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1.
Kidney Int ; 99(1): 22-24, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33390229

RESUMO

Recent advances in material engineering and gene editing techniques have now made it possible to use sheeted stem cells as distributors of therapeutic factors in clinical practice (e.g., as beating sheets for patients with heart failure). In this issue, Park et al. report the effects of sheets of genome-engineered human umbilical cord-derived mesenchymal stem cells in preserving kidney function after ischemia-reperfusion injury, demonstrating a possible application for acute kidney injury treatment.


Assuntos
Lesão Renal Aguda , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Traumatismo por Reperfusão , Lesão Renal Aguda/terapia , Animais , Humanos , Traumatismo por Reperfusão/terapia , Cordão Umbilical
2.
Nihon Yakurigaku Zasshi ; 156(1): 21-25, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390475

RESUMO

Ischemic stroke is one of the most prevalent brain disorders and the major cause of long-term disability. In particularly, hippocampal injury after ischemia-reperfusion is a serious problem as it contributes to vascular dementia. Many researches have revealed that ischemia-reperfusion causes increase in reactive oxygen species production and disruption of neuronal Zn2+ homeostasis in the hippocampus, which induces hippocampal neuron death. Glutathione (GSH) is present in all mammalian cells and plays a crucial role in neuronal cell defense against oxidative stress. On the other hand, thiol group of GSH chemically chelates Zn2+ and functions as a regulator of neuronal Zn2+ homeostasis. These evidences suggest that neuronal GSH levels could be an important factor affecting neuronal surviving. The synthesis of GSH is largely influenced by intracellular cysteine availability. In neurons, excitatory amino acid carrier type 1 (EAAC1) acts as a cysteine transporter and provides cysteine substrate for GSH synthesis. Recently, several animal studies have revealed that promotion of neuronal GSH synthesis through EAAC1 reduces ischemia-induced hippocampal neuron death. This review aims to describe neuroprotective role of GSH against hippocampal injury following ischemia-reperfusion, focusing on EAAC1.


Assuntos
Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Transportador 3 de Aminoácido Excitatório/metabolismo , Glutationa/metabolismo , Glutationa/farmacologia , Hipocampo/metabolismo , Isquemia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Reperfusão
3.
Life Sci ; 264: 118628, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131670

RESUMO

Acute myocardial infarction is associated with high rates of morbidity and mortality and can cause irreversible myocardial damage. Timely reperfusion is critical to limit infarct size and salvage the ischemic myocardium. However, reperfusion may exacerbate lethal tissue injury, a phenomenon known as myocardial ischemia/reperfusion (I/R) injury. Pharmacological postconditioning (PPC), a strategy involving medication administration before or during the early minutes of reperfusion, is more efficient and flexible than preconditioning or ischemic conditioning. Previous studies have shown that various mechanisms are involved in the effects of PPC. In this review, we summarize the relative effects and potential underlying mechanisms of PPC to provide a foundation for future research attempting to develop novel treatments against myocardial I/R injury.


Assuntos
Cardiotônicos/uso terapêutico , Pós-Condicionamento Isquêmico/métodos , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Apoptose , Autofagia , Cálcio/metabolismo , Ensaios Clínicos como Assunto , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Proteína HMGB1/metabolismo , Humanos , Inflamação , Precondicionamento Isquêmico Miocárdico , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão , Transdução de Sinais , Fatores de Tempo
4.
Life Sci ; 264: 118626, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33148417

RESUMO

AIMS: Circular RNAs (circRNAs) have been shown to play crucial roles in various biological processes and human diseases. However, their exact functions in ischemic stroke remain largely unknown. In this study, we explored the functional role of circRNA HECTD1 (circ-HECTD1) and its underlying mechanism in cerebral ischemia/reperfusion injury. METHODS: Mouse middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation (OGD) model in HT22 cells were used to mimic the cerebral ischemia/reperfusion injury. Brain infarct volume, flow cytometry, caspase 3 activity, NF-κB activity, and TUNEL staining were performed to evaluate the function of circ-HECTD1. Luciferase report assay was used to explore the regulatory mechanism. FINDINGS: The results showed that the expression of circ-HECTD1 and tumor necrosis factor receptor-associated factor 3 (TRAF3) was remarkably up-regulated, while miR-133b was down-regulated in oxygen-glucose deprivation (OGD)-induced HT22 cells and mouse middle cerebral artery occlusion (MCAO) model. circ-HECTD1 knockdown relieved OGD-caused neuronal cell death in vitro. Simultaneously, circ-HECTD1 knockdown improved cerebral infarction volume and neuronal apoptosis in MCAO mice. circ-HECTD1 was able to negatively regulate the expression of miR-133b, and TRAF3 is one of the targets of miR-133b. Upregulation of miR-133b inhibited the expression of TRAF3 in OGD-stimulated cells, whereas circ-HECTD1 upregulation reversed this effect. Furthermore, upregulation of miR-133 was able to inhibit OGD-caused cell apoptosis and NF-κB activation, whereas upregulation of circ-HECTD1 attenuated these effects of miR-133b mimics. SIGNIFICANCE: Taken together, circ-HECTD1 knockdown inhibited the expression of TRAF3 by targeting miR-133b, thereby attenuating neuronal injury caused by cerebral ischemia.


Assuntos
/genética , MicroRNAs/genética , Neurônios/patologia , RNA Circular/genética , Fator 3 Associado a Receptor de TNF/genética , Ubiquitina-Proteína Ligases/genética , Animais , Apoptose , Glicemia/metabolismo , Encéfalo/patologia , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Regulação para Baixo , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Artéria Cerebral Média/patologia , Neuroproteção , Oxigênio/metabolismo , Traumatismo por Reperfusão/patologia
5.
Life Sci ; 264: 118641, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33148420

RESUMO

Pancreatitis is an inflammatory disease of the pancreas characterized by acinar cell injury and is associated with the abnormal release of trypsin, which results in high mortality due to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). The inflammatory response, impaired autophagic flux, endoplasmic reticulum stress (ERS) and their interactions are involved in the development of pancreatitis. Molecular hydrogen (H2) is a novel antioxidant that possesses the features of selective scavenging of oxygen free radicals and nontoxic metabolites and has been shown to be efficacious for treating infection, injury, tumors, ischemia-reperfusion organ injury, metabolic disease and several other diseases. Recent studies have found that H2 is also useful in the treatment of pancreatitis, which may be related to the mechanism of antioxidative stress, anti-inflammation, anti-apoptosis, regulation of immunity and regulation of molecular pathways. This review focuses on the pathogenesis of pancreatitis and the research progress and potential mechanisms of H2 against pancreatitis to provide theoretical bases for future research and clinical application of H2 therapy for pancreatitis.


Assuntos
Hidrogênio/uso terapêutico , Pancreatite/terapia , Animais , Antioxidantes/metabolismo , Apoptose , Autofagia/efeitos dos fármacos , Morte Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Inflamação , Sistema de Sinalização das MAP Quinases , Insuficiência de Múltiplos Órgãos , Estresse Oxidativo , Pâncreas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Tripsina/química
6.
Life Sci ; 265: 118834, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33249096

RESUMO

Renal injury might originate from multiple factors like ischemia reperfusion (I/R), drug toxicity, cystic fibrosis, radio contrast agent etc. The four adenosine receptor subtypes have been identified and found to show diverse physiological and pathological roles in kidney diseases. The activation of A1 adenosine receptor (A1) protects against acute kidney injury by improving renal hemodynamic alterations, decreasing tubular necrosis and its inhibition might facilitate removal of toxin or drug metabolite in chronic kidney disease models. Furthermore, recent findings revealed that A2A receptor subtype activation regulates macrophage phenotype in experimental models of nephritis. Interestingly the emerging role of adenosine kinase inhibitors in kidney diseases has been discussed which act by increasing adenosine availability at target sites and thereby promote A2A receptor stimulation. In addition, the least explored adenosine receptor subtype A3 inhibition was observed to exert anti- oxidant, immunosuppressive and anti-fibrotic effects, but more studies are required to confirm its benefits in other renal injury models. The clinical studies targeting A1 receptor in patients with pre-existing kidney disease have yielded disappointing results, perhaps owing to the origin of unexpected neurological complications during the course of trial. Importantly, conducting well designed clinical trials and testing adenosine modulators with lesser brain penetrability could clear the way for clinical approval of these agents for patients with renal functional impairments.


Assuntos
Adenosina/metabolismo , Nefropatias/fisiopatologia , Receptores Purinérgicos P1/metabolismo , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/fisiopatologia , Adenosina Quinase/antagonistas & inibidores , Adenosina Quinase/metabolismo , Animais , Humanos , Nefropatias/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologia
7.
Toxicol Appl Pharmacol ; 410: 115340, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33264646

RESUMO

BACKGROUND AND AIM: The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75µg/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-κB dependent manner. METHODS: Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion. RESULTS: OCT pretreatment at doses (50 or 75 µg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group. CONCLUSION: OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.


Assuntos
Melatonina/administração & dosagem , NF-kappa B/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Octreotida/administração & dosagem , Piroptose/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Antioxidantes/administração & dosagem , Quimioterapia Combinada , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/fisiologia , Distribuição Aleatória , Ratos , Traumatismo por Reperfusão/metabolismo , Receptor 4 Toll-Like/metabolismo
8.
Chem Biol Interact ; 333: 109307, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33159969

RESUMO

Renal ischemia-reperfusion injury (R-IRI) is the main cause of acute renal failure. Carvedilol has been shown to protect against R-IRI. However, the underlying mechanisms are still not completely clarified. This study aimed to investigate the role of lipid signaling in mediating carvedilol protective effects against R-IRI in insulin-resistant mice by using two different lipid signaling modulators, quercetin and lithium chloride (LiCl). Mice were fed high-fructose, high-fat diet (HFrHFD) for 16 weeks to induce insulin resistance. At the end of feeding period, mice were randomly distributed into five groups; Sham, R-IRI, Carvedilol (20 mg/kg, i.p.), Carvedilol + Quercetin (10 mg/kg, i.p.), Carvedilol + LiCl (200 mg/kg, i.p.). R-IRI was performed by applying 30 min of unilateral renal ischemia followed by one hour of reperfusion. Quercetin and LiCl were administered 30 min before carvedilol administration and carvedilol was administered 30 min before ischemia. Changes in kidney function tests, histopathology, fibrosis area, lipid signaling, inflammatory, apoptosis and oxidative stress markers in the kidney were measured. Results showed that R-IRI decreased kidney function, impaired renal tissue integrity, modulated lipid signaling and increased renal inflammation, apoptosis and oxidative stress. Carvedilol treatment decreased the detrimental effects induced by R-IRI. In addition, pre-injection of both quercetin and LiCl potentiated the reno-protective effects of carvedilol against R-IRI independent of changes in lipid mediators like phosphatidyl inositol 4,5 bisphosphate (PIP2) and diacylglycerol (DAG). In conclusion, quercetin and LiCl potentiate the protective effects of carvedilol against R-IRI in HFrHFD-fed mice by reducing inflammation and oxidative stress independent of lipid signaling.


Assuntos
Carvedilol/farmacologia , Dieta Hiperlipídica/efeitos adversos , Frutose/administração & dosagem , Rim/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Quercetina/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Sinergismo Farmacológico , Rim/irrigação sanguínea , Rim/metabolismo , Rim/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/induzido quimicamente , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos
9.
Life Sci ; 264: 118660, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127512

RESUMO

AIMS: To evaluate the impact of galangin treatment on cerebral ischemia-reperfusion (I/R) injury in gerbils and to identify potential mechanisms of the protective effect of galangin on hippocampal neurons after I/R injury. PRINCIPAL METHODS: A cerebral ischemia model using bilateral common carotid artery ligation in gerbils was established. The Morris water maze (MWM) test was used to evaluate the learning and memory ability of gerbils. The cell viability was evaluated with an MTT assay. The levels of lipid peroxide biomarkers were measured to estimate the injury due to lipid peroxide. The morphology was detected by electron micrography, immunofluorescence and Nissl staining. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to measure the molecular characteristics. KEY FINDINGS: In the MWM, gerbils treated with galangin after I/R injury showed significant improvements in learning and memory. In addition, galangin treatment reduced the levels of lipid peroxide in the brains of gerbils that underwent I/R as well as reduced the amount of cell death and increased the expression of SLC7A11 and glutathione peroxidase 4 (GPX4). Furthermore, the expression of the marker of ferroptosis was decreased in galangin-treated gerbils, and the effect of galangin was weakened when SLC7A11 was knocked down. These results show that galangin can inhibit ferroptosis by enhancing the expressions of SLC7A11 and GPX4 as well as reduce neuronal cell death. SIGNIFICANCE: Galangin inhibits ferroptosis through activation of the SLC7A11/GPX4 axis and has a protective effect on hippocampal neurons in gerbils after I/R.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Isquemia Encefálica/tratamento farmacológico , Ferroptose , Flavonoides/uso terapêutico , Glutationa Peroxidase/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/fisiopatologia , Ferroptose/efeitos dos fármacos , Flavonoides/farmacologia , Gerbillinae , Hipocampo/patologia , Aprendizagem/efeitos dos fármacos , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos
10.
Life Sci ; 265: 118806, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33249098

RESUMO

AIMS: Neuronal apoptosis acts as the pivotal pathogenesis of cerebral ischemia/reperfusion (I/R) injury after ischemic stroke. PAQR3 (progestin and adipoQ receptor family member 3) is a crucial player who participates in the regulation of cell death. We aim to explore the specific function and the underlying mechanism of PAQR3 in cerebral I/R induced neuronal injury. MAIN METHODS: We established a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model and rat adrenal pheochromocytoma (PC12) cell oxygen-glucose deprivation/reperfusion (OGD/R) model to detect the expression and of PAQR3 after I/R treatment in vivo and in vitro. We used lentivirus to knockdown PAQR3 and investigated the function of PAQR3 in I/R induced neuronal apoptosis. KEY FINDINGS: PAQR3 expression is markedly increased in the ischemic hemisphere of C57BL/6 mice and PC12 cells after I/R stimulation. Knockdown PAQR3 can attenuate neuronal apoptosis induced by I/R in PC12 cells and exerts neuroprotective effects. PAQR3 deficiency can significantly raise cell viability and suppress LDH leakage under I/R treatment. Silencing PAQR3 attenuates neuronal apoptosis remarkably with fewer TUNEL-positive cells and lower apoptosis rate under I/R treatment. Mechanistically, knockdown of PAQR3 can inhibit the apoptosis pathway through inducing anti-apoptotic proteins and inhibiting pro-apoptotic proteins. Besides, PI3K/AKT signaling suppression with LY294002 abolished the neuroprotective functions induced by silencing PAQR3. SIGNIFICANCE: Our results elucidate that silencing PAQR3 can protect PC12 from OGD/R injury via activating PI3K/AKT pathway. And therefore, provide a novel therapeutic target for the prevention of cerebral I/R injury.


Assuntos
Isquemia Encefálica/metabolismo , Glucose/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas de Membrana/biossíntese , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose/fisiologia , Isquemia Encefálica/genética , Isquemia Encefálica/prevenção & controle , Hipóxia Celular/fisiologia , Inativação Gênica/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Células PC12 , Ratos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle
11.
Vasc Endovascular Surg ; 55(1): 11-17, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32878581

RESUMO

INTRODUCTION: Naftidrofuryl and cilostazol are drugs with proven efficacy in the treatment of claudication in peripheral vascular disease. In this experimental study, we evaluated the effects of naftidrofuryl and cilostazol in ischemia-reperfusion (IR) injury on various tissues. MATERIALS AND METHODS: 40 male albino Wistar rats (8-12 weeks old, 250-350 g.) are randomly divided into 4 groups: Control (Group 1), sham (group 2), cilostazol pre-treatment (group 3), naftidrofuryl pre-treatment (group 4). During 21 days placebo is given to group 2, 12 mg/kg/day cilostazol is given to group 3, 50 mg/kg/day naftidrofuryl is given to group 4 orally. Ischemia and reperfusion are induced at the lower hind limb in Groups 2, 3 and 4. Ischemic muscle, kidney, liver, heart, brain and blood samples are obtained. The total antioxidant capacity, oxidant levels and oxidative stress index are studied for each group. RESULTS: Both drugs have protective effects of remote organ injury following IR. Systemic effects are similar to each other, both have protective effects of IR injury. It showed no statistical significance in the total antioxidant capacity. Total oxidant levels are significantly affected by cilostazol in the heart (p < 0.01) and by naftidrofuryl in the liver (p < 0.01). The effect on oxidative stress was only significant with cilostazol on the heart (p < 0.01). CONCLUSION: Cilostazol and naftidrofuryl had beneficial effects in all tissues against tissue damage caused by IR injury. In ischemic muscle, kidney and heart cilostazol had improved outcomes comparing to naftidrofuryl. Naftidrofuryl had benefits over cilostazol in liver tissue.


Assuntos
Antioxidantes/farmacologia , Encéfalo/irrigação sanguínea , Cilostazol/farmacologia , Rim/irrigação sanguínea , Fígado/irrigação sanguínea , Músculo Esquelético/irrigação sanguínea , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Nafronil/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
12.
Equine Vet J ; 53(1): 125-133, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32119148

RESUMO

BACKGROUND: Pharmacological preconditioning of dexmedetomidine on small intestinal ischaemia/reperfusion injury has been reported in different animal models including horses. OBJECTIVES: The objective was to assess if xylazine and lidocaine have a preconditioning effect in an experimental model of equine jejunal ischaemia. STUDY DESIGN: Terminal in vivo experiment. METHODS: Ten horses under general anaesthesia were either preconditioned with xylazine (group X; n = 5) or lidocaine (group L; n = 5). A historical untreated control group (group C; n = 5) was used for comparison. An established experimental model of equine jejunal ischaemia was applied, and intestinal samples were taken pre-ischaemia, after ischaemia and following reperfusion. Histomorphological examination was performed based on a modified Chiu score. Immunohistochemical staining for cleaved caspase-3, TUNEL and calprotectin was performed, and positive cell counts were expressed in cells/mm2 . RESULTS: There was no progression of histomorphological mucosal injury from ischaemia to reperfusion, and there were no differences in histomorphology between the groups. After ischaemia, group X had significantly less caspase-positive cells compared to the control group with a median difference of 227% (P = .01). After reperfusion, group X exhibited significantly lower calprotectin-positive cell counts compared to the control group, with a median difference of 6.8 cells/mm2 in the mucosa and 44 cells in the serosa (P = .02 and .05 respectively). All groups showed an increase in caspase- and calprotectin-positive cells during reperfusion (P < .05). TUNEL-positive cells increased during ischaemia, followed by a decrease after reperfusion (P < .05). MAIN LIMITATIONS: The small sample size and the use of a historical control group. Preconditioning effects of the tested drugs may be masked by the protective effects of isoflurane in the anaesthetic protocol. CONCLUSIONS: Preconditioning with lidocaine did not have any effect on the tested variables. The lower cell counts of caspase- and calprotectin-positive cells in group X may indicate a beneficial effect of xylazine on ischaemia/reperfusion injury. Due to the absence of a concurrent reduction of histomorphological injury, the clinical significance remains uncertain.


Assuntos
Doenças dos Cavalos , Traumatismo por Reperfusão , Animais , Doenças dos Cavalos/prevenção & controle , Cavalos , Isquemia/veterinária , Lidocaína/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/veterinária , Xilazina/farmacologia
13.
Phytomedicine ; 80: 153363, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33070081

RESUMO

BACKGROUND: The ingestion of flavonoids has been reported to be associated with reduced cardiovascular disease risk. Quercitrin is a common flavonoid in nature, and it exhibits antioxidant properties. Although the process of thrombogenesis is intimately related to cardiovascular disease risk, it is unclear whether quercitrin plays a role in thrombogenesis. PURPOSE: The aim of this study was to examine the antiplatelet effect of quercitrin in platelet activation. METHODS: Platelet aggregation, granule secretion, calcium mobilization, and integrin activation were used to assess the antiplatelet activity of quercitrin. Antithrombotic effect was determined in mouse using ferric chloride (FeCl3)-induced arterial thrombus formation in vivo and thrombus formation on collagen-coated surfaces under arteriolar shear in vitro. Transection tail bleeding time was used to evaluate whether quercitrin inhibited primary hemostasis. RESULTS: Quercitrin significantly impaired collagen-related peptide-induced platelet aggregation, granule secretion, reactive oxygen species generation, and intracellular calcium mobilization. Outside-in signaling of αIIbß3 integrin was significantly inhibited by quercitrin in a concentration-dependent manner. The inhibitory effect of quercitrin resulted from inhibition of the glycoprotein VI-mediated platelet signal transduction during cell activation. Further, the antioxidant effect is derived from decreased phosphorylation of components of the TNF receptor-associated factor 4/p47phox/Hic5 axis signalosome. Oral administration of quercitrin efficiently blocked FeCl3-induced arterial thrombus formation in vivo and thrombus formation on collagen-coated surfaces under arteriolar shear in vitro, without prolonging bleeding time. Studies using a mouse model of ischemia/reperfusion-induced stroke indicated that treatment with quercitrin reduced the infarct volume in stroke. CONCLUSIONS: Our results demonstrated that quercitrin could be an effective therapeutic agent for the treatment of thrombotic diseases.


Assuntos
Fibrinolíticos/farmacologia , Hemostasia/efeitos dos fármacos , Quercetina/análogos & derivados , Trombose/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Artérias , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Quercetina/efeitos adversos , Quercetina/farmacologia , Traumatismo por Reperfusão/induzido quimicamente , Trombose/induzido quimicamente , Trombose/metabolismo
14.
Nat Commun ; 11(1): 6408, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328478

RESUMO

Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small polyanions (SPAs) (~0.9-1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.


Assuntos
Armadilhas Extracelulares/efeitos dos fármacos , Histonas/metabolismo , Polímeros/farmacologia , Sepse/sangue , Sepse/tratamento farmacológico , Animais , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Feminino , Histonas/toxicidade , Humanos , Bicamadas Lipídicas , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/sangue , Ativação Plaquetária/efeitos dos fármacos , Polímeros/química , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Sepse/patologia
15.
J Vis Exp ; (166)2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33369603

RESUMO

Spinal cord injury is a devastating complication of aortic repair. Despite developments for the prevention and treatment of spinal cord injury, its incidence is still considerably high and therefore, influences patient outcome. Microcirculation plays a key role in tissue perfusion and oxygen supply and is often dissociated from macrohemodynamics. Thus, direct evaluation of spinal cord microcirculation is essential for the development of microcirculation-targeted therapies and the evaluation of existing approaches in regard to spinal cord microcirculation. However, most of the methods do not provide real-time assessment of spinal cord microcirculation. The aim of this study is to describe a standardized protocol for real-time spinal cord microcirculatory evaluation using laser-Doppler needle probes directly inserted in the spinal cord. We used a porcine model of ischemia/reperfusion to induce deterioration of the spinal cord microcirculation. In addition, a fluorescent microsphere injection technique was used. Initially, animals were anesthetized and mechanically ventilated. Thereafter, laser-Doppler needle probe insertion was performed, followed by the placement of cerebrospinal fluid drainage. A median sternotomy was performed for exposure of the descending aorta to perform aortic cross-clamping. Ischemia/reperfusion was induced by supra-celiac aortic cross-clamping for a total of 48 min, followed by reperfusion and hemodynamic stabilization. Laser-Doppler Flux was performed in parallel with macrohemodynamic evaluation. In addition, automated cerebrospinal fluid drainage was used to maintain a stable cerebrospinal pressure. After completion of the protocol, animals were sacrificed, and the spinal cord was harvested for histopathological and microsphere analysis. The protocol reveals the feasibility of spinal cord microperfusion measurements using laser-Doppler probes and shows a marked decrease during ischemia as well as recovery after reperfusion. Results showed comparable behavior to fluorescent microsphere evaluation. In conclusion, this new protocol might provide a useful large animal model for future studies using real-time spinal cord microperfusion assessment in ischemia/reperfusion conditions.


Assuntos
Traumatismo por Reperfusão/patologia , Traumatismos da Medula Espinal/patologia , Isquemia do Cordão Espinal/patologia , Medula Espinal/patologia , Animais , Aorta/cirurgia , Modelos Animais de Doenças , Feminino , Hemodinâmica , Masculino , Microcirculação , Medula Espinal/irrigação sanguínea , Suínos
16.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(10): 1155-1163, 2020 Oct 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33268575

RESUMO

OBJECTIVES: Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) controls mitochondrial biogenesis, but its role in cardiovascular diseases is unclear. The purpose of this study is to explore the effect of PGC1α on myocardial ischemia-reperfusion injury and the underlying mechanisms. METHODS: The transverse coronary artery of SD rat was ligated for 30 minutes followed by 2 hours of reperfusion. Triphenyltetrazolium chloride (TTC) staining was performed to measure the area of myocardial infarction. Immunohistochemistry and Western blotting were used to detect the PGC1α expression in myocardium. The rat cardiomyocyte H9C2 was subjected to hypoxia/reoxygenation (H/R) with the knockdown of PGC1α or hypoxia- inducible factor 1α (HIF-1α), or with treatment of metformin. Western blotting was used to detect the expression of PGC1α, HIF-1α, p21, BAX, and caspase-3. CCK-8 was performed to detect cell viability, and flow cytometry was used to detect apoptosis and mitochondrial superoxide (mitoSOX) release. RT-qPCR was used to detect the mRNA expression of PGC1α and HIF-1α. Besides, chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter gene assay were applied to detect the transcriptional regulation effect of HIF-1α on PGC1α. RESULTS: After I/R, the PGC1α expression was increased in infarcted myocardium. H/R induced H9C2 cell apoptosis (P<0.001). The release of mitoSOX (P<0.001) and protein expression of PGC1α, and apoptosis-related p21, BAX, and caspase-3 were increased. However, knockdown of PGC1α reduced apoptosis (P<0.01) and mitoSOX release (P<0.001), and decreased protein expression of apoptosis-related gene. HIF-1α is bound to the promoter region of PGC1α. Knockdown of HIF-1α inhibited the transcription and protein expression of PGC1α and further to reduce the apoptosis (all P<0.001) and mitoSOX release (P<0.01). While overexpression of PGC1α reversed the effects caused by HIF-1α knockdown (all P<0.001). Metformin effectively reduced H/R-induced apoptosis (P=0.013), mitoSOX release (P<0.001), HIF-1α, PGC1α and apoptosis-related protein expression, recovered the cell viability (P<0.001), and reduced myocardial infarction (P=0.003). CONCLUSIONS: After I/R, HIF-1α up-regulates the expression of PGC1α, leading to an increase in ROS production and aggravation of injury. Metformin can inhibit the accumulation of HIF-1α during hypoxia and effectively protect myocardium from ischemia/reperfusion injury.


Assuntos
Traumatismo por Reperfusão Miocárdica , Traumatismo por Reperfusão , Animais , Apoptose , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Zhen Ci Yan Jiu ; 45(11): 888-94, 2020 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-33269832

RESUMO

OBJECTIVE: To explore the protective effect of electroacupuncture (EA) on hepatic ischemia-reperfusion injury (HIRI) and the expression of high mobility group protein 1 (HMGB1) in liver tissues in rats. METHODS: A total of 40 male SD rats were randomly divided into 4 groups, namely sham control, HIRI model, "Ganshu"(BL18) -"Yanglingquan"(GB34) and non-acupoint group, with 10 rats in each group. The HIRI model was induced by blocking the arteries, veins and bile ducts supplying the middle and left lobes of the liver for 1 h, and reperfusion for 4 h to induce an area of about 70% HIRI. EA was applied to bila-teral BL18 and GB34, or non-acupoints about 6-8 mm to the bilateral BL18 for 30 min before modeling. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels were measured by using an automatic biochemical analyzer. Serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and HMGB1 levels were assayed by ELISA. Hematoxylin - eosin (H.E.) staining was used to observe histopathological changes of the liver tissue by using tissue injury scaling (0-3 scores). The expression of HMGB1 protein in liver tissues was detected by immunohistochemical staining, Western blot and PCR, separately. RESULTS: Following modeling and compared with the sham group, the levels of serum ALT, AST, TNF-α, IL-6, and HMGB1 contents, the number of HMGB1 immunoreaction (IR)-positive cells, and HMGB1 protein and mRNA were significantly increased (P<0.01). After the treatment, the contents of serum ALT, AST, TNF-α, IL-6, and HMGB1, liver HMGB1 IR-positive cells, protein and mRNA were considerably down-regulated in the BL18-GB34 group (P<0.05), rather than in the non-acupoint group (P>0.05) in contrast to the model group. H.E. stain showed a higher liver injury score in the model group than in the sham group (P<0.01), and a lower liver injury score in the BL18-GB34 group (not the non-acupoint group) relevant to the model group (P<0.05). CONCLUSION: EA of BL18 and GB34 points has a protective effect on ischemic liver injury in rats with HIRI, which may be associated with its functions in inhibiting the migration and release of HMGB1 from the nucleus to the cytoplasm and in down-regulating the expression of inflammatory factors.


Assuntos
Eletroacupuntura , Proteína HMGB1 , Traumatismo por Reperfusão , Animais , Proteína HMGB1/genética , Fígado , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/terapia
18.
Angiol Sosud Khir ; 26(4): 176-183, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33332321

RESUMO

Reperfusion syndrome is a complex series of clinical manifestations resulting from restoration of blood flow to previously ischaemic tissues. It is accompanied by damage to cells, tissues and organs at various levels, followed by the development of multiple organ failure. This review deals with the main pathophysiological mechanisms of the development of reperfusion syndrome in lesions of cardiac, cerebral and lower-limb vessels. Oxidative stress is considered to be the most important marker of ischaemia-reperfusion injury irrespective of the type of tissues affected. Presented herein are the data on contemporary possibilities of influencing various stages and components of the development of reperfusion injury by means of drug therapy, demonstrating that due to the importance of oxidative stress as a key link of reperfusion injury, antioxidant therapy should be the main component of prevention and treatment of reperfusion injury.


Assuntos
Traumatismo por Reperfusão , Antioxidantes , Humanos , Isquemia , Estresse Oxidativo , Reperfusão , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle
19.
Int J Nanomedicine ; 15: 9181-9195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33239875

RESUMO

Purpose: Stem cell therapy for ischemic stroke has shown success in experimental settings, but its translation into clinical practice is challenging. The choroid plexus (CP) plays a regulatory role in neural regeneration. Mesenchymal stem cells (MSCs) promote neurogenesis in the ventricular-subventricular zone. However, it is unclear whether MSCs interact with the CP in brain tissue repair. Methods: Rat (r)MSCs were labeled with iron oxide nanoparticles (IONs) and transduced with red fluorescent protein, and then injected into the brain of rats with ischemic stroke and monitored over time by magnetic resonance imaging. The functional recovery of rats was determined by the corner test score, Modified Neurological Severity score, and stroke volume. MSCs and CP were also co-cultured for 14 days, and the medium was analyzed with a cytokine array. Results: In vivo imaging and histologic analysis revealed that ION-labeled MSCs were mainly located at the injection site and migrated to the infarct area and to the CP. Functional recovery was greater in rats treated with MSCs as compared to those that received mock treatment. Bidirectional enhancement of proliferation in MSCs and CP was observed in the co-culture; moreover, MSCs migrated to the CP. Cytokine analysis revealed elevated levels of proliferation- and adhesion-related cytokines and chemokines in the culture medium. Wikipathway predictions indicated that insulin-like growth factor 1/Akt signaling (WP3675), chemokine signaling pathway (WP2292), and spinal cord injury (WP2432) are involved in the increased proliferation and migration of MSCs co-cultured with the CP. Conclusion: Crosstalk with the CP enhances MSC proliferation and migration in a transwell assay. Moreover, MRI reveals MSC migration towards the CP in an ischemic stroke model. The secreted factors resulting from this interaction have therapeutic potential for promoting functional recovery in the brain after ischemic stroke.


Assuntos
Plexo Corióideo/citologia , /química , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/química , Animais , Proliferação de Células , Quimiocinas/metabolismo , Plexo Corióideo/metabolismo , Técnicas de Cocultura , Citocinas/metabolismo , Modelos Animais de Doenças , Células HEK293 , Humanos , /patologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Imagem por Ressonância Magnética , Masculino , Células-Tronco Mesenquimais/citologia , Regeneração Nervosa , Ratos , Traumatismo por Reperfusão
20.
Am J Physiol Renal Physiol ; 319(6): F1054-F1066, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33135478

RESUMO

In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE2 is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE2 signaling, as they could be blocked by pharmacological inhibition of PGE2 synthesis. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A2A receptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.


Assuntos
Lesão Renal Aguda/prevenção & controle , Adenosina/metabolismo , Dinoprostona/metabolismo , Inibidores Enzimáticos/farmacologia , Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Piridinas/farmacologia , Receptor A2A de Adenosina/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Circulação Renal/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Tiofenos/farmacologia , Vasodilatação/efeitos dos fármacos , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Animais , Velocidade do Fluxo Sanguíneo , Modelos Animais de Doenças , Hidroxiprostaglandina Desidrogenases/metabolismo , Rim/enzimologia , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais
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