RESUMO
INTRODUCTION: Ischemia-reperfusion (I/R) injury, resulting from blood flow interruption and its subsequent restoration, is a prevalent complication in liver surgery. The liver, as a crucial organ for carbohydrate and lipid metabolism, exhibits decreased tolerance to hepatic I/R in patients with diabetes mellitus (DM), resulting in a significant increase in hepatic dysfunction following surgery. This may be attributed to elevated oxidative stress and inflammation. Our prior research established sinomenine's (SIN) protective role against hepatic I/R injury. Nevertheless, the impact of SIN on hepatic I/R injury in DM rats remains unexplored. OBJECTIVE AND METHODS: This study aimed to investigate the therapeutic potential of SIN in hepatic I/R injury in DM rats and elucidate its mechanism. Diabetic and hepatic I/R injury models were established in rats through high-fat/sugar diet, streptozotocin injection, and hepatic blood flow occlusion. Liver function, oxidative stress, inflammatory reaction, histopathology, and Nrf-2/HO-1 signaling pathway were evaluated by using UV spectrophotometry, biochemical assays, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, and Western blot analysis. RESULTS: High-dose SIN (300 mg/kg) significantly attenuated hepatic I/R injury in DM rats, reducing serum activities of ALT and AST, decreasing the AST/ALT ratio, enhancing tissue contents of SOD and GSH-Px, suppressing the levels of TNF-α and IL-6, improving the liver histopathology, and activating Nrf-2/HO-1 signaling by promoting Nrf-2 trans-location from cytoplasm to nucleus. Low-dose SIN (100 mg/kg) was ineffective. CONCLUSIONS: This study demonstrates that high-dose sinomenine's mitigates hepatic I/R-induced inflammation and oxidative stress in diabetes mellitus (DM) rats via Nrf-2/HO-1 activation, suggesting its potential as a preventive strategy for hepatic I/R injury in DM patients.
Assuntos
Diabetes Mellitus Experimental , Fígado , Morfinanos , Estresse Oxidativo , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Estresse Oxidativo/efeitos dos fármacos , Morfinanos/farmacologia , Morfinanos/administração & dosagem , Morfinanos/uso terapêutico , Ratos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Ischemia reperfusion (I/R) injury is a frequent occurrence during liver transplantation surgery, resulting from the temporary cessation of blood flow and subsequent restoration of blood flow. Serious I/R injury is a significant factor causing transplant failure. Hepatic I/R process is characterized by excessive inflammation, oxidation, and apoptosis. Crocetin (Crt) is a natural compound exhibiting beneficial roles in various I/R-induced organ damages. However, Crt's potential role in hepatic I/R remains unexplored. OBJECTIVE AND METHODS: In order to reveal the impact of Crt on hepatic I/R and the associated signaling pathway, we utilized a syngeneic orthotopic liver transplantation rat model to induce hepatic I/R injury. RESULTS: Pretreatment with Crt significantly mitigated hepatic I/R injury. This was evident by decreased activities of serum ALT, AST and LDH, indicating improved liver function. Crt treatment also alleviated oxidative stress, as demonstrated by decreased serum MDA content and elevated serum SOD and GSH-Px activities. Furthermore, Crt suppressed inflammatory responses by downregulating both the serum and liver IL-1ß, IL-6 and TNF-α while upregulating IL-10 expression. Additionally, Crt reduced apoptosis by decreasing pro-apoptotic Bax, cleaved caspase-3 and cleaved caspase-9, while increasing anti-apoptotic Bcl2 expression. Notably, these protective effects of Crt were dose-dependent. Moreover, our data indicates that Crt plays protective functions during hepatic I/R via disrupting Keap1/Nrf2 interaction and activating Nrf2/HO-1 signaling. This was further supported by observations of alleviated hepatic histopathological changes in I/R rats treated with Crt. CONCLUSIONS: Crt shows potential as a therapeutic agent for preventing hepatic I/R injury during clinical liver transplantation.
Assuntos
Carotenoides , Proteína 1 Associada a ECH Semelhante a Kelch , Fígado , Fator 2 Relacionado a NF-E2 , Traumatismo por Reperfusão , Transdução de Sinais , Vitamina A , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Carotenoides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ratos , Vitamina A/análogos & derivados , Vitamina A/farmacologia , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Transplante de Fígado , Apoptose/efeitos dos fármacosRESUMO
INTRODUCTION: Ischemia-reperfusion (IR) injury is induced by an interrupted blood flow and succeeding blood restoration, which is common in the operation of liver transplantation. Serious IR injury is a major reason leading to transplant failure. Hepatic IR is featured by excessive inflammatory response, oxidative stress, and apoptosis. Sinomenine (SIN) is derived from the herb Sinomeniumacutum and shows properties of anti-inflammation and antiapoptosis in multiple IR-induced organ injuries. However, the effect of SIN in hepatic IR has not been investigated. METHODS: This study aims to investigate impacts of SIN on hepatic IR and the involved signaling pathway. An in vivo rat model of syngeneic orthotopic liver transplantation was constructed to induce the hepatic IR injury. RESULTS: Results showed that SIN pretreatment provided a significant prevention against IR-induced hepatic injury as manifested by the downregulated activities of serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, the alleviatedoxidative stress as shown by increased activities of serum superoxide dismutase and glutathione peroxidase, and decreased serum level of malondialdehyde, the suppressed inflammatory responses as shown by downregulated serum tumor necrosis factor-α, interleukin (IL)-6, IL-8 levels, and upregulated IL-10 level, as well as attenuated apoptosis as shown by decreased protein expression of cleaved caspase-3 and -9. In line with these results, SIN pretreatment also alleviatedthe hepatic histopathological changes in IR rats and induced Nrf-2/HO-1 activation. The use of brusatol, a selective inhibitor for Nrf-2, effectively reversed SIN-induced above effects. CONCLUSIONS: Altogether, our results demonstrate that SIN might be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.
Assuntos
Hepatopatias , Traumatismo por Reperfusão , Alanina/uso terapêutico , Alanina Transaminase/metabolismo , Alanina Transaminase/uso terapêutico , Animais , Aspartato Aminotransferases/metabolismo , Aspartato Aminotransferases/uso terapêutico , Caspase 3/metabolismo , Glutationa Peroxidase/uso terapêutico , Interleucina-10 , Interleucina-8 , Lactato Desidrogenases , Hepatopatias/patologia , Malondialdeído , Morfinanos , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Superóxido Dismutase/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Due to their atomically ultrathin thickness, the development of high-performance transition-metal dichalcogenides (TMDCs) based photodetectors demands device designs distinct from architectures adopted in conventional bulk semiconductor devices. Here, we demonstrate a field-induced Schottky barrier photodiode with three different TMDC materials, WSe2, MoTe2, and WS2. Owing to the high gate efficiency of a high-κ dielectric film, the Schottky barrier at metal contacts is effectively modulated by external bias, giving rise to a strong diode-like rectifying characteristic with high current on/off ratio. The WSe2 photodiode shows a linear dynamic range of 112 dB, a responsivity of 0.17 A/W, and response time of 8 ns. When this fast WSe2 device is employed for visible light communication data linking, a maximum real-time data transmission rate of 110 Mbps is achieved. Meanwhile, infrared light communication was also realized with a maximum data rate of 30 Mbps using a field-induced MoTe2 Schottky barrier photodiode as a light sensor. This work provides a general CMOS-compatible and controllable fabrication strategy for TMDC-based photodetectors.