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1.
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
2.
Mol Med Rep ; 22(6): 4485-4491, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33173966

RESUMO

In December 2019, an emergence of pneumonia was detected in patients infected with a novel coronavirus (CoV) in Wuhan (Hubei, China). The International Committee on Taxonomy of Viruses named the virus severe acute respiratory syndrome­CoV­2 and the disease CoV disease­19 (COVID­19). Patients with COVID­19 present with symptoms associated with respiratory system dysfunction and hematological changes, including lymphopenia, thrombocytopenia and coagulation disorders. However, to the best of our knowledge, the pathogenesis of COVID­19 remains unclear. Therefore, understanding the mechanisms underlying the hematological changes that manifest during COVID­19 may aid in the development of treatments and may improve patient prognosis.


Assuntos
Betacoronavirus , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Microambiente Celular , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/sangue , Testes Diagnósticos de Rotina , Endotélio Vascular/patologia , Testes Hematológicos , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Hipoalbuminemia/etiologia , Fígado/fisiopatologia , Pulmão/fisiopatologia , Linfopenia/etiologia , Linfopenia/fisiopatologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/terapia , Traumatismo por Reperfusão/etiologia , Trombocitopenia/etiologia , Trombocitopenia/fisiopatologia , Trombofilia/etiologia
3.
Life Sci ; 263: 118559, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33038374

RESUMO

AIMS: Ginseng and ginsenosides are known for their remarkable effects on the central nervous system. However, pharmacokinetic studies have suggested that the Ginsenoside Rg1 (Rg1) cannot be efficiently transported through the blood-brain barrier. To investigate the effects of Rg1 in combination with mannitol protects neurons against glutamate-induced ER stress via the PERK-eIF2 -ATF4 signaling pathway. MAIN METHODS: Rg1, along with the BBB permeabilizer mannitol, exhibited a potent neuroprotective effect by significantly reducing the neurological scores and infarct volume in rats exposed to middle cerebral artery occlusion. We evaluated the effect of Rg1 on neuroprotection after MCAO, and also explored its potential mechanism of action. KEY FINDINGS: Our results show that Rg1 reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive neurons. This neuroprotection may be dependent, at least in part, on the preservation of the endoplasmic reticulum and mitochondrial function. Ischemia-induced brain injury is largely caused by the excessive release of glutamate, which results in excitotoxicity and cell death. Neurons were pretreated with Rg1 before inducing endoplasmic reticulum stress with glutamate. A reduction in the expression of Bax and a concomitant increase in Bcl2 expression prevented the induction of apoptosis. Furthermore, Rg1 downregulated the expression of endoplasmic reticulum stress genes. SIGNIFICANCE: Our results indicate that Rg1 modulation of stress-responsive genes helps prevent glutamate-induced endoplasmic reticulum stress in neurons through the PERK-eIF2-α-ATF4 signaling pathway.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ginsenosídeos/farmacologia , Ácido Glutâmico/toxicidade , Manitol/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Apoptose , Fármacos do Sistema Nervoso Central/farmacologia , Diuréticos Osmóticos/farmacologia , Quimioterapia Combinada , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
4.
Sci Rep ; 10(1): 14906, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913241

RESUMO

Aryl hydrocarbon receptor (AhR) antagonism can mitigate cellular damage associated with cerebral ischaemia and reperfusion (I/R) injury. This study investigated the neuroprotective effects of AhR antagonist administration before reperfusion in a rat stroke model and influence of the timing of AhR antagonist administration on its neuroprotective effects. Magnetic resonance imaging (MRI) was performed at baseline, immediately after, and 3, 8, and 24 h after ischaemia in the sham, control (I/R injury), TMF10 (trimethoxyflavone [TMF] administered 10 min post-ischaemia), and TMF50 (TMF administered 50 min post-ischaemia) groups. The TMF treatment groups had significantly fewer infarcts than the control group. At 24 h, the relative apparent diffusion coefficient values of the ischaemic core and peri-infarct region were significantly higher and relative T2 values were significantly lower in the TMF10 groups than in the control group. The TMF treatment groups showed significantly fewer terminal deoxynucleotidyl transferase dUTP nick-end labelling positive (+) cells (%) in the peri-infarct region than the control group. This study demonstrated that TMF treatment 10 or 50 min after ischaemia alleviated brain damage. Furthermore, the timing of AhR antagonist administration affected the inhibition of cellular or vasogenic oedema formation caused by a transient ischaemic stroke.


Assuntos
Isquemia Encefálica/prevenção & controle , Lactamas/farmacologia , Mupirocina/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Masculino , Mupirocina/farmacologia , Ratos , Ratos Sprague-Dawley , Reperfusão , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia
5.
Life Sci ; 260: 118403, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926923

RESUMO

AIMS: To explore the therapeutic effect and possible mechanism of exosomes from MSCs overexpressing miR-223 on cerebral ischemia and microglia polarization mediated inflammation. MAIN METHODS: Rats after middle cerebral artery occlusion and reperfusion (MCAO/R) surgery and microglia BV-2 exposed to oxygen and glucose deprivation (OGD) and cysteinyl leukotrienes (CysLTs) stimulation were subject to exosomes from miR-223-3p transfected MSCs treatment, respectively. Behavioral tests were applied to assess the rats' neurological function. FACS was used to analyze M1/M2 microglia BV-2. production of cytokines in the ischemic hemisphere and BV-2 was detected by ELISA or qRT-PCR. Western blotting and qRT-PCR were also used to examine the expression of cysteinyl leukotriene receptor 2 (CysLT2R) in vivo and in vitro. KEY FINDINGS: Exosomes from MSCs over expressing miR-223-3p decreased MCAO/R induced cerebral infarct volume, improved neurological deficits, promoted learning and memorizing abilities. They suppressed pro-inflammatory factors expression and promoted anti-inflammatory factors secretion in the ischemic cortex and hippocampus. In vitro, exosomal miR-223-3p exhibited a more evident impact on modulating mRNA expression and protein production of cytokines. It promoted M2 microglia transformation of M1 microglia induced by NMLTC4 with a concentration-dependent manner. Western blot and qRT-PCR also revealed exosomal miR-223-3p decreased mRNA and protein expression of CysLT2R in vitro and in vivo. SIGNIFICANCE: Exosomal miR-223-3p from MSCs attenuated cerebral ischemia/reperfusion injury through inhibiting microglial M1 polarization mediated pro-inflammatory response, which may be related with inhibitory effect of exosomal miR-223-3p on CysLT2R.


Assuntos
Isquemia Encefálica/prevenção & controle , Exossomos/genética , Inflamação/prevenção & controle , MicroRNAs/genética , Microglia/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Infarto da Artéria Cerebral Média/complicações , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Microglia/imunologia , Microglia/patologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
6.
Life Sci ; 260: 118418, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931799

RESUMO

AIMS: Stroke is a devastating event with a limited choice of intervention. Benzoinum is frequently used to treat stroke in traditional Chinese medicine. Our team has found that the neuroprotection of benzoinum may related to angiogenesis, but the exact biological mechanism is unclear. The objective of this study was to explore its biological mechanism of angiogenesis in cerebral ischemia model rats. MAIN METHODS: First, network pharmacology and molecular docking were performed to predict the possible targets and mechanisms of benzoinum in treating ischemic stroke. The best dose was then selected according to pharmacodynamic indexes such as those for neurological deficit, cerebral infarction rate, and brain histopathology in middle cerebral artery occlusion (MCAO) model rats. Finally, RT-PCR, Western Blot and immunohistochemical analysis were applied to verify the prediction results from molecular docking. KEY FINDINGS: Network pharmacology and molecular docking demonstrated that the targets of treating cerebral ischemia were PDE4D, ACE and TTR, and the mechanism may be related to the ACE-AngI-VEGF signaling pathway. Experimental verification results suggested that 0.50 g/kg and 1.00 g/kg benzoinum could significantly protect against neurological deficit and reduce cerebral infarction rate in the cerebral cortex and hippocampus in MCAO model rats. At an optimal dose, benzoinum could significantly up-regulate VEGF, SHH and ANG-1, yet down-regulate ACE expression in MCAO model rats. SIGNIFICANCE: Balsamic acid is the active ingredient of benzoinum that protects against ischemic stroke and the possible mechanism is related to the promotion of angiogenesis via regulating ACE-AngI-VEGF pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Masculino , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
BMC Surg ; 20(1): 193, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32854681

RESUMO

BACKGROUND: Open surgical repair (OSR) for thoracoabdominal aortic aneurysms (TAA) is associated with a high pulmonary and renal morbidity rate. Ischemic preconditioning (IPC) is a mechanism of protection against the deleterious effects of ischemia-reperfusion. To our knowledge IPC has never been tested during OSR for TAA. METHODS: The primary objective of the study is to evaluate the efficacy of IPC during OSR for TAA with respect to acute kidney injury (AKI) according to KDIGO and pneumonia/prolonged ventilation-time during the first 8 postoperative days. The secondary objectives are to compare both arms with respect to cardiac complications within 48 h, renal and pulmonary complications within 21 days and mortality at 60 days. To assess the efficacy of IPC with respect to pulmonary and renal morbidity, a cox model for competing risks will be used. Assuming that the event occurs among 36% of the patients when no IPC is performed, the allocation of 55 patients to each arm should allow detecting a hazard ratio of at least 2.75 with a power of 80% when admitting 5% for an error of first kind. This means that 110 patients, enrolled in this multicenter study, may be randomised within 36 months of the first randomization. Randomization will be performed to allocate patients either to surgery with preconditioning before aortic cross clamping (Arm 1) or to surgery without preconditioning before aortic cross clamping (Arm 2). Randomization takes place during the intervention after intravenous injection of heparin, or after the start of femoral assistance. The procedure for IPC will be a supra-visceral thoracic aortic cross clamping for 5 min followed by an unclamping period of 5 min. This procedure will be repeated twice before starting thoracic aortic cross clamping needed to perform surgery. CONCLUSIONS: Our hypothesis is that ischemic preconditioning could reduce clinical morbidity and the incidence of lung damage associated with supra-visceral aortic clamping. TRIAL REGISTRATION: EPICATAStudy registered in ClinicalTrial.gov / number: NCT03718312 on Oct.24.2018 URL number.


Assuntos
Aneurisma da Aorta Torácica , Precondicionamento Isquêmico , Traumatismo por Reperfusão/prevenção & controle , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Aorta/cirurgia , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular , Ponte Cardiopulmonar , Constrição , Cardiopatias/etiologia , Cardiopatias/prevenção & controle , Humanos , Hipotermia Induzida , Isquemia/etiologia , Isquemia/prevenção & controle , Precondicionamento Isquêmico/métodos , Pneumopatias/etiologia , Pneumopatias/prevenção & controle , Morbidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Traumatismo por Reperfusão/etiologia , Resultado do Tratamento
9.
Hum Cell ; 33(4): 1026-1035, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32683553

RESUMO

Ischemic stroke is characterized by loss of brain function because of cerebral ischemia. Evidence has been shown that miR-217-5p is significantly downregulated in infarcted brain areas following focal cerebral ischemia. However, the role of miR-217-5p in ischemic stroke is still unclear. To mimic ischemia/reperfusion (I/R) injury conditions in vitro, SH-SY5Y cells were treated with oxygen-glucose deprivation/reperfusion (OGD/R). Our data found that PTEN was the directly target of miR-217-5p in SH-SY5Y cells. The level of miR-217-5p was significantly decreased, while the level of PTEN was notably increased in SH-SY5Y cells following OGD/R treatment. Overexpression of miR-217-5p markedly promoted the proliferation and cell cycle progression, and inhibited apoptosis in OGD/R-treated SH-SY5Y cells. In addition, overexpression of miR-217-5p significantly decreased the expressions of PTEN and FOXO1, but increased the expression of p-Akt in OGD/R-treated SH-SY5Y cells. Moreover, methylation specific PCR (MSP) results indicated the CpG islands in the promoter region of miR-217-5p were hypermethylated in SH-SY5Y cells under OGD/R. Meanwhile, the DNA methylation of miR-217-5p promoter region decreased expression of miR-217-5p. Our data indicated that miR-217-5p could attenuate ischemic injury by inhibiting PTEN. In addition, DNA methylation-mediated silencing of miR-217-5p may serve as a promising therapeutic target of ischemic stroke.


Assuntos
Expressão Gênica/genética , Glucose/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/fisiologia , Neurônios/patologia , Oxigênio/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Traumatismo por Reperfusão/genética , Regulação para Cima/genética , Células Cultivadas , Metilação de DNA , Humanos , Terapia de Alvo Molecular , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/terapia
10.
Int J Surg ; 80: 68-73, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32619621

RESUMO

BACKGROUND: Severe ischemic changes of the liver remnant after hepatectomy could expedite tumor recurrence on the residual liver. Our study aimed at assessing the effect of warm ischemic/reperfusion (I/R) injuries on surgery-to-local recurrence interval and patient overall survival, during major hepatectomies under inflow and outflow vascular control. METHODS: One hundred and eighteen patients were subjected to liver resection under total inflow and outflow vascular clamping and were assigned as study group. These individuals were retrospectively matched to 112 counterparts, who underwent liver surgery applying inflow and outflow vascular clamping only of the segment harboring the tumor, sparing the liver remnant from any I/R injury (control group). The two cohorts were compared regarding recurrence-free survival and overall survival. RESULTS: Reversible I/R injuries of the liver remnant subjected to vascular clamping were manifested, with increase of AST values at postoperative day 2 in the study group, as compared to the control group (603 ± 270 U/L vs. 450 ± 290 U/L, p < 0.001), reversing to normal by day 7. Recurrence-free survival and overall survival were no significantly different between the two groups (log rank statistic p = 0.298 and 0.639, respectively). CONCLUSION: Reversible I/R injuries of the liver remnant do not seem to be implicated in the precipitation of local malignant recurrence or in shorter long-term survival, in comparison to a technique sparing the residual liver of I/R injury. This retrospective cohort study was registered at clinicaltrials.gov under unique identifying number: NCT04257240.


Assuntos
Hepatectomia/efeitos adversos , Neoplasias Hepáticas/cirurgia , Fígado/irrigação sanguínea , Recidiva Local de Neoplasia/etiologia , Complicações Pós-Operatórias/etiologia , Traumatismo por Reperfusão/etiologia , Adulto , Constrição , Feminino , Humanos , Fígado/cirurgia , Neoplasias Hepáticas/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Traumatismo por Reperfusão/patologia , Estudos Retrospectivos
11.
Sci Rep ; 10(1): 11359, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647374

RESUMO

We compared therapeutic properties of natural and engineered chemokine (C-X-C motif) receptor 4 (CXCR4) agonists in a rat acute respiratory distress syndrome (ARDS) model utilizing the PaO2/FiO2-ratio as a clinically relevant primary outcome criterion. Ventilated rats underwent unilateral lung ischemia from t = 0-70 min plus hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg from t = 40-70 min, followed by reperfusion/fluid resuscitation until t = 300 min. Natural CXCR4 agonists (CXCL12, ubiquitin) and engineered CXCL12 variants (CXCL121, CXCL22, CXCL12K27A/R41A/R47A, CXCL12 (3-68)) were administered within 5 min of fluid resuscitation. Animals treated with vehicle or CXCL12 (3-68) reached criteria for mild and moderate ARDS between t = 90-120 min and t = 120-180 min, respectively, and remained in moderate ARDS until t = 300 min. Ubiquitin, CXCL12, CXCL121 and CXCL122 prevented ARDS development. Potencies of CXCL12/CXCL121/CXCL122 were higher than the potency of ubiquitin. CXCL12K27A/R41A/R47A was inefficacious. CXCL121 > CXCL12 stabilized MAP and reduced fluid requirements. CXCR4 agonists at doses that preserved lung function reduced histological injury of the post-ischemic lung and reduced mortality from 55 to 9%. Our findings suggest that CXCR4 protein agonists prevent development of ARDS and reduce mortality in a rat model, and that development of new engineered protein therapeutics with improved pharmacological properties for ARDS is possible.


Assuntos
Receptores CXCR4/agonistas , Traumatismo por Reperfusão/prevenção & controle , Ressuscitação/métodos , Choque Hemorrágico/terapia , Ferimentos e Lesões/terapia , Animais , Quimiocina CXCL12/administração & dosagem , Quimiocina CXCL12/genética , Modelos Animais de Doenças , Hidratação/métodos , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Engenharia de Proteínas , Ratos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/mortalidade , Traumatismo por Reperfusão/patologia , /mortalidade , Choque Hemorrágico/etiologia , Choque Hemorrágico/mortalidade , Choque Hemorrágico/patologia , Toracotomia/efeitos adversos , Ubiquitina/administração & dosagem , Ferimentos e Lesões/complicações , Ferimentos e Lesões/mortalidade
13.
J Surg Res ; 255: 510-516, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32629333

RESUMO

BACKGROUND: Supraceliac aortic clamping and unclamping produces ischemia-reperfusion (I/R) injury of the splanchnic organs. The protective effects of tachykinin receptor antagonists, SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor), against I/R-induced inhibition of intestinal motility were tested in rats. MATERIAL AND METHODS: The intestinal transit of Evans blue was measured in untreated rats and animals subjected to skin incision, I/R (1 h superior mesenteric artery occlusion followed by 24 h reperfusion) or sham operation. Surgical procedures were conducted under diethyl ether anesthesia. RESULTS: The gastrointestinal transit has not been markedly affected in rats, which were anesthetized or subjected to skin incision in comparison with untreated animals. In contrast, a sham operation and I/R have significantly reduced the intestinal motility. Pretreatment with NK1-3 blockers (SR140333 [3-30 µg/kg]; SR48968 [3-100 µg/kg]; and SB222200 [10-100 µg/kg]) reversed dose dependently the effects of I/R to the level observed after sham operation only. A combination of NK1+NK2+NK3 inhibitors exerted an additive effect compared with NK1 and NK2 antagonists used as single agents. Similarly, combined NK1+NK2 were more effective than NK2 alone. Sham operation and I/R have shifted the in vitro carbachol concentration-response curves to the right in comparison with untreated animals, a phenomenon partially reversed by NK1-NK3 pretreatment. CONCLUSIONS: Single-agent and combined treatment with NK1-3 antagonists markedly attenuated the gastrointestinal dysmotility evoked by I/R injury. The pretreatment with NK3 blocker proved to be the most active in this experimental setting.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Motilidade Gastrointestinal/efeitos dos fármacos , Receptores de Taquicininas/antagonistas & inibidores , Traumatismo por Reperfusão/tratamento farmacológico , Circulação Esplâncnica/efeitos dos fármacos , Animais , Benzamidas/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Masculino , Piperidinas/administração & dosagem , Quinolinas/administração & dosagem , Quinuclidinas/administração & dosagem , Ratos , Receptores de Taquicininas/metabolismo , Traumatismo por Reperfusão/etiologia , Taquicininas/metabolismo
14.
Int J Nanomedicine ; 15: 4125-4138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606668

RESUMO

Purpose: To investigate the effect and mechanism of macrophage membrane-coated nanoparticles (M-NPs) on hepatic ischemia-reperfusion injury (I/RI) caused by orthotopic liver transplantation. In addition, the advantages of TLR4+/M-NPs compared to M-NPs are discussed. Materials and Methods: We prepared biomimetic M-NPs and identified their characteristics. M-NPs were injected into an SD rat model of orthotopic liver transplantation, and the anti-inflammatory and anti-I/RI activities of M-NPs were studied in vivo and in vitro. In addition, we overexpressed macrophage membrane Toll-like receptor 4 (TLR4) in vitro and prepared TLR4+/M-NPs. Then, we assessed the characteristics and advantages of TLR4+/M-NPs. Results: The M-NPs neutralized endotoxin, inhibited the overactivation of Kupffer cells (KCs) and suppressed the secretion of inflammatory factors by inhibiting the endotoxin-mediated TLR4/MyD88/IRAK1/NF-κB signaling pathway. In an orthotopic liver transplantation model in SD rats, M-NPs showed significant therapeutic efficacy by neutralizing endotoxin and suppressing the secretion of inflammatory factors. Moreover, overexpression of TLR4 on the macrophage membrane by using a TLR4+-plasmid in vitro effectively reduced the amount of M-NPs needed to neutralize an equivalent dose of endotoxin, reducing the potential risks of NP overuse. Conclusion: This study indicates that M-NPs can effectively alleviate I/RI induced by liver transplantation.


Assuntos
Membrana Celular/metabolismo , Endotoxinas/metabolismo , Transplante de Fígado/efeitos adversos , Fígado/irrigação sanguínea , Macrófagos/metabolismo , Nanopartículas/química , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/terapia , Animais , Anti-Inflamatórios/farmacologia , Fluorescência , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Nanopartículas/ultraestrutura , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo
15.
Transplantation ; 104(9): 1842-1852, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32590607

RESUMO

BACKGROUND: Lung ischemia-reperfusion injury after transplantation is associated with worse clinical outcomes. MicroRNA (miR) are critical regulators of gene expression that could provide potential targets for novel gene therapy. Herein, we aim to examine the feasibility of using the ex vivo lung perfusion (EVLP) platform to examine the changes in miR expression in human lungs in response to cold ischemia and ex vivo reperfusion (CI/EVR). METHODS: Twenty-four human lungs were perfused in cellular EVLP system for 2 h, and tissue samples were obtained before and after EVLP as well as from control donors. MicroRNA expression profiling of the lung tissue was performed using next-generation sequencing and downstream predicted target genes were examined. In situ hybridization assay of the validated miR was used to identify the expressing cell type. RESULTS: After 2 h of EVLP, cytokines production was significantly increased (IL-1ß, IL-6, IL-8, IL-10, and TNF-α). MicroRNA sequencing identified a significant change in the expression of a total of 21 miR after CI and 47 miR after EVR. Validation using quantitative polymerase chain reaction showed significant upregulation of miR-17 and miR548b after CI/EVR. Downstream analysis identified abundant inflammatory and immunologic targets for miR-17 and miR-548b that are known mediators of lung injury. In situ hybridization assays detected positive signals of the 2 miR expression in alveolar epithelial cells. CONCLUSIONS: This study demonstrates the feasibility of using the EVLP platform to study miR signature in human lungs in response to CI/EVR. We found that miR-17 and miR-548b were upregulated in alveolar epithelial cells after CI/EVR, which merit further exploration.


Assuntos
Isquemia Fria , Transplante de Pulmão , Pulmão/metabolismo , MicroRNAs/fisiologia , Reperfusão , Citocinas/biossíntese , Humanos , Traumatismo por Reperfusão/etiologia , Análise de Sequência de RNA , Regulação para Cima
16.
J Cardiothorac Surg ; 15(1): 134, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32522213

RESUMO

BACKGROUND: In a rabbit model of cardiopulmonary bypass (CPB) and cardioplegic arrest, we previously showed that hyperoxic myocardial reperfusion was associated with increased left ventricular (LV) systolic dysfunction and myocardial injury compared with normoxic reperfusion. The aim of this study was to evaluate in our experimental model the impact of post-CPB reperfusion conditions on other organs potentially vulnerable to ischemic injury such as the brain and kidney. METHODS: After 60 min of CPB, aortic cross-clamp, and cold cardioplegic arrest, rabbits were reperfused under hyperoxic or normoxic conditions for 120 min. Left ventricular systolic contractility (LV + dP/dt) and diastolic relaxation (LV -dP/dt) were continuously recorded, and end-organ injury was assessed by measuring circulating biomarkers specific for kidney (cystatin C and creatinine) and brain injury [S100B and neuron specific enolase (NSE)]. At completion of the protocol, kidney and brain tissues were harvested for measuring oxidant stress (OS), inflammation and apoptosis. RESULTS: Following aortic cross-clamp removal, rabbits exposed to normoxic reperfusion demonstrated preserved LV systolic and diastolic function compared with hyperoxic reperfusion (LV + dP/dt: 70 ± 14% of pre-CPB vs. 36 ± 21%, p = 0.018; LV -dP/dt: 72 ± 36% of pre-CPB vs. 33 ± 20%, p = 0.023). Similarly, CPB increased plasma creatinine, S100B and NSE that were significantly attenuated by normoxic reperfusion compared with hyperoxic reperfusion (creatinine: 4.0 ± 0.5 vs. 7.1 ± 0.8 mg/dL, p = 0.004; S100B: 4.0 ± 0.8 vs. 6.7 ± 1.0 ng/mL, p = 0.047; NSE: 57.7 ± 6.8 vs. 101.3 ± 16.1 pg/mL, p = 0.040). Furthermore, both kidney and brain tissues showed increased mRNA expression and activation of pathways for OS, inflammation, and apoptosis, that were reduced under normoxic compared with hyperoxic conditions. CONCLUSIONS: Normoxic reperfusion ameliorates cardiac, renal and neural injury compared with hyperoxic reperfusion in an in vivo animal model of CPB and cardioplegic arrest. This protective effect of normoxic reperfusion may be due to a reduction in signaling pathways for OS, inflammation, and apoptosis.


Assuntos
Isquemia Encefálica/sangue , Ponte Cardiopulmonar/efeitos adversos , Parada Cardíaca Induzida/efeitos adversos , Nefropatias/sangue , Oxigênio/administração & dosagem , Traumatismo por Reperfusão/sangue , Animais , Apoptose , Biomarcadores/sangue , Encéfalo/fisiopatologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Creatinina/sangue , Cistatina C/sangue , Inflamação/metabolismo , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/fisiopatologia , Masculino , Estresse Oxidativo/genética , Fosfopiruvato Hidratase/sangue , RNA Mensageiro/metabolismo , Coelhos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/fisiopatologia , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Função Ventricular Esquerda
17.
Transplant Proc ; 52(8): 2454-2458, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32448654

RESUMO

BACKGROUND: Orthotopic liver transplantation (LT) is a technically complex surgical procedure associated with a major risk of hemodynamic instability and metabolic derangement, especially in patients with coexisting renal dysfunction. Some centers have applied intraoperative renal replacement therapy (ioRRT) to support patients with preoperative renal failure and prevent critical complications. Although there is a strong theoretical rationale for this treatment, there remains a paucity of definite data demonstrating its benefits. METHODS: This was a retrospective observational study of all adult patients undergoing intraoperative dialysis in our center from January 2010 till December 2016. RESULTS: The study group consisted of 88 patients with a mean MELD score of 31.4. Six patients underwent simultaneous liver and kidney transplantation. Forty-four (50%) recipients were admitted to the intensive care unit before transplantation, and 19 (21.6%) needed mechanical ventilation. Twenty-eight (31.8%) of the procedures were retransplantations, and 40 (45.4%) patients had been undergoing renal replacement therapy before LT. The mean preoperative serum creatinine was 2.82 ± 1.13 mg/dL. The majority of patients (54.5%) was operated on using the veno-venous bypass technique. The mean arterial blood pH and potassium levels after reperfusion were 7.2 ± 0.12 and 4.04 ± 0.95 mmol/L, respectively. Postreperfusion syndrome (PRS) occurred in 11 (13.9%) patients in whom dialysis started at least 15 minutes before reperfusion. Dialysis circuit clotting occurred in 9.1% of cases. There were no other adverse events of ioRRT. CONCLUSION: Our data suggests that intraoperative dialysis in severely ill patients with a high MELD score is safe and effective. Lower than expected PRS occurrence needs to be confirmed in a study with a control group.


Assuntos
Transplante de Fígado/métodos , Diálise Renal/métodos , Adulto , Feminino , Humanos , Transplante de Rim , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Estudos Retrospectivos
18.
BMC Surg ; 20(1): 111, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448270

RESUMO

BACKGROUND: Laparoscopy induces adhesion due to ischemia-reperfusion injury. However, the detail pathomechanism is poorly understood. This study aimed to investigate the impact of laparoscopy on mast cell and mesothelium morphological changes in the rat. METHODS: Forty-nine males of Sprague-Dawley Rattus norvegicus were divided into four groups: a) control and b) intervention groups P1, P2, and P3 that underwent 60 min laparoscopic using carbon dioxide (CO2) insufflation at 8, 10, and 12 mmHg groups, respectively. Serum hydrogen peroxide (H2O2), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and oxidative stress index (OSI) levels were determined 24 h after laparoscopy. Histopathological analyses of mast cell infiltration and degranulation and mesothelium thickness in the liver, greater omentum, mesenterium, small intestine, and peritoneum were performed 7 days after the procedure. RESULTS: H2O2, MDA, and OSI levels were significantly increased in the intervention groups compared with the control (p<0.05), while the SOD and CAT levels were decreased in the intervention groups compared with the control (p<0.05). Mast cell infiltration and degranulation were higher in the intervention groups than in control (p<0.05), while the mesothelium thickness was significantly lower in the laparoscopic groups than in control (p<0.05). Interestingly, the decrease in mesothelium thickness was strongly associated with the increase in mast cell infiltration and degranulation (p<0.01). CONCLUSIONS: Our study shows that laparoscopy in rats increases mast cell infiltration and degranulation, which also results in and correlates with a decrease in mesothelial thickness.


Assuntos
Degranulação Celular/fisiologia , Laparoscopia/efeitos adversos , Mastócitos/patologia , Traumatismo por Reperfusão/etiologia , Animais , Epitélio/patologia , Peróxido de Hidrogênio/sangue , Intestino Delgado/patologia , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
19.
J Surg Res ; 253: 8-17, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32305498

RESUMO

BACKGROUND: Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids, which exert anti-inflammatory effects and alleviate oxidative stress in the cardiovascular system. Our previous work revealed that CYP2J2 is expressed in pulmonary artery endothelial cells. It was therefore hypothesized that CYP2J2 overexpression may prevent lung ischemia/reperfusion injury (LIRI) in 3-week-old C57BL/6 mice during deep hypothermic low flow (DHLF). This study aimed to establish whether CYP2J2 protects against LIRI and the mechanisms of CYP2J2 overexpression during DHLF in mice. The aim of this study was to explore the effects of DHLF on lung tissue in mice and to find out the regularity of this process, so as to provide theoretical data for lung tissue protection in children undergoing this process in clinic. METHODS: A 3-week-old C57BL/6 mouse model was used to mimic LIRI conditions during DHLF by clamping the left pulmonary artery and left main bronchus for 120 min, followed by reperfusion for 2 h. The body temperature of the mice was maintained between 18°C and 19°C to induce DHLF. RESULTS: During DHLF, lung ischemia/reperfusion increased the left lung wet/dry weight, the left lung weight/body weight ratio, the protein concentration in bronchoalveolar lavage fluid, and the concentration of proinflammatory mediators in the lungs, including interleukin (IL)-1, IL-8, and necrosis factor (NF)-α, and decreased the concentration of the anti-inflammatory mediator IL-10. Furthermore, activation of NF-κB p65 and degradation of IKBα were remarkably increased in lung tissues after ischemia/reperfusion. The CYP2J2 overexpression group showed the opposite results (P < 0.05), and p-Akt1 and p-GSK-3ß expression were significantly higher in the CYP2J2 overexpression group (P < 0.05). Moreover, the changes in IL-1, IL-8, tumor necrosis factor-α, IL-10, p-Akt1, p-GSK-3ß, NF-κB p65, and IKBα were reversed in the Akt1 gene heterozygous knockout group, and lung damage was significantly higher in the Akt1 gene heterozygous knockout group than in the CYP2J2 overexpression group. CYP2J2 overexpression can protect against LIRI, whereas Akt1 gene heterozygous knockout in mice can abolish this protective effect. CONCLUSIONS: CYP2J2 overexpression can protect against LIRI by activating the P13K/Akt/GSK-3ß/NF-kB signaling pathway during DHLF. Thus, changing CYP2J2 expression can be a novel strategy for the prevention and treatment of LIRI during DHLF.


Assuntos
Ponte Cardiopulmonar/efeitos adversos , Sistema Enzimático do Citocromo P-450/metabolismo , Terapia Genética/métodos , Lesão Pulmonar/terapia , Traumatismo por Reperfusão/terapia , Animais , Ponte Cardiopulmonar/métodos , China , Sistema Enzimático do Citocromo P-450/genética , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Cardiopatias Congênitas/cirurgia , Humanos , Pulmão , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Transgênicos , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Transfecção
20.
Surgery ; 168(1): 160-166, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32223984

RESUMO

BACKGROUND: Donor hepatectomy time is associated with graft survival after liver transplantation. The aim of this study was to identify the impact of donor hepatectomy time on biliary injury during donation after circulatory death liver transplantation. METHODS: First, bile duct biopsies of livers included in (pre)clinical machine perfusion research were analyzed. Secondly, of the same livers, bile samples were collected during normothermic machine perfusion. Lastly, a nationwide retrospective cohort study was performed including 273 adult patients undergoing donation after circulatory death liver transplantation between January 1, 2002 and January 1, 2017. Primary endpoint was development of non-anastomotic biliary strictures within 2 years of donation after circulatory death liver transplantation. Cox proportional-hazards regression analyses were used to assess the influence of hepatectomy time on the development of non-anastomotic biliary strictures. RESULTS: Livers with severe histological bile duct injury had a higher median hepatectomy time (P = .03). During normothermic machine perfusion, livers with a hepatectomy time >50 minutes had lower biliary bicarbonate and bile pH levels. In the nationwide retrospective study, donor hepatectomy time was an independent risk factor for non-anastomotic biliary strictures after donation after circulatory death liver transplantation (Hazard Ratio 1.18 per 10 minutes increase, 95% Confidence Interval 1.06-1.30, P value = .002). CONCLUSION: Donor hepatectomy time negatively influences histological bile duct injury before normothermic machine perfusion and bile composition during normothermic machine perfusion. Additionally, hepatectomy time is a significant independent risk factor for the development of non-anastomotic biliary strictures after donation after circulatory death liver transplantation.


Assuntos
Doenças Biliares/etiologia , Hepatectomia , Transplante de Fígado , Duração da Cirurgia , Traumatismo por Reperfusão/etiologia , Adulto , Ductos Biliares/patologia , Doenças Biliares/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Perfusão , Estudos Retrospectivos
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