- Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation. [Journal Article]
- BBBiochim Biophys Acta 2018 Feb 18
- Uncoupled endothelial nitric oxide synthase (eNOS) produces O2-instead of nitric oxide (NO). Earlier, we reported rapamycin, an autophagy inducer and inhibitor of cellular proliferation, attenuated l...
Uncoupled endothelial nitric oxide synthase (eNOS) produces O2-instead of nitric oxide (NO). Earlier, we reported rapamycin, an autophagy inducer and inhibitor of cellular proliferation, attenuated low shear stress (SS) induced O2-production. Nevertheless, it is unclear whether autophagy plays a critical role in the regulation of eNOS uncoupling. Therefore, this study aimed to investigate the modulation of autophagy on eNOS uncoupling induced by low SS exposure. We found that low SS induced endothelial O2-burst, which was accompanied by reduced NO release. Furthermore, inhibition of eNOS by L-NAME conspicuously attenuated low SS-induced O2-releasing, indicating eNOS uncoupling. Autophagy markers such as LC3 II/I ratio, amount of Beclin1, as well as ULK1/Atg1 were increased during low SS exposure, whereas autophagic degradation of p62/SQSTM1 was markedly reduced, implying impaired autophagic flux. Interestingly, low SS-induced NO reduction could be reversed by rapamycin, WYE-354 or ATG5 overexpression vector via restoration of autophagic flux, but not by N-acetylcysteine or apocynin. eNOS uncoupling might be ascribed to autophagic flux blockade because phosphorylation of eNOS Thr495 by low SS or PMA stimulation was also regulated by autophagy. In contrast, eNOS acetylation was not found to be regulated by low SS and autophagy. Notably, although low SS had no influence on eNOS Ser1177 phosphorylation, whereas boosted eNOS Ser1177 phosphorylation by rapamycin were in favor of the eNOS recoupling through restoration of autophagic flux. Taken together, we reported a novel mechanism for regulation of eNOS uncoupling by low SS via autophagy-mediated eNOS phosphorylation, which is implicated in geometrical nature of atherogenesis.
- Bet 1: A slower rate of initial N-acetylcysteine infusion in the treatment of acute paracetamol overdose to reduce adverse reactions. [Journal Article]
- EMEmerg Med J 2018; 35(3):199-201
- The Interaction of N-Acetylcysteine and Serum Transferrin Promotes Bacterial Biofilm Formation. [Journal Article]
- CPCell Physiol Biochem 2018 Feb 15; 45(4):1399-1409
- CONCLUSIONS: NAC used intravenously or in the presence of blood increases bacterial biofilm formation rather than inhibits it.
- N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis. [Journal Article]
- SBSchizophr Bull 2018 Feb 15; 44(2):317-327
- Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) ...
Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.
- Inhalation Injury in the Burned Patient. [Journal Article]
- APAnn Plast Surg 2018 Feb 15
- Inhalation injury causes a heterogeneous cascade of insults that increase morbidity and mortality among the burn population. Despite major advancements in burn care for the past several decades, ther...
Inhalation injury causes a heterogeneous cascade of insults that increase morbidity and mortality among the burn population. Despite major advancements in burn care for the past several decades, there remains a significant burden of disease attributable to inhalation injury. For this reason, effort has been devoted to finding new therapeutic approaches to improve outcomes for patients who sustain inhalation injuries.The three major injury classes are the following: supraglottic, subglottic, and systemic. Treatment options for these three subtypes differ based on the pathophysiologic changes that each one elicits.Currently, no consensus exists for diagnosis or grading of the injury, and there are large variations in treatment worldwide, ranging from observation and conservative management to advanced therapies with nebulization of different pharmacologic agents.The main pathophysiologic change after a subglottic inhalation injury is an increase in the bronchial blood flow. An induced mucosal hyperemia leads to edema, increases mucus secretion and plasma transudation into the airways, disables the mucociliary escalator, and inactivates hypoxic vasocontriction. Collectively, these insults potentiate airway obstruction with casts formed from epithelial debris, fibrin clots, and inspissated mucus, resulting in impaired ventilation. Prompt bronchoscopic diagnosis and multimodal treatment improve outcomes. Despite the lack of globally accepted standard treatments, data exist to support the use of bronchoscopy and suctioning to remove debris, nebulized heparin for fibrin casts, nebulized N-acetylcysteine for mucus casts, and bronchodilators.Systemic effects of inhalation injury occur both indirectly from hypoxia or hypercapnia resulting from loss of pulmonary function and systemic effects of proinflammatory cytokines, as well as directly from metabolic poisons such as carbon monoxide and cyanide. Both present with nonspecific clinical symptoms including cardiovascular collapse. Carbon monoxide intoxication should be treated with oxygen and cyanide with hydroxocobalamin.Inhalation injury remains a great challenge for clinicians and an area of opportunity for scientists. Management of this concomitant injury lags behind other aspects of burn care. More clinical research is required to improve the outcome of inhalation injury.The goal of this review is to comprehensively summarize the diagnoses, treatment options, and current research.
- Sodium bicarb vs sodium chloride, and acetylcysteine vs placebo, did not differ for adverse events after angiography. [Journal Article]
- AIMAnn Intern Med 2018 Feb 20; 168(4):JC22
- Stimulation of JNK Phosphorylation by the PTTH in Prothoracic Glands of the Silkworm,Bombyx mori. [Journal Article]
- FPFront Physiol 2018; 9:43
- In this study, phosphorylation of c-Jun N-terminal kinase (JNK) by the prothoracicotropic hormone (PTTH) was investigated in prothoracic glands (PGs) of the silkworm,Bombyx mori. Results showed that ...
In this study, phosphorylation of c-Jun N-terminal kinase (JNK) by the prothoracicotropic hormone (PTTH) was investigated in prothoracic glands (PGs) of the silkworm,Bombyx mori. Results showed that JNK phosphorylation was stimulated by the PTTH in time- and dose-dependent manners.In vitroactivation of JNK phosphorylation in PGs by the PTTH was also confirmed in anin vivoexperiment, in which a PTTH injection greatly increased JNK phosphorylation in PGs of day-6 last instar larvae. JNK phosphorylation caused by PTTH stimulation was greatly inhibited by U73122, a potent and specific inhibitor of phospholipase C (PLC) and an increase in JNK phosphorylation was also detected when PGs were treated with agents (either A23187 or thapsigargin) that directly elevated the intracellular Ca2+concentration, thereby indicating involvement of PLC and Ca2+. Pretreatment with an inhibitor (U0126) of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) and an inhibitor (LY294002) of phosphoinositide 3-kinase (PI3K) failed to significantly inhibit PTTH-stimulated JNK phosphorylation, indicating that ERK and PI3K were not related to JNK. We further investigated the effect of modulation of the redox state on JNK phosphorylation. In the presence of either an antioxidant (N-acetylcysteine, NAC) or diphenylene iodonium (DPI), PTTH-stimulated JNK phosphorylation was blocked. The JNK kinase inhibitor, SP600125, markedly inhibited PTTH-stimulated JNK phosphorylation and ecdysteroid synthesis. The kinase assay of JNK in PGs confirmed its stimulation by PTTH and inhibition by SP600125. Moreover, PTTH treatment did not affect JNK or Jun mRNA expressions. Based on these findings, we concluded that PTTH stimulates JNK phosphorylation in Ca2+- and PLC-dependent manners and that the redox-regulated JNK signaling pathway is involved in PTTH-stimulated ecdysteroid synthesis inB. moriPGs.
- Reactive oxygen species-independent apoptotic pathway by gold nanoparticles in Candida albicans. [Journal Article]
- MRMicrobiol Res 2018; 207:33-40
- Candida albicans is the most common pathogenic fungus in humans, causing cutaneous and life-threatening systemic infections. In this study, we confirmed using propidium iodide influx that gold nanopa...
Candida albicans is the most common pathogenic fungus in humans, causing cutaneous and life-threatening systemic infections. In this study, we confirmed using propidium iodide influx that gold nanoparticles (AuNPs), which are promising materials for use as antimicrobial agents, did not affect the membrane permeability of C. albicans. Thus, the fungal cell death mechanisms induced by AuNPs were assessed at intracellular levels including DNA damage, mitochondrial dysfunction, and reactive oxygen species (ROS) overproduction. AuNPs interacted with C. albicans DNA leading to increased nuclear condensation and DNA fragmentation. Changes in the mitochondria induced by AuNPs involving mass, Ca2+concentrations, and membrane potential indicated dysfunction, though the level of intracellular and mitochondrial ROS were maintained. Although ROS signaling was not disrupted, DNA damage and mitochondrial dysfunction triggered the release of mitochondrial cytochrome c into the cytosol, metacaspase activation, and phosphatidylserine externalization. Additionally, the AuNPs-induced apoptotic pathway was not influenced by N-acetylcysteine, an ROS scavenger. This indicates that ROS signaling is not linked with the apoptosis. In conclusion, AuNPs induce ROS-independent apoptosis in C. albicans by causing DNA damage and mitochondria dysfunction.
- N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials. [Journal Article]
- APActa Psychiatr Scand 2018 Feb 18
- CONCLUSIONS: Adjunctive NAC appears to be a safe treatment that has efficacy for schizophrenia, but not for bipolar disorder or MDD. Further higher quality RCTs are warranted to determine the role of adjunctive NAC in the treatment of major psychiatric disorders.
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- Idh2 Deficiency Exacerbates Acrolein-Induced Lung Injury through Mitochondrial Redox Environment Deterioration. [Journal Article]
- OMOxid Med Cell Longev 2017; 2017:1595103
- Acrolein is known to be involved in acute lung injury and other pulmonary diseases. A number of studies have suggested that acrolein-induced toxic effects are associated with depletion of antioxidant...
Acrolein is known to be involved in acute lung injury and other pulmonary diseases. A number of studies have suggested that acrolein-induced toxic effects are associated with depletion of antioxidants, such as reduced glutathione and protein thiols, and production of reactive oxygen species. Mitochondrial NADP+-dependent isocitrate dehydrogenase (idh2) regulates mitochondrial redox balance and reduces oxidative stress-induced cell injury via generation of NADPH. Therefore, we evaluated the role ofidh2in acrolein-induced lung injury usingidh2short hairpin RNA- (shRNA-) transfected Lewis lung carcinoma (LLC) cells andidh2-deficient (idh2-/-) mice. Downregulation ofidh2expression increased susceptibility to acrolein via induction of apoptotic cell death due to elevated mitochondrial oxidative stress.Idh2deficiency also promoted acrolein-induced lung injury inidh2knockout mice through the disruption of mitochondrial redox status. In addition, acrolein-induced toxicity inidh2shRNA-transfected LLC cells and inidh2knockout mice was ameliorated by the antioxidant, N-acetylcysteine, through attenuation of oxidative stress resulting fromidh2deficiency. In conclusion,idh2deficiency leads to mitochondrial redox environment deterioration, which causes acrolein-mediated apoptosis of LLC cells and acrolein-induced lung injury inidh2-/-mice. The present study supports the central role ofidh2deficiency in inducing oxidative stress resulting from acrolein-induced disruption of mitochondrial redox status in the lung.