Nitric oxide : biology and chemistry
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The accumulation of dysfunctional mitochondria induced by the impairment of the autophagy-lysosome pathway (ALP), especially mitophagy is an important cause of cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture (EA) exerts remarkable effects in treating ischemic stroke; however, the detailed mechanism remains unclear. In this study, rats were treated with mitochondrial permeability transition pore (mPTP) opening inhibitor, peroxynitrite (ONOO-) scavenger, or selective inhibitor of mitophagy activation during 2-h middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion in combination with EA treatment. ⋯ The treatment with EA, cyclosporine-A (CsA, a potent inhibitor of mPTP opening) or FeTMPyP (a type of ONOO- scavenger) could significantly increase MMP and/or ATP levels, improve mitochondrial function and decrease neuronal injury. At the same time, EA also improved ALP dysfunction and the deficiency of mitophagy clearance; however, mitochondrial division inhibitor-1 (Mdivi-1, a selective inhibitor of mitophagy activation) blocked mitophagy clearance and aggravated neuronal injury. Taken together, EA ameliorates nitro/oxidative stress-induced mitochondrial functional damage and decreases the accumulation of damaged mitochondria via Pink1/Parkin-mediated mitophagy clearance to protect cells against neuronal injury in cerebral I/R.
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Increasing evidence has demonstrated that dexmedetomidine (DEX) possesses multiple pharmacological actions. Herein, we explored the protective effect and potential molecular mechanism of DEX on lipopolysaccharide (LPS)-induced early acute kidney injury (AKI) from the perspective of antioxidant stress. We found that DEX (30 μg/kg, i.p.) ameliorated the renal dysfunction and histopathological damage (tubular necrosis, vacuolar degeneration, infiltration of inflammatory cells and cast formation) induced by LPS (10 mg/kg). ⋯ Notably, DEX pretreatment had the same effect as intraperitoneal injection of an inhibitor of inducible nitric oxide synthase inhibitor (1400W; 15 mg/kg), and inhibited the activity of renal inducible nitric oxide synthase (iNOS) and decreased the expression of iNOS mRNA and NO production. However, the protective effect of DEX on LPS-induced early AKI was reversed by the alpha 2 adrenal receptor (α2-AR) inhibitor atipamezole, whereas the imidazoline receptor inhibitor idazoxan did not. Taken together, DEX protects against LPS-induced early AKI in rats by inhibiting the iNOS/NO signaling pathway, mainly by acting on α2-ARs instead of IRs.
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Randomized Controlled Trial Multicenter Study
Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial.
To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. ⋯ NCT01939301.
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Cardiac abnormalities are observed frequently after aneurysmal subarachnoid hemorrhage (aSAH). A subset of aSAH patients develops neurogenic cardiomyopathy, likely induced by catecholamine excess. Genetic polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been linked to decreased nitric oxide (NO) levels, coronary artery spasm, and myocardial infarction. The role of the eNOS single nucleotide polymorphism (SNP) -786 T/C in cardiac instability following aSAH has not been previously investigated. ⋯ The C allele of the eNOS SNP -786 T/C was independently associated with an increased risk for cardiac instability following aSAH. Cardiac instability itself was a risk factor for an unfavorable functional outcome upon discharge from the hospital.
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We previously showed that hydrogen sulfide (H2S) upregulates peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α in primary hepatocytes. PGC-1α is a crucial regulator of mitochondrial biogenesis, a process required to maintain cellular energy homeostasis. We investigated the regulation of hepatic mitochondrial biogenesis by cystathionine γ-lyase (CSE)-generated H2S under physiological conditions. ⋯ Finally, knockdown of either PGC-1α or PPRC significantly decreased NaHS-stimulated mitochondrial biogenesis in hepatocytes, where knockdown of both genes were required to abolish NaHS-induced mitochondrial biogenesis. Endogenous H2S-induced liver mitochondrial biogenesis is dependent upon PGC-1α and PPRC signaling in primary hepatocytes. This study may offer clues to the regulation of energy homeostasis under physiological conditions as well as mitochondrial dysregulation.