Dataset Information

N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs.

ABSTRACT: The clinical use of gentamicin over prolonged periods is limited because of dose and time-dependent nephrotoxicity, in which intracellular oxidative stress and heightened inflammation have been implicated. Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. The aim of this study was to determine changes in autophagy in response to the antioxidant N-acetylcysteine (NAC), via its effects on oxidative stress, inflammation, apoptosis, and renal function, following treatment with gentamicin in mini pigs. Adult mini pigs were divided into isotonic saline solution, gentamicin, and gentamicin plus NAC combination treatment groups. Gentamicin-induced histopathological changes, including inflammatory cell infiltration and tubular necrosis, were attenuated by NAC. NAC ameliorated the gentamicin-induced decreases in the levels of autophagy-related proteins, such as LC3 (microtubule-associated protein 1 light chain 3), PINK1 (phosphatase and tensin homologue deleted on chromosome10-induced kinase 1), phospho-parkin, AMBRA1 (activatingmolecule in Beclin 1-regulated autophagy), p62/SQSTM1 (sequestosome protein 1), and polyubiquitinated protein aggregates. NAC also caused a significant reduction in oxidative damage markers, including 4-hydroxy-2-nonenal, protein carbonyls, ?-H2AX (gamma histone variant H2AX), and 8-hydroxy-2'-deoxyguanosine, in gentamicin-treated animals. These data show that the protective effects of NAC might be related, at least in part, to a reduced inflammatory response, as observed in animals treated with both gentamicin and NAC. These results suggest that autophagy could be a new therapeutic target for preventing gentamicin-induced kidney injury, and that NAC might ameliorate gentamicin-induced nephrotoxicity by autophagy.

SUBMITTER: Cui J

PROVIDER: S-EPMC6855429 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs.

Cui Jing J Tang Li L Hong Quan Q Lin Shupeng S Sun Xuefeng X Cai Guangyan G Bai Xue-Yuan XY Chen Xiangmei X

Shock (Augusta, Ga.) 20191201 6

The clinical use of gentamicin over prolonged periods is limited because of dose and time-dependent nephrotoxicity, in which intracellular oxidative stress and heightened inflammation have been implicated. Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. The aim of this study was to determine changes in autophagy in response to the antioxidant N-acetylcysteine (NAC), ...[more]

PMID: 30676497

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Project description:BackgroundApplication of the immunomodulatory selective cytopheretic device (SCD) to enhance renal replacement therapy and improve outcomes of acute kidney injury in pediatric patients is impeded by safety concerns. Therapy using a pediatric hemodialysis system could overcome these limitations.MethodsYucatan minipigs (8-15 kg) with induced septic shock underwent continuous hemodiafiltration with the CARPEDIEM™ pediatric hemodialysis system using regional citrate anticoagulation (RCA) with or without SCD (n = 5 per group). Circuit function plus hemodynamic and hematologic parameters were assessed for 6 h.ResultsSCD was readily integrated into the CARPEDIEM™ system and treatment delivered for 6 h without interference with pump operation. SCD-treated pigs maintained higher blood pressure (p = 0.009) commensurate with lesser degree of lactic acidosis (p = 0.008) compared to pigs only receiving hemodiafiltration. Renal failure occurred in untreated pigs while urine output was sustained with SCD therapy. Neutrophil activation levels and ss-SOFA scores at 6 h trended lower in the SCD-treated cohort.ConclusionsSCD therapy under RCA was safely administered using the CARPEDIEM™ pediatric hemodialysis system for up to 6 h and no circuit compatibility issues were identified. Sepsis progression and organ dysfunction was diminished with SCD treatment in this model supportive of therapeutic benefit of this immunomodulatory therapy.ImpactSCD therapy with regional citrate anticoagulation has the potential to be administered safely to patients weighing <20 kg using the Carpediem renal replacement therapy platform. Use of a renal replacement therapy platform designed specifically for neonates/infants overcomes safety concerns for delivery of SCD treatment in this population. SCD therapy using the Carpediem renal replacement therapy platform retained the suggestive efficacy seen in larger children and adults to reduce organ injury and dysfunction from sepsis.

Project description:Alzheimer's disease (AD), a neurodegenerative disorder, causes short-term memory and cognition declines. It is estimated that one in three elderly people die from AD or other dementias. Chinese herbal medicine as a potential drug for treating AD has gained growing interest from many researchers. Moschus, a rare and valuable traditional Chinese animal medicine, was originally documented in Shennong Ben Cao Jing and recognized for its properties of reviving consciousness/resuscitation. Additionally, Moschus has the efficacy of "regulation of menstruation with blood activation, relief of swelling and pain" and is used for treating unconsciousness, stroke, coma, and cerebrovascular diseases. However, it is uncertain whether Moschus has any protective effect on AD patients. We explored whether Moschus could protect glutamate (Glu)-induced PC12 cells from cellular injury and preliminarily explored their related action mechanisms. The chemical compounds of Moschus were analyzed and identified by GC-MS. The Glu-induced differentiated PC12 cell model was thought to be the common AD cellular model. The study aims to preliminarily investigate the intervention effect of Moschus on Glu-induced PC12 cell damage as well as their related action mechanisms. Cell viability, lactate dehydrogenase (LDH), mitochondrial reactive oxygen species, mitochondrial membrane potential (MMP), cell apoptosis, autophagic vacuoles, autolysosomes or autophagosomes, proteins related to apoptosis, and the proteins related to autophagy were examined and analyzed. Seventeen active compounds of the Moschus sample were identified based on GC-MS analysis. In comparison to the control group, Glu stimulation increased cell viability loss, LDH release, mitochondrial damage, loss of MMP, apoptosis rate, and the number of cells containing autophagic vacuoles, and autolysosomes or autophagosomes, while these results were decreased after the pretreatment with Moschus and 3-methyladenine (3-MA). Furthermore, Glu stimulation significantly increased cleaved caspase-3, Beclin1, and LC3II protein expression, and reduced B-cell lymphoma 2/BAX ratio and p62 protein expression, but these results were reversed after pretreatment of Moschus and 3-MA. Moschus has protective activity in Glu-induced PC12 cell injury, and the potential mechanism might involve the regulation of autophagy and apoptosis. Our study may promote research on Moschus in the field of neurodegenerative diseases, and Moschus may be considered as a potential therapeutic agent for AD.

Dataset Information

N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs.

Publications

N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs.

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