reduced chlorophyll degradation, and enhanced cryoprotective solutes accumulation, which led to increased reproductive functioning and finally improved seed yield and harvest index. Lastly, the priming response is variable and cultivar-specific but overall improve plant tolerance.

Phenotypic evaluation of agronomic and root related traits for drought tolerance in recombinant inbred line population derived from a chickpea cultivar (C. arietinum L.) and its wild relative (C. reticulatum).

Drought is a major abiotic stress that drastically reduces chickpea yields. The present study was aimed to identify drought-responsive traits in chickpea by screening a recombinant inbred line population derived from an inter-specific cross between drought cultivar of GPF2 (C. arietinum L.) and drought sensitive accession of ILWC292 (C. reticulatum), at two locations in India. Twenty-one traits, including twelve morphological and physiological traits and nine root-related traits were measured under rainfed (drought-stress) and irrigated conditions (no-stress). High genotypic variation was observed among RILs for yield and root traits indicated that selection in these germplasms would be useful in achieving genetic progress. Both correlation and principal component analysis revealed that plant height, number of pods per plant, biomass, 100-seed weight, harvest index, membrane permeability index, and relative leaf water content were significantly correlated with yield under both irrigated and drought stress environments. Root length had significant positive correlations with all root-related traits except root length density in drought-stressed plants. Path analysis and multiple and stepwise regression analyses showed that number of pods per plant, biomass, and harvest index were major contributors to yield under drought stress conditions. Thus, a holistic approach across these analyses identified number of pods per plant, biomass, harvest index, and root length as key traits for improving chickpea yield through indirect selection for developing drought-tolerant cultivars. Overall, on the basis of yield components morphological and root traits, a total of 15 promising RILs were identified for their use in chickpea breeding programs for developing drought tolerant cultivars. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01218-z.

Hypoxia-inducible factor-1 drives divergent immunomodulatory functions in the pathogenesis of autoimmune diseases.

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric (HIF-1α/ HIF-1ß) transcription factor in which the oxygen-sensitive HIF-1α subunit regulates gene transcription to mediate adaptive tissue responses to hypoxia. HIF-1 is a key mediator in both regulatory and pathogenic immune responses, because ongoing inflammation in localized tissues causes increased oxygen consumption and consequent hypoxia within the inflammatory lesions. In autoimmune diseases, HIF-1 plays complex and divergent roles within localized inflammatory lesions by orchestrating a critical immune interplay sponsoring the pathogenesis of the disease. In this review, we have summarized the role of HIF-1 in lymphoid and myeloid immunomodulation in autoimmune diseases. HIF-1 drives inflammation by controlling the Th17/Treg /Tr1 balance through the tipping of the differentiation of CD4+ T cells in favour of pro-inflammatory Th17 cells while suppressing the development of anti-inflammatory Treg /Tr1 cells. On the other hand, HIF-1 plays a protective role by facilitating the expression of anti-inflammatory cytokine IL-10 in and expansion of CD1dhi CD5+ B cells, known as regulatory B cells or B10 cells. Apart from lymphoid cells, HIF-1 also controls the activation of macrophages, neutrophils and dendritic cells, thus eventually further influences the activation and development of effector/regulatory T cells by facilitating the creation of a pro/anti-inflammatory microenvironment within the autoinflammatory lesions. Based on the critical immunomodulatory roles that HIF-1 plays, this master transcription factor seems to be a potent druggable target for the treatment of autoimmune diseases.

Vascular and immunopathological role of Asymmetric Dimethylarginine (ADMA) in Experimental Autoimmune Encephalomyelitis.

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor/uncoupler inducing vascular pathology. Vascular pathology is an important factor for the development and progression of CNS pathology of MS, yet the role of ADMA in MS remains elusive. Patients with multiple sclerosis (MS) are reported to have elevated blood levels of ADMA, and mice with experimental autoimmune encephalomyelitis (EAE, an animal model of MS) generated by auto-immunization of myelin oligodendrocyte glycoprotein (MOG) and blood-brain barrier (BBB) disruption by pertussis toxin also had increased blood ADMA levels in parallel with induction of clinical disease. To explore the role of ADMA in EAE pathogenesis, EAE mice were treated with a daily dose of ADMA. It is of special interest that ADMA treatment enhanced the BBB disruption in EAE mice and exacerbated the clinical and CNS disease of EAE. ADMA treatment also induced the BBB disruption and EAE disease in MOG-immunized mice even without pertussis toxin treatment, suggesting the role of ADMA in BBB dysfunction in EAE. T-cell polarization studies also documented that ADMA treatment promotes TH 1- and TH 17-mediated immune responses but without affecting Treg-mediated immune response in EAE mice as well as in in vitro T-cell culture. Taken together, these data, for the first time, document the vascular and immunopathogenic roles of ADMA in EAE, thus pointing to the potential of ADMA-mediated mechanism as a new target of potential therapy for MS.

Systemic vascular distensibility relates to exercise capacity in connective tissue disease.

OBJECTIVE: Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO2). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO2) in CTD patients. METHODS: Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls. RESULTS: During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P =0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO2) and decreased systemic oxygen extraction. CONCLUSION: Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.

Asymmetric dimethylarginine exacerbates cognitive dysfunction associated with cerebrovascular pathology.

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor and uncoupler of nitric oxide synthase, has gained attention as a risk factor for cardiac disease, metabolic syndrome, and cerebrovascular disease. In this study, we investigated the role of systemic ADMA overburden in cerebromicrovascular pathology associated with cognitive dysfunction using APPSwDI transgenic mice expressing human ß-amyloid precursor protein Swedish (Tg-SwDI), a model of cerebrovascular ß-amyloidosis. To induce systemic overburden of ADMA, Tg-SwDI mice were treated with a daily dose of exogenous ADMA. ADMA treatment resulted in elevated ADMA levels in the blood and brain of Tg-SwDI mice. ADMA treatment induced the brain nitrosative stress and inflammation as well as enhanced the brain Aß deposition and cognitive impairment in Tg-SwDI mice. However, ADMA treatment had no such effects on wild type mice. ADMA treatment also exacerbated brain microvascular pathology in Tg-SwDI mice as observed by increased blood-brain barrier dysfunction, loss of tight junction proteins, increased endothelial stress fibers, and decreased microvessel density in the brain. In addition, similar observations were made in cultured human brain microvessel endothelial cells, where ADMA in the presence of VEGF-induced endothelial cell signaling for F-actin stress fiber inducing endothelial barrier dysfunction. Overall, these data document the potential role of ADMA in the cognitive pathology under conditions of cerebrovascular ß-amyloidosis.

Chronic Thromboembolic Pulmonary Hypertension: the Bedside.

PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH), included in group 4 PH, is an uncommon complication of acute pulmonary embolism (PE), in which emboli in the pulmonary vasculature do not resolve but rather form into an organized scar-like obstruction which can result in right ventricular (RV) failure. Here we provide an overview of current diagnosis and management of CTEPH. RECENT FINDINGS: CTEPH management is complex with treatments that range from surgery, percutaneous interventions, to medical therapies. Current CTEPH medical therapies have largely been repurposed from pulmonary arterial hypertension (PAH). The diagnosis of CTEPH can be challenging, requiring a multimodality approach to differentiate from disease mimics. While these treatments improve symptoms, they may not reverse the underlying pathology of CTEPH.

Chronic Thromboembolic Pulmonary Hypertension: the Bench.

PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary embolism (PE), in which the red, platelet-rich thrombus does not resolve but forms into an organized yellow, fibrotic scar-like obstruction in the pulmonary vasculature. Here we review the pathobiology of CTEPH. RECENT FINDINGS: Our current knowledge has predominantly been informed by studies of human samples and animal models that are inherently limited in their ability to recapitulate all aspects of the disease. These studies have identified alterations in platelet biology and inflammation in the formation of a scar-like thrombus that comprised endothelial cells, myofibroblasts, and immune cells, along with a small vessel pulmonary arterial hypertension-like vasculopathy. The development of CTEPH-specific therapies is currently hindered by a limited knowledge of its pathobiology. The development of new CTEPH medical therapies will require new insights into its pathobiology that bridge the gap from bench to bedside.

Molecular mapping of quantitative trait loci for ascochyta blight and botrytis grey mould resistance in an inter-specific cross in chickpea (Cicer arietinum L.) using genotyping by sequencing.

Ascochyta blight (AB) and botrytis grey mould (BGM) are the most devastating fungal diseases of chickpea worldwide. The wild relative of chickpea, C. reticulatum acc. ILWC 292 was found resistant to BGM whereas, GPF2 (Cicer arietinum L.) is resistant to AB. A total of 187 F8 Recombinant Inbred Lines (RILs) developed from an inter-specific cross of GPF2 × C. reticulatum acc. ILWC 292 were used to identify quantitative trait loci (QTLs) responsible for resistance to AB and BGM. RILs along with parents were evaluated under artificial epiphytotic field/laboratory conditions for two years. Highly significant differences (P < 0.001) were observed for reaction to both pathogens in both years. Parents and RILs were genotyped-by-sequencing to identify genome wide single nucleotide polymorphism (SNPs). A total of 1365 filtered and parental polymorphic SNPs were used for linkage map construction, of which, 673 SNPs were arranged on eight linkage groups. Composite interval mapping revealed three QTLs for AB and four QTLs for BGM resistance. Out of which, two QTLs for AB and three QTLs for BGM were consistent in both years. These QTLs can be targeted for further fine mapping for deployment of resistance to AB and BGM in elite chickpea cultivars using marker-assisted-selection.

Phenotypic evaluation of genetic variability and selection of yield contributing traits in chickpea recombinant inbred line population under high temperature stress.

Heat is a major abiotic stress that drastically reduces chickpea yield. This study aimed to identify heat-responsive traits to sustain crop productivity by screening a recombinant inbred line (RILs) population at two locations in India (Ludhiana and Faridkot). The RIL population was derived from an inter-specific cross between heat-tolerant genotype GPF 2 (C. arietinum L.) and heat sensitive accession ILWC 292 (C. reticulatum). The pooled analysis of variance showed highly significant differences for all the traits in RILs and most of the traits were significantly affected by heat stress at both locations. High values of genotypic coefficient of variation (19.52-38.53%), phenotypic coefficient of variation (20.29-39.85%), heritability (92.50-93.90%), and genetic advance as a percentage of mean (38.68-76.74%) have been observed for plant height, number of pods per plant, biomass, yield, and hundred seed weight across the heat stress environments. Association studies and principal component analysis showed a significant positive correlation of plant height, number of pods per plant, biomass, hundred seed weight, harvest index, relative leaf water content, and pollen viability with yield under both timely-sown and late-sown conditions. Path analysis revealed that biomass followed by harvest index was the major contributor to yield among the environments. Both step-wise and multiple regression analyses concluded that number of pods per plant, biomass and harvest index consistently showed high level of contribution to the total variation in yield under both timely-sown and late-sown conditions. Thus, the holistic approach of these analyses illustrated that the promising traits provide a framework for developing heat-tolerant cultivars in chickpea. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-00977-5.

Physicians' Reactions to COVID-19: The Results of a Preliminary International Internet Survey.

OBJECTIVES: Physicians across the world have been disproportionately affected by the COVID-19 pandemic. This study was designed and conducted to assess the emotional and behavioural reactions of physicians to the initial phase of the COVID-19 pandemic. SUBJECTS AND METHODS: An online survey questionnaire using the google forms platform was constructed by the authors. The items in the questionnaire were based on clinical experience, relevant literature review and discussion with peers. A list of issues that were deemed as essential components of the experience of the pandemic relevant to physicians was arrived at. Thereafter these issues were operationalized into question form and hosted on the google forms platform. The link to this questionnaire was circulated by the authors among their peer groups in the month of April 2020. RESULTS: We received 295 responses and 3 were unusable. Most of the responses were from India, the United States of America, Australia, Canada and the United Kingdom. About 60% of the respondents identified themselves as frontline and had a decade of clinical experience. Most respondents reported being anxious due to the pandemic and also observed the same in their peers and families. A majority also observed changes in behaviour in self and others and advanced a variety of reasons and concerns. A sense of duty was the most commonly employed coping mechanism. CONCLUSION: Physicians are not immune from information and misinformation, or cues in the environment. Behavioural choices are not always predicted by knowledge but by a combination of knowledge, emotional state, personality and environment. Healthcare settings need to be ready for emergencies and should focus on reducing uncertainty in physicians. These factors may also be gainfully used in the mental health promotion of physicians in COVID-19 care roles.

Peroxisomal footprint in the pathogenesis of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a form of fatty liver disease where benign hepatic steatosis leads to chronic inflammation in the steatotic liver of a patient without any history of alcohol abuse. Mechanisms underlying the progression of hepatic steatosis to NASH have long been investigated. This review outlines the potential role of peroxisomal dysfunctions in exacerbating the disease in NASH. Loss of peroxisomes as well as impaired peroxisomal functions have been demonstrated to occur in inflammatory conditions including NASH. Because peroxisomes and mitochondria co-operatively perform many metabolic functions including O2 and lipid metabolisms, a compromised peroxisomal biogenesis and function can potentially contribute to defective lipid and reactive oxygen species metabolism which in turn can lead the progression of disease in NASH. Impaired peroxisomal biogenesis and function may be due to the decreased expression of peroxisomal proliferator-activated receptor-α (PPAR-α), the major transcription factor of peroxisomal biogenesis. Recent studies indicate that the reduced expression of PPAR-α in NASH is correlated with the activation of the toll-like receptor-4 pathway (TLR-4). Further investigations are required to establish the mechanistic connection between the TLR-4 pathway and PPAR-α-dependent impaired biogenesis/function of peroxisomes in NASH.

Introgression of productivity enhancing traits, resistance to pod borer and Phytopthora stem blight from Cajanus scarabaeoides to cultivated pigeonpea.

The study aimed at introgression of productivity enhancing traits and resistance to pod borer and Phytophthora stem blight from wild to cultivated pigeonpea through an inter-specific cross between Cajanus scarabaeoides (ICP 15683) and C. cajan (ICPL 20329). Progenies derived from the direct segregating (without backcross) population and backcross population were evaluated for yield and yield contributing traits namely fruiting branches and pods plant-1 and 100-seed weight. Introgressed progenies having higher fruiting branches, pods and yield plant-1 compared to the cultivated parent were identified in both populations. A few progenies with significantly shorter plant height, early flowering and early maturity as compared to both cultivated and wild parents were also recovered in both populations. Progenies from both the populations were identified with higher resistance to pod borer and Phytophthora stem blight. However, some introgressed progenies having lower seed weight and seeds per pod were also recovered. The promising progenies are currently being used in the breeding programme to develop cultivars with improved productivity and resistance to pod borer and Phytophthora stem blight.

Regulation of endothelial barrier integrity by redox-dependent nitric oxide signaling: Implication in traumatic and inflammatory brain injuries.

Nitric oxide (NO) synthesized by eNOS plays a key role in regulation of endothelial barrier integrity but underlying cell signaling pathway is not fully understood at present. Here, we report opposing roles of two different redox-dependent NO metabolites; peroxynitrite (ONOO-) vs. S-nitrosoglutathione (GSNO), in cell signaling pathways for endothelial barrier disruption. In cultured human brain microvessel endothelial cells (hBMVECs), thrombin induced F-actin stress fiber formation causes barrier disruption via activating eNOS. Thrombin induced eNOS activity participated in cell signaling (e.g. RhoA and calcium influx mediated phosphorylation of myosin light chain) for F-actin stress fiber formation by increasing ONOO- levels. On the other hand, thrombin had no effect on intracellular levels of S-nitrosoglutathione (GSNO), another cellular NO metabolite. However, exogenous GSNO treatment attenuated the thrombin-induced cell signaling pathways for endothelial barrier disruption, thus suggesting the role of a shift of NO metabolism (GSNO vs. ONOO-) toward ONOO- synthesis in cell signaling for endothelial barrier disruption. Consistent with these in vitro studies, in animal models of traumatic brain injury and experimental autoimmune encephalomyelitis (EAE), ONOO- scavenger treatment as well as GSNO treatment were effective for attenuation of BBB leakage, edema formation, and CNS infiltration of mononuclear cells. Taken together, these data document that eNOS-mediated NO production and following redox-dependent NO metabolites (ONOO- vs. GSNO) are potential therapeutic target for CNS microvascular disease (traumatic and inflammatory) pathologies.