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1.
Life Sci ; 276: 119402, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785335

RESUMO

In our previous study, we observed that donor pulmonary intravascular nonclassical monocytes play a major role in early PGF, but the specific mechanism remained unclear. In this study, we investigated the mechanistic role of monocytes in inducing pyroptosis of human pulmonary microvascular endothelial cells (HPMECs) during IRI. A murine hilar ligation model of IRI was utilized whereby left lungs underwent 1 h of ischemia and 23 h of reperfusion. Monocyte depletion by intraperitoneal clodronate-liposome treatment on pulmonary edema and pyroptosis activation were determined. In vitro experiments, we performed the co-culture experiments under hypoxia-reoxygenation (H/R) conditions to mimic the IRI environment. We monitored the expression of NLRP3, caspase-1 and IL-1ß in co-cultures of monocytes (U937 cells) and HPMECs under H/R conditions. NLRP3, IL-1ß and IL-1R siRNA knockdown, caspase-1 and NF-κB pathway inhibitors were employed to elucidate the mechanism modulating HPMEC pyroptosis during H/R. Treatment of mice with clodronate-liposome attenuated IR-induced pulmonary edema, cytokine production and pyroptosis activation. In vitro, NLRP3 knockdown in monocytes reduced caspase-1 and IL-1ß secretion in co-cultures of monocytes and HPMECs. Reduced HPMEC pyroptosis was also observed either containing HPMECs with genetically engineered IL-1R knockdown or in co-culture treated with a Triplotide inhibitor that disrupts NF-κB signaling. Monocytes play a vital role in the development of transplant-associated ischemia-reperfusion injury. A potential role is that monocytes secrete IL-1ß to induce HPMEC pyroptosis via the IL-1R/NF-κB/NLRP3 pathway.


Assuntos
Endotélio Vascular/patologia , Inflamação/patologia , Pneumopatias/complicações , Monócitos/patologia , Piroptose , Traumatismo por Reperfusão/complicações , Doenças Vasculares/patologia , Animais , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamassomos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Células U937 , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo
2.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33604682

RESUMO

The inflammatory response and apoptosis are key factors in cerebral ischemia­reperfusion injury. The severity of the inflammatory reaction and apoptosis has an important impact on the prognosis of stroke. The ultrasmall superparamagnetic iron oxide particle has provided an effective magnetic resonance molecular imaging method for dynamic observation of the cell infiltration process in vivo. The aims of the present study were to investigate the inflammatory response of cerebral ischemia­reperfusion injury in mice using ferumoxytol­enhanced magnetic resonance imaging, and to observe the dynamic changes of inflammatory response and apoptosis. In the present study a C57BL/6n mouse cerebral ischemia­reperfusion model was established by blocking the right middle cerebral artery with an occluding suture. Subsequently, the mice were injected with ferumoxytol via the tail vein, and magnetic resonance scanning was performed at corresponding time points to observe the signal changes. Furthermore, blood samples were used to measure the level of serum inflammatory factors, and histological staining was performed to assess the number of iron­swallowing microglial cells and apoptotic cells. The present results suggested that there was no significant difference in the serum inflammatory factors tumor necrosis factor­α and interleukin 1ß between the middle cerebral artery occlusion (MCAO) and MCAO + ferumoxytol groups injected with ferumoxytol and physiological saline. The lowest signal ratio in the negative enhancement region was decreased 24 h after reperfusion in mice injected with ferumoxytol. The proportion of iron­swallowing microglial cells and TUNEL­positive cells were the highest at 24 h after reperfusion, and decreased gradually at 48 and 72 h after reperfusion. Therefore, the present results indicated that ferumoxytol injection of 18 mg Fe/kg does not affect the inflammatory response in the acute phase of cerebral ischemia and reperfusion. Ferumoxytol­enhanced magnetic resonance imaging can be used as an effective means to monitor the inflammatory response in the acute phase of cerebral ischemia­reperfusion injury. Furthermore, it was found that activation of the inflammatory response and apoptosis in the acute stage of cerebral ischemia­reperfusion injury is consistent.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Traumatismo por Reperfusão/diagnóstico por imagem , Animais , Apoptose/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Meios de Contraste/farmacologia , Modelos Animais de Doenças , Óxido Ferroso-Férrico/farmacologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Interleucina-1beta/sangue , Imagem por Ressonância Magnética , Masculino , Camundongos , Microglia/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Fator de Necrose Tumoral alfa/sangue
3.
Arq Bras Cir Dig ; 33(4): e1551, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33503111

RESUMO

BACKGROUND: Tacrolimus and mycophenolate mofetil are immunosuppressive agents widely used on the postoperative period of the transplants. AIM: To evaluate the influence of the association of them on the abdominal wall healing in rats. METHODS: Thirty-six Wistar rats were randomly assigned in three groups of 12. On the early postoperative period, four of the control group and three of the experimental groups died. The three groups were nominated as follow: control group (GC, n=8); group I (GI, n=11, standard operation, mycophenolate mofetil and tacrolimus); group II (GII, n=10, standard operation, mycophenolate mofetil and tacrolimus). The standard operation consisted of right total nephrectomy and 20 min ischemia of the left kidney followed by reperfusion. Both NaCl 0.9% and the immunosuppressive agents were administered starting on the first postoperative day and continuing daily until the day of death on the 14th day. On the day of their deaths, two strips of the anterior abdominal wall were collected and submitted to breaking strength measurement and histological examination. RESULTS: There were no significant differences in wound infection rates (p=0,175), in the breaking strength measurement and in the histological examination among the three groups. CONCLUSION: The combination of the immunosuppressive agents used in the study associated with renal ischemia and reperfusion does not interfere in the abdominal wall healing of rats.


Assuntos
Parede Abdominal/cirurgia , Imunossupressores/farmacologia , Rim/irrigação sanguínea , Ácido Micofenólico/farmacologia , Traumatismo por Reperfusão/complicações , Tacrolimo/farmacologia , Animais , Isquemia , Ácido Micofenólico/administração & dosagem , Ratos , Ratos Wistar , Reperfusão , Tacrolimo/administração & dosagem
4.
Life Sci ; 269: 119062, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33476635

RESUMO

AIMS: Cyclin-dependent kinase 5 (CDK5) is a potential target for the treatment of cerebral ischemia. CDK5 is one of the upstream regulators for Dynamin-related protein 1 (Drp1) phosphorylation. This study intends to discuss whether CDK5 inhibition conferring neuroprotection in cerebral ischemia through regulating Drp1 phosphorylation. MATERIALS AND METHODS: Mouse neuroblastoma N2a cells and N1E-115 cells were cultured and subjected to oxygen-glucose deprivation/reperfusion (OGDR). N2a cells and N1E-115 cells were treated with Roscovitine, a pharmacological inhibitor of CDK5, or transfected with CDK5 siRNA to knock down CDK5 expression. N2a cells were transfected with different plasmids (Drp1-Myc, the dephosphorylation-mimic mutant Drp1S616A-Myc and the phosphorylation-mimic mutant Drp1S616D-Myc). The expression of CDK5 and its activator p35, Drp1 and phosphorylated Drp1 on S616 was determined by western blot. The morphology of mitochondria was detected by immunofluorescence staining and the proportion of N2a cells with apoptosis was detected by flow cytometry analysis. KEY FINDINGS: Expression of CDK5, p35 and phosphorylated Drp1 on S616 was strongly upregulated after 4 h and 12 h reperfusion following 4 h oxygen-glucose deprivation (OGD) at protein level. CDK5 inhibition by pre-treated with Roscovitine or transfection with CDK5 siRNA significantly ameliorated OGDR induced mitochondrial fragmentation and apoptosis. Overexpression of the phosphorylation-mimic mutant Drp1S616D abrogated the protective effect of CDK5 inhibition against OGDR induced mitochondrial fragmentation and apoptosis. SIGNIFICANCE: Our data indicate that the neuroprotective effect of CDK5 inhibition against OGDR induced neuronal damage is Drp1S616 phosphorylation dependent. A better understanding of the neuroprotective mechanisms of CDK5 inhibition in cerebral ischemia will help to develop safe and efficacious drugs targeting CDK5 signaling for clinical use.


Assuntos
Apoptose , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Dinaminas/metabolismo , Glucose/deficiência , Mitocôndrias/patologia , Neuroblastoma/prevenção & controle , Oxigênio/metabolismo , Animais , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Dinaminas/genética , Camundongos , Mitocôndrias/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fármacos Neuroprotetores , Fosforilação , Traumatismo por Reperfusão/complicações , Transdução de Sinais , Células Tumorais Cultivadas
5.
Mil Med ; 186(Suppl 1): 339-345, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33499468

RESUMO

INTRODUCTION: Lung injury has several inciting etiologies ranging from trauma (contusion and hemorrhage) to ischemia reperfusion injury. Reflective of the injury, tissue and cellular injury increases proportionally with the injury stress and is an area of potential intervention to mitigate the injury. This study aims to evaluate the therapeutic benefits of recombinant human MG53 (rhMG53) protein in porcine models of acute lung injury (ALI). MATERIALS AND METHODS: We utilized live cell imaging to monitor the movement of MG53 in cultured human bronchial epithelial cells following mechanical injury. The in vivo efficacy of rhMG53 was evaluated in a porcine model of hemorrhagic shock/contusive lung injury. Varying doses of rhMG53 (0, 0.2, or 1 mg/kg) were administered intravenously to pigs after induction of hemorrhagic shock/contusive induced ALI. Ex vivo lung perfusion system enabled assessment of the isolated porcine lung after a warm ischemic induced injury with rhMG53 supplementation in the perfusate (1 mg/mL). RESULTS: MG53-mediated cell membrane repair is preserved in human bronchial epithelial cells. rhMG53 mitigates lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury. Ex vivo lung perfusion administration of rhMG53 reduces warm ischemia-induced injury to the isolated porcine lung. CONCLUSIONS: MG53 is an endogenous protein that circulates in the bloodstream. Therapeutic treatment with exogenous rhMG53 may be part of a strategy to restore (partially or completely) structural morphology and/or functional lung integrity. Systemic administration of rhMG53 constitutes a potential effective therapeutic means to combat ALI.


Assuntos
Lesão Pulmonar Aguda , Traumatismo por Reperfusão , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Animais , Proteínas de Transporte , Modelos Animais de Doenças , Pulmão , Proteínas Recombinantes/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Suínos
6.
Life Sci ; 266: 118879, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310030

RESUMO

Acute renal injury (AKI) is a risk factor for the development of hypertension, which involves oxidative stress, changes in Na+ handling, and the intrarenal renin-angiotensin-aldosterone system (RAAS) as underlying mechanisms. We investigated in rats whether renal ischemia-reperfusion (IR) leads to changes in the proximal tubule ATP-dependent Na+ transport and the intrarenal content of RAAS components, as well as the role of NADPH oxidase. Rats weighing 300-350 g were submitted to AKI by bilateral IR (n = 25). After IR injury, the animals were followed up for 4 weeks. One part (n = 7) received daily treatment with the NADPH oxidase inhibitor apocynin (100 mg/kg, drinking water), while another part (n = 9) received apocynin 24 h before and after IR. One group was submitted to sham surgery (n = 8). Four weeks after IR, the rats presented elevated systolic blood pressure, as well as increased lipid peroxidation, NADPH oxidase activity, (Na++K+)ATPase activity, and upregulation of type 1 angiotensin II receptor in the renal cortex. On the other hand, there was a decrease in Na+-ATPase activity and downregulation of the isoforms 1 and 2 of the angiotensin-converting enzyme, type 2 angiotensin II receptor, and of the α and ε isoforms of protein kinase C. Most of these alterations was prevented by both apocynin treatment protocols. Thus, we conclude that AKI-induced by IR may induce changes in proximal tubule ATPases and RAAS components compatible with renal Na+ retention and hypertension. These data also indicate that the NADPH oxidase represents a key factor in the origin of these alterations.


Assuntos
Lesão Renal Aguda/complicações , Hipertensão/patologia , Túbulos Renais Proximais/patologia , NADPH Oxidases/metabolismo , Sistema Renina-Angiotensina , Traumatismo por Reperfusão/complicações , Sódio/metabolismo , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Aldosterona/metabolismo , Animais , Hipertensão/enzimologia , Hipertensão/etiologia , Túbulos Renais Proximais/metabolismo , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
7.
Life Sci ; 266: 118882, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310046

RESUMO

AIMS: Cilostazol (Cilo), a phosphodiesterase-III inhibitor, has signified its efficacy against different ischemia/reperfusion (IS/RE) models. Nevertheless, it has not fully illuminated its potential effect against intestinal IS/RE-induced lung injury. Consequently, the study was fashioned to evaluate the feasible mechanism of action of Cilo against intestinal IS/RE-induced lung injury. MAIN METHODS: Wistar rats were treated with Cilo (0.1 g/kg, p.o.) or with a vehicle for 14 days prior to IS/RE, induced by clamping of the superior mesenteric artery for 30 min with subsequent clamp removal for 2 h. KEY FINDINGS: The mechanistic study disclosed that Cilo protected the two studied organs, viz., lung, and intestine partially by intensifying the expression/content of PPAR-γ accompanied by reducing the expression/content of NF-қB-p65 and STAT3. In addition to normalizing MDA, iNOS, and NOx, the Cilo antioxidant power was confirmed by intensifying tissues content of the total antioxidant capacity. With regard to the anti-inflammatory effect, Cilo reduced the effects of TNF-α, IL-6, and ICAM-1, which were reflected in MPO activity. Furthermore, Cilo had an anti-apoptotic attribute demonstrated by enhancing Bcl-2 content and lessening caspase-3 level. SIGNIFICANCE: Cilo provided conceivable protective mechanisms to modulate events concomitant with mesenteric IS/RE partly by modulating oxidative stress, inflammation, and apoptosis feasibly via the participation of PPAR-γ, STAT3, and NF-κB p65 signaling pathways.


Assuntos
Cilostazol/farmacologia , Pneumopatias/prevenção & controle , Isquemia Mesentérica/complicações , NF-kappa B/metabolismo , PPAR gama/metabolismo , Traumatismo por Reperfusão/complicações , Fator de Transcrição STAT3/metabolismo , Animais , Broncodilatadores/farmacologia , Regulação da Expressão Gênica , Pneumopatias/etiologia , Pneumopatias/metabolismo , Pneumopatias/patologia , Masculino , NF-kappa B/genética , Estresse Oxidativo , PPAR gama/genética , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Transdução de Sinais
8.
Food Chem ; 345: 128672, 2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-33352403

RESUMO

I/R (cerebral ischemia reperfusion injury) is the secondary complication of ischemic stroke patients that are immediately treated with drug thrombolysis or vascular recanalization in clinic. Diosgenin (DIO) purified from medicine food homologous (MFH) Dioscorea yam source is served as a fatal starting material to synthesize multifarious steroidal anti-inflammatory drugs in medicinal field, and has previously been demonstrated the potential prevention of I/R. However, the detailed mechanisms of neuroprotective effects against I/R remain elusively understood. Here, a global proteomic dynamics of rat right hemisphere brains was executed to investigate the protein expression patterns with a quantitative LC-MSn. In total, 5043 proteins were identified and 418 ones were determined to be significantly dysregulated DEPs (differentially expressed proteins) in comparison of Sham verse I/R and I/R verse DIO after onset stage of I/R, among which 5 DEPs namely BICD2, HNRNPK, CEP41, PPM1K, and ARL2BP, whose biological functions were mainly clustered into the mediation of nervous system, were selected for further validation in vitro and in vivo, and the change tendency expectedly supported the proteomic findings. Additionally, the AUC value of the combined ROC of these 5 DEPs was 0.988 with P < 0.0001, higher than every single one. Collectively, these scientific findings attributed to a typical investigation of dietary Dioscorea-enriched diosgenin in MFH research, suggesting that diosgenin or its derivatives were potential to be developed into food supplements or healthy food products to reveal healthy benefits in natural prevention and reduction risk of I/R. This work also promoted reasonable consumption of Dioscorea yams and contributed to the function of diosgenin-derived products and their applications in food industry.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/complicações , Dioscorea/química , Diosgenina/farmacologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/prevenção & controle , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Suplementos Nutricionais , Proteômica , Ratos , Traumatismo por Reperfusão/metabolismo
9.
Int J Mol Sci ; 22(1)2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374656

RESUMO

Pressure ulcers are preventable, yet highly prevalent, chronic wounds that have significant patient morbidity and high healthcare costs. Like other chronic wounds, they are characterized by impaired wound healing due to dysregulated immune processes. This review will highlight key biochemical pathways in the pathogenesis of pressure injury and how this signaling leads to impaired wound healing. This review is the first to comprehensively describe the current literature on microRNA (miRNA, miR) regulation of pressure ulcer pathophysiology.


Assuntos
Regulação da Expressão Gênica , Imunidade , MicroRNAs/genética , Lesão por Pressão/etiologia , Lesão por Pressão/terapia , Animais , Apoptose , Gerenciamento Clínico , Suscetibilidade a Doenças , Matriz Extracelular , Redes Reguladoras de Genes , Humanos , Imunidade/genética , Estresse Oxidativo , Lesão por Pressão/metabolismo , Lesão por Pressão/patologia , Interferência de RNA , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Cicatrização/genética
10.
Int J Nanomedicine ; 15: 7481-7489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116483

RESUMO

Introduction: We aimed to investigate the effects of cerium oxide, applied before the sevoflurane anesthesia, on lung tissue in rats with lower extremity ischemia-reperfusion (IR). Materials and Methods: A total of 30 rats were randomly divided into five groups as; control (C), IR, cerium oxide-IR (CO-IR), IR-sevoflurane (IRS), and cerium oxide-IR-sevoflurane (CO-IRS). In the CO-IR group, 30 minutes after the injection of cerium oxide (0.5 mg/kg, intraperitoneal (i.p)), an atraumatic microvascular clamp was placed on the infrarenal abdominal aorta for 120 minutes. Then, the clamp was removed and reperfused for 120 minutes. Sevoflurane was applied in 100% oxygen at a rate of 2.3% at 4 L/min during IR. The blood samples were taken for biochemical analysis and the lung tissue samples were taken for histological analysis. Results: Neutrophil infiltration/aggregation was significantly higher in the IR group than in the C and CO-IRS groups. The alveolar wall thickness and total lung injury scores were significantly higher in the IR group than in the C, IRS, CO-IR and CO-IRS groups. Discussion: We determined that the administration of 0.5 mg/kg dose of cerium oxide with sevoflurane reduces the oxidative stress and corrects IR-related damage in lung tissue. Our results show that the administration of cerium oxide before IR and the administration of sevoflurane during IR have a protective effect in rats.


Assuntos
Cério/farmacologia , Lesão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Sevoflurano/farmacologia , Animais , Extremidade Inferior/irrigação sanguínea , Pulmão/fisiopatologia , Lesão Pulmonar/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia
11.
Am J Physiol Renal Physiol ; 319(4): F563-F570, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32799675

RESUMO

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glomerulonefrite/prevenção & controle , Hipertensão/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Enalapril/farmacologia , Inibidores Enzimáticos/toxicidade , Epóxido Hidrolases/antagonistas & inibidores , Fibrose , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/patologia , Mesângio Glomerular/fisiopatologia , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Camundongos , Compostos de Fenilureia/toxicidade , Piperidinas/toxicidade , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia
12.
Life Sci ; 256: 117972, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32544464

RESUMO

Acute kidney injury (AKI) has a high morbidity and mortality, and there is no targeted treatment yet. One of the main causes of AKI is ischemia-reperfusion (IR). Increased release of adenosine under stress and hypoxia exerts anti-inflammatory and antioxidant effects. Adenosine kinase (ADK) is an important enzyme that eliminates adenosine in cells, and can maintain low adenosine concentration in cells. Our previous studies have shown that pretreatment of adenosine kinase inhibitor ABT-702 could markedly attenuate cisplatin-induced nephrotoxicity both in vivo and in vitro. This study is designed to investigate the effect of ADK inhibition on IR-induced AKI. The results showed that ADK expression was positively correlated with the degree of renal tubular injury, which suggested that the degree of ADK inhibition reflected the severity of acute tubular necrosis. In vivo, ADK inhibitor could reduce IR-induced renal injury, which might play a protective role by increasing tissue adenosine level, inhibiting oxidative stress, and reducing cell apoptosis. In HK2 cells, cobaltous dichloride (CoCl2) increased the level of oxidative stress, up-regulated the production of pro-inflammatory factor, and induced apoptosis, ADK inhibition could alleviate the above damaging effects. Moreover, the anti-apoptotic effect exerted by ADK inhibition was independent of inosine. In summary, our results support the idea that ADK inhibition has protective effects on IR-induced AKI. Adenosine kinase inhibition might provide a new target for AKI prevention and treatment.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Adenosina Quinase/antagonistas & inibidores , Morfolinas/uso terapêutico , Pirimidinas/uso terapêutico , Traumatismo por Reperfusão/complicações , Adenosina Quinase/metabolismo , Adulto , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Cobalto , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Inflamação/patologia , Inosina/farmacologia , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Necrose , Estresse Oxidativo/efeitos dos fármacos , Pirimidinas/farmacologia
13.
Am J Physiol Renal Physiol ; 319(2): F304-F311, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32567350

RESUMO

Acute kidney injury (AKI) significantly increases the risk of development of chronic kidney disease (CKD). Recently, our laboratory generated a mouse model with the typical phenotypes of AKI to CKD transition in the unilateral kidney. However, AKI, CKD, and even the transition from AKI to CKD usually occur bilaterally rather than unilaterally in patients. Therefore, in the present study, we further modified the strategy and developed a new model of CKD transitioned from bilateral ischemia-reperfusion injury (IRI) in C57BL/6 mice. In this new model, unilateral severe IRI was performed in one kidney while the contralateral kidney was kept intact to maintain animal survival; then, following 14 days of recovery, when the renal function of the injured kidney restored above the survival threshold, the contralateral intact kidney was subjected to a similar IRI. Animals of these two-stage bilateral IRI models with pedicle clamping of 21 and 24 min at a body temperature of 37°C exhibited incomplete recovery from AKI and subsequent development of CKD with characteristics of progressive decline in glomerular filtration rate, increases in plasma creatinine, worsening of proteinuria, and deleterious histopathological changes, including interstitial fibrosis and glomerulosclerosis, in both kidneys. In conclusion, a new bilateral AKI to CKD transition animal model with a typical phenotype of CKD was generated in C57BL/6 mice.


Assuntos
Lesão Renal Aguda/complicações , Lesão Renal Aguda/patologia , Insuficiência Renal Crônica/patologia , Traumatismo por Reperfusão/patologia , Animais , Modelos Animais de Doenças , Fibrose/metabolismo , Taxa de Filtração Glomerular/fisiologia , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteinúria/fisiopatologia , Traumatismo por Reperfusão/complicações
14.
J Med Chem ; 63(13): 6909-6923, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32545964

RESUMO

Advancements in recanalization therapies have rendered reperfusion injury an important challenge for stroke management. It is essential to work toward effective therapeutics that protect the ischemic brain from reperfusion injury. Here, we report a new concept of neuroprognostic agents, which combine molecular diagnostic imaging and targeted neuroprotection for treatment of reperfusion injury after stroke. These neuroprognostic agents are inflammation-targeted gadolinium compounds conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs). Our results demonstrated that gadolinium-based MRI contrast agents conjugated with NSAIDs suppressed the increase in cyclooxygenase-2 (COX-2) levels, ameliorated glial activation, and neuron damage that are phenotypic for stroke by mitigating neuroinflammation, which prevented reperfusion injury. In addition, this study showed that the neuroprognostic agents are promising T1 molecular MRI contrast agents for detecting precise reperfusion injury locations at the molecular level. Our results build on this new concept of neuroprognostics as a novel management strategy for ischemia-reperfusion injury, combining neuroprotection and molecular diagnostics.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Gadolínio/química , Imagem por Ressonância Magnética , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/prevenção & controle , Acidente Vascular Cerebral/complicações , Animais , Anti-Inflamatórios não Esteroides/química , Meios de Contraste/química , Ciclo-Oxigenase 2/química , Masculino , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/química , Conformação Proteica , Ratos , Ratos Sprague-Dawley
15.
Int. j. morphol ; 38(3): 804-810, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098323

RESUMO

Honey is a natural antioxidant that its protective effects have been proven against ischemia-reperfusion (IR) injury. The aim of this study was to evaluate the ameliorative effect of Persian Honey, Apis mellifera meda skorikov, on gastrocnemius muscle IR injury. Eighty adult male Sprague-Dawley rats weighing 250-300 g were used. They were divided into ten groups (N=8 per group). The ischemia was conducted with a silk suture 6-0 using the slipknot technique. All groups were rendered in ischemic for 3 h, and reperfused for various times of 3 days (3-day reperfusion), 7 days (7-day reperfusion), 14 days (14-day reperfusion), and 28 days (28-day reperfusion). Half of the groups had experimental honey (5 %) treatment immediately after ischemia. After reperfusion, the rats, based on the grouping, were killed with high doses of anesthetic, and the gastrocnemius muscles were removed and fixed. After the tissue processing, the evaluation of edema and mast cells infiltration was performed with hematoxylin-eosin and toluidine blue staining, respectively. TNF-α was detected with immunohistochemistry method. The amount of TNF-α as an index of acute inflammatory except the 3rd day significantly decreased on the other day of reperfusion (7th, 147th and 287th days). The mast cells infiltration was significantly decreased on 77th and 147th days. The tissue edema was decreased significantly in honey administrated group in the comparison with placebo groups. Honey administration can reduce damage caused by ischemia-reperfusion in the rat gastrocnemius muscle.


La miel es un antioxidante natural; sus efectos protectores han sido probados contra la lesión por isquemiareperfusión (IR). El objetivo de este estudio fue evaluar el efecto de mejora de la miel persa Apis mellifera meda skorikov, en la lesión por IR del músculo gastrocnemio. Se utilizaron 80 ratas Sprague-Dawley macho adultas con un peso entre 250 y 300 g divididas en diez grupos (N = 8 por grupo). La isquemia se realizó con una sutura de seda 6-0 utilizando la técnica slipknot permaneciendo isquémicos durante 3 h. La reperfusión se realizó durante varios tiempos de 3 días, 7 días (reperfusión de 7 días), 14 días (reperfusión de 14 días) y 28 días (28 días reperfusión). La mitad de los grupos recibió tratamiento experimental con miel (5 %) inmediatamente después de la isquemia. Después de la reperfusión, las ratas, fueron sacrificadas con altas dosis de anestésico, y los músculos gastrocnemios fueron removidos y fijados. Después de procesar el tejido, se realizó la evaluación del edema y la infiltración de mastocitos se realizó con tinción de hematoxilina-eosina y azul de toluidina, respectivamente. TNF-α se detectó con el método de inmunohistoquímica. La cantidad de TNF-α como índice de inflamación inflamatoria aguda, excepto en el tercer día, disminuyó significativamente al día siguiente de la reperfusión (7, 14 y 28 días). La infiltración de mastocitos disminuyó significativamente a los 7 y 14 días. El edema tisular disminuyó significativamente en el grupo administrado con miel en comparación con los grupos placebo. El tratamiento con miel puede reducir el daño causado por la isquemia-reperfusión en el músculo gastrocnemio de la rata.


Assuntos
Animais , Masculino , Ratos , Traumatismo por Reperfusão/complicações , Apis mellifica/administração & dosagem , Músculo Esquelético/lesões , Mel , Imuno-Histoquímica , Traumatismo por Reperfusão/tratamento farmacológico , Apis mellifica/farmacologia , Ratos Sprague-Dawley , Músculo Esquelético/efeitos dos fármacos , Substâncias Protetoras
16.
Mol Immunol ; 123: 74-87, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32438202

RESUMO

BACKGROUND: Idebenone is a well-appreciated mitochondrial protectant while the mechanisms underlying the neuroprotection in cerebral ischemia and reperfusion (I/R) remain elusive. It has been manifested NLRP3 inflammasom activation contributed to I/R induced damage. It raises questions how exactly NLRP3 inflammasom was activated in microglia and neuron and whether idebenone reverses the process in I/R. METHODS: I/R rat model was utilized and BV2, primary microglia and PC12 cells were subjected to oxygen-glucose deprivation (OGD). Then, western-blotting, q-PCR, immunofluorescence staining, ELISA, flow cytometry and immunoprecipitation analysis were performed. RESULTS: We found ROS-NLRP3 singaling was activated in BV2 cells at OGD/R 24 h. Importantly, microglial NLRP3 activation was essential for NLRP3 activation in PC12 cells under microglial-neuronal co-culture circumstance, which has been confirmed to induced neuronal apoptosis. Further, we found mitochondrial dysfunction in OGD/R led to mt-DNA translocation as well as generation of mt-ROS, resulting cytosolic accumulation of oxidized mt-DNA. Ultimately, oxidized mt-DNA binding to NLRP3 contributed to further activation of NLRP3 and dramatically augmented inflammation in BV2 and PC12 cells. Furthermore, idebenone treatment inhibited the process, thus suppressing the NLRP3-mediated inflammatory injury after OGD/R. In vivo, NLRP3 was activated in microglia of I/R rats and inhibition of NLRP3 was observed in idebenone treatment group, which had less neurological deficit and less infarct volume. INTERPRETATION: Our data revealed the anti-inflammatory effects of idebenone via suppressing activation of NLRP3 and ameliorating NLRP3-mediating damage in I/R, which may provide new insight in therapeutic strategy for ischemic stroke.


Assuntos
Isquemia Encefálica , Encefalite/prevenção & controle , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuroproteção/efeitos dos fármacos , Traumatismo por Reperfusão , Ubiquinona/análogos & derivados , Animais , Animais Recém-Nascidos , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/imunologia , Isquemia Encefálica/metabolismo , Células Cultivadas , Encefalite/etiologia , Inflamassomos/metabolismo , Inflamassomos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células PC12 , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico
17.
Surgery ; 168(3): 478-485, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32439208

RESUMO

BACKGROUND: Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.


Assuntos
Intestinos/irrigação sanguínea , Fragmentos de Peptídeos/uso terapêutico , Proteínas de Ligação a RNA/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Proteínas de Ligação a RNA/imunologia , Proteínas de Ligação a RNA/farmacologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo
18.
J Pharmacol Sci ; 143(3): 226-233, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32446726

RESUMO

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), characterized by tubulointerstitial inflammation. Currently, progress in developing effective therapies to prevent or ameliorate AKI by anti-inflammation remains slow. Emerging studies have suggested that NLRP3 (the NOD-, LRR- and pyrin domain-containing 3) inflammasome plays a key role in a wide spectrum of kidney disease models including I/R injury. In this study, we investigated the renal protective effects of A68930, a specific agonist for the D-1 dopamine receptor (DRD1), which was recently recognized to downregulate NLRP3 inflammasome via DRD1 signaling. AKI was induced by renal I/R injury and A68930 was intraperitoneally injected 3 times after renal reperfusion. We showed that A68930 significantly ameliorated renal dysfunction. Meanwhile, A68930 markedly reduced macrophages and T cells infiltration, renal pro-inflammatory cytokines production (TNF-α, IL-6, IL-1ß), serum pro-inflammatory cytokine (TNF-α and IL-6) and NLRP3 inflammasome activation. Additionally, A68930 attenuated I/R-induced mitochondria injury, which was observed by transmission electron microscopy. In summary, our results demonstrated that activation of DRD1 by A68930 inhibited renal and systematic inflammation, and improved kidney function in I/R induced AKI model, which was probably related to the inhibition of the NLRP3 inflammasome activation.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/genética , Cromanos/farmacologia , Cromanos/uso terapêutico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/complicações , Fator de Necrose Tumoral alfa/metabolismo
19.
Life Sci ; 254: 117793, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32416164

RESUMO

AIMS: Oxygen and glucose deprivation and reperfusion (OGD/R) injury contributes to the pathophysiology after ischemic stroke, which needs to urgently develop treatment strategies. Previous studies have demonstrated that autophagy in reperfusion period exerted adverse effects on the cerebral ischemic injury. Ginsenoside monomer compound K (CK) is the main intestinal metabolite of ginseng that exerts the pharmacological activities and has a protective effect against cerebral OGD/R injury. However, the specific molecular mechanism of CK protects against OGD/R injury in neurons is still unclear. MATERIALS AND METHODS: In this study, cell viability, reactive oxygen species (ROS) generation, Ca2+ overload, mitochondrial membrane potential depolarization, autophagy and apoptosis were investigated in OGD/R-induced neuronal cells injury after pretreatment with CK and in combination with BML-275 or rapamycin. KEY FINDINGS: Our study found that pretreatment with CK protected neurons against OGD/R injury by increasing cell viability and decreasing the ROS generation, mitochondrial damage, and Ca2+ overload. Moreover, CK cut down autophagy-mediated apoptosis via promoting the process of forming autophagosomes into phagocytic precursors. Furthermore, our study clarified the neuroprotective of CK against OGD/R-induced neural autophagy and apoptosis through the regulation of the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway. SIGNIFICANCE: Taken together, our study provides credible experimental evidence and explains the potential molecular mechanism of CK as one of the main bioactive ingredients of ginseng for the treatment of cerebral ischemia/reperfusion injury.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Morte Celular Autofágica/efeitos dos fármacos , Ginsenosídeos/farmacologia , Glucose/deficiência , Hipóxia/metabolismo , Traumatismo por Reperfusão/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagossomos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Hipóxia/complicações , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Traumatismo por Reperfusão/complicações , Transdução de Sinais/efeitos dos fármacos
20.
Transplant Proc ; 52(4): 1202-1205, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32164959

RESUMO

BACKGROUND: Severe ischemia-reperfusion injury (SIRI) seems to be the key factor that can significantly affect the function of both native kidneys and renal allografts. Therefore, the development of a successful strategy is of a paramount importance in both basic and clinical research. METHODS: To determine the effects of SIRI on the native kidney function, a murine model was planned as follows: group 1 (n = 6) mice underwent to nephrectomy plus ischemia-reperfusion injury for 30 minutes; group 2 (n = 6) mice underwent to nephrectomy without ischemia-reperfusion injury and thus served as sham controls for SIRI. The results of serum creatinine (SCr) were analyzed using Mann-Whitney U tests to calculate the significance between mean values. Survival between groups was measured by Kaplan-Meier test. RESULTS: To reliably achieve an elevation of SCr levels animals were exposed to a SIRI. The values of SCr increased from 0.35 (SD, 0.09) mg/dL to about 2-fold within 2 days and 3-fold within the following 5 days. Under these given conditions the mice displayed signs and histologic findings of severe kidney damage. The survival rate was about 83% of the animals within a week, and they showed no capacity of complete spontaneous self-regeneration. CONCLUSIONS: In this study, we aim to establish a murine model with extensive structural kidney damage and significant elevation of SCr levels, which could be used in basic and translational research of transplantation and regenerative therapies.


Assuntos
Modelos Animais de Doenças , Transplante de Rim , Insuficiência Renal/etiologia , Traumatismo por Reperfusão/complicações , Animais , Creatinina/sangue , Rim/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Insuficiência Renal/patologia , Insuficiência Renal/fisiopatologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia
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