Dexmedetomidine Suppressing Apoptosis to Release Rats’ Liver Ischemia-Reperfusion Injury

2021 ◽  
Vol 11 (8) ◽  
pp. 1536-1542
Author(s):  
Zhao Hai-Fan ◽  
Li Chong ◽  
Hu Zhi-Duo ◽  
Chen Hong ◽  
Jiang Tao ◽  
...  
Keyword(s):  
Western Blot ◽  
Liver Tissue ◽  
Caspase 3 ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Pathological State ◽  
Inhibitory Effects ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Purpose: Explore the dexmedetomidine’s therapeutic impact on hepatic ischemia-reperfusion (I/R) injury and the related principle. Methods: The work established the rats’ liver I/R model. Liver tissues’ pathological state from each rat was evaluated by HE staining. ELISA was utilized to confirm the activity of MDA and SOD in the liver tissue, AST in the serum, and the ALT’s concentration. The apoptotic state of liver tissue was detected by TUNEL assay. Bcl-2, Caspase-3, HO-1, and BAX’s expressions of each rat’s liver tissue had been confirmed through immunohistochemistry and western blot. Results: Rats’ liver injury from I/R group and DEX+A group was rat’s liver tissue had been confirmed through immunohistochemistry and western blot. severer than that from Sham group in terms of HE staining and ELISA. The injured tissue has been improved by the introduction of Dexmedetomidine. The TUNEL, Immunohistochemistry and Western Blot results indicated that the high apoptotic rate in I/R model was inhibited using Dexmedetomidine. However, the inhibitory effects were reversed by the co-administration of Atipamezole. Conclusion: Dexmedetomidine suppressed apoptosis to alleviate rats’ hepatic ischemia-reperfusion injuries.

scholarly journals Vildagliptin Attenuates Hepatic Ischemia/Reperfusion Injury via the TLR4/NF-κB Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Iman O. Sherif ◽  
Nora H. Al-Shaalan
Keyword(s):  
Signaling Pathway ◽  
Normal Saline ◽  
Caspase 3 ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Histopathological Examination ◽  
Ischemia Reperfusion ◽  
Sham Operation ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

The Toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway is vital in the pathogenesis of hepatic ischemia/reperfusion (HIR) injury. Dipeptidyl peptidase-4 (DPP4) inhibitors exert protective effects on IR injury of the kidney, heart, and lung; however, their effect on the liver is still unknown. Thus, the purpose of this study was to examine whether pretreatment with vildagliptin (Vilda), a DPP4 inhibitor, produces hepatic protection against IR injury and to investigate its influence on TLR4/NF-κB signaling in a rat model. Thirty male Wistar rats were divided into 3 groups: the sham group: subjected to a sham operation and received normal saline; the HIR group: subjected to HIR and received normal saline; and the Vilda + HIR group: subjected to HIR with pretreatment of 10 mg/kg/day Vilda for 10 days intraperitoneally. Hepatic ischemia lasted for 45 minutes followed by 3-hour reperfusion; then blood and liver samples were collected for biochemical and histopathological examination. The HIR group produced a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) levels and a significant reduction in the hepatic catalase level in comparison to the sham group. Moreover, a significant upregulation of gene and protein expressions of TLR4, NF-κB, and high-mobility group box-1 (HMGB1) along with caspase-3 protein expression was observed in the HIR group when compared with the sham group. Histopathological examination of the liver from the HIR group showed necrosis, sinusoidal congestion, hemorrhage, and hepatocyte degeneration. Administration of Vilda ameliorated the biochemical and histopathological changes caused by HIR. Vildagliptin showed for the first time a hepatoprotective effect in HIR injury through downregulation of TLR4/NF-κB/HMGB1 and caspase-3 hepatic expressions.

scholarly journals Preconditioning with L-alanyl-glutamine reduces hepatic ischemia-reperfusion injury in rats

2011 ◽  
Vol 26 (suppl 1) ◽  
pp. 8-13 ◽  
Author(s):  
Raimundo José Cunha Araújo Júnior ◽  
Raimundo Gerônimo da Silva Júnior ◽  
Marcelo Pinho Pessoa de Vasconcelos ◽  
Sérgio Botelho Guimarães ◽  
Paulo Roberto Leitão de Vasconcelos ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Average Weight ◽  
Sham Operation ◽  
Hepatic Ischemia ◽  
Portal Triad ◽  
Hepatic Ischemia Reperfusion ◽  
Control Sham

PURPOSE: To evaluate the effects of pre-conditioning with L-alanyl- glutamine (L-Ala-Gln) in rats subjected to total hepatic ischemia. METHODS: Thirty Wistar rats, average weight 300g, were randomly assigned to 3 groups (n=10): G-1 - Saline, G-2- L-Ala-Gln, G-3-control (Sham). G-1 and G-3 groups were treated with saline 2.0 ml or L-Ala-Gln (0.75mg/Kg) intraperitoneally (ip) respectively, 2 hours before laparotomy. Anesthetized rats were subjected to laparotomy and total hepatic ischemia (30 minutes) induced by by clamping of portal triad. Control group underwent peritoneal puncture, two hours before the sham operation (laparotomy only). At the end of ischemia (G1 and G2), the liver was reperfused for 60 minutes. Following reperfusion blood samples were collected for evaluation of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels. Liver (medium lobe) was removed for immunohistochemistry study with antibody for Caspase-3. RESULTS: It was found a significant decrease (p<0.05) of ALT levels (270.6 +40.8 vs 83.3 +5.5 - p <0.05), LDH (2079.0 +262.4 vs. 206.6 +16.2 - p <0.05) and Caspase-3 expression (6.72 +1.35 vs. 2.19 +1.14, p <0.05) in rats subjected to I / R, comparing the group treated with L-Ala -Gln with G-2. Also, the ALT level was significantly lower (P<0.05) in G-1 and G-2 groups than in G-3 (control group). CONCLUSION: L-Ala-Gln preconditioning in rats submitted to hepatic I/R significantly reduces ALT, LDH and Caspase-3 expression, suggesting hepatic protection.

scholarly journals D-Pinitol Protected Against Endoplasmic Reticulum Stress and Apoptosis in Hepatic Ischemia-Reperfusion Injury Via Modulation of AFT4-CHOP/GRP78 and Caspase-3 Signaling Pathways

2021 ◽  
Author(s):  
Lei Yan ◽  
Heng Luo ◽  
Xingsheng Li ◽  
Yongyong Li
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Reperfusion Injury ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Clinical Problem ◽  
Hepatic Ischemia ◽  
Pre Treatment ◽  
Hepatic Ischemia Reperfusion

Abstract Background: Hepatic ischemia-reperfusion injury (IRI) is a major unavoidable clinical problem often occurs during various liver surgery and transplantation. D-Pinitol, a cyclic polyol, showed its hepatoprotective efficacy in clinical and experimental settings. Aim: To determine the potential and possible mechanism of pinitol against ER stress regulation-mediated hepatic IRI in experimental rats.Materials and methods: Male SD rats were pre-treated with pinitol for 21 days and then subjected to 60 min. of partial hepatic ischemia followed by 24 h. of reperfusion. Various parameters were evaluated, including liver function tests, inflammatory release, endoplasmic reticulum (ER) stress, apoptosis, and structural modifications.Results: Pre-treatment with pinitol (10 and 20 mg/kg) effectively protected IRI-induced hepatic damage reflected by attenuation of elevated AST, ALT, oxidative stress (SOD, GSH, MDA and NO) and pro-inflammatory cytokines (TNF-α and IL’s) release. Interestingly, western blot and ELISA analysis suggested that pinitol significantly down-regulated the expression of ER stress apoptotic markers, namely GRP78, CHOP, AFT-4, AFT-6α, XBP-1, and caspase-3, 9 and 12. Additionally, pinitol pre-treatment improved mitochondrial function and phosphorylation of ERK1/2 and P38. Pinitol markedly protected IRI-induced hepatic apoptosis determined by flow cytometry. The hepatic histological and ultrastructural aberration induced by IRI was effectively protected by pinitol. Conclusion: Findings of the present investigation suggested that pinitol offered protection against ER stress-mediated phosphorylation of ERK1/2 and p38, thereby inhibited AFT4-CHOP/GRP78 signaling response and induction of caspase-3 induced hepatocellular apoptosis during hepatic ischemia-reperfusion insults.

Electroacupuncture stimulation at Yanglingquan acupoint ameliorates hepatic ischemia-reperfusion injury by down-regulating ET-1 to inhibit TAK1-JNK/p38 pathway

2021 ◽  
Author(s):  
Lai Wei ◽  
Yinyin Su ◽  
Siyou Tan ◽  
Yi Zou ◽  
Yixun Tang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Expression Patterns ◽  
Hepatic Ischemia ◽  
Tnf Α ◽  
Hepatic Ischemia Reperfusion ◽  
Liver Tissues

The current study set out to investigate the molecular mechanism of electroacupuncture (EA) stimulation at Yanglingquan acupoint (GB34) in hepatic ischemia-reperfusion injury (HIRI) in rats via regulation of the endothelin-1 (ET-1) mediated transforming growth factor-β-activated kinase-1 (TAK1)-c-Jun NH2-terminal kinase (JNK)/p38 signaling pathway. First, EA stimulation was applied to the constructed rat model of HIRI at GB34. Subsequently, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and myeloperoxidase (MPO) in liver tissues were measured. Apoptotic changes in liver tissues in rats with HIRI were observed using TUNEL staining. Western blot assay was employed to determine the expression patterns of Bcl-2, Bax, c-caspase-3 and the activation of TAK1-JNK/p38 signaling pathway, and immunohistochemistry was conducted to determine the protein expression patterns of c-caspase-3 and ET-1. In addition, ELISA was performed to determine the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in serum. The results demonstrated a significant decline in the activities of AST and ALT and hepatocyte apoptosis in rats with HIRI following EA stimulation. Meanwhile, EA stimulation brought about decreases in the expression levels of Bcl-2, Bax and c-caspase-3, MPO activity, TNF-α, IL-1β and IL-6 in serum, and diminished those of ET-1 in liver tissues, in addition to inhibiting the TAK1-JNK/p38 signaling pathway. Over-expression of ET-1 could counter the inhibitory effects of EA stimulation of HIRI in rats. Together, our findings indicate that EA stimulation at GB34 down-regulates the expression of ET-1, which inhibits the TAK1-JNK/p38 signaling pathway, consequently alleviating HIRI in rats.

scholarly journals d-Pinitol protects against endoplasmic reticulum stress and apoptosis in hepatic ischemia-reperfusion injury via modulation of AFT4-CHOP/GRP78 and caspase-3 signaling pathways

2021 ◽  
Vol 35 ◽  
pp. 205873842110320
Author(s):  
Lei Yan ◽  
Heng Luo ◽  
Xingsheng Li ◽  
Yongyong Li
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Reperfusion Injury ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Binding Protein ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Pre Treatment ◽  
Hepatic Ischemia Reperfusion

Hepatic ischemia-reperfusion injury (IRI) is a major unavoidable clinical problem often accompanying various liver surgery and transplantation. d-Pinitol, a cyclic polyol, exhibits hepatoprotective efficacy. The objective of this study is to determine the possible mechanism of action of pinitol against endoplasmic reticulum (ER) stress regulation-mediated hepatic IRI and compare its effects with thymoquinone (TQ) in experimental rats. Male Sprague Dawley rats were pre-treated orally with either vehicle (DMSO) or d-Pinitol (5, 10, and 20 mg/kg) or TQ (30 mg/kg) for 21 days and subjected to 60 min of partial hepatic ischemia followed by 24 h of reperfusion. Pre-treatment with pinitol (10 and 20 mg/kg) effectively ( P  < 0.05) protected against IRI-induced hepatic damage reflected by attenuation of elevated oxidative stress and pro-inflammatory cytokines. Additionally, western blot and ELISA analyses suggested that pinitol significantly ( P  < 0.05) down-regulated expression of endoplasmic reticulum stress apoptotic markers, namely glucose-regulated protein (GRP)-78, CCAAT/enhancer-binding protein homologous protein (CHOP), activating transcription factor (AFT)-4 and -6α, X-box binding protein-1, and caspase-3, 9, and 12. Additionally, pinitol pre-treatment effectively ( P  < 0.05) improved mitochondrial function and phosphorylation of Extracellular signal-regulated kinase (ERK)-1/2 and p38. Pinitol markedly ( P  < 0.05) protected hepatic apoptosis determined by flow cytometry. Further, pinitol provided effective ( P  < 0.05) protection against hepatic histological and ultrastructural aberrations induced by IRI. TQ showed more pronounced protective effect against attenuation of IRI-induced hepatic injury as compared to d-Pinitol. Pinitol offered protection against endoplasmic reticulum stress-mediated phosphorylation of ERK1/2 and p38, thereby inhibiting AFT4-CHOP/GRP78 signaling response and caspase-3 induced hepatocellular apoptosis during hepatic ischemia-reperfusion insults. Thus, Pinitol can be considered as a viable option for the management of hepatic IRI.

Secretome of Adipose-Derived Stem Cells Protect Ischemia-Reperfusion and Partial Hepatectomy by Attenuating Autophagy

2020 ◽  
Author(s):  
Yajun Ma ◽  
Zhihui Jiao ◽  
Xiaoning Liu ◽  
Qianzhen Zhang ◽  
Chenxi Piao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Partial Hepatectomy ◽  
Liver Tissue ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Laparoscopic Technique ◽  
Therapeutic Effects ◽  
Hepatic Ischemia ◽  
Significant Difference ◽  
Hepatic Ischemia Reperfusion

Abstract Background: The therapeutic effects of adipose-derived mesenchymal stem cells (ADSCs) may mainly come from their paracrine effects. ADSCs can ameliorate hepatic ischemia-reperfusion injury (IRI). We explored the therapeutic effect of ADSCs secretome from the perspective of excessive autophagy of hepatocytes induced by hepatic IRI.Methods: In this study, we established a miniature pig model of hepatic ischemia-reperfusion (I/R) combined with hepatectomy using laparoscopic technique, and transplanted ADSCs and adipose-derived mesenchymal stem cell-conditioned medium (ADSC-CM) into the liver parenchyma immediately after surgery. Histopathological and TEM examinations were performed on liver tissue samples collected. We analyzed the roles of ADSC-CM and ADSCs in autophagy by RT-qPCR, western-blot and immunohistochemistry. Results: The results showed that ADSCs and ADSC-CM all alleviated the pathological changes of liver tissue and the microstructural damage of hepatocytes after IRI. Moreover, the expression of the critical markers of autophagy including Beclin-1, ATG5, ATG12 and LC3II all decreased, whereas expression of p62 increased. And the data of autophagy regulation between ADSC-CM and ADSCs showed no significant difference. Finally, we found that ADSC-CM possibly inhibited autophagy by regulating the PI3K/Akt/mTOR pathway.Conclusion: ADSC-CM can ameliorate excessive autophagy injury in hepatic I/R combined with partial hepatectomy, which is possibly involved with the modulation of the PI3K/Akt/mTOR signaling pathway. There was no significant difference between ADSCs and ADSC-CM in the regulation of hepatocyte autophagy. Therefore, ADSCs may improve the excessive autophagy injury of hepatocytes in hepatic I/R combined with hepatectomy through paracrine effect, thus protecting the liver and promoting the liver tissue repair.

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