Puerarin protects the fatty liver from ischemia-reperfusion injury by regulating the PI3K/AKT signaling pathway

Abstract The incidence of non-alcoholic fatty liver (NAFLD) remains high, and many NAFLD patients suffer from severe ischemia-reperfusion injury (IRI). Currently, no practical approach can be used to treat IRI. Puerarin plays a vital role in treating multiple diseases, such as NAFLD, stroke, diabetes, and high blood pressure. However, its role in the IRI of the fatty liver is still unclear. We aimed to explore whether puerarin could protect the fatty liver from IRI. C57BL/6J mice were fed with a high‐fat diet (HFD) followed by ischemia reperfusion injury. We showed that hepatic IRI was more severe in the fatty liver compared with the normal liver, and puerarin could significantly protect the fatty liver against IRI and alleviate oxidative stress. The PI3K-AKT signaling pathway was activated during IRI, while liver steatosis decreased the level of activation. Puerarin significantly protected the fatty liver from IRI by reactivating the PI3K-AKT signaling pathway. However, LY294002, a PI3K-AKT inhibitor, attenuated the protective effect of puerarin. In conclusion, puerarin could significantly protect the fatty liver against IRI by activating the PI3K-AKT signaling pathway.

Breviscapine alleviates myocardial ischemia-reperfusion injury in diabetes rats

Purpose: To investigate the protective effect of breviscapine on myocardial ischemia-reperfusion injury (MIRI) in diabetes rats. Methods: Forty rats were divided into control, diabetes, MIRI of diabetes, and treatment groups. The MIRI of diabetes model was established in the latter two groups. Then, the treatment group was treated with 100 mg/kg breviscapine by intraperitoneal injection for 14 consecutive days. Results: After treatment, compared with MIRI of diabetes group, in treatment group the serum fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance, and glycosylated hemoglobin levels decreased, the serum total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol levels decreased, the serum high-density lipoprotein cholesterol level increased, the heart rate decreased, the mean arterial pressure, left ventricular ejection fraction, and fractional shortening increased, the serum cardiac troponin I, and creatine kinase-MB levels decreased, the myocardial tumor necrosis factor α and interleukin-6 levels decreased, the myocardial superoxide dismutase level increased, and the myocardial malondialdehyde level decreased (all P < 0.05). Conclusions: For treating MIRI of diabetes in rats, the breviscapine can reduce the blood glucose and lipid levels, improve the cardiac function, reduce the myocardial injury, and decrease the inflammatory response and oxidative stress, thus exerting the alleviating effect.

Identification of potential crucial cuproptosis-related genes in myocardial ischemia-reperfusion injury through the bioinformatic analysis

Abstract Background: Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains unclear. Methods: For this purpose, the MI/RI microarray datasets GSE61592 were downloaded from the Gene Expression Omnibus (GEO) database, and the Differently Expressed Genes (DEGs) in MI/RI were identified using R software. Moreover, the MI/RI mice model was established to confirm further the diagnostic value of Pyruvate Dehydrogenase B (Pdhb), Dihydrolipoamide S-acetyltransferase (Dlat), and Pyruvate dehydrogenase E1 subunit alpha 1 (Pdhα1). Results: The analysis of microarray datasets GSE61592 revealed that 798 genes were upregulated and 768 were downregulated in the myocardial tissue of the ischemia-reperfusion injury mice. Furthermore, Dlat, Pdhb, Pdhα1, and cuproptosis-related genes belonged to the downregulated genes. The receiver operating characteristics curve analysis results indicated that the Dlat, Pdhb, and Pdhα1 levels were downregulated in MI/RI and were found to be potential biomarkers for MI/RI diagnosis and prognosis. Similarly, analysis of Dlat, Pdhb, and Pdhα1 levels in the MI/RI mice revealed Pdhb being the key diagnostic marker. Conclusions: This study demonstrated the prognostic value of cuproptosis-related genes (Dlat, Pdhb, and Pdhα1), especially Pdhb, MI/RI, providing new insight into the MI/RI treatment.

Precondicionamiento isquémico remoto: bases de la protección y resultados clínicos / Remote ischemic preconditioning: Bases and clinical results

El precondicionamiento isquémico remoto es una manera eficaz de disminuir el daño por isquemia y reperfusión en el corazón y otros órganos como cerebro o riñón, en modelos experimentales. Este consiste en realizar entre 3 y 5 ciclos de 5 minutos de isquemia seguidos del mismo tiempo de reperfusión, en un tejido alejado del que se quiere proteger, normalmente una extremidad. Estudios preclínicos en animales indican que la isquemia precondicionante inicia señales nerviosas y humorales en el tejido isquémico remoto, que en el corazón activan mecanismos de protección. La señal nerviosa se origina en fibras sensoriales que a nivel cerebral producen una activación del sistema parasimpático. El nervio vago activa ganglios cardíacos intrínsecos del corazón lo que induce protección. Además, desde el tejido isquémico se liberan a la circulación diferentes mediadores que viajan en forma libre o en vesículas lipídicas (exosomas) que inician vías de señalización protectoras en el corazón. A pesar del éxito del precondicionamiento isquémico remoto en animales de experimentación, su aplicación en seres humanos no ha tenido resultados claros. Esta discrepancia puede deberse a una diversidad de factores tales como la edad, la existencia de otras patologías, uso de fármacos u otros tratamientos que afectan la respuesta de los pacientes. Se requiere un mayor conocimiento de las bases moleculares de este mecanismo de protección para que su aplicación en clínica sea exitosa.

In experimental models, remote ischemic preconditioning effectively decreases ischemia reperfusion injury to the heart and other organs such as the brain or kidney. It consists of 3 to 5 cycles of 5 minutes of ischemia followed by 5 minutes of reperfusion, in a remote tissue, usually a limb. Preclinical studies in animals indicate that preconditioning ischemia initiates neural and humoral signals in the remote ischemic tissue, which activate protective mechanisms in the heart. The nervous signal originates in sensory fibers that activate the parasympathetic system in the brain. The vagus nerve activates the intrinsic cardiac ganglia of the heart, leading to protection from ischemic injury. Furthermore, mediators are released from the ischemic tissue into the circulation that travels freely or in lipid vesicles (exosomes) to the heart where they initiate protective signaling pathways. Despite the success of remote ischemic preconditioning in experimental animals, its application in humans has not produced clear results. This discrepancy may be due to a variety of factors such as age, the existence of other pathologic processes, or the use of drugs or other treatments that affect the patient´s response. An increased knowledge of the molecular bases of this protective mechanism is required for its clinical application to be successful.

Vitamin A could be a Therapeutic Agent in Ischemia/Reperfusion Induced Kidney Injury / La vitamina A podría ser un agente terapéutico en la lesión renal inducida por isquemia/reperfusión

ABSTRACT Introduction: Renal ischemia (I) could develop due to decreased or ceased blood flow to the kidney in some clinical conditions such as shock, sepsis, and kidney transplantation. The re-supply of blood to the kidney is called reperfusion (R). Ischemia and reperfusion periods can cause severe kidney damage. Objectives: When we examined the I/R molecular progression, antioxidant molecules such as vitamin A seem promising treatment agents. This study aimed to investigate the effects of vitamin A on renal I/R injury. Material and Methods: In the study, 40 Sprague-Dawley male rats were divided into five groups (n=8): the control group, only I/R, I/R+1000, I/R+3000, and I/R+9000 IU/kg of Vitamin A groups. Vitamin A was administrated to each group for seven days via oral gavage. Blood and kidney tissue samples were collected at the end of the experiment. We took blood samples for Superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), blood urea nitrogen (BUN), and creatinine (Cr) levels, and determined their values. The tissue samples were stained with hematoxylin/eosin to examine the renal changes histopathologically and stereologically under a light microscope. Results: Histopathological changes caused by I/R were decreased with vitamin A administration in a dose-dependent manner (p<0.05). Vitamin A administration decreased MDA levels and increased SOD and CAT activities (p<0.05). The most effective dose among treatment groups was 9000 IU/kg. There was no significant difference between the controls and all other groups regarding BUN and Cr concentrations. Conclusions: Consequently, administration of vitamin A after renal I/R reduced the histological damage and ameliorated the antioxidant state. These results showed that vitamin A could be a promising agent in treating I/R-induced acute kidney injury.

RESUMEN Introducción: La isquemia renal (I) puede desarrollarse debido a la disminución o interrupción del flujo sanguíneo al riñón en algunas condiciones clínicas como shock, sepsis y trasplante renal. El reabastecimiento de sangre al riñón se denomina reperfusión (R). Tanto la isquemia como los períodos de reperfusión pueden causar graves daños renales. Objetivos: Cuando examinamos la progresión molecular I/R, las moléculas antioxidantes como la vitamina A parecen agentes de tratamiento prometedores. El objetivo de este estudio fue investigar los efectos de la vitamina A sobre la lesión renal I/R. Material y Métodos: En el estudio, 40 ratas macho Sprague-Dawley se dividieron en 5 grupos (n=8) como: control, solo I/R, I/R+1000, I/R+3000 e I/R+9000 UI/kg de la Vitamina A. La vitamina A se administró a cada grupo durante 7 días por vía oral forzada. Al final del experimento se recolectaron muestras de sangre y tejido del riñón. A partir de muestras de sangre se determinaron los niveles de superóxido dismutasa (SOD), malondialdehído (MDA), catalasa (CAT), nitrógeno ureico en sangre (BUN) y creatinina (Cr). Las muestras de tejido se tiñeron con hematoxilina/eosina y los cambios en la histología renal se examinaron histopatológicamente y estereológicamente al microscopio de luz. Resultados: Los cambios histopatológicos causados por I/R disminuyeron con la administración de la vitamina A de manera dependiente de la dosis (p<0,05). La administración de la vitamina A disminuyó los niveles de MDA, aumentó las actividades de SOD y CAT (p<0,05). La dosis más eficaz entre los grupos del tratamiento fue de 9000 UI/kg. No hubo una diferencia significativa entre el grupo control y todos los demás grupos con respecto a las concentraciones de BUN y Cr. Conclusiones: Consiguientemente, la administración de la vitamina A, después de I/R renal, redujo el daño histológico y mejoró el estado antioxidante. Estos resultados mostraron que la vitamina A puede ser un agente promisorio en el tratamiento de la lesión renal aguda (LRA) inducida por I/R.

Comparison of Lower and Upper Limb Remote Ischemic Preconditioning to Prevent Contrast-Induced Nephropathy: A Randomized Pilot Study with a Control Group / Comparación del preacondicionamiento isquémico remoto de la extremidad inferior y superior para evitar la nefropatía inducida por el contraste: Un estudio piloto aleatorizado con un grupo de control

ABSTRACT Background: The role of remote ischemic preconditioning (RIPC) in preventing the development of contrast-induced nephropathy (CIN) and whether there is a difference between the results of applications of RIPC to the upper or lower extremities has not been adequately demonstrated. Methods: We included the patients who underwent coronary angiography due to stable angina pectoris in this single center, randomized, pilot study. We randomly enrolled a total of 168 patients in one of three groups (60 patients in the upper limb RIPC group, 58 patients in the lower limb RIPC group, and 50 patients in the control group). Results: According to the Acute Kidney Injury Network (AKIN), CIN did not develop in any RIPC patients and developed in 6% of controls (OR: 3.511, 95% CI: 2.757-4.471, p=0.025). According to the European Society of Urogenital Radiology (ESUR) guidelines, CIN developed in 1.7% of RIPC patients and 8% of controls (p=0.065). It was found that creatinine levels increased in the control group and decreased in the RIPC groups (baseline: 0.81±0.19mg/dL and 0.86±0.25mg/dL and control: 0.76±0.17mg/dL and 0.91±0.36mg/ dL, p <0.001). When the upper and lower limb RIPC results were compared, there was no statistically significant difference in the incidence of CIN. In multivariate analyses we found out that baseline eGFR, baseline mean blood pressure, contrast agent volume, and RIPC were independently associated with the development of CIN. Conclusions: RIPC is a practically useful method in preventing CIN in patients undergoing coronary angiography. Upper or lower-limb RIPC applications seem to have a similar effect.

RESUMEN No se ha demostrado adecuadamente el papel del preacondicionamiento isquémico remoto (RIPC) en la prevención del desarrollo de nefropatía inducida por contraste (NIC) y si existe una diferencia entre los resultados de las aplicaciones de RIPC en las extremidades superiores o inferiores. Se incluyó a los pacientes sometidos a coronariografía por angina de pecho estable en este estudio piloto, aleatorizado, unicéntrico. Inscribimos al azar a un total de 168 pacientes en uno de los tres grupos (60 pacientes en el grupo de RIPC de miembros superiores, 58 pacientes en el grupo de RIPC de miembros inferiores, 50 pacientes en el grupo de control). De acuerdo con la Acute Kidney Injury Network (AKIN), NIC no se desarrolló en ningún paciente con RIPC y se desarrolló en el 6% de los controles (OR: 3,511, IC del 95%: 2,757-4,471, p = 0,025). Según las directrices de la Sociedad Europea de Radiología Urogenital (ESUR), la NIC se desarrolló en el 1,7% de los pacientes con RIPC y en el 8% de los controles (p = 0,065). Se encontró que los niveles de creatinina aumentaron en el grupo de control y disminuyeron en los grupos de RIPC (línea de base: 0,81 ± 0,19 mg / dL y 0,86 ± 0,25 mg / dL y control: 0,76 ± 0,17 mg / dL y 0,91 ± 0,36 mg / dL, p <0,001). Cuando se compararon los resultados de RIPC de miembros superiores e inferiores, no hubo diferencias estadísticamente significativas en la incidencia de NIC. En análisis multivariado descubrimos que la TFGe basal, la presión arterial media basal, el volumen del agente de contraste y la RIPC se asociaron de forma independiente con el desarrollo de NIC. La RIPC es un método prácticamente útil en la prevención de NIC en pacientes sometidos a coronariografía. Las aplicaciones de RIPC de miembros superiores o inferiores parecen tener un efecto similar.

Erector Spinae Plane Block. A narrative review / Bloqueo del plano del músculo erector de la espina. Revisión narrativa de la literatura

Abstract The erector spinae plane (ESP) block is an interfascial block described in 2016 by Forero and collaborators, with wide clinical uses and benefits when it comes to analgesic control in different surgeries. This block consists of the application of local anesthetic (LA) in a deep plane over the transverse process, anterior to the erector spinae muscle in the anatomical site where dorsal and ventral branches of the spinal nerve roots are located. This review will cover its clinical uses according to different surgical models, the existing evidence and complications described to date.

Resumen El bloqueo del plano del músculo erector de la espina (ESP, por sus siglas en inglés) es un bloqueo interfascial descrito en 2016 por Forero y colaboradores, con amplios usos clínicos y beneficios en relación con el control analgésico de diferentes modelos quirúrgicos. Este consiste en la aplicación de anestésico local (AL) en un plano profundo sobre apófisis transversa anterior al músculo erector de la espina, sitio anatómico donde se encuentra la bifurcación de los ramos dorsal y ventral de las raíces nerviosas espinales. En esta revisión, se expondrán los usos clínicos según diferentes modelos quirúrgicos, la evidencia que existe de ellos y las complicaciones descritas hasta la actualidad.

Post-cardiac arrest syndrome in adult hospitalized patients / Síndrome posparo cardiaco en pacientes adultos hospitalizados

Abstract Adult In-hospital Cardiac Arrest (IHCA) is defined as the loss of circulation of an in-patient. Following high-quality cardiopulmonary resuscitation (CPR), if the return of spontaneous circulation (ROSC) is achieved, the post-cardiac arrest syndrome develops (PCAS). This review is intended to discuss the current diagnosis and treatment of PCAS. To approach this topic, a bibliography search was conducted through direct digital access to the scientific literature published in English and Spanish between 2014 and 2020, in MedLine, SciELO, Embase and Cochrane. This search resulted in 248 articles from which original articles, systematic reviews, meta-analyses and clinical practice guidelines were selected for a total of 56 documents. The etiologies may be divided into 56% of in-hospital cardiac, and 44% of non-cardiac arrests. The incidence of this physiological collapse is up to 1.6 cases/1,000 patients admitted, and its frequency is higher in the intensive care units (ICU), with an overall survival rate of 13% at one year. The primary components of PCAS are brain injury, myocardial dysfunction and the persistence of the precipitating pathology. The mainstays for managing PCAS are the prevention of cardiac arrest, ventilation support, control of peri-cardiac arrest arrythmias, and interventions to optimize neurologic recovery. A knowledgeable healthcare staff in PCAS results in improved patient survival and future quality of life. Finally, there is clear need to do further research in the Latin American Population.

Resumen El paro cardiaco intrahospitalario en el adulto (IHCA) se define como el cese de circulación ocurrido dentro de las instalaciones hospitalarias. Después de la reanimación cardiopulmonar (RCP) de alta calidad, si se logra el retorno de circulación espontánea (ROSC), aparece entonces el síndrome posparo cardiaco (SPPC). En esta revisión se pretende presentar el estado actual del diagnóstico y tratamiento del SPPC. Para abordar este tema, se realizó una búsqueda bibliográfica mediante la consulta digital directa de la literatura científica publicada entre 2014 y 2020 en inglés y español recogida en las bases de datos MedLine, SciELO, Embase y Cochrane. La búsqueda inicial arrojó 248 artículos, de los cuales se eligieron artículos originales, revisiones sistemáticas, metaanálisis y guías de práctica clínica, para una selección final de 56 documentos. Las etiologías del paro cardiaco intrahospitalario se pueden dividir en cardiacas y no cardiacas, en el 56 % y 44 %, respectivamente. El colapso fisiológico tiene incidencias de hasta 1,6 casos/1.000 pacientes admitidos, y es más frecuente en las unidades de cuidado intensivo (UCI), con una tasa de supervivencia general de 1 año del 13 %. Los componentes principales del SPPC son la lesión cerebral, la disfunción miocárdica y la persistencia de la patología precipitante. Los pilares del manejo del SPPC son la prevención del paro cardiaco, soporte ventilatorio, control de arritmias periparo cardiaco y las intervenciones para optimizar la recuperación neurológica. El conocimiento del SPPC por parte del personal de la salud ofrece mejor sobrevida y futura calidad de vida a los pacientes. Finalmente, se resalta la clara necesidad de ahondar en mayores investigaciones en la población latinoamericana.

The effects of methanol extract of Galium verum L on cardiac redox state in hypertensive rats

Abstract The aim of this study was to assess the effects of methanol extract of G. verum on redox status of isolated heart of spontaneously hypertensive rats after ischemia. Twenty-four Wistar albino rats were divided into three groups: untreated control rats and rats that received 125 and 250 mg/kg G. verum extract for 4 weeks per os. Index of lipid peroxidation (measured as TBARS) and parameters of antioxidative defence system such as level of reduced glutathione (GSH) and activities of catalase (CAT) and superoxide dismutase (SOD) were spectrophotometrically determined in heart homogenate. The index of lipid peroxidation in heart tissue was lower in both treated groups compared to the control group. On the other hand, the activity of SOD was significantly higher after consumption of both doses, while the activity of CAT was significantly higher only after treatment with a higher dose of extract. Based on our results we might conclude that 4-week treatment with methanol extracts of G. verum has the potential to modulate myocardial redox signaling after ischemia, thus significantly alleviating cardiac oxidative stress and exerting dose-dependent antioxidant properties. Future studies are certainly necessary to fully clarify the role of this plant species in myocardial I-R injury.

Dexmedetomidine pretreatment alleviates cerebral ischemia/reperfusion injury by inhibiting neuroinflammation through the JAK2/STAT3 pathway

Dexmedetomidine (DEX) is known to provide neuroprotection against cerebral ischemia and reperfusion injury (CIRI), but the exact mechanisms remain unclear. This study was conducted to investigate whether DEX pretreatment conferred neuroprotection against CIRI by inhibiting neuroinflammation through the JAK2/STAT3 signaling pathway. Middle cerebral artery occlusion (MCAO) was performed to establish a cerebral ischemia/reperfusion (I/R) model. Specific-pathogen-free male Sprague-Dawley rats were randomly divided into Sham, I/R, DEX, DEX+IL-6, and AG490 (a selective inhibitor of JAK2) groups. The Longa score, TTC staining, and HE staining were used to evaluate brain damage. ELISA was used to exam levels of TNF-α. Western blotting was used to assess the levels of JAK2, phosphorylated-JAK2 (p-JAK2), STAT3, and phosphorylated-STAT3 (p-STAT3). Our results suggested that both pretreatment with DEX and AG490 decreased the Longa score and cerebral infarct areas following cerebral I/R. After treatment with IL-6, the effects of DEX on abrogating these pathological changes were reduced. HE staining revealed that I/R-induced neuronal pathological changes were attenuated by DEX application, consistent with the AG490 group. However, these effects of DEX were abolished by IL-6. Furthermore, TNF-α levels were significantly increased in the I/R group, accompanied by an increase in the levels of the p-JAK2 and p-STAT3. DEX and AG490 pretreatment down-regulated the expressions of TNF-α, p-JAK2, and p-STAT3. In contrast, the down-regulation of TNF-α, p-JAK2, and p-STAT3 induced by DEX was reversed by IL-6. Collectively, our results indicated that DEX pretreatment conferred neuroprotection against CIRI by inhibiting neuroinflammation via negatively regulating the JAK2/STAT3 signaling pathway.

Effects of Urtica dioica Seeds on Oxidative/ Nitrosative Stress Levels and Myeloperoxidase Activity in Muscle Ischemia/Reperfusion Injury

Abstract The purpose of this study is to evaluate the preventive effects of Urtica dioica (UD) on muscle ischemia/reperfusion (I/R) injury. A total of 27 male Wistar rats were divided into three groups as the control group (1), I/R + saline group (2), and I/R+UD group (3). Group 1 did not receive any treatment. Group 2 was administered a total of 2mL/kg saline (1mL/kg before ischemia and 1 mL/kg after reperfusion), and group 3 was given a total of 2mL of UD (1mL/kg before ischemia and 1mL/kg after reperfusion) as treatment. Saline and UD were administered via intraesophageal canula once a day for five days. At the end of five days, all the rats were exposed to muscle ischemia for 60 min followed by 60 min of reperfusion of the bilateral hindlimbs induced using a tourniquet. Muscle tissue histopathologies were evaluated by light microscopy. Furthermore, oxidative/nitrosative stress biomarkers such as catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), nitrotyrosine (3-NT), nitric oxide (NO), and myeloperoxidase (MPO) as an inflammatory marker in tissue samples were measured. UD treatment significantly decreased oxidative/nitrosative stress biomarker levels and MPO (p<0.05). We established that UD treatment could alleviate muscle injury induced by muscle I/R in rats by inhibiting the inflammation and oxidative/nitrosative stress

Naringin and trimetazidine improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal ischemia-reperfusion injury / Naringin and trimetazidine improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal ischemia-reperfusion injury

Resumo Fundamento: O núcleo do trato solitário (NTS) é uma área do cérebro que desempenha um papel fundamental na regulação renal e cardiovascular através dos impulsos dos barorreceptores. Objetivos: O objetivo deste estudo foi avaliar o efeito da Naringina (NAR) e trimetazidina (TMZ), isoladamente e combinadas, na atividade elétrica do NTS e na sensibilidade barorreflexa (SBR) na lesão de isquemia e reperfusão (I/R) renal. Métodos: Foram utilizados quarenta ratos machos Sprague-Dawley (200-250 g), alocados em 5 grupos com 8 ratos cada. Grupos: 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; e 5) TMZ5 + NAR100. A veia femoral esquerda foi canulada para infundir a solução salina ou droga e avaliar a SBR. A I/R foi induzida por oclusão dos pedículos renais por 45 min, seguida de reperfusão de 4 horas. O eletroencefalograma local do NTS foi registrado antes, durante a isquemia e durante a reperfusão. A fenilefrina foi injetada por via intravenosa para avaliar a SBR ao final do tempo de reperfusão. Os dados foram analisados por ANOVA de duas vias com medidas repetidas seguida pelo teste post hoc de Tukey. Um valor de p<0,05 foi considerado como significativo. Resultados: As ondas elétricas do NTS não se alteraram durante o tempo de isquemia, mas diminuíram significativamente durante todos os tempos de reperfusão. A atividade elétrica do NTS e a SBR foram reduzidas drasticamente em ratos com lesão I/R; no entanto, a administração de NAR e TMZ, isoladamente e combinadas, melhorou significativamente essas alterações em ratos com lesão I/R. Conclusões: Os resultados mostraram que a lesão de I/R leva à redução da atividade elétrica da SBR e do NTS, e pode haver uma ligação entre a I/R e a diminuição da SBR. Além disso, a NAR e a TMZ são agentes promissores para tratar complicações de I/R.

Abstract Background: Nucleus tractus solitarius (NTS) is a brain area that plays a key role in kidney and cardiovascular regulation via baroreceptors impulses. Objectives: The aim of this study was to evaluate the effect of naringin (NAR) and trimetazidine (TMZ) alone and their combination on NTS electrical activity and baroreceptor sensitivity (BRS) in renal ischemia- reperfusion (I/R) injury. Methods: Forty male Sprague-Dawley rats (200- 250 g) were allocated into 5 groups with 8 in each. 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; and 5) TMZ5+ NAR100. The left femoral vein was cannulated to infuse saline solution or drug and the BRS was evaluated. I/R was induced by occlusion of renal pedicles for 45 min, followed by 4 hours of reperfusion. The NTS local electroencephalogram (EEG) was recorded before, during ischemia and throughout the reperfusion. Phenylephrine was injected intravenously to evaluate BRS at the end of reperfusion time. The data were analyzed by two-way repeated measurement ANOVA followed by Tukey's post hoc test. A p-value <0.05 was considered significant. Results: NTS electrical waves did not change during ischemia time, while they significantly decreased during the entire reperfusion time. NTS electrical activity and BRS dramatically reduced in rats with I/R injury; however, administration of NAR, TMZ alone or their combination significantly improved these changes in rats with I/R injury. Conclusions: The results showed that I/R injury leads to reduced BRS and NTS electrical activity and there may be an association between I/R and decreased BRS. In addition, NAR and TMZ are promising agents to treat I/R complications.

Ventajas y limitaciones del uso del torniquete en ortopedia y traumatología / Advantages and Limitations of the Use of Tourniquet in Orthopedics and Traumatology

Introducción: El torniquete es ampliamente usado en la cirugía ortopédica y traumatológica con el objetivo de disminuir las pérdidas sanguíneas intraoperatorias y mejorar la visibilidad de las estructuras anatómicas, aunque su empleo es controversial. Objetivo: Describir las aplicaciones prácticas y las limitaciones del torniquete en la cirugía ortopédica y traumatológica. Método: Se realizó una revisión no sistemática de la literatura en bases de datos científicas como Cochrane Database of Systematic Reviews, Pubmed/Medline, EMBASE, Scopus, Web of Science, EBSCOhost, ScienceDirect, OVID y el buscador académico Google Scholar, en el mes de septiembre de 2020. Conclusiones: Aunque el torniquete es ampliamente utilizado durante la cirugía ortopédica y traumatológica, debido a que contribuye a reducir las pérdidas hemáticas intraoperatorias, se ha demostrado su efecto en el aumento de las pérdidas sanguíneas totales, así como su asociación con dolor perioperatorio, pérdida de la fuerza muscular del miembro, lesiones de nervios periféricos, trombosis venosa profunda y daño a órganos a distancia por el fenómeno de isquemia-reperfusión(AU)

Introduction: Although controversial, tourniquets are widely used in orthopedic and trauma surgery with the aim of reducing intraoperative blood losses and improving the visibility of anatomical structures. Objective: To describe the practical applications and limitations of tourniquets in orthopedic and trauma surgery. Method: A non-systematic review of the literature was carried out, in scientific databases such as Cochrane Database of Systematic Reviews, Pubmed / Medline, EMBASE, Scopus, Web of Science, EBSCOhost, ScienceDirect, OVID and the academic search engine Google Scholar, in the month of September 2020. Conclusions: Although tourniquets are widely used during orthopedic and trauma surgery, since they contribute to reducing intraoperative blood loss, the effect on increasing total blood loss has been demonstrated, as well as the association with perioperative pain, blood loss, limb muscle strength, peripheral nerve injuries, deep vein thrombosis and damage to distant organs due to the ischemia-reperfusion phenomenon(AU)

Thymoquinone ameliorates acute kidney injury induced by renal ischemia-reperfusion / La timoquinona mejora la lesión renal aguda inducida por isquemia-reperfusión renal

SUMMARY: Renal ischemia-reperfusion injury (IRI)is an unavoidable consequence in renal transplantation and multiple clinical settings. A debate has been raised about the particular role of hypoxia-inducible factor (HF-1α) in the renal injury pathogenesis and the renal cortex ultrastructural alterations. Also, we investigated the antioxidant/anti-inflammatory effect of thymoquinone and its modulatory role on HIF-1α in protection against renal IRI.Adult male Wister albino rats were assigned into 3 groups (n=16); 1) Sham-operated, 2) IRI model and 3) renal IRI pre-treated with thymoquinone 10 mg.kg-1.day-1 (TQ-IRI) for 10 days and at the reperfusion onset. Following the operation, 8 rats from each group were euthanized after 3 hours and the remaining 8 rats at 24 hours. Renal injury was assessed by the increased blood urea nitrogen, creatinine level, and the EGTI histological injury scoreat both 3 and 24h. HIF-1α was upregulated (p<0.01) and was correlated with renal tissue reactive oxygen species (ROS) production and total oxidant capacity (TAC) consumption. Elevated inflammatory markers (NFkB, MCP-1 and VCAM-1) were associated with renal IRI.Thymoquinone treatment inhibited the accumulation of HIF-1α (p<0.01), reduced renal oxidation/inflammation process and markedly diminished renal injury.

RESUMEN: La lesión por isquemia-reperfusión renal (IRR) es una consecuencia inevitable en el trasplante renal como también en múltiples contextos clínicos. Se ha suscitado una discusión referente a la relación particular del factor inducible por hipoxia (HF- 1α) en la patogénesis de la lesión renal y las alteraciones ultraestructurales de la corteza renal. Además, investigamos el efecto antioxidante / antiinflamatorio de la timoquinona y su papel modulador sobre HIF-1α en la protección contra IRR. Se utilizaron ratas albinas Wister macho adultas divididas en 3 grupos (n = 16); 1) Intervención simulada, 2) modelo IRR y 3) IRR pretratado con timoquinona 10 mg/kg-1. día-1 (TQ-IRR) durante 10 días y al inicio de la reperfusión. Posterior a la operación, 8 ratas de cada grupo fueron sacrificadas después de 3 horas y las 8 ratas restantes a las 24 horas. La lesión renal se evaluó por el aumento de nitrógeno ureico en sangre, el nivel de creatinina y la puntuación de lesión histológica EGTI tanto a las 3 como a las 24 horas. HIF-1α se incrementó (p <0,01) y se correlacionó con la producción de especies de oxígeno reactivo (ROS) del tejido renal y el consumo de capacidad oxidante total. Los marcadores inflamatorios elevados (NFkB, MCP-1 y VCAM-1) se asociaron con IRR. El tratamiento con timoquinona inhibió la acumulación de HIF-1α (p <0,01), redujo el proceso de oxidación / inflamación renal y disminuyó notablemente la lesión renal.

Protective effects of sodium ferulate on flap transplantation via anti-inflammatory modulation and oxidative stress inhibition

Ischemia-reperfusion injury (IRI) has brought attention to flap failure in reconstructive surgery. To improve the prognosis of skin transplantation, we performed experimental IRI by surgical obstruction of blood flow and used sodium ferulate (SF) to prevent IRI in rats. After SF treatment, the morphological and histological changes of the skin flaps were observed by H&E and Masson's trichrome staining. We also detected the expression levels of COX-1, HO-1, and Ki67 by immunohistochemical and western blot analysis. Moreover, enzyme-linked immunosorbent assay was used to identify the content of tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO) in peripheral blood and skin tissue. Compared with the model group, SF treatment significantly improved the recovered flap area (%) and promoted collagen synthesis. Cyclooxygenase-2 (COX-2) expression was significantly inhibited by heme oxygenase-1 (HO-1) induction after SF treatment. Furthermore, SF significantly inhibited the levels of TNF-α in peripheral blood, MPO and MDA in the skin tissue, and the increased synthesis of NO. Our results showed the protective effects of SF on IRI after flap transplantation and we believe that the protective effects of SF was closely related to the alleviation of the inflammatory response and the inhibition of the oxidative stress injury.

Estradiol prevented intestinal ischemia and reperfusion-induced changes in intestinal permeability and motility in male rats

OBJECTIVES: Ischemia and reperfusion (I/R) in the intestine could lead to severe endothelial injury, compromising intestinal motility. Reportedly, estradiol can control local and systemic inflammation induced by I/R injury. Thus, we investigated the effects of estradiol treatment on local repercussions in an intestinal I/R model. METHODS: Rats were subjected to ischemia via the occlusion of the superior mesenteric artery (45 min) followed by reperfusion (2h). Thirty minutes after ischemia induction (E30), 17β-estradiol (E2) was administered as a single dose (280 μg/kg, intravenous). Sham-operated animals were used as controls. RESULTS: I/R injury decreased intestinal motility and increased intestinal permeability, accompanied by reduced mesenteric endothelial nitric oxide synthase (eNOS) and endothelin (ET) protein expression. Additionally, the levels of serum injury markers and inflammatory mediators were elevated. Estradiol treatment improved intestinal motility, reduced intestinal permeability, and increased eNOS and ET expression. Levels of injury markers and inflammatory mediators were also reduced following estradiol treatment. CONCLUSION: Collectively, our findings indicate that estradiol treatment can modulate the deleterious intestinal effects of I/R injury. Thus, estradiol mediates the improvement in gut barrier functions and prevents intestinal dysfunction, which may reduce the systemic inflammatory response.

Protective effects of honey, Apis mellifera meda skorikov, on ischemia-reperfusion induced muscle injury / Efectos protectores de la miel, Apis mellifera meda skorikov, sobre la lesión muscular inducida por isquemia-reperfusión

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.

Edaravone alleviates cell apoptosis and mitochondrial injury in ischemia-reperfusion-induced kidney injury via the JAK/STAT pathway

BACKGROUND: Kidney ischemia-reperfusion injury is a common pathophysiological phenomenon in the clinic. A large number of studies have found that the tyrosine protein kinase/signal transducer and activator of transcription (JAK/STAT) pathway is involved in the development of a variety of kidney diseases and renal protection associated with multiple drugs. Edaravone (EDA) is an effective free radical scavenger that has been used clinically for the treatment of postischemic neuronal injury. This study aimed to identify whether EDA improved kidney function in rats with ischemia-reperfusion injury by regulating the JAK/STAT pathway and clarify the underlying mechanism. METHODS: Histomorphological analysis was used to assess pathological kidney injury, and mitochondrial damage was observed by transmission electron microscopy. Terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) staining was performed to detect tubular epithelial cell apoptosis. The expression of JAK2, P-JAK2, STAT3, P-STAT3, STAT1, P-STAT1, BAX and Bcl-2 was assessed by western blotting. Mitochondrial function in the kidney was assessed by mitochondrial membrane potential (ΔψM) measurement. RESULTS: The results showed that EDA inhibited the expression of p-JAK2, p-STAT3 and p-STAT1, accompanied by downregulation of the expression of Bax and caspase-3, and significantly ameliorated kidney damage caused by ischemia-reperfusion injury (IRI). Furthermore, the JC-1 dye assay showed that edaravone attenuated ischemia-reperfusion-induced loss of kidney (ΔψM). CONCLUSION: Our findings indicate that EDA protects against kidney damage caused by ischemia-reperfusion through JAK/STAT signaling, inhibiting apoptosis and improving mitochondrial injury.

Identification of potential molecular mechanisms and small molecule drugs in myocardial ischemia/reperfusion injury

Myocardial ischemia/reperfusion (MI/R) injury is a complex phenomenon that causes severe damage to the myocardium. However, the potential molecular mechanisms of MI/R injury have not been fully clarified. We identified potential molecular mechanisms and therapeutic targets in MI/R injury through analysis of Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were found between MI/R injury and normal samples, and overlapping DEGs were found between GSE61592 and GSE67308. Gene Ontology (GO) and pathway analysis were performed for overlapping DEGs by Database for Annotation, Visualization and Integration Discovery (DAVID). Then, a network of protein-protein interaction (PPI) was constructed through the Search Tool for the Retrieval of Interacting Genes (STRING) database. Potential microRNAs (miRNAs) and therapeutic small molecules were screened out using microRNA.org database and the Comparative Toxicogenomics database (CTD), respectively. Finally, we identified 21 overlapping DEGs related to MI/R injury. These DEGs were significantly enriched in IL-17 signaling pathway, cytosolic DNA-sensing pathway, chemokine signaling, and cytokine-cytokine receptor interaction pathway. According to the degree in the PPI network, CCL2, LCN2, HP, CCL7, HMOX1, CCL4, and S100A8 were found to be hub genes. Furthermore, we identified potential miRNAs (miR-24-3p, miR-26b-5p, miR-2861, miR-217, miR-4251, and miR-124-3p) and therapeutic small molecules like ozone, troglitazone, rosiglitazone, and n-3 polyunsaturated fatty acids for MI/R injury. These results identified hub genes and potential small molecule drugs, which could contribute to the understanding of molecular mechanisms and treatment for MI/R injury.