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1.
Oxid Med Cell Longev ; 2022: 7547269, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35251481

RESUMEN

Chronic kidney disease (CKD) and cardiovascular disease are known to be linked, and the involvement of indoxyl sulfate (IS), a type of uremic toxin, has been suggested as one of the causes. It is known that IS induces vascular dysfunction through overproduction of reactive oxygen species (ROS). On the other hand, the involvement of IS in the vascular dysfunction associated with acute kidney injury (AKI) is not fully understood. Therefore, we investigated this issue using the thoracic aorta of rats with ischemic AKI. Ischemic AKI was induced by occlusion of the left renal artery and vein for 45 min, followed by reperfusion 2 weeks after contralateral nephrectomy. One day after reperfusion, there was marked deterioration in renal function evidenced by an increase in plasma creatinine. Furthermore, blood IS levels increased markedly due to worsening renal function. Seven days and 28 days after reperfusion, blood IS levels decreased with the improvement in renal function. Of note, acetylcholine-induced vasorelaxation deteriorated over time after reperfusion, contradicting the recovery of renal function. In addition, 28 days after reperfusion, we observed a significant increase in ROS production in the vascular tissue. Next, we administered AST-120, a spherical adsorbent charcoal, after reperfusion to assess whether the vascular endothelial dysfunction associated with the ischemic AKI was due to a temporary increase in blood IS levels. AST-120 reduced the temporary increase in blood IS levels after reperfusion without influencing renal function, but did not restore the impaired vascular reactivity. Thus, in ischemic AKI, we confirmed that the vascular endothelial function of the thoracic aorta is impaired even after the recovery of kidney injury, probably with excessive ROS production. IS, which increases from ischemia to early after reperfusion, may not be a major contributor to the vascular dysfunction associated with ischemic AKI.


Asunto(s)
Lesión Renal Aguda/sangre , Lesión Renal Aguda/complicaciones , Aorta Torácica/metabolismo , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Indicán/sangre , Isquemia/sangre , Isquemia/complicaciones , Daño por Reperfusión/sangre , Daño por Reperfusión/complicaciones , Transducción de Señal/efectos de los fármacos , Animales , Carbono/administración & dosificación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Masculino , Óxido Nítrico/metabolismo , Óxidos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Recuperación de la Función/efectos de los fármacos , Insuficiencia Renal Crónica/metabolismo
2.
Oxid Med Cell Longev ; 2022: 1197061, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35126806

RESUMEN

BACKGROUND: Recent meta-analyses have shown that sodium-glucose cotransporter 2 (SGLT-2) inhibitors alleviate chronic kidney disease and acute kidney injury in diabetic patients. In this study, we aimed to investigate the effect of empagliflozin on renal ischemia/reperfusion (I/R) in nondiabetic rats and find the possible mechanisms. Experimental Approach. Eighteen male Wistar rats were randomly divided into three groups, including healthy control, ischemic control, and empagliflozin-treated group. Thirty minutes of bilateral renal ischemia was induced by clamping the renal hilum. Forty-eight hours after reopening the clamps, rats' blood samples and tissue specimens were collected. Empagliflozin 10 mg/kg was administered by gavage, 2 hours before ischemia and 24 hours after the first dose. RESULTS: I/R injury led to a significant rise in serum creatinine and blood urea nitrogen which was significantly decreased after treatment with empagliflozin. Empagliflozin also alleviated tubulointerstitial and glomerular damage and significantly decreased tissue histology scores. Empagliflozin decreased the increased levels of malondialdehyde, interleukin 1ß, and tumor necrosis factor α. SGLT2 inhibition increased the decreased expression of nuclear factor erythroid 2-related factor 2 and PPARG coactivator 1 alpha that conduct antioxidant defense and mitochondrial biogenesis, respectively. Furthermore, empagliflozin markedly increased LC3-II/LC3-I and bcl2/bax ratios, showing its beneficial effect on activation of autophagy and inhibition of apoptosis. Despite its effects on diabetic nephropathy, empagliflozin did not activate the Sestrin2/AMP-activated protein kinase pathway in this study. CONCLUSION: Empagliflozin improved renal I/R injury in nondiabetic rats in this study by promoting autophagy and mitochondrial biogenesis and attenuation of oxidative stress, inflammation, and apoptosis.


Asunto(s)
Antioxidantes/administración & dosificación , Autofagia/efectos de los fármacos , Compuestos de Bencidrilo/administración & dosificación , Glucósidos/administración & dosificación , Enfermedades Renales/complicaciones , Enfermedades Renales/tratamiento farmacológico , Biogénesis de Organelos , Daño por Reperfusión/complicaciones , Daño por Reperfusión/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Enfermedades Renales/sangre , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Daño por Reperfusión/sangre , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismo
3.
Mol Biol Rep ; 49(1): 341-349, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34727292

RESUMEN

BACKGROUND: Hepatic ischemia-reperfusion injury (I/R) is an important factor affecting the prognosis of patients undergoing liver surgery. This study aimed to explore the value of intravenous immunoglobulin (IVIG) in hepatic I/R and its mechanism in a rat model. MATERIALS AND METHODS: Forty eight adult male Sprague-Dawley (SD) rats were divided into six groups randomly: (1-2) treated with normal saline (NS) without ischemia or reperfusion; (3-4) treated with NS + 30 min ischemia; (5-6) treated with IVIG + 30 min ischemia. Rats of group 1/3/5 were euthanized at 12 h after operation (sham + NS + 12 h, I/R + NS + 12 h, I/R + IVIG + 12 h group) while group 2/4/6 were euthanized at 24 h (sham + NS + 24 h, I/R + NS + 24 h, I/R + IVIG + 24 h group). Interleukin 10 (IL-10), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) were quantified as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Hepatic pathological changes were observed while nuclear factor kappa B p65 (NF-κB p65), Inhibitory Subunit of NF Kappa B Alpha (IKB-alpha) and cleaved caspase-3 were detected. CONCLUSION: ALT, AST, IL-6, TNF-alpha, NF-κB p65 and cleaved caspase-3 were increased by I/R whereas IL-10 and IKB-alpha were decreased. However, IVIG pretreatment reduced ALT, AST, IL-6, TNF-alpha, NF-κB p65 and cleaved caspase-3, but increased IL-10 and IKB-alpha. IVIG treatment attenuates the infiltration of inflammatory cell and cell apoptosis which were observed in I/R groups. IVIG may alleviate hepatic I/R in rats by inhibiting the classical NF-κB signaling pathway, reducing IL-6, TNF-alpha, promoting IL-10, and inhibiting cell apoptosis.


Asunto(s)
Antiinfecciosos/administración & dosificación , Inmunoglobulinas Intravenosas/administración & dosificación , Hepatopatías/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Alanina Transaminasa/sangre , Animales , Antiinfecciosos/farmacología , Aspartato Aminotransferasas/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Inmunoglobulinas Intravenosas/farmacología , Interleucina-10/sangre , Interleucina-6/sangre , Hepatopatías/sangre , Hepatopatías/etiología , Hepatopatías/inmunología , Masculino , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/sangre , Daño por Reperfusión/etiología , Daño por Reperfusión/inmunología , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangre
4.
Int J Mol Med ; 49(2)2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34878156

RESUMEN

Exosomes are an emerging therapeutic tool for the treatment of tissue injuries. In the present study, the protective effect of isolated exosomes from adipose­derived stem cells (ADSCs­exo) against hepatic ischemia­reperfusion (I/R) injury was explored. Hepatic I/R injury was achieved by inducing ischemia for 60 min followed by reperfusion for 2 and 6 h. Pre­treatment with ADSCs­exo revealed a significant reduction in necrosis and apoptosis in liver tissue induced by I/R injury. Hypoxic oxidative stress was managed by exosome­mediated reduced reactive oxygen species and increased superoxide dismutase that in turn protected mitochondrial damage and apoptosis. Reduction in inflammatory mediators such as IL­1ß and TNF­α was also observed and protection of hepatocytes from I/R injury was evidenced by a significant decrease in biochemical markers of liver damage (alanine transaminase, aspartate transaminase and lactate dehydrogenase). Exosomal prostaglandin E2 (PGE2)­mediated ERK1/2 and GSK­3ß phosphorylation were revealed to increase Bcl­2 and decrease Bax expression with mitochondrial permeability transition pore­inhibition which may be considered a prime mechanism of exosome­mediated hepatoprotection. In conclusion, our results indicated that ADSCs­exo pre­treatment is effective in protecting liver I/R injury.


Asunto(s)
Exosomas/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hígado/irrigación sanguínea , Sistema de Señalización de MAP Quinasas , Células Madre Mesenquimatosas/metabolismo , Daño por Reperfusión/enzimología , Daño por Reperfusión/terapia , Animales , Apoptosis , Biomarcadores/sangre , AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Exosomas/ultraestructura , Peroxidación de Lípido , Hígado/patología , Hígado/ultraestructura , Masculino , Modelos Biológicos , Necrosis , Estrés Oxidativo , Ratas Sprague-Dawley , Daño por Reperfusión/sangre , Daño por Reperfusión/patología , Proteína X Asociada a bcl-2/metabolismo
5.
Int J Mol Sci ; 22(22)2021 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-34829984

RESUMEN

Renal ischaemia reperfusion (I/R) triggers a cascade of events including oxidative stress, apoptotic body and microparticle (MP) formation as well as an acute inflammatory process that may contribute to organ failure. Macrophages are recruited to phagocytose cell debris and MPs. The tyrosine kinase receptor MerTK is a major player in the phagocytosis process. Experimental models of renal I/R events are of major importance for identifying I/R key players and for elaborating novel therapeutical approaches. A major aim of our study was to investigate possible involvement of MerTK in renal I/R. We performed our study on both natural mutant rats for MerTK (referred to as RCS) and on wild type rats referred to as WT. I/R was established by of bilateral clamping of the renal pedicles for 30' followed by three days of reperfusion. Plasma samples were analysed for creatinine, aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), kidney injury molecule -1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels and for MPs. Kidney tissue damage and CD68-positive cell requirement were analysed by histochemistry. monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), and histone 3A (H3A) levels in kidney tissue lysates were analysed by western blotting. The phagocytic activity of blood-isolated monocytes collected from RCS or WT towards annexin-V positive bodies derived from cultured renal cell was assessed by fluorescence-activated single cell sorting (FACS) and confocal microscopy analyses. The renal I/R model for RCS rat described for the first time here paves the way for further investigations of MerTK-dependent events in renal tissue injury and repair mechanisms.


Asunto(s)
Lesión Renal Aguda/genética , Riñón/metabolismo , Daño por Reperfusión/genética , Tirosina Quinasa c-Mer/genética , Lesión Renal Aguda/sangre , Lesión Renal Aguda/patología , Animales , Aspartato Aminotransferasas/sangre , Moléculas de Adhesión Celular/sangre , Quimiocina CCL2/sangre , Creatinina/sangre , Humanos , Riñón/patología , L-Lactato Deshidrogenasa/sangre , Lipocalina 2/sangre , Macrófagos/metabolismo , Macrófagos/patología , Óxido Nítrico/genética , Óxido Nítrico Sintasa de Tipo II/sangre , Peroxidasa/sangre , Fagocitosis/genética , Ratas , Daño por Reperfusión/sangre , Daño por Reperfusión/patología
6.
Clin Sci (Lond) ; 135(23): 2643-2658, 2021 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-34796904

RESUMEN

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia-reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia-reperfusion (H/R) induced G2/M cell cycle arrest, epithelial-mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition.


Asunto(s)
Lesión Renal Aguda/sangre , Carbono/uso terapéutico , Indicán/antagonistas & inhibidores , Nefroesclerosis/prevención & control , Óxidos/uso terapéutico , Insuficiencia Renal Crónica/prevención & control , Lesión Renal Aguda/complicaciones , Animales , Butilaminas , Carbono/farmacología , Evaluación Preclínica de Medicamentos , Indicán/sangre , Indicán/aislamiento & purificación , Ratones Endogámicos C57BL , Nefroesclerosis/sangre , Nefroesclerosis/etiología , Óxidos/farmacología , Insuficiencia Renal Crónica/etiología , Daño por Reperfusión/sangre , Daño por Reperfusión/etiología , Fenotipo Secretor Asociado a la Senescencia/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos
7.
Nutrients ; 13(6)2021 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-34205251

RESUMEN

Quadriceps muscle atrophy following total knee arthroplasty (TKA) can be caused by tourniquet-induced ischemia-reperfusion (IR) injury, which is often accompanied by oxidative stress and inflammatory responses. n-3 long-chain polyunsaturated fatty acids (LCPUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert antioxidant and anti-inflammatory effects against IR injury, whereas n-6 LCPUFAs, particularly arachidonic acid (AA), exhibit pro-inflammatory effects and promote IR injury. This study aimed to examine whether preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio are associated with oxidative stress immediately after TKA. Fourteen eligible patients with knee osteoarthritis scheduled for unilateral TKA participated in this study. The levels of serum EPA, DHA, and AA were measured immediately before surgery. Derivatives of reactive oxygen metabolites (d-ROMs) were used as biomarkers for oxidative stress. The preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio were found to be significantly negatively correlated with the serum d-ROM levels at 96 h after surgery, and the rate of increase in serum d-ROM levels between baseline and 96 h postoperatively. This study suggested the preoperative serum EPA + DHA levels and the (EPA + DHA)/AA ratio can be negatively associated with oxidative stress immediately after TKA.


Asunto(s)
Artroplastia de Reemplazo de Rodilla , Ácidos Grasos Insaturados/sangre , Estrés Oxidativo/fisiología , Proyectos Piloto , Periodo Preoperatorio , Anciano , Ácido Araquidónico/sangre , Artroplastia de Reemplazo de Rodilla/efectos adversos , Atrofia/etiología , Ácidos Docosahexaenoicos/sangre , Ácido Eicosapentaenoico/sangre , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Músculo Cuádriceps/patología , Especies Reactivas de Oxígeno/sangre , Daño por Reperfusión/sangre , Daño por Reperfusión/complicaciones
8.
Am J Physiol Regul Integr Comp Physiol ; 321(2): R273-R278, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34259042

RESUMEN

Prior data suggest that, relative to the early follicular phase, women in the late follicular phase are protected against endothelial ischemia-reperfusion (I/R) injury when estradiol concentrations are highest. In addition, endothelial I/R injury is consistently observed in men with naturally low endogenous estradiol concentrations that are similar to those of women in the early follicular phase. Therefore, the purpose of this study was to determine whether the vasodeleterious effect of I/R injury differs between women in the early follicular phase of the menstrual cycle and age-matched men. We tested the hypothesis that I/R injury would attenuate endothelium-dependent vasodilation to the same extent in women and age-matched men with similar circulating estradiol concentrations. Endothelium-dependent vasodilation was assessed via brachial artery flow-mediated dilation (duplex ultrasound) in young healthy men (n = 22) and women (n = 12) before (pre-I/R) and immediately after (post-I/R) I/R injury, which was induced via 20 min of arm circulatory arrest followed by 20-min reperfusion. Serum estradiol concentrations did not differ between sexes (men 115.0 ± 33.9 pg·mL-1 vs. women 90.5 ± 40.8 pg·mL-1; P = 0.2). The magnitude by which I/R injury attenuated endothelium-dependent vasodilation did not differ between men (pre-I/R 5.4 ± 2.4% vs. post-I/R 3.0 ± 2.7%) and women (pre-I/R 6.1 ± 2.8% vs. post-I/R 3.7 ± 2.7%; P = 0.9). Our data demonstrate that I/R injury similarly reduces endothelial function in women in the early follicular phase of the menstrual cycle and age-matched men with similar estradiol concentrations.


Asunto(s)
Brazo/irrigación sanguínea , Arteria Braquial/fisiopatología , Endotelio Vascular/fisiopatología , Estradiol/sangre , Fase Folicular/sangre , Daño por Reperfusión/fisiopatología , Vasodilatación , Adulto , Arteria Braquial/diagnóstico por imagen , Femenino , Humanos , Masculino , Daño por Reperfusión/sangre , Daño por Reperfusión/diagnóstico por imagen , Factores Sexuales , Adulto Joven
9.
BMC Nephrol ; 22(1): 266, 2021 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-34271871

RESUMEN

BACKGROUND: To investigate if remote ischemic preconditioning (RIPC) can offer any renoprotective value by counteracting the deleterious effect of partial nephrectomy (PN) under warm ischemia on renal function. METHODS: Four groups, each with 5 Wistar albino rats, were constructed; RIPC + PN, PN, RIPC and sham. Right nephrectomy was performed to constitute a solitary kidney model. RIPC denoted sequential clamping/declamping of the femoral artery/vein complex. PN was performed under warm-ischemia following RIPC. Blood samples were collected on multiple occasions until euthanasia on day 7. Immunoassays were conducted to measure the serum and tissues levels of kidney injury markers. Kidneys were examined histologically and morphometric analyzes were performed using digital scanning. RESULTS: IL-33 levels did not differ significantly between the groups. Serum levels of KIM-1, NGAL, and aldose reductase in RIPC + PN, PN and RIPC groups were significantly lower than that of sham group. Tissue biomarker levels were similar across groups. The observed trend in mean necrosis area of PN group was higher than that of RIPC + PN group (p > 0.05). The transitional zone between necrosis and healthy tissue showed a trend towards increasing width in the rats subjected to RIPC before PN vs. those who underwent PN without RIPC (p > 0.05). CONCLUSION: RIPC failed to counteract the renal functional consequences of PN under warm ischemia in a solitary kidney animal model. The supportive but marginal histological findings in favor of RIPC's renoprotective potential were not supplemented with the changes in serum and tissue biomarker levels.


Asunto(s)
Moléculas de Adhesión Celular/análisis , Precondicionamiento Isquémico/métodos , Riñón , Lipocalina 2/análisis , Nefrectomía , Daño por Reperfusión , Aldehído Reductasa/análisis , Animales , Biomarcadores/análisis , Modelos Animales de Enfermedad , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Pruebas de Función Renal , Nefrectomía/efectos adversos , Nefrectomía/métodos , Ratas , Ratas Wistar , Daño por Reperfusión/sangre , Daño por Reperfusión/etiología , Daño por Reperfusión/patología , Resultado del Tratamiento , Isquemia Tibia/métodos
10.
Theranostics ; 11(14): 6922-6935, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34093862

RESUMEN

Rationale: Early diagnosis of hepatic ischemia-reperfusion injury (HIRI), the major cause of early allograft dysfunction or primary non-function, is critical in orthotopic liver transplantation. However, liver biopsy is still the primary method for HIRI evaluation in clinical practice despite its numerous complications and shortcomings such as hemorrhage and inaccuracy. Herein, we aimed to develop a non-invasive, highly accurate, and specific method for detecting HIRI. Methods: We developed a top-down and bottom-up strategy to fabricate neutrophil biomimetic microbubbles (MBneu). Neutrophil membrane was mixed with liposomes at a defined mass ratio by sonication. The air in the vial was exchanged with perfluoropropane, and then the solution was mechanically vibrated to form MBneu. Results: MBneu retained the neutrophil proteins, preferentially targeted inflamed hepatic tissue in a rat model of HIRI, and demonstrated physicochemical properties typical of liposome-based MBs because of its artificial phospholipid content. With MBneu we can quantitively evaluate the severity of HIRI, which is helpful for early diagnosis and the prediction of outcome. In addition, MBneu was shown to be safe and showed no immunogenicity. Conclusion: We demonstrated molecular ultrasound imaging of HIRI with MBneu. This new synthesis strategy may be applied to different clinical scenarios using other cell types in the future.


Asunto(s)
Hígado/diagnóstico por imagen , Neutrófilos/metabolismo , Daño por Reperfusión/diagnóstico por imagen , Daño por Reperfusión/diagnóstico , Ultrasonografía/métodos , Animales , Biomimética , Liposomas , Hígado/metabolismo , Hígado/patología , Masculino , Microburbujas , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/sangre
11.
Cytokine ; 146: 155626, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34157522

RESUMEN

BACKGROUND: Ischemic stroke is caused by a sudden neurological defect following a vascular occlusion and elicits a local and systemic inflammation in brain tissue. Interleukin-38 is an anti-inflammatory cytokine associated with ischemic and inflammatory diseases. This study was designed to analyze the effect of tPA therapy on interleukin-38 serum level changes and the serum level of IL-38 in the prognosis of ischemic stroke patients in the next three months. METHODS: We enrolled 29 ischemic stroke patients confirmed by a neurologist based on radiologic and clinical manifestation between 2019 September to 2020 February. The patients who had NIHSS more than 6 with no underlying inflammatory diseases were selected for tPA therapy. On admission and 24 h after tPA therapy, the IL-38 serum level was measured by ELISA kit. RESULTS: The results showed that serum levels of IL-38 were significantly increased after tPA therapy (P < 0.001). A remarkable relationship was observed between the modified Rankin Score (mRS) and IL-38 serum changes in response to tPA therapy (P < 0.001). Besides, IL-38 serum changes following tPA were dramatically related to NIHSS at hospitalization (P = 0.007). Also, our analysis posed a positive relation between NIHSS at hospitalization and mRs criteria (P = 0.023). No notable relation has been observed between IL-38 serum levels before and after tPA and mRs (P = 0.601 and P = 0.074, respectively). Furthermore, there was no evidence for the relation between NIHSS at hospitalization and IL-38 levels before and after tPA (P = 0.457 and P = 0.105, respectively). CONCLUSION: The results indicate that tPA could meaningfully increase the IL-38 serum level. Also, a negative correlation has been found between IL-38 serum changes in response to tPA and mRS. Since the lower changes in IL-38 serum level result in a poorer prognosis, we conclude that IL-38 serum changes might be a novel early predictor factor for ischemic stroke prognosis.


Asunto(s)
Isquemia Encefálica/sangre , Interleucinas/sangre , Accidente Cerebrovascular Isquémico/sangre , Anciano , Isquemia Encefálica/complicaciones , Femenino , Humanos , Accidente Cerebrovascular Isquémico/complicaciones , Masculino , Pronóstico , Daño por Reperfusión/sangre , Daño por Reperfusión/complicaciones
12.
Gastroenterol Hepatol ; 44(10): 687-695, 2021 Dec.
Artículo en Inglés, Español | MEDLINE | ID: mdl-34023468

RESUMEN

BACKGROUND: Ischemic type biliary lesions (ITBLs), a particular subset of non-anastomotic biliary strictures (NAS), are characterized by intra and extrahepatic strictures that occur in the absence of either hepatic artery thrombosis or stenosis. When they occur within the first year after liver transplantation their development is mostly related to ischemia-reperfusion injury (IRI). The indocyanine green plasma disappearance rate (ICG-PDR) might be able to predict the probability of IRI-induced graft damage after liver transplantation. OBJECTIVE: Our aim was to evaluate the association between ICG-PDR and the occurrence of ITBLs. Secondly, we searched for evidence of IRI in patients presenting ITBLs. METHODS: This retrospective single-center observational study assessed a cohort of 60 liver transplant patients. Each patient underwent ICG-PDR on the 1st postoperative day. ITBLs were identified by means of either cholangiography or magnetic resonance imaging evidence of a deformity and narrowing of the biliary tree in the absence of hepatic artery thrombosis/stenosis. RESULTS: ITBLs were discovered in 10 patients out of 60 liver recipients (16.67%) within one year after transplantation. A low ICG-PDR value was found to be a significant predictive factor for ITBL development, with an OR of 0.87 and a 95% CI of 0.77-0.97. Liver biopsies were performed in 56 patients presenting unexplained abnormal liver function test results. A statistically significant association was found between the development of ITBLs and anatomopathological evidence of IRI. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: The findings from this study show a relationship between low ICG-PDR values on first post-operative-day and the occurrence of ITBLs within 1 year after transplantation.


Asunto(s)
Sistema Biliar/irrigación sanguínea , Colorantes/farmacocinética , Verde de Indocianina/farmacocinética , Trasplante de Hígado/métodos , Complicaciones Posoperatorias/diagnóstico por imagen , Daño por Reperfusión/diagnóstico por imagen , Constricción Patológica/sangre , Constricción Patológica/diagnóstico por imagen , Femenino , Humanos , Inmunosupresores/uso terapéutico , Isquemia/complicaciones , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/sangre , Daño por Reperfusión/sangre , Espectrofotometría , Esteroides/uso terapéutico , Factores de Tiempo
13.
PLoS One ; 16(5): e0251474, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34003831

RESUMEN

The dissection of the veins is the trickiest step of Uterine transplantation (UTx). Performing the anastomosis of a single uterine vein could bring a therapeutic benefit and simplification of surgery and serve for managing unilateral venous thromboses. The objectives of this project were to evaluate the expression of early markers of ischemia-reperfusion and to compare findings following one or two vein anastomoses. Orthotopic uterine auto-transplantations were performed on an ovine model with anastomosis of either two (group 1) or one utero-ovarian veins (group 2). Blood gases, histology and ischemia- reperfusion markers transcripts (PTGS2, IL6, IL8, SOD2, C3, BAX/BCL2 and TLR4) were analyzed as well as PTGS2 protein expression using Western Blot and fluorescence immunolocalization on endometrial biopsies after 3h of reperfusion. Ten ewes were included in the experimentation, 4 were in group1, 3 in group 2, the others being sham operated controls. No significant differences were observed between the two phenotypes. Based on these results, the anastomosis of one single uterine vein appears to be an approach consistent with short-term graft survival. Further experiments will be needed to confirm the reliability of this approach, especially the long-term follow-up of the uterine graft including its ability to support gestation to term.


Asunto(s)
Útero/trasplante , Anastomosis Quirúrgica , Animales , Endometrio/metabolismo , Femenino , Daño por Reperfusión/sangre , Daño por Reperfusión/diagnóstico , Daño por Reperfusión/genética , Ovinos , Transcriptoma , Útero/irrigación sanguínea
14.
Biomed Pharmacother ; 140: 111686, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34015581

RESUMEN

OBJECTIVES: The present study examined the effects of ferulic acid (FA) and Zinc oxide nanoparticles (ZnO-NPs) and a combination of both on renal ischemia/reperfusion injury (IRI) in rats and their possible underlying mechanisms. METHODS: two-hundreds male Sprague Dawley rats were randomly allocated into the 5 groups; i) sham group, ii) control (IRI) group (occlusion of the left renal pedicle for 45 min), iii) FA group as IRI group with FA (100 mg/Kg oral 24 hrs before ischemia), iv) ZnO-NPs group as IRI group with ZnO-NPs single 5 mg/Kg i.p. 2 hrs before ischemia and v) FA + ZnO-NPs group as IRI group with both FA and ZnO-NPs in the same previous doses. According to the reperfusion times, each group was further subdivided into 4 hr, 24 hr, 48 hr and 7 days reperfusion subgroups. RESULTS: administration of either FA or ZnO-NPs caused significant improvement in the elevated serum creatinine and BUN and malondialdehyde (MDA) concentrations and expression of TNF-α, Bax, caspase-3 in kidney tissues with significant rise in the creatinine clearance, the activities of catalase (CAT) and superoxide dismutase (SOD) and the expression of HO-1, HIF-1α genes and proliferation marker (ki67) in kidney tissues compared to IRI group (p < 0.05). Moreover, a combination of both agents produced more significant improvement in the studied parameters than each agent did alone (p < 0.05). CONCLUSIONS: Both FA and ZnO-NPs exerted cytoprotective effects against ischemic kidney injury and a combination of both exhibited more powerful renoprotective effect. This renoprotective effect might be due to suppression of oxidative stress, enhancement of cell proliferation (ki67), upregulation of antioxidant genes (Nrf2, HO-1 and HIF-1α) and downregulation of inflammatory cytokine (TNF-α) and apoptotic genes (caspase-3 and Bax).


Asunto(s)
Ácidos Cumáricos/farmacología , Enfermedades Renales/tratamiento farmacológico , Nanopartículas/administración & dosificación , Daño por Reperfusión/tratamiento farmacológico , Óxido de Zinc/farmacología , Animales , Antioxidantes/metabolismo , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Riñón/efectos de los fármacos , Riñón/metabolismo , Enfermedades Renales/sangre , Enfermedades Renales/metabolismo , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/sangre , Superóxido Dismutasa/metabolismo
15.
Aging (Albany NY) ; 13(8): 11877-11888, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33893248

RESUMEN

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) can cause brain tissue inflammation, neuronal degeneration, and apoptosis. There is increasing evidence that microRNAs (miRNA) exert neuroprotective effects by regulating the inflammatory process during cerebral ischemia-reperfusion injury. Additionally, it is increasingly acknowledged that neuroinflammation is regulated by Toll-like receptor 4 (TLR4). However, it is unclear whether miRNA can exert its neuroprotective effects by regulating TLR4-mediated inflammation. METHODS: The effects of BMSCs over-expressing miR-202-3p on CIRI, angiogenesis in midbrain tissue, and the release of inflammatory factors (IFs) in the serum were measured using in vivo rat models. We also used SH-SY5Y cells to establish an ischemia-reperfusion in vitro cell model. The interaction between miR-202-3p and TLR4 was analyzed by overexpressing miR-202-3p and knocking down TLR4. Knockdown of TLR4 was performed using siRNA. RESULTS: Overexpression of miR-202-3p in BMSCs could significantly improve brain function and reduce brain damage. Simultaneously, miR-202-3p could significantly promote angiogenesis, increase the expression of vWF and VEGF, and reduce the expression of IFs. When the expression of TLR4 was significantly reduced in SH-SY5Y cells, the expression of IFs increased. Therefore, miRNA-202-3p may interact with TLR4 to modulate inflammation. CONCLUSION: Our data indicated that miR-202-3p potentially exerts its neuroprotective effects and protects against CIRI by regulating TLR4-mediated inflammation.


Asunto(s)
Isquemia Encefálica/terapia , Trasplante de Células Madre Mesenquimatosas , Neovascularización Fisiológica/genética , Daño por Reperfusión/prevención & control , Animales , Apoptosis/genética , Isquemia Encefálica/sangre , Isquemia Encefálica/complicaciones , Isquemia Encefálica/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Vectores Genéticos/genética , Humanos , Inflamación/sangre , Inflamación/genética , Inflamación/inmunología , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Lentivirus/genética , Masculino , Mesencéfalo/irrigación sanguínea , Mesencéfalo/inmunología , Mesencéfalo/patología , Células Madre Mesenquimatosas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Cultivo Primario de Células , Ratas , Daño por Reperfusión/sangre , Daño por Reperfusión/inmunología , Daño por Reperfusión/patología , Receptor Toll-Like 4/genética , Transfección
16.
Biochem Biophys Res Commun ; 557: 166-173, 2021 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-33865225

RESUMEN

BACKGROUND: Renal ischemia reperfusion injury (IRI) has become a growing concern in clinical practice with high morbidity and mortality rates. There is currently no effective prophylactic regimen available to prevent its occurrence and to improve its clinical prognosis. Dl-3-n-butylphthalide (NBP) has been used for stroke treatment in China for years. Little is known about its role in preventing kidney injury. METHODS: The kidneys of male C57BL/6J mice were subjected to 33 min of ischemia followed by 24 h of reperfusion. NBP was administered by gavage prior to surgery. The reno-protective effect of NBP was evaluated by serum creatinine, kidney injury markers and renal pathological changes. Furthermore, the inflammation, oxidative stress, and apoptosis markers in kidney tissue were examined. In vitro, HK2 cells were treated prophylactically with NBP and then exposed to hypoxia/reoxygenation (H/R). Cell viability and apoptosis related protein were quantified to verify the protective effect of NBP. Pro-inflammation genes expression as well as ROS generation were further investigated also. RESULTS: NBP pretreatment significantly improved renal dysfunction and alleviated pathological injury, renal inflammation response, oxidative stress and cell apoptosis. Consistently, NBP attenuated H/R induced increases in ROS, pro-inflammatory genes expression, apoptosis and cleaved caspase-3 levels in HK2 cells. CONCLUSION: Our promising results validated for the first time that NBP could ameliorate renal IRI via attenuating inflammation, oxidative stress, and apoptosis, which indicated that NBP might be a good candidate against AKI.


Asunto(s)
Apoptosis/efectos de los fármacos , Benzofuranos/farmacología , Riñón/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Animales , Benzofuranos/administración & dosificación , Caspasa 3/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Creatinina/sangre , Modelos Animales de Enfermedad , Inmunohistoquímica , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Daño por Reperfusión/sangre , Daño por Reperfusión/genética , Daño por Reperfusión/patología
17.
Neurosci Lett ; 754: 135885, 2021 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-33862142

RESUMEN

Brain edema is a major cause of death in patients who suffer an ischemic stroke. Diabetes has been shown to aggravate brain edema after cerebral ischemia-reperfusion, but few studies have focused on the heterogeneity of this response across different brain regions. Aquaporin 4 plays an important role in the formation and regression of brain edema. Here, we report that hyperglycemia mainly affects the continuity of aquaporin 4 distribution around blood vessels in the cortical penumbra after ischemia-reperfusion; however, in the striatal penumbra, in addition to affecting the continuity of distribution, it also substantially affects the fluorescence intensity and the polarity distribution in astrocytes. Accordingly, hyperglycemia induces a more significant increase in the number of swelling cells in the striatal penumbra than in the cortical penumbra. These results can improve our understanding of the mechanism underlying the effects of diabetes in cerebral ischemic injury and provide a theoretical foundation for identification of appropriate therapeutic modalities.


Asunto(s)
Acuaporina 4/metabolismo , Edema Encefálico/patología , Hiperglucemia/complicaciones , Infarto de la Arteria Cerebral Media/complicaciones , Daño por Reperfusión/patología , Animales , Acuaporina 4/análisis , Edema Encefálico/sangre , Edema Encefálico/etiología , Corteza Cerebral/patología , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Humanos , Hiperglucemia/sangre , Hiperglucemia/inducido químicamente , Infarto de la Arteria Cerebral Media/sangre , Infarto de la Arteria Cerebral Media/patología , Masculino , Neostriado/patología , Ratas , Daño por Reperfusión/sangre , Daño por Reperfusión/etiología , Estreptozocina/administración & dosificación , Estreptozocina/toxicidad
18.
Sci Rep ; 11(1): 7953, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846468

RESUMEN

The molecular mechanism for acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) continues to be unclear. In this study, we investigated the pathophysiological role of the acute phase protein α1-acid glycoprotein (AGP) in AKI and its progression to CKD using AGP KO mice. Plasma AGP levels in WT mice were increased by about 3.5-fold on day 1-2 after renal ischemia-reperfusion (IR), and these values then gradually decreased to the level before renal IR on day 7-14. On day 1 after renal IR, the AGP KO showed higher renal dysfunction, tubular injury and renal inflammation as compared with WT. On day 14, renal function, tubular injury and renal inflammation in WT had recovered, but the recovery was delayed, and renal fibrosis continued to progress in AGP KO. These results obtained from AGP KO were rescued by the administration of human-derived AGP (hAGP) simultaneously with renal IR. In vitro experiments using RAW264.7 cells showed hAGP treatment suppressed the LPS-induced macrophage inflammatory response. These data suggest that endogenously induced AGP in early renal IR functions as a renoprotective molecule via its anti-inflammatory action. Thus, AGP represents a potential target molecule for therapeutic development in AKI and its progression CKD.


Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Antiinflamatorios/uso terapéutico , Progresión de la Enfermedad , Insuficiencia Renal Crónica/tratamiento farmacológico , alfa-Macroglobulinas/uso terapéutico , Lesión Renal Aguda/sangre , Lesión Renal Aguda/complicaciones , Animales , Antiinflamatorios/farmacología , Humanos , Inflamación/sangre , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiopatología , Pruebas de Función Renal , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células RAW 264.7 , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/patología , Daño por Reperfusión/sangre , alfa-Macroglobulinas/administración & dosificación , alfa-Macroglobulinas/farmacología
19.
Mol Med ; 27(1): 18, 2021 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-33632134

RESUMEN

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury can be a major complication following liver surgery contributing to post-operative liver dysfunction. Maresin 1 (MaR1), a pro-resolving lipid mediator, has been shown to suppress I/R injury. However, the mechanisms that account for the protective effects of MaR1 in I/R injury remain unknown. METHODS: WT (C57BL/6J) mice were subjected to partial hepatic warm ischemia for 60mins followed by reperfusion. Mice were treated with MaR1 (5-20 ng/mouse), Boc2 (Lipoxin A4 receptor antagonist), LY294002 (Akt inhibitor) or corresponding controls just prior to liver I/R or at the beginning of reperfusion. Blood and liver samples were collected at 6 h post-reperfusion. Serum aminotransferase, histopathologic changes, inflammatory cytokines, and oxidative stress were analyzed to evaluate liver injury. Signaling pathways were also investigated in vitro using primary mouse hepatocyte (HC) cultures to identify underlying mechanisms for MaR1 in liver I/R injury. RESULTS: MaR1 treatment significantly reduced ALT and AST levels, diminished necrotic areas, suppressed inflammatory responses, attenuated oxidative stress and decreased hepatocyte apoptosis in liver after I/R. Akt signaling was significantly increased in the MaR1-treated liver I/R group compared with controls. The protective effect of MaR1 was abrogated by pretreatment with Boc2, which together with MaR1-induced Akt activation. MaR1-mediated liver protection was reversed by inhibition of Akt. CONCLUSIONS: MaR1 protects the liver against hepatic I/R injury via an ALXR/Akt signaling pathway. MaR1 may represent a novel therapeutic agent to mitigate the detrimental effects of I/R-induced liver injury.


Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Hepatopatías/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Formil Péptido/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Supervivencia Celular/efectos de los fármacos , Citocinas/sangre , Ácidos Docosahexaenoicos/farmacología , Glutatión Peroxidasa/metabolismo , Hepatocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hepatopatías/sangre , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Malondialdehído/metabolismo , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Receptores de Formil Péptido/genética , Daño por Reperfusión/sangre , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos
20.
J Cardiovasc Transl Res ; 14(2): 338-347, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-32681452

RESUMEN

Previous experiments demonstrated improved outcome following prolonged cerebral ischemia given controlled brain reperfusion using extracorporeal circulation. The current study further investigates this. Young adult pigs were exposed to 30 min of global normothermic cerebral ischemia, achieved through intrathoracic clamping of cerebral arteries, followed by 20 min of isolated mechanical brain reperfusion. Leukocyte-filtered blood was delivered by a roller-pump at fixed pressure and flow. One experimental group additionally had a custom-made buffer solution delivered at 1:8 ratio with the blood. Hemodynamics including intracranial pressure were monitored. Blood gases were from peripheral arteries and the sagittal sinus, and intraparenchymal brain microdialysis was performed. The brains were examined by a neuropathologist. The group with the added buffer showed lower intracranial pressure as well as decreased intraparenchymal glycerol and less signs of excitotoxicity and ischemia, although histology revealed similar degrees of injury. A customized mechanical reperfusion improves multiple parameters after prolonged normothermic global cerebral ischemia. Graphical Abstract The current study investigates if it possible to improve neurological outcomes following prolonged global brain ischemia. The results indicate that a customized mechanical reperfusion protocol can attenuate neurological injury.


Asunto(s)
Transfusión Sanguínea , Lesiones Encefálicas/prevención & control , Isquemia Encefálica/terapia , Encéfalo/irrigación sanguínea , Procedimientos de Reducción del Leucocitos , Daño por Reperfusión/prevención & control , Reperfusión , Animales , Encéfalo/patología , Lesiones Encefálicas/sangre , Lesiones Encefálicas/etiología , Lesiones Encefálicas/fisiopatología , Isquemia Encefálica/sangre , Isquemia Encefálica/fisiopatología , Circulación Cerebrovascular , Modelos Animales de Enfermedad , Hemodinámica , Reperfusión/efectos adversos , Daño por Reperfusión/sangre , Daño por Reperfusión/etiología , Daño por Reperfusión/fisiopatología , Sus scrofa , Factores de Tiempo
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