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1.
Pediatr Surg Int ; 35(12): 1413-1420, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31576469

RESUMO

AIM OF THE STUDY: Notch signaling plays important roles in maintaining intestinal epithelial homeostasis. When Notch signaling is blocked, proliferation ceases and epithelial cells become secretory. The purpose of the present study was to evaluate the role of Notch signaling pathway following intestinal ischemia-reperfusion (IR) injury in a rat model. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly divided into four experimental groups: Sham-24 and Sham-48 rats underwent laparotomy and were killed 24 or 48 h later, respectively; IR-24 and IR-48 rats underwent occlusion of SMA and portal vein for 30 min followed by 24 or 48 h of reperfusion, respectively. Enterocyte proliferation and enterocyte apoptosis were determined at killing. Notch-related gene and protein expression were determined using Real Time PCR, Western blotting and immunohistochemistry 48 h followed IR. MAIN RESULTS: IR-48 rats demonstrated significantly increased rates of cell proliferation and increased cell apoptosis in both jejunum and ileum compared to Sham rats. IR-48 rats exhibited a significant decrease in Notch-1 protein expression (Western blot) that was coincided with a significant decrease in the number of Notch-1 positive cells (immunohistochemistry) in jejunum (35% decrease, p < 0.05) and ileum (twofold decrease, p < 0.05) as well as Hes-1 positive cells in jejunum (28% decrease, p < 0.05) and ileum (31% decrease, p < 0.05) compared to Sham-48 rats. CONCLUSIONS: Forty-eight hours following intestinal IR in rats, accelerated cell turnover was associated by inhibited Notch signaling pathway. Intestinal stem cells differentiation toward secretory progenitors rather than differentiation toward absorptive cells is important at this phase of intestinal recovery.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Enteropatias/fisiopatologia , Mucosa Intestinal/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/fisiologia , Animais , Western Blotting , Modelos Animais de Doenças , Enterócitos/metabolismo , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Tempo
2.
Acta Cir Bras ; 34(7): e201900707, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31531528

RESUMO

PURPOSE: To evaluate the effects of splenic ischemic preconditioning (sIPC) on oxidative stress induced by hepatic ischemia-reperfusion in rats. METHODS: Fifteen male Wistar rats were equally divided into 3 groups: SHAM, IRI and sIPC. Animals from IRI group were subjected to 45 minutes of partial liver ischemia (70%). In the sIPC group, splenic artery was clamped in 2 cycles of 5 min of ischemia and 5 min of reperfusion (20 min total) prior to hepatic ischemia. SHAM group underwent the same surgical procedures as in the remaining groups, but no liver ischemia or sIPC were induced. After 1h, hepatic and splenic tissue samples were harvested for TBARS, CAT, GPx and GSH-Rd measurement. RESULTS: sIPC treatment significantly decreased both hepatic and splenic levels of TBARS when compared to IRI group (p<0.01). Furthermore, the hepatic and splenic activities of CAT, GPx and GSH- Rd were significantly higher in sIPC group than in IRI group. CONCLUSION: sIPC was able to attenuate hepatic and splenic IRI-induced oxidative stress.


Assuntos
Precondicionamento Isquêmico/métodos , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Estresse Oxidativo/fisiologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Modelos Animais de Doenças , Fígado/fisiologia , Hepatopatias/fisiopatologia , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia
3.
Int J Mol Sci ; 20(19)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546635

RESUMO

Visual impairment and blindness are often caused by retinal ischemia-reperfusion (I/R) injury. We aimed to characterize a new model of I/R in pigs, in which the intraocular pathways were not manipulated by invasive methods on the ocular system. After 12 min of ischemia followed by 20 h of reperfusion, reactivity of retinal arterioles was measured in vitro by video microscopy. Dihydroethidium (DHE) staining, qPCR, immunohistochemistry, quantification of neurons in the retinal ganglion cell layer, and histological examination was performed. Retinal arterioles of I/R-treated pigs displayed marked attenuation in response to the endothelium-dependent vasodilator, bradykinin, compared to sham-treated pigs. DHE staining intensity and messenger RNA levels for HIF-1α, VEGF-A, NOX2, and iNOS were elevated in retinal arterioles following I/R. Immunoreactivity to HIF-1α, VEGF-A, NOX2, and iNOS was enhanced in retinal arteriole endothelium after I/R. Moreover, I/R evoked a substantial decrease in Brn3a-positive retinal ganglion cells and noticeable retinal thickening. In conclusion, the results of the present study demonstrate that short-time ocular ischemia impairs endothelial function and integrity of retinal blood vessels and induces structural changes in the retina. HIF-1α, VEGF-A, iNOS, and NOX2-derived reactive oxygen species appear to be involved in the pathophysiology.


Assuntos
Endotélio Vascular/fisiopatologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Artéria Retiniana/patologia , Células Ganglionares da Retina/patologia , Animais , Arteríolas/metabolismo , Arteríolas/patologia , Bradicinina/farmacologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isquemia/metabolismo , Isquemia/fisiopatologia , NADPH Oxidase 2/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Retina/patologia , Artéria Retiniana/metabolismo , Células Ganglionares da Retina/metabolismo , Suínos , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Exp Eye Res ; 188: 107784, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31476280

RESUMO

Ischaemia/reperfusion contributes to the pathophysiological process of many retinal diseases. Previous studies have shown that retinal ischaemia/reperfusion mainly results in neuronal degeneration, including thinning of the retina, retinal ganglion cell death and reductions in electroretinography. A high-salt diet contributes to the inflammatory response and tissue hypoperfusion and may be associated with ischaemia/reperfusion injury. In the present study, we investigated the influence of a high-salt diet on retinal ischaemia/reperfusion injury and explored the potential mechanism in a rat model. The results revealed that the high-salt diet aggravated ischaemia/reperfusion-induced thinning of the retina. A TUNEL assay and Brn-3a staining revealed substantially more severe cell death and loss of retinal ganglion cells, and electroretinography confirmed worse retinal function in the ischaemia/reperfusion eyes of rats fed the high-salt diet. These effects may be associated with upregulation of Caspase-3, Bax, Interleukin-1ß and Interleukin-6 and decreased expression of nitric oxide. In summary, a high-salt diet aggravates ischaemia/reperfusion-induced retinal neuronal impairment by activating pro-apoptotic and pro-inflammatory signalling pathways and inhibiting vasodilation.


Assuntos
Traumatismo por Reperfusão/metabolismo , Doenças Retinianas/metabolismo , Cloreto de Sódio na Dieta/administração & dosagem , Animais , Western Blotting , Caspase 3/metabolismo , Contagem de Células , Eletrorretinografia , Ensaio de Imunoadsorção Enzimática , Marcação In Situ das Extremidades Cortadas , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Doenças Retinianas/patologia , Doenças Retinianas/fisiopatologia , Células Ganglionares da Retina/patologia , Fator de Transcrição Brn-3A/metabolismo , Proteína X Associada a bcl-2/metabolismo
5.
Exp Neurol ; 321: 113028, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31377404

RESUMO

Owing to the continued high morbidity and high mortality rate after stroke, it is important to seek treatments other than conventional thrombolysis. Notch1 up-regulation participates in inflammatory responses after cerebral ischemia-reperfusion (I/R) injury, and it has been reported that Botch binds to and blocks Notch1 maturation. In this study, we investigated the role of Botch during cerebral (I/R) injury and explored its potential mechanisms. A middle-cerebral-artery occlusion/reperfusion (MCAO/R) model was established in adult male Sprague-Dawley rats in vivo, and cultured neurons and microglia were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. The results showed that protein levels of Botch and the Notch1 intracellular domain (NICD) were increased after MCAO/R. Furthermore, after overexpression of Botch, the generation of the activated form of Notch1, NICD, was decreased, while Botch knockdown or mutation led to an increase in NICD generation. As a result, Botch overexpression exhibited neuroprotective effects by significantly decreasing neurobehavioral phenotypes, improving infiltration of activated microglia, ameliorating inflammatory cytokine release, and inhibiting neuronal cell death. Conversely, Botch knockdown and mutation induced opposite effects. In addition, NICD was found to translocate to the mitochondria after OGD/R in neurons and microglia, which stimulated accumulation of reactive oxygen species in mitochondria and resulted in neuronal cell death and microglial activation. Botch overexpression inhibited the generation of NICD and decreased the translocation of NICD to the mitochondria, which inhibited neuronal cell death and ameliorated neuroinflammation. In conclusion, we found that Botch exerts neuroprotective effects via antagonizing the maturation of Notch1-induced neuronal injury and neuroinflammation, which may provide insights into novel therapeutic targets for the treatment of I/R injury.


Assuntos
Inflamação/metabolismo , Neurônios/metabolismo , Receptor Notch1/metabolismo , Acidente Vascular Cerebral/metabolismo , gama-Glutamilciclotransferase/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Inflamação/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia
6.
Eur J Pharmacol ; 861: 172620, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437429

RESUMO

The reno-protective effects of antidiabetic dipeptidyl peptidase (DPP)-4 inhibitors have been studied regarding their antioxidant and anti-inflammatory properties. However, the potential ability of saxagliptin to ameliorate renal injury by enhancing neovascularization has not been elucidated. To address this issue, saxagliptin (10 and 30 mg/kg) was administered to Wistar rats after the induction of renal ischaemia/reperfusion (I/R). Our results showed that saxagliptin operated through different axes to ameliorate I/R injury. By inhibiting DPP-4, saxagliptin maintained stromal cell-derived factor-1α expression and upregulated its chemokine receptor CXCR4 to trigger vasculogenesis through the enhanced migration of endothelial progenitor cells (EPCs). Additionally, this compound rescued the levels of glucagon-like peptide-1 and its downstream mediator cAMP to increase vascular endothelial growth factor (VEGF) and CXCR4 levels. Moreover, saxagliptin stimulated atrial natriuretic peptide/endothelial nitric oxide synthase to increase nitric oxide levels and provoke angiogenesis and renal vasodilation. In addition to inhibiting DPP-4, saxagliptin increased the renal kidney injury molecule-1/pY705-STAT3/hypoxia-inducible factor-1α/VEGF pathway to enhance angiogenesis. Similar to other gliptins, saxagliptin exerted its anti-inflammatory and antioxidant effects by suppressing the renal contents of p (S536)-nuclear factor-κB p65, tumour necrosis factor-α, monocyte chemoattractant protein-1, myeloperoxidase, and malondialdehyde while boosting the glutathione content. These events improved the histological structure and function of the kidney, as evidenced by decreased serum creatinine, blood urea nitrogen, and cystatin C and increased serum albumin. Accordingly, in addition to its anti-inflammatory and antioxidant activities, saxagliptin dose-dependently ameliorated I/R-induced renal damage by enhancing neovascularization through improved tissue perfusion and homing of bone marrow-derived EPCs to mediate repair processes.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Fator Natriurético Atrial/metabolismo , Moléculas de Adesão Celular/metabolismo , Quimiocina CXCL12/metabolismo , AMP Cíclico/metabolismo , Dipeptídeos/uso terapêutico , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glutationa/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos , Ratos Wistar , Receptores CXCR4/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Anesthesiology ; 131(4): 866-882, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31453815

RESUMO

BACKGROUND: In multiple-organ dysfunction, an injury affecting one organ remotely impacts others, and the injured organs synergistically worsen outcomes. Recently, several mediators, including extracellular histones and neutrophil extracellular traps, were identified as contributors to distant organ damage. This study aimed to elucidate whether these mediators play a crucial role in remote organ damage induced by intestinal ischemia-reperfusion. This study also aimed to evaluate the protective effects of recombinant thrombomodulin, which has been reported to neutralize extracellular histones, on multiple-organ dysfunction after intestinal ischemia-reperfusion. METHODS: Intestinal ischemia was induced in male C57BL/6J mice via clamping of the superior mesenteric artery. Recombinant thrombomodulin (10 mg/kg) was administered intraperitoneally with the initiation of reperfusion. The mice were subjected to a survival analysis, histologic injury scoring, quantitative polymerase chain reaction analysis of tumor necrosis factor-α and keratinocyte-derived chemokine expression, Evans blue dye vascular permeability assay, and enzyme-linked immunosorbent assay analysis of histones in the jejunum, liver, lung, and kidney after 30- or 45-min ischemia. Neutrophil extracellular trap formation was evaluated by immunofluorescence staining. RESULTS: Recombinant thrombomodulin yielded statistically significant improvements in survival after 45-min ischemia (ischemia-reperfusion without vs. with 10 mg/kg recombinant thrombomodulin: 0% vs. 33%, n = 21 per group, P = 0.001). Recombinant thrombomodulin reduced the histologic injury score, expression of tumor necrosis factor-α and keratinocyte-derived chemokine, and extravasation of Evans blue dye, which were augmented by 30-min ischemia-reperfusion, in the liver, but not in the intestine. Accumulated histones and neutrophil extracellular traps were found in the livers and intestines of 30-min ischemia-reperfusion-injured mice. Recombinant thrombomodulin reduced these accumulations only in the liver. CONCLUSIONS: Recombinant thrombomodulin improved the survival of male mice with intestinal ischemia-reperfusion injury. These findings suggest that histone and neutrophil extracellular trap accumulation exacerbate remote liver injury after intestinal ischemia-reperfusion. Recombinant thrombomodulin may suppress these accumulations and attenuate liver injury.


Assuntos
Armadilhas Extracelulares/metabolismo , Mucosa Intestinal/metabolismo , Neutrófilos/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Trombomodulina/metabolismo , Animais , Modelos Animais de Doenças , Mucosa Intestinal/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Adv Exp Med Biol ; 1155: 101-112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468389

RESUMO

Perinatal taurine depletion and high sugar intake from weaning onward worsen cardiac damage and arterial pressure control after ischemia/reperfusion (IR) in adult male and female rats, which can be ameliorated by high taurine diets or inhibition of renin-angiotensin system. This study tests if taurine supplementation ameliorates cardiac damage and arterial pressure control in adult female rats via alterations of both cardiac and systemic renin-angiotensin system. Female Sprague-Dawley rats were fed normal rat chow and drank water alone (control, C) or water containing 3% beta-alanine (taurine depletion, TD) from conception to weaning, and female offspring were subjected to high sugar intake (normal rat chow and 5% glucose in water; CG and TDG) or the normal rat diet (CW and TDW). At 7 weeks of age, half of the rats in each group received 3% taurine in water (CW+T, CG+T, TDW+T, and TDG+T). One week later, rats were subjected to IR or Sham procedures followed by renal nerve recording, plasma and cardiac angiotensin II measurements. Cardiac angiotensin II levels significantly elevated in CG, TDW, and TDG. Further, plasma angiotensin II concentrations were significantly elevated only in the TDG, in consistent with a significant increase in renal nerve activity to juxtaglomerular cells, but not renal vessels and tubules. These abnormalities were ameliorated by short-term taurine supplementation. Thus, in adult female rats that are perinatally depleted of taurine followed by high sugar intake after weaning, taurine supplementation decreases the adverse effects of cardiac IR via inhibition of both cardiac and systemic renin-angiotensin system overactivity.


Assuntos
Isquemia Miocárdica , Sistema Renina-Angiotensina , Traumatismo por Reperfusão/fisiopatologia , Taurina/farmacologia , Animais , Açúcares da Dieta/administração & dosagem , Suplementos Nutricionais , Feminino , Gravidez , Ratos , Ratos Sprague-Dawley , Taurina/deficiência
9.
PLoS One ; 14(8): e0220185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31465457

RESUMO

Ischemia reperfusion (IR) injury can cause acute kidney injury. It has previously been reported that kidney oxygen consumption (QO2) in relation to glomerular filtration rate (GFR), and thus tubular sodium load, is markedly increased following IR injury, indicating reduced electrolyte transport efficiency. Since proximal tubular sodium reabsorption (TNa) is a major contributor to overall kidney QO2, we investigated whether inhibition of proximal tubular sodium transport through carbonic anhydrase (CA) inhibition would improve renal oxygenation following ischemia reperfusion. Anesthetized adult male Sprague Dawley rats were administered the CA inhibitor acetazolamide (50 mg/kg bolus iv), or volume-matched vehicle, and kidney function, hemodynamics and QO2 were estimated before and after 45 minutes of unilateral complete warm renal ischemia. CA inhibition per se reduced GFR (-20%) and TNa (-22%), while it increased urine flow and urinary sodium excretion (36-fold). Renal blood flow was reduced (-31%) due to increased renal vascular resistance (+37%) without affecting QO2. IR per se resulted in similar decrease in GFR and TNa, independently of CA activity. However, the QO2/TNa ratio following ischemia-reperfusion was profoundly increased in the group receiving CA inhibition, indicating a significant contribution of basal oxygen metabolism to the total kidney QO2 following inhibition of proximal tubular function after IR injury. Ischemia increased urinary excretion of kidney injury molecule-1, an effect that was unaffected by CA. In conclusion, this study demonstrates that CA inhibition further impairs renal oxygenation and does not protect tubular function in the acute phase following IR injury. Furthermore, these results indicate a major role of the proximal tubule in the acute recovery from an ischemic insult.


Assuntos
Anidrases Carbônicas/metabolismo , Rim/lesões , Rim/fisiopatologia , Recuperação de Função Fisiológica , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/fisiopatologia , Animais , Rim/metabolismo , Rim/patologia , Túbulos Renais Proximais/patologia , Masculino , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-31469655

RESUMO

Cardioprotection is a very challenging area in the field of cardiovascular sciences. Myocardial damage accounts for nearly 50% of injury due to reperfusion, yet there is no effective strategy to prevent this to reduce the burden of heart failure. During last couple of decades, by combining genetic and bimolecular studies, many new drugs have been developed to treat hypertension, heart failure, and cancer. The use of percutaneous coronary intervention has reduced the mortality and morbidity of acute coronary syndrome dramatically. However, there is no standard therapy available that can mitigate cardiac reperfusion injury, which contributes to up to half of myocardial infarcts. Literature shows that the activation of sphingosine receptors, which are G protein-coupled receptors, induces cardioprotection both in vitro and in vivo. The exact mechanism of this protection is not clear yet. In this review, we discuss the mechanism of ischemia reperfusion injury and the role of the FDA-approved sphingosine 1 phosphate drug fingolimod in cardioprotection.


Assuntos
Cardiotônicos/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologia , Animais , Humanos , Modelos Biológicos
11.
Life Sci ; 235: 116795, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470002

RESUMO

OBJECTIVE: Cerebral ischemia is the most common type of neuronal injury and is characterized by a reduction in the function and number of hippocampal neurons. Carvacrol has a significant neuroprotective effect in cerebral ischemia. However, the mechanisms by which carvacrol affects cerebral ischemia, especially with respect to the regulation of neuronal damage by iron levels, have never been systematically studied. This study aimed to reveal the mechanisms by which carvacrol protects against hippocampal neuron impairment after ischemic stroke in gerbils. MATERIALS AND METHODS: The Morris water maze test was performed to evaluate learning and memory impairments. Iron ion content and oxidative stress index were detected by the kit. MTT assay was performed to assess the cell viability. The morphology and molecular characteristics were detected by electron micrographs and western blot. RESULTS: In the present study, we demonstrated the neuroprotective effects of carvacrol in vivo and in vitro. The Morris water maze test showed that the learning and memory abilities of the gerbils treated with carvacrol were significantly improved. Lipid peroxide injury was evaluated by measuring the levels of lipid peroxide biomarkers; the results indicated that carvacrol decreased the level of lipid peroxide in ischemic gerbil brain tissue. Histopathological examinations and western blotting were performed to evaluate injury in neurons, and carvacrol reduced cell death. Moreover, ferroptosis in the hippocampus was evaluated by measuring the levels of proteins involved in this iron-dependent form of regulated cell death. These results indicated that carvacrol reduced cell death and that carvacrol inhibited ferroptosis by increasing the expression of glutathione peroxidase 4(GPx4). This study showed that carvacrol may be a valuable drug for treating cerebral ischemia. CONCLUSION: Carvacrol provides protection for hippocampal neurons against I/R in gerbils by inhibiting ferroptosis through increasing the expression of GPx4.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/fisiopatologia , Hipocampo/efeitos dos fármacos , Monoterpenos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/fisiopatologia , Animais , Gerbillinae , Glutationa Peroxidase/metabolismo , Hipocampo/patologia , Masculino , Neurônios/patologia , Estresse Oxidativo
12.
Life Sci ; 235: 116796, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470003

RESUMO

AIM: Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. METHODS: Non-diabetic (ND) and Streptozotocin-induced diabetes mellitus (DM) rats were subjected to ischemic renal injury (IRI). Rats underwent IRI were treated with an AT2R agonist, C21 (0.3 mg/kg/day, i.p.) or ACE2 activator, Dize, (5 mg/kg/day, p.o.) either alone or as combination therapy. Renal histopathology and immunohistochemistry, proximal tubular fraction isolation, ELISA, immunoblotting and qRT-PCR were performed for subsequent analysis. KEY FINDINGS: Rats subjected to IRI displayed an increase in plasma ACE, AT1R, AT2R, Ang II, and reduction in ACE2, Ang-(1-7) expressions, with augmented renal inflammation and apoptosis. These changes were more prominent in diabetic rats with IRI. Co-administration of C21 and Dize augmented ACE2, Ang-(1-7), AT2R and MasR expressions, and attenuated tubular injury in both DM and ND rats. CONCLUSION: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Estresse Oxidativo , Peptidil Dipeptidase A/química , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/química
13.
Mol Med Rep ; 20(3): 2365-2372, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322214

RESUMO

The current study used a rat middle cerebral artery occlusion (MCAO) model with the aim to explore the effects of compound porcine cerebroside and ganglioside injection (CPCGI) on brain ischemia/reperfusion injury in rats. Improvement in the infarct­side microcirculation and the overall recovery of neurological function were detected by triphenyltetrazolium chloride staining, laser speckle blood flow monitoring, latex perfusion, immunofluorescence and immunoblotting. The results revealed that administration of CPCGI for 7 consecutive days following ischemic stroke contributed to the recovery of neurological function and the reduction of cerebral infarct volume in rats. Blood flow monitoring results demonstrated that the administration of CPCGI effectively promoted cerebral blood flow following stroke, and contributed to the protection of the ischemic side blood vessels. In addition, CPCGI treatment increased the numbers of new blood vessels in the peripheral ischemic region, and upregulated the expression levels of vascular endothelial growth factor, angiopoietin 1 and its receptor TEK receptor tyrosine kinase, fibroblast growth factor and Wnt signaling pathway­associated proteins. Taken together, the present results indicated that CPCGI improved the blood circulation and neurological function following cerebral ischemia/reperfusion in rats.


Assuntos
Cerebrosídeos/uso terapêutico , Gangliosídeos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cerebrosídeos/administração & dosagem , Gangliosídeos/administração & dosagem , Infarto da Artéria Cerebral Média/fisiopatologia , Injeções , Masculino , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/fisiopatologia
14.
Curr Med Sci ; 39(4): 513-522, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31346984

RESUMO

Necroptosis is a non-apoptotic programmed cell death pathway, which causes necrosis-like morphologic changes and triggers inflammation in the surrounding tissues. Accumulating evidence has demonstrated that necroptosis is involved in a number of pathological processes that lead to cardiovascular diseases. However, the exact molecular pathways linking them remain unknown. Herein, this review summarizes the necroptosis-related pathways involved in the development of various cardiovascular diseases, including atherosclerosis, cardiac ischemia-reperfusion injury, cardiac hypertrophy, dilated cardiomyopathy and myocardial infarction, and may shed light on the diagnosis and treatment of these diseases.


Assuntos
Apoptose/genética , Doenças Cardiovasculares/genética , Morte Celular/genética , /genética , Aterosclerose/genética , Aterosclerose/fisiopatologia , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/genética
15.
Biomed Res Int ; 2019: 3487607, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355256

RESUMO

Object: Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many ophthalmic diseases; there are no effective therapeutic approaches available currently. Increasing evidence indicates that microglia mediated neuroinflammation plays an important role in the retinal I/R injury. In this study, we aimed to investigate the roles of chemokine receptor CXCR5 in the pathological process of retinal I/R injury model. Method: Retinal I/R injury model was established in CXCR5 knockout and wild mice by the acute elevation of intraocular pressure (AOH) for 60 minutes, and the eyes were harvested for further analyses. The cellular location of CXCR5 was detected by immunofluorescence staining; the expressions of CXCR5 and CXCL13 after I/R injury were analyzed by quantitative RT-PCR. The retinal microglia were detected as stained for Iba1 (+). Leakage of inflammatory cells was observed on the H&E stained cryosections. The protein expression and quantification of zonula occludens (ZO-1) were determined by Western blotting and densitometry. Capillary degeneration was identified on the intact retinal vasculatures prepared by trypsin digestion. Results: The number of activated microglia marked by Iba1 antibody in the retina was increased after retinal I/R injury in both KO and WT mice, more significant in KO mice. The leakage of inflammatory cells was observed largely at 2 days after injury, but there was no or little leakage at 7 days. The number of inflammatory cells (mainly neutrophils) was greater in CXCR5 KO mice than in WT mice, mainly located under internal limiting membrane. CXCR5 deficiency led to more ZO-1 degradation in CXCR5 KO mice compared to C57BL6 WT mice 2 days after reperfusion. The cellular capillaries were also significantly increased in the KO mice compared to the WT mice. Conclusion: Our findings suggest that the chemokine receptor CXCR5 may protect retina from ischemia-reperfusion injury by its anti-inflammatory effects. Thus, CXCR5 may be a promising therapeutic target for the treatment of retinal I/R injury.


Assuntos
Inflamação/genética , Receptores CXCR5/genética , Traumatismo por Reperfusão/genética , Retina/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Quimiocina CXCL13/genética , Regulação da Expressão Gênica/genética , Humanos , Inflamação/metabolismo , Inflamação/patologia , Pressão Intraocular/genética , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Retina/patologia
16.
Turk J Med Sci ; 49(4): 1249-1255, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31342735

RESUMO

Background/aim: Since the nature of ischemia/reperfusion (IR)-induced tissue damage is multifactorial and complex, in the current study, the effects of multiple treatment strategies via concomitant administration of erythropoietin (EPO) and N-acetylcysteine (NAC) with an ischemic preconditioning (IPC) regimen on renal IR injury were examined. Materials and methods: Thirty male Wistar rats were subjected to bilateral occlusion of the renal pedicles for 50 min followed by reperfusion. EPO (1000 IU/kg) was administered for 3 days, as well as IPC before the IR and NAC (150 mg/kg) administration for 4 days after IR. The animals were randomly allocated into 6 groups (n = 5): sham, IR, EPO+IR, IPC+IR, NAC+IR, and EPO+IPC+NAC+IR. Kidney tissues and blood samples were obtained for oxidative stress, proinflammatory cytokines, and renal functional evaluations. Results: IR caused significant inflammatory response, oxidative stress, and reduced renal function. Treatment with EPO, IPC, and NAC or a combination of two of them attenuated renal dysfunction and reduced the oxidative stress and inflammatory markers. Rats treated with the combination of EPO, IPC, and NAC showed a higher degree of protection compared to the other groups. Conclusion: These results showed that concomitant administration of EPO and IPC along with posttreatment NAC may have additive beneficial effects on kidney IR injury during IR-induced acute renal failure.


Assuntos
Acetilcisteína/farmacologia , Eritropoetina/farmacologia , Precondicionamento Isquêmico/métodos , Rim , Traumatismo por Reperfusão , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Citocinas/sangue , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Rim/lesões , Rim/fisiopatologia , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia
17.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 473-476, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357768

RESUMO

Toll-like receptor 4 (TLR4) is a member of the toll-like receptor family and belongs to the family of pattern recognition receptors. The role of TLR4 signaling pathway in liver ischemia-reperfusion injury has been widely studied in recent years, and its control methods in inflammatory response is becoming the most important research hotspot. In this paper, the research progress of the molecules and their regulatory mechanisms involved with TLR4 signaling pathway in liver ischemia-reperfusion injury is reviewed, which act as a new foundation of clinical research to study the pathogenic mechanisms and treatment plan.


Assuntos
Traumatismo por Reperfusão , Transdução de Sinais , Receptor 4 Toll-Like , Humanos , Fígado/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Receptor 4 Toll-Like/metabolismo
18.
J Stroke Cerebrovasc Dis ; 28(10): 104276, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31350168

RESUMO

BACKGROUND: We tested the hypothesis that inhibition of p70 ribosomal S6 kinase (S6K1) would decrease infarct size and improve microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. METHODS: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 hour and reperfusion for 2 hours with or without PF-4708671 (S6K1 inhibitor, 75 mg/kg, 15 minutes after blockade). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small vessel (20-60 µm diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. RESULTS: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex with many areas of low O2 saturation (23 of 80 veins with O2 saturation below 45%). PF-4708671 did not significantly alter cerebral blood flow or O2 consumption. However, it significantly reduced the number of small veins with low O2 saturations in the reperfused region (6 of 80 veins with O2 saturation below 45%). This was associated with a significantly reduced cortical infarct size after S6K1 inhibition (12.9 ± .8% control versus 6.6 ± .3% PF-4708671). CONCLUSION: This suggests that S6K1 inhibition is important for cell survival and that it reduces the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Microcirculação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/sangue , Piperazinas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Quinases S6 Ribossômicas/metabolismo
19.
Mol Cell Biochem ; 460(1-2): 151-164, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280436

RESUMO

Diallyl trisulfide (DATS) is distinguished as the most potent polysulfide isolated from garlic. The aim of our study was to investigate effects of oral administration of DATS on healthy and diabetic rats, with special attention on heart function. Rats were randomly divided into four groups: CTRL (healthy rats), DATS (healthy rats treated with DATS), DM (diabetic rats), DM + DATS (diabetic rats treated with DATS). DATS (40 mg/kg of body weight) was administered every other day for 3 weeks, at the end of which rats underwent echocardiography, glycemic measurement and redox status assessment. Isolated rat hearts were subjected to 30 min global ischemia and 60 min reperfusion, after which heart tissue was counterstain with hematoxylin and eosin and cardiac Troponin T staining (cTnT), while expression of Bax, B cell lymphoma 2 (Bcl-2), caspase-3, caspase-9 and superoxide dismutase-2 were examined in the left ventricle. DATS treatment significantly reduced blood glucose levels of diabetic rats, and improved cardiac function recovery, diminished oxidation status, attenuated cardiac remodeling and inhibited myocardial apoptosis in healthy and diabetic rats. DATS treatment causes promising cardioprotective effects on ex vivo-induced ischemia/reperfusion (I/R) injury in diabetic and healthy rat heart probably mediated by inhibited myocardial apoptosis. Moreover, appropriate DATS consumption may provide potential co-therapy or prevention of hyperglycemia and various cardiac complications in rats with DM.


Assuntos
Compostos Alílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Sulfetos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia
20.
Food Chem Toxicol ; 131: 110591, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31212009

RESUMO

Kidney ischemia reperfusion injury (IRI) is an acute kidney injury associated with high number of mortality. We have examined the molecular mechanism and found that oxidative stress and hypoxia leads to induction of autophagy. In IRI induced autophagy, TFEB translocated to nucleus in response to IRI and induced a number of target genes of Coordinated Lysosomal Expression and Regulation (CLEAR) network. Real-time PCR analyses result showed IRI dependent increase in mRNA level to lysosomal hydrolases (Ctsa, Psap), lysosomal membranes (Lamp1), lysosomal acidification (Atp6ap1) non-lysosomal proteins involved in lysosomal biogenesis (M6pr, Nagpa) and autophagy (Becn1, VPS11). Overall, both lysosomal biogenesis and autophagy pathways were induced. Two key players of TFEB dependent proteins in autophagy, LAMP1 and BECN1 were verified by protein analyses. Pretreatment with urolithin A promoted autophagy and attenuated renal injury in kidney IRI and thus inverse relationship existed between TFEB-CLEAR pathway and kidney injury. Urolithin A also attenuated IRI induced pro-inflammatory cytokines TNFα, IL1ß, MIP1α and MIP2 mRNA and associated kidney injury. Overall, our results explored the understanding of autophagy and CLEAR network to kidney IRI and those insights may help to develop new therapeutic strategies to protect against IRI.


Assuntos
Lesão Renal Aguda/prevenção & controle , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Cumarínicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/fisiopatologia , Animais , Autofagia/fisiologia , Núcleo Celular/metabolismo , Citocinas/metabolismo , Inflamação/prevenção & controle , Rim/patologia , Rim/fisiopatologia , Lisossomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Traumatismo por Reperfusão/fisiopatologia
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