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1.
Ulus Travma Acil Cerrahi Derg ; 27(4): 381-388, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34213003

RESUMO

BACKGROUND: Ischemia-reperfusion injury (IRI) is cellular damage that emerges from re-oxygenation of a hypoxic organ. In the present study, we aimed to examine the effects of a combination of levosimendan, an inotropic agent, and N-Acetylcysteine, the precursor of antioxidants and glutathione, in an experimental liver IRI model. METHODS: In this study, 38 rats were randomly divided into five groups. Before the ischemia, study arms were given physiological saline solution, N-Acetylcysteine (NAS), levosimendan or a combination of NAS+levosimendan in a predetermined amount and duration, and the infusion was continued until the end of this study. The hepatic pedicle was occluded using an atraumatic vein clamp, and 60 minutes of ischemia was achieved. The clamp was then opened and 60 minutes of reperfusion was ensured. Liver tissue samples were obtained after sacrifice, and tissue malondialdehyde (MDA) and myeloperoxidase (MPO) levels were determined. Serum Tumor Necrosis Factor (TNF)-α, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and MPO levels of blood samples were also measured. RESULTS: Among the histopathological changes in the liver tissue after IRI, differences between groups were statistically significant in the injury scoring system based on congestion, vacuolization and necrosis levels. Histopathological injury score, plasma MPO, AST, ALT, tissue MPO and tissue MDA values were statistically significantly lower in the treatment groups, prominently in the levosimendan and NAS combination group concerning liver histopathological damage. CONCLUSION: The use of a levosimendan plus NAS combination in liver IRI markedly suppressed inflammation and oxidative stress and significantly reduced liver ischemia-reperfusion injury and can be recommended for decreasing IRI instead of single agent use of levosimendan or NAS.


Assuntos
Acetilcisteína/farmacologia , Hepatopatias/metabolismo , Fígado , Traumatismo por Reperfusão/metabolismo , Simendana/farmacologia , Animais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos
2.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208631

RESUMO

Thiosulfate in the form of sodium thiosulfate (STS) is a major oxidation product of hydrogen sulfide (H2S), an endogenous signaling molecule and the third member of the gasotransmitter family. STS is currently used in the clinical treatment of acute cyanide poisoning, cisplatin toxicities in cancer therapy, and calciphylaxis in dialysis patients. Burgeoning evidence show that STS has antioxidant and anti-inflammatory properties, making it a potential therapeutic candidate molecule that can target multiple molecular pathways in various diseases and drug-induced toxicities. This review discusses the biochemical and molecular pathways in the generation of STS from H2S, its clinical usefulness, and potential clinical applications, as well as the molecular mechanisms underlying these clinical applications and a future perspective in kidney transplantation.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Oxirredução , Tiossulfatos/metabolismo , Animais , Hormônios Gastrointestinais/metabolismo , Humanos , Redes e Vias Metabólicas , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo
3.
Biochemistry (Mosc) ; 86(6): 680-692, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225591

RESUMO

The incidence of Alzheimer's disease (AD) increases significantly following chronic stress and brain ischemia which, over the years, cause accumulation of toxic amyloid species and brain damage. The effects of global 15-min ischemia and 120-min reperfusion on the levels of expression of the amyloid precursor protein (APP) and its processing were investigated in the brain cortex (Cx) of male Wistar rats. Additionally, the levels of expression of the amyloid-degrading enzymes neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), and insulin-degrading enzyme (IDE), as well as of some markers of oxidative damage were assessed. It was shown that the APP mRNA and protein levels in the rat Cx were significantly increased after the ischemic insult. Protein levels of the soluble APP fragments, especially of sAPPß produced by ß-secretase, (BACE-1) and the levels of BACE-1 mRNA and protein expression itself were also increased after ischemia. The protein levels of APP and BACE-1 in the Cx returned to the control values after 120-min reperfusion. The levels of NEP and ECE-1 mRNA also decreased after ischemia, which correlated with the decreased protein levels of these enzymes. However, we have not observed any changes in the protein levels of insulin-degrading enzyme. Contents of the markers of oxidative damage (di-tyrosine and lysine conjugates with lipid peroxidation products) were also increased after ischemia. The obtained data suggest that ischemia shifts APP processing towards the amyloidogenic ß-secretase pathway and accumulation of the neurotoxic Aß peptide as well as triggers oxidative stress in the cells. These results are discussed in the context of the role of stress and ischemia in initiation and progression of AD.


Assuntos
Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/enzimologia , Córtex Cerebral/enzimologia , Enzimas Conversoras de Endotelina/genética , Enzimas Conversoras de Endotelina/metabolismo , Regulação da Expressão Gênica , Insulisina/genética , Insulisina/metabolismo , Masculino , Neprilisina/genética , Neprilisina/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo
4.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201112

RESUMO

The Semax (Met-Glu-His-Phe-Pro-Gly-Pro) peptide is a synthetic melanocortin derivative that is used in the treatment of ischemic stroke. Previously, studies of the molecular mechanisms underlying the actions of Semax using models of cerebral ischemia in rats showed that the peptide enhanced the transcription of neurotrophins and their receptors and modulated the expression of genes involved in the immune response. A genome-wide RNA-Seq analysis revealed that, in the rat transient middle cerebral artery occlusion (tMCAO) model, Semax suppressed the expression of inflammatory genes and activated the expression of neurotransmitter genes. Here, we aimed to evaluate the effect of Semax in this model via the brain expression profiling of key proteins involved in inflammation and cell death processes (MMP-9, c-Fos, and JNK), as well as neuroprotection and recovery (CREB) in stroke. At 24 h after tMCAO, we observed the upregulation of active CREB in subcortical structures, including the focus of the ischemic damage; downregulation of MMP-9 and c-Fos in the adjacent frontoparietal cortex; and downregulation of active JNK in both tissues under the action of Semax. Moreover, a regulatory network was constructed. In conclusion, the suppression of inflammatory and cell death processes and the activation of recovery may contribute to the neuroprotective action of Semax at both the transcriptome and protein levels.


Assuntos
Hormônio Adrenocorticotrópico/análogos & derivados , Isquemia Encefálica/prevenção & controle , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteoma/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Transcriptoma/efeitos dos fármacos , Hormônio Adrenocorticotrópico/farmacologia , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Masculino , RNA-Seq , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
5.
Theranostics ; 11(15): 7450-7470, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158860

RESUMO

Rationale: Annexin-A1 (ANXA1) has previously been proposed to play a crucial role in neuronal apoptosis during ischemic stroke injury. Our recent study demonstrated that ANXA1 was modified by SUMOylation, and that this modification was greatly weakened after cerebral ischemia, but its effect on neuronal death and the underlying mechanism have not been fully elucidated. Methods: Mice subjected to middle cerebral artery occlusion were established as the animal model and primary cultured neurons treated with oxygen-glucose deprivation and reperfusion was established as the cell model of ischemic stroke. The Ni2+-NTA agarose affinity pull-down assay was carried out to determine the SUMOylation level of ANXA1. Co-immunoprecipitation assays was utilized to explore the protein interaction. Immunoblot analysis, quantitative real-time PCR, Luciferase reporter assay were performed to identify the regulatory mechanism. LDH release and TUNEL staining was performed to investigate the neuronal cytotoxicity and apoptosis, respectively. Results: In this study, we identified the deSUMOylating enzyme sentrin/SUMO-specific protease 6 (SENP6) as a negative regulator of ANXA1 SUMOylation. Notably, we found that SENP6-mediated deSUMOylation of ANXA1 induced its nuclear translocation and triggered neuronal apoptosis during cerebral ischemic injury. A mechanistic study demonstrated that SENP6-mediated deSUMOylation of ANXA1 promoted TRPM7- and PKC-dependent phosphorylation of ANXA1. Furthermore, blocking the deSUMOylation of ANXA1 mediated by SENP6 inhibited the transcriptional activity of p53, decreased Bid expression, suppressed caspase-3 pathway activation and reduced the apoptosis of primary neurons subjected to oxygen-glucose deprivation and reperfusion. More importantly, SENP6 inhibition by overexpression of a SENP6 catalytic mutant in neurons resulted in significant improvement in neurological function in the mouse model of ischemic stroke. Conclusions: Taken together, the results of this study identified a previously unidentified function of SENP6 in neuronal apoptosis and strongly indicated that SENP6 inhibition may provide therapeutic benefits for cerebral ischemia.


Assuntos
Anexina A1/metabolismo , Apoptose , Núcleo Celular/metabolismo , Cisteína Endopeptidases/metabolismo , AVC Isquêmico/metabolismo , Neurônios/metabolismo , Traumatismo por Reperfusão/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Núcleo Celular/patologia , AVC Isquêmico/patologia , Camundongos , Neurônios/patologia , Traumatismo por Reperfusão/patologia
7.
FASEB J ; 35(7): e21706, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34160104

RESUMO

Acute kidney injury (AKI) is a devastating condition with high morbidity and mortality rates. The pathological features of AKI are tubular injury, infiltration of inflammatory cells, and impaired vascular integrity. Pyruvate kinase is the final rate-limiting enzyme in the glycolysis pathway. We previously showed that pyruvate kinase M2 (PKM2) plays an important role in regulating the glycolytic reprogramming of fibroblasts in renal interstitial fibrosis. The present study aimed to determine the role of PKM2 in fibroblast activation during the pathogenesis of AKI. We found increased numbers of S100A4 positive cells expressing PKM2 in renal tissues from mice with AKI induced via folic acid or ischemia/reperfusion (I/R). The loss of PKM2 in fibroblasts impaired fibroblast proliferation and promoted tubular epithelial cell death including apoptosis, necroptosis, and ferroptosis. Mechanistically, fibroblasts produced less hepatocyte growth factor (HGF) in response to a loss of PKM2. Moreover, in two AKI mouse models, fibroblast-specific deletion of PKM2 blocked HGF signal activation and aggravated AKI after it was induced in mice via ischemia or folic acid. Fibroblast proliferation mediated by PKM2 elicits pro-survival signals that repress tubular cell death and may help to prevent AKI progression. Fibroblast activation mediated by PKM2 in AKI suggests that targeting PKM2 expression could be a novel strategy for treating AKI.


Assuntos
Injúria Renal Aguda/metabolismo , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Células Epiteliais/metabolismo , Fibroblastos/metabolismo , Piruvato Quinase/metabolismo , Animais , Apoptose/fisiologia , Morte Celular/fisiologia , Linhagem Celular , Modelos Animais de Doenças , Fibrose/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necroptose/fisiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/fisiologia
8.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067475

RESUMO

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.


Assuntos
Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Endocanabinoides/metabolismo , Adulto , Idoso , Animais , Ácidos Araquidônicos/metabolismo , Caenorhabditis elegans/metabolismo , Restrição Calórica/métodos , Modelos Animais de Doenças , Feminino , Humanos , Rim/metabolismo , Longevidade/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Alcamidas Poli-Insaturadas/metabolismo , Traumatismo por Reperfusão/metabolismo
9.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065421

RESUMO

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Células Dendríticas/efeitos dos fármacos , Isquemia/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Sirolimo/farmacologia , Injúria Renal Aguda/metabolismo , Transferência Adotiva/métodos , Animais , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células HEK293 , Humanos , Inflamação/metabolismo , Isquemia/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Biochemistry (Mosc) ; 86(5): 540-550, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33993861

RESUMO

Ischemia/reperfusion (I/R) is among the most frequent neurological problems and early intervention to limit the damage is crucial in decreasing mortality and morbidity. Based on reports regarding beneficial effects of melatonin, we investigated its impact on Na+-K+/Mg2+ ATPase and Ca2+/Mg2+ ATPase activities and ultrastructure of gray and white matter in the rat forebrain I/R model. Adult Wistar-albino rats (n = 78), were randomized into control, ischemia (I), ischemia/reperfusion (I/R), low (I/R + melatonin 400 µg/kg), moderate (I/R + melatonin 1200 µg/kg), and high (I/R + melatonin 2400 µg/kg) dose melatonin. Two-vessel occlusion combined with hypotension (15 min) induced ischemia and reperfusion (75 min) achieved by blood reinfusion were performed. Activities of the membrane-bound enzyme, brain malondialdehyde levels, and brain matter ultrastructure were examined in frontoparietal cortices. Melatonin lowered production of malondialdehyde in a dose-dependently. The enzyme activities attenuated under I and I/R, improved with melatonin treatment. I and I/R severely disturbed gray and white matter morphology. Melatonin, in all applied doses, decreased ultrastructural damages in both gray and white matter. Favorable effects of melatonin can be attributed to its antioxidant properties suggesting that it could be a promising neuroprotective agent against I/R injury being effective both for gray and white matter due to favorable biological properties.


Assuntos
Adenosina Trifosfatases/metabolismo , Substância Cinzenta/enzimologia , Melatonina/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Substância Branca/enzimologia , Animais , Isquemia Encefálica , Modelos Animais de Doenças , Substância Cinzenta/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo , Substância Branca/metabolismo
11.
Biomed Pharmacother ; 140: 111698, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029954

RESUMO

Glycoprotein (GP) Ib is a platelet membrane receptor complex exposed to vascular injury, proposed as an effective target for stroke therapy. Previously, we have observed that the GPIb antagonist anfibatide (ANF) could mitigate blood-brain barrier (BBB) disruption following cerebral ischemia/reperfusion (CI/R) injury. The current study was designed to investigate whether the amelioration of the BBB by ANF is mediated via the Epac signaling pathway. A murine model of CI/R injury was induced following 90 min of transient middle cerebral artery occlusion (MCAO). ANF (4 µg/kg) was intravenously injected 1 h after reperfusion. Herein, ANF ameliorated BBB disruption, increased the expression of tight junction proteins, suppressed F-actin cytoskeleton rearrangement, decreased the permeability of the ischemic brain tissue, and relieved brain edema. ANF-treated mice had smaller infarct volumes and less severe neurological deficits than the MCAO mice. Moreover, the effects of ANF and Epac1 agonists were very similar in the MCAO mice. Epac activation with a cAMP analog, 8-CPT-2'-O-Me-cAMP, mitigated the breakdown of BBB function and CI/R injury. The Epac specific antagonist, ESI-09, worsened barrier damage and cerebral impairment, antagonizing the protective effects afforded by ANF. In addition, ANF upregulated the expression of Epac1 protein in the ischemic cerebral cortex. Collectively, our results indicate that the protective effect of ANF on the BBB after CI/R could be attributed to the activation of the Epac pathway.


Assuntos
Plaquetas/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/metabolismo , AVC Isquêmico/tratamento farmacológico , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores , Animais , Plaquetas/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Edema Encefálico/tratamento farmacológico , Edema Encefálico/metabolismo , Isquemia Encefálica/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , AVC Isquêmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Biomed Pharmacother ; 140: 111696, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34044281

RESUMO

Glutamate-induced neurotoxicity is one of the most important pathogenic mechanisms in neurological diseases and is widely used as an in vitro model for ischemic stroke. Senkyunolide I (SEI), an active constituent derived from traditional Chinese medicine Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has been shown to have beneficial effects against focal cerebral ischemia-reperfusion in rats. However, the mechanisms underlying SEI-mediated neuroprotection remain not well understood. Thus, we explored the influence of SEI in glutamate-mediated injury to mouse neuroblastoma (Neuro2a) cells and determined the mechanisms involved. Neuro2a cells were treated with SEI under exposure to glutamate for 24 h. Cell viability was assessed by using WST-1 reagents, and apoptosis was evaluated using Annexin V-FITC and a PI double staining kit. The protein expression levels of p-AKT, AKT, p-GSK3ß, GSK3ß, p-p38, p38, p-ERK, ERK, p-JNK, JNK, Bcl-2, Bax, Bcl-xl, p-Bad, Bad, p53, and cleaved caspase-3 were determined by Western blot analysis. Glutamate significantly decreased cell viability and elevated the level of apoptosis. Treatment with SEI reversed those effects. Furthermore, the expression of p-JNK/JNK and cleaved caspase-3 were also reduced after treatment with SEI. Our findings demonstrate that SEI protected Neuro2a cells against glutamate toxicity by regulating JNK/caspase-3 pathway and apoptosis. Thus, SEI maybe a promising candidate for neuroprotection.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Camundongos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroproteção/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Aging (Albany NY) ; 13(9): 13333-13348, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33982674

RESUMO

This study aimed to explore effects of Sevoflurane on ischemia-reperfusion (I/R) injury after total knee arthroplasty (TKA). To explore potential molecular mechanism, Ras related dexamethasone induced 1 (RASD1), a Protein kinase A (PKA) activator, frequently associated with various models of I/R injury, was also investigated. In vivo mouse models with I/R injury after TKA and in vitro cell models with I/R injury were induced. Contents of creatinine kinase (CK), lactic dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA), serum levels of inflammatory factors, expression of PKA pathway-related genes and cell proliferation and apoptosis were measured. RASD1 was altered and PKA pathway was inhibited in mice and cells to elucidate the involvement of RASD1 and PKA pathway in Sevoflurane treatment on I/R injury. RASD1 was upregulated in I/R injury after TKA. Sevoflurane treatment or silencing RASD1 reduced RASD1 expression, CK, LDH and MDA contents, inflammation, apoptosis, but increased proliferation, SOD content, cAMP expression, and extents of PKA and cAMP responsive element binding protein (CREB) phosphorylation in skeletal muscle cells of I/R injury. Additionally, PKA pathway activation potentiated the therapeutic effect of Sevoflurane on I/R injury after TKA. Altogether, Sevoflurane treatment confines I/R injury after TKA via RASD1-mediated PKA pathway activation.


Assuntos
Proliferação de Células/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Sevoflurano/farmacologia , Proteínas ras/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Artroplastia do Joelho/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Camundongos , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/metabolismo
16.
Molecules ; 26(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946587

RESUMO

Acute and chronic transplant rejections due to alloreactivity are essential contributors to graft loss. However, the strength of alloreactivity is biased by non-immunological factors such as ischemia reperfusion injury (IRI). Accordingly, protection from IRI could be favorable in terms of limiting graft rejection. Caveolin-1 (Cav-1) is part of the cell membrane and an important regulator of intracellular signaling. Cav-1 has been demonstrated to limit IRI and to promote the survival of a variety of cell types including renal cells under stress conditions. Accordingly, Cav-1 could also play a role in limiting anti-graft immune responses. Here, we evaluated a possible association between pre-transplant serum concentrations of Cav-1 and the occurrence of rejection during follow-up in a pilot study. Therefore, Cav-1-serum concentrations were analyzed in 91 patients at the time of kidney transplantation and compared to the incidence of acute and chronic rejection. Higher Cav-1 levels were associated with lower occurrence of acute cellular tubulointerstitial rejection episodes.


Assuntos
Caveolina 1/sangue , Rejeição de Enxerto/sangue , Transplante de Rim/efeitos adversos , Nefrite Intersticial/sangue , Nefrite Intersticial/etiologia , Adulto , Idoso , Biomarcadores , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/mortalidade , Período Perioperatório , Prognóstico , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo
17.
Biomed Res Int ; 2021: 5598869, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33954183

RESUMO

Objective: Acute kidney injury (AKI) is a common and severe complication in critically ill patients, often caused by renal ischemia-reperfusion (RIR). Previous studies have confirmed that lung injury, rather than renal injury, is one of the leading causes of AKI-induced death. The pathophysiological mechanisms of acute lung injury (ALI) resulting from AKI are very complex and remain unclear. In the present study, we aimed to explore the protective effects and potential mechanism of sodium hydrosulfide (NaHS) on lung injury in RIR mice. Methods: The RIR model was established in wild-type and Nrf2-/- mice. Different groups of mice were treated with NaHS and MCC950. Lung tissues were harvested to detect lung injury, mitochondrial function, cell apoptosis, the NLRP3 inflammasome, and Nrf2 pathway-related molecules. Results: RIR led to a deterioration in lung histology, the wet/dry weight ratio, PaO2/FiO2, and mitochondrial function, in addition to stimulating the activation of the NLRP3 and Nrf2 pathways. MCC950 alleviated mitochondrial dysfunction, lung apoptosis, and histology injury in the lungs after RIR. NaHS treatment markedly improved the lung histological scores, the wet/dry weight ratio, bronchoalveolar lavage fluid (BALF) cell counts, BALF neutrophil counts, BALF neutrophil elastase activity, BALF protein concentration, PaO2/FiO2, mitochondrial morphology, the red/green fluorescence intensity that indicates changes in mitochondrial membrane potential, respiratory control rate (RCR), ATP, reactive oxygen species (ROS) release, and cell apoptosis via Nrf2-mediated NLRP3 pathway inhibition. Conclusion: NaHS protected against RIR-induced lung injury, mitochondrial dysfunction, and inflammation, which is associated with Nrf2 activation-mediated NLRP3 pathway inhibition.


Assuntos
Injúria Renal Aguda , Lesão Pulmonar Aguda , Traumatismo por Reperfusão , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Injúria Renal Aguda/complicações , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Células Cultivadas , Modelos Animais de Doenças , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/efeitos dos fármacos , Rim/química , Rim/efeitos dos fármacos , Pulmão/química , Pulmão/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Sulfonas/farmacologia
18.
Life Sci ; 278: 119511, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33864818

RESUMO

Effective Ca2+ dependent mitochondrial energy supply is imperative for proper cardiac contractile activity, while disruption of Ca2+ homeostasis participates in the pathogenesis of multiple human diseases. This phenomenon is particularly prominent in cardiac ischemia and reperfusion (I/R) and heart failure, both of which require strict clinical intervention. The interface between endoplasmic reticula (ER) and mitochondria, designated the mitochondria-associated membrane (MAM), is now regarded as a crucial mediator of Ca2+ transportation. Thus, interventions targeting this physical and functional coupling between mitochondria and the ER are highly desirable. Increasing evidence supports the notion that restoration, and maintenance, of the physiological contact between these two organelles can improve mitochondrial function, while inhibiting cell death, thereby sufficiently ameliorating I/R injury and heart failure development. A better understanding regarding the underlying mechanism of MAM-mediated transport will pave the way for identification of novel treatment approaches for heart disease. Therefore, in this review, we summarize the crucial functions and potential mechanisms of MAMs in the pathogenesis of I/R and heart failure.


Assuntos
Cálcio/metabolismo , Insuficiência Cardíaca/metabolismo , Mitocôndrias/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Sinalização do Cálcio , Linhagem Celular , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Homeostase , Humanos , Camundongos , Mitocôndrias Cardíacas/metabolismo , Membranas Mitocondriais/metabolismo , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Resultado do Tratamento
19.
Kidney Blood Press Res ; 46(3): 257-265, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33910212

RESUMO

INTRODUCTION/AIMS: Hydrogen sulfide (H2S) is considered to be the third most important endogenous gasotransmitter in organisms. GYY4137 is a long-acting donor for H2S, a gas transmitter that has been shown to prevent multi-organ damage in animal studies. We previously reported the effect of GYY4137 on cardiac ischaemia reperfusion injury (IRI) in diabetic mice. However, the role and mechanism of GYY4137 in renal IRI are poorly understood. The aims of this study were to determine whether GYY4137 can effectively alleviate the injury induced by renal ischaemia reperfusion and to explore its possible mechanism. METHODS: Mice received right nephrectomy and clipping of the left renal pedicle for 45 min. GYY4137 was administered by intraperitoneal injection for 2 consecutive days before the operation. The model of hypoxia/reoxygenation injury was established in HK-2 cells, which were pre-treated with or without GYY4137. Renal histology, function, apoptosis, and oxidative stress were measured. Western blot was used to measure the target -protein after renal IRI. RESULTS: The results indicated that GYY4137 had a clear protective effect on renal IRI as reflected by the attenuation of renal dysfunction, renal tubule injury, and apoptosis. Moreover, GYY4137 remarkably reduced renal IRI-induced oxidative stress. GYY4137 significantly elevated the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2) and the expression of antioxidant enzymes regulated by Nrf2, including SOD, HO-1, and NQO-1. CONCLUSIONS: GYY4137 alleviates ischaemia reperfusion-induced renal injury through activating the antioxidant effect mediated by Nrf2 signalling.


Assuntos
Antioxidantes/uso terapêutico , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Morfolinas/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Organotiofosforados/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo
20.
Biomed Res Int ; 2021: 6615685, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816617

RESUMO

Ischemic stroke, accompanied with high mortality and morbidity, may produce heavy economic burden to societies and families. Therefore, it is of great significance to explore effective therapies. Hyperbaric oxygen (HBO) is a noninvasive, nondrug treatment method that has been proved able to save ischemic penumbra by improving hypoxia, microcirculation, and metabolism and applied in various ischemic diseases. Herewith, we fully evaluated the effect of HBO on ischemic stroke and investigated its potential mechanism in the rat ischemia/reperfusion(I/R) model. Sixty Sprague-Dawley male rats were randomly divided into three groups-sham group, MCAO group, and MCAO+HBO group. In the latter two groups, the middle cerebral artery occlusion was performed (MCAO) for 2 hours, and then the occlusion was removed in order to establish the ischemic/reperfusion model. Subsequently, HBO was performed immediately after I/R (2 hours per day for 3 days). 72 hours after MCAO, the brain was dissected for our experiment. Finally, the data from three groups were analyzed by one-way analysis of variance (ANOVA) and followed by a Bonferroni test. In this article, we reported that HBO effectively reduced the infarction and edema and improved neurological functions to a certain extent. As shown by western blot analysis, HBO significantly reduced autophagy by regulating autophagy-related proteins (mTOR, p-mTOR, Atg13, LC3B II and LC3B II) in the hippocampus 72 hours after I/R, which was accompanied by inhibiting the expression of hypoxia inducible factor-1α (HIF-1α) in hippocampus. The results suggest that HBO may improve cerebral I/R injury, possibly via inhibiting HIF-1α, the upstream molecule of autophagy, and therefore, subsequently inhibiting autophagy in the rat model of ischemic stroke.


Assuntos
Autofagia , Isquemia Encefálica , Regulação para Baixo , Oxigenação Hiperbárica , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia
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