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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.

Aims To discuss treatment strategies for non-traumatic, non-iatrogenic hepatic artery aneurysms (HAAs) in the presence of an arteriobiliary fistula, illustrated by a case and followed by a comprehensive review of the literature. Methods Following the PRISMA guidelines, 24 eligible HAA cases presenting with haemobilia were identified. Characteristics of patients, aneurysms, treatment strategies and their outcomes were collected. Results A 69 year old patient with no previous hepatobiliary intervention or trauma, presented with jaundice and haemobilia caused by a HAA. Initial treatment by endovascular stenting was chosen to prevent ischaemic liver complications. Unfortunately, this strategy failed because of stent migration due to ongoing infection leading to a type 1A endoleak. The patient had to be converted to open surgery with ligation of the HAA. The patient recovered uneventfully and no complications occurred during the following 12 months. Comprehensive literature review Of the 24 cases, nine had a true HAA and 15 were pseudo/mycotic aneurysms, mainly caused by endocarditis or cholecystitis. The majority were located in the right hepatic artery. In 20 cases, an endovascular first approach was chosen with embolisation, none with covered stents. Three of these cases had to be converted to open surgery because of rebleeding. In all open (primary or secondary) cases, ligation of the HAA was performed. One patient in these series died. No liver ischaemia or abscesses were reported, although one patient developed an ischaemic gallbladder. Conclusions Patients who present with a HAA and haemobilia may be treated safely by embolisation or open ligation. Using a covered stent graft in these patients can cause problems due to ongoing infection and should be monitored closely by imaging. Publication bias and lack of long term follow up imply cautious interpretation of these findings., Highlights In patients presenting with haemobilia in the presence of a non-traumatic and non-iatrogenic hepatic artery aneurysm•Endocarditis and cholecystitis are the most common causes•The main treatment modality is embolisation•Liver ischaemia and liver abscesses have not been reported after treatment•Close surveillance is recommended as the area has to be considered contaminated•Treatment should be performed by a multidisciplinary team

Background: Hepatic ischemia/reperfusion (I/R) is a frequent and major complication during liver transplantation. Baicalein, a plant flavonoid, has anti-inflammatory and antioxidant effects. However, whether these effects mediate its protective effects in liver I/R injury remains poorly understood. Objective: This study was designed to investigate the effects of baicalein preconditioning on liver I/R in rats and the underlying mechanisms. Methods: Baicalein (300 mg/kg) was intraperitoneally injected 30 min before 45 min of ischemia followed by 1 h of reperfusion. Results: Baicalein preconditioning attenuated liver I/R injury, as indicated by a reduction in serum aminotransferase activities and an improvement of histopathological abnormalities. Baicalein also significantly reduced the activity of the cellular hepatic proapoptotic enzyme caspase-3 in response to I/R injury. Moreover, baicalein significantly reduced nuclear factor kappa-B expression and the subsequent proinflammatory cytokine production, tumor necrosis factor alpha (TNF-α) level, increased interleukin-10 (IL-10), an anti-inflammatory cytokine, reduced the TNF-α/IL-10 ratio, and suppressed leukocyte infiltration. It increased hepatic antioxidants and reduced lipid peroxidation. Conclusion: Taken together, bai­calein preconditioning would seem to protect against liver I/R injury via antioxidant, antiapoptotic, and anti-inflam­matory effects.

Aim: Ischemia/reperfusion (I/R) procedure applied during liver resection and transplantation in clinic settings causes liver oxidative damage. The aim of this study was to examine the effects of taxifolin on liver injury induced by I/R in rats. Methods: Albino Wistar male rats divided into three groups with 6 rats in each group: liver ischemia-reperfusion (LIR), 50 mg/kg taxifolin + liver ischemia reperfusion (TLIR) and sham operation (SHAM). An hour before thiopental sodium anesthesia, 50 mg/kg taxifolin was orally administered to the TLIR group and distilled water to the LIR and SHAM groups. In the TLIR and LIR groups, a clamp was placed in the hepatic artery, portal vein and bile duct, thereby inducing ischemia for one hour, and reperfusion for six hours. In the SHAM group, the abdominal cavity was closed by surgical suture without any procedure. At the end of this period, rats were sacrificed with high dose anesthesia. Liver tissues were removed for biochemical and histopathological examinations Results: I/R procedure significantly increased MDA (P

Ischemia reperfusion (IR) injury is defined as a pathological process which initiates with tissue deoxygenation, continues with oxidative stress, and spreads with inflammation. Increased intracellular calcium is responsible for oxidative stress and inflammation during this process. Benidipine is an antihypertensive drug acting as an T/L-type calcium channel blocker. The effect of benidipine on cyclooxygenase-2 (COX-2) activity is not known. Benidipine being a calcium channel blocker suggests that it may suppress oxidant and proinflammatory COX-2 production. The aim of this study was to examine the effect of benidipine on IR induced liver injury in albino Wistar male rats. Animals were divided into three groups: liver ischemia reperfusion (LIR), 2 mg/kg benidipine + liver ischemia reperfusion (BLIR), and sham surgery (SHAM). Hepatic artery, portal vein and bile duct were clamped to obtain ischemia for one hour and reperfusion for six hours. Malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and COX-2 levels were higher, whereas total glutathione (tGSH) and cyclooxygenase-1 (COX-1) levels were lower in the LIR group. Liver tissue of the LIR group showed marked dilated congested blood vessels and increased bile duct proliferation, polymorphonuclear leukocyte infiltration, edema, hemorrhage and destruction. MDA, ALT, AST and COX-2 levels were lower, and tGSH and COX-1 levels were higher in the BLIR group treated with benidipine. Liver tissue of the BLIR group was found to be normal except for mild dilated blood vessels. These experimental findings indicate that benidipine may be useful in the treatment of liver IR injury.

Liver ischemia-reperfusion (I/R) injury occurs during transplantation and major hepatic surgery, which may lead to postoperative liver dysfunction. More and more traditional Chinese medicines (TCMs) have been used to treat liver ischemia-reperfusion injury. The purpose of this review is to evaluate the different protective effects of TCMs in the treatment of liver ischemia-reperfusion injury and to summarize its possible mechanisms. The results indicate that TCMs attenuate liver I/R injury via multiple mechanisms, including antioxidation stress, anti-inflammatory response, antiapoptosis, and inhibiting endoplasmic reticulum stress. However, the in-depth mechanism of the protective effects of these traditional Chinese medicines still remains unknown.

Purpose Itaconate is well known for its strong anti-inflammatory and antioxidant effect, but little is known about the potential role of long non-coding RNAs (lncRNAs) in the underlying mechanisms of hepatic ischemia-reperfusion (IR) injury. The aim of our study is to identify lncRNAs related to IR injury and itaconate-mediated protection and to demonstrate the mechanism by which itaconate acts in liver IR injury from the new perspective of lncRNAs. Methods 4-Octyl itaconate (OI), a membrane-permeable derivative of itaconate, was used as a substitute for itaconate in our study. By using a mouse model of hepatic IR injury, serum and liver samples were collected to measure indexes of liver injury. Then, the liver samples of the mice were subjected to RNA sequencing (RNA-seq) and subsequent bioinformatics analysis. Results Itaconate attenuated liver IR injury. A total of 138 lncRNAs and 156 messenger RNAs (mRNAs) were markedly differentially expressed in the IR-damaged liver tissues pretreated with OI compared with the matched liver tissues treated with vehicle. Functional analysis indicated that lncRNAs may indirectly participate in the effects of itaconate. Furthermore, 41 mRNAs were examined for the protein–protein interaction (PPI) network analysis, and a key gene cluster was defined. Then, combined the coexpression analysis and the cis and trans regulatory function prediction of lncRNAs, some “candidate” lncRNA-mRNA pairs which might relate to itaconate-mediated liver protection were identified, while the relationship requires future validation. Conclusion Our study revealed that itaconate could protect the liver against IR injury and that lncRNAs might play a role in this process. Our study provides a novel way to investigate the mechanism by which itaconate affects hepatic IR injury and exerts its anti-inflammatory and antioxidative stress effects., Graphical Abstract

BACKGROUND: The aim of this study was to analyze the potential protective effect of Carvedilol against liver ischemia-reperfusion (I/R) injury in rats. METHODS: A total of 40 Wistar albino rats were randomly divided into four groups (n=10 each). Group I (Sham/Control group) underwent only laparotomy, Group II (Carvedilol group) was administered carvedilol and then underwent laparotomy, Group III (I/R group) underwent laparotomy and hepatic ischemia/reperfusion, and Group IV (I/R + Carvedilol group) was administered carvedilol and then underwent laparotomy and hepatic ischemia/reperfusion. Blood samples were collected for malondialdehyde, glutathione (GSH), and myeloperoxidase (MPO) analysis. Liver sections were obtained for histopathological analysis and stained with hematoxy lin-eosin. Tumor necrosis factor-α (TNF-α) and Caspase-3 primary antibodies were used for the immunohistochemical analysis. RESULTS: Serum GSH levels increased in the I/R + Carvedilol group. MPO activity was increased significantly in the IR group. In I/R + Carvedilol group, serum MPO levels were similar to the control group. Histopathological findings showed reduced dilatation and congestion in vena centralis, regenerative changes in hepatocyte cells with the protected nucleus structure in the I/R + Carvedilol group. Hepatocyte nuclei with increased pycnosis and apoptosis and the dilated vena centralis were observed in I/R group. In the control group, TNF-α showed a positive reaction in macrophage cells around vena centralis. An increase in TNF-α expression was observed in hepatocyte cells of I/R group. Positive expression of caspase-3 in hepatocyte cells and a small number of endothelial and Kupffer cells were seen in I/R group. However, negative caspase-3 expression was seen in hepatocyte, endothelial, and Kupffer cells in I/R + Carvedilol group. CONCLUSION: Carvedilol may prevent initiation of oxidative stress process, inflammation induction and apoptotic progression. AMAÇ: Bu çalışmanın amacı, karvedilol’ün sıçanlarda karaciğer iskemi-reperfüzyon (I/R) hasarına karşı potansiyel koruyucu etkisini analiz etmektir. GEREÇ VE YÖNTEM: Toplam 40 Wistar albino sıçan rastgele dört gruba ayrıldı (her biri n=10). Grup I’e (Sham/Kontrol grubu) sadece laparotomi, Grup II’ye (Karvedilol grubu) karvedilol uygulandı ve ardından laparotomi yapıldı, Grup III’e (I/R grubu) laparotomi uygulandı ve hepatik iskemi/ reperfüzyon yapıldı ve Grup IV’e (I/R+Karvedilol grubuna) karvedilol uygulandı ve ardından laparotomi ve hepatik iskemi/reperfüzyon yapıldı. Malondialdehyde (MDA), glutatyon (GSH) and miyeloperoksidaz (MPO) analizi için kan örnekleri toplandı. Histopatolojik analiz için karaciğer kesitleri alındı ve hematoksilen-eozin ile boyandı. İmmünohistokimyasal analiz için tümör nekroz faktor-α (TNF-α) ve kaspaz-3 primer antikorları kullanıldı. BULGULAR: Serum GSH seviyeleri I/R+Karvedilol grubunda arttı. IR grubunda MPO aktivitesi önemli ölçüde artmıştır. I/R+Karvedilol grubunda serum MPO seviyeleri kontrol grubuna benzerdi. Histopatolojik bulgular, vena centralis’te azalmış dilatasyon ve tıkanıklık, I/R+Karvedilol grubunda korunmuş çekirdek yapısı ile hepatosit hücrelerinde rejeneratif değişiklikler gösterdi. I/R grubunda artmış piknoz ve apoptozlu hepatosit çekirdekleri ve dilate vena centralis izlendi. Kontrol grubunda TNF-α, vena centralis çevresindeki makrofaj hücrelerinde pozitif reaksiyon gösterdi. I/R grubu hepatosit hücrelerinde TNF-α ekspresyonunda artış gözlendi. Hepatosit hücrelerinde Kaspaz-3’ün pozitif ekspresyonu ve I/R grubunda az sayıda endotel ve Kupffer hücre görüldü. Ancak I/R+Karvedilol grubunda hepatosit, endotelyal, kupffer hücrelerinde negatif Kaspaz-3 ekspresyonu görüldü. TARTIŞMA: Karvedilol oksidatif stres sürecinin başlamasını, enflamasyon indüksiyonunu ve apoptotik ilerlemeyi önleyebilir

Liver surgery has entered the era of precision surgery. Therefore, how to optimize the resection of lesions and reduce the unnecessary time of liver ischemia and hypoxia have become the focus. A total of 11 patients who underwent fluorescence laparoscopic liver mass resection and preoperative three-dimensional (3D) reconstruction between August 2018 and July 2020 were evaluated. Liver cirrhosis occurred in 3 patients. The mean intraoperative blood loss was 166.8 ± 105.7 mL. The average length of the operation time was 152.0 ± 45.3 minutes. The average intraoperative hilar occlusion time was 9.3 minutes (except for hilar cholangiocarcinoma). The liver function of all patients, except patients with hilar bile duct carcinoma, returned to the preoperative level at 72 hours, and no serious complications occurred. 3D reconstruction combined with fluorescence laparoscopic imaging is safe and effective for precision liver resection.

Although aggravated liver injury has been reported in aged livers post‐ischemia and reperfusion (IR), the underlying mechanism of innate immune activation of aged macrophages is not well understood. Here, we investigated whether and how Stimulator of interferon genes (STING) signaling regulated macrophage proinflammatory activation and liver IR injury. Mice were subjected to hepatic IR in vivo. Macrophages isolated from IR‐stressed livers and bone marrow‐derived macrophages (BMDMs) from young and aged mice were used for in vitro studies. Enhanced nucleotide‐binding domain and leucine‐rich repeat containing protein 3 (NLRP3) activation was found in both livers and macrophages of aged mice post‐IR. NLRP3 knockdown in macrophages inhibited intrahepatic inflammation and liver injury in both young and aged mice. Interestingly, enhanced activation of the STING/ TANK‐binding kinase 1 (TBK1) signaling pathway was observed in aged macrophages post‐IR and mitochondria DNA (mtDNA) stimulation. STING suppression blocked over‐activation of NLRP3 signaling and excessive secretion of proinflammatory cytokines/chemokines in the mtDNA‐stimulated BMDMs from aged mice. More importantly, STING knockdown in macrophages abrogated the detrimental role of aging in aggravating liver IR injury and intrahepatic inflammation. Finally, peripheral blood from the recipients undergoing liver transplantation was collected and analyzed. The results showed that the elderly recipients had much higher levels of TNF‐α, IL‐6, IL‐1β, and IL‐18 post‐transplantation, indicating increased NLRP3 activation in lR‐stressed livers of elderly recipients. In summary, our study demonstrated that the STING‐NLRP3 axis was critical for the proinflammatory response of aged macrophages and would be a novel therapeutic target to reduce IR injury in elderly patients., Liver IR triggered mtDNA release from stressed hepatocytes. Aging promoted STING over‐activation, leading to enhanced NLRP3 inflammasome activation and increased proinflammatory cytokines/chemokines production of macrophages, which ultimately aggravated IR injury.

Background: the aim of this study was to investigate the anti-inflammatory and antioxidant effects of Coriandrum sativum extract on liver ischemia reperfusion injury at light microscopic and biochemical levels. Material and methods: sham, ischemia/reperfusion injury (IRI), IRI+Coriandrum sativum extract and only Coriandrum sativum extract groups were formed. Sixty minutes of ischemia and 60 minutes of reperfusion were performed. In the treatment group, 300 mg/kg/day Coriandrum sativum was given by gavage. Hepatic tissues were fixed in 4% paraformaldehyde. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) enzymes were measured. Nuclear factor- kappa beta (NF-kappa B), Tumor necrosis factor-alpha (TNF-α) and Caspase-3 (Cas-3) 2 immunohistochemistry staining was performed. Microscopic scoring was performed in terms of sinusoidal congestion, vacuolization, and necrosis. Results: sinusoidal enlargement and diffuse congestion, Kupffer cell increase, neutrophil increase in necrotic areas, and vacuolization in hepatocytes, and bile duct proliferation in the portal triad were observed in ischemia/reperfusion hepatic tissue. Very rare, necrotic areas were observed in the Coriandrum sativum treatment group, while congestion and vacuolization and bile duct proliferation were decreased compared to the ischemic group. The AST and ALT levels were increased in the IRI and IRI+Coriandrum sativum groups. When compared to the IRI group, the AST and ALT levels of the Coriandrum sativum were considerably decreased. The IRI and IRI+Coriandrum sativum groups had statistically significant differences in ALP compared to that of the Coriandrum sativum and Sham groups. There was no significant difference between the ALP levels of the IRI and IRI+Coriandrum sativum groups TNF-α, NF-kappa B and Cas-3 immune positive stained hepatocytes were numerous and widely observed in the injury group. There were positive TNF-α immunohistochemical staining Kupffer cells in the IRI group. In the group treated with Coriandrum sativum, Kupffer cells were not stained, while TNF-α, NF-kappa B and Cas-3 expressing hepatocytes were found to be decreased compared to the IRI group. When the expression values of the TNF-α, NF-kappa B and Cas-3 groups were evaluated statistically, it was seen that there was a significant decrease in the group treated with Coriandrum sativum. Conclusions: it was found that Coriandrum sativum extract decreased proinflammatory cytokine TNF-α and apoptotic cell death and liver enzymes in liver ischemia reperfusion injury., NA

Aim: The transient receptor potential melastatin (TRPM) channel is subfamilies of the transient receptor potential (TRP) channels, cation permeable channels. Ischemia and reperfusion (I / R) injury is a phenomenon highlighting cellular damage of the liver caused by oxygen. Lidocaine is a local anesthetic that blocks sodium channels and suppresses mitochondrial functions of neutrophils. In this study, we purpose to investigate the effects of TRPM2/8 and TRPM6/7 expressions after lidocaine treatment in liver ischemia/reperfusion rat model. Materials and Methods: The study was carried out on 32 male Wistar rats. The animals were randomly divided into 4 groups including sham, lidocaine, I/R group and I/R- lidocaine group. The portal vein and the hepatic artery branches were clamped for 60 minutes for complete ischemia. TRPM2/8 and TRPM6/7 gene expression levels were assessed by RT-qPCR. Results: The expression levels of TRPM2 were significantly higher in liver-I/R group compared to sham and lidocaine groups (p

Uncontrolled hemorrhage is a leading cause of tactical trauma-related deaths. Hemorrhage from the pelvis and junctional regions are particularly difficult to control due to the inability of focal compression. The Abdominal Aortic and Junctional Tourniquet (AAJT) occludes aortic blood flow by compression of the abdomen. The survivability of tourniquet release beyond 120 minutes is unknown and fluid requirements to maintain sufficient blood pressure during prolonged application are undetermined. We therefore compared 60-minute and 240-minute applications and release of the AAJT for 30 minutes, with crystalloid fluid therapy, after a Class II hemorrhage.Sixty-kilogram anesthetized pigs were subjected to 900-mL hemorrhage and AAJT application for 60 minutes (n = 5), 240 minutes (n = 5), and fluid therapy only for 240 minutes (n = 5) and reperfusion for 30 minutes.The AAJT application was hemodynamically and respiratory tolerable for 60 minutes and 240 minutes. Cumulative fluid requirements decreased by 64%, comparable to 3000 mL of crystalloids. Mechanical ventilation was impaired. AAJT increased the core temperature by 0.9°C compared with fluid therapy. Reperfusion consequences were reversible after 60 minutes but not after 240 minutes. A 240-minute application resulted in small intestine and liver ischemia, persisting hyperkalemia, metabolic acidosis, and myoglobinemia, suggesting rhabdomyolysis.The AAJT application for 240 minutes with reperfusion was survivable in an intensive care setting and associated with abdominal organ damage. Long time consequences and spinal cord effects was not assessed. We propose an application time limit within 60 minutes to 240 minutes, though further studies are needed to increase the temporal resolution. The AAJT application may be considered as a rescue option to maintain central blood pressure and core temperature in cases of hemorrhagic shock from extremity bleedings, if fluid therapy is unavailable or if the supply is limited.Therapeutic study, level II.

Background Liver ischemia reperfusion (I/R) damage which is frequently seen in clinical hepatobiliary surgeries has no effective treatment for it. Liv-52, known to have hepatoprotective effects, is a natural antioxidant drug licensed by the Ministry of Health of India. The aim of our study is to investigate the effect of Liv-52 on liver damage induced by I/R in rats. Methods Albino Wistar male rats were divided into three groups; liver I/R (IR), 20 mg/kg Liv-52 + liver ischemia reperfusion (LIR) and sham operation applied to control group (HG). Liv-52 was administered to the LIR group (n = 6) 1 h prior to I/R application and distilled water was given orally to IR (n = 6) and HG (n = 6) groups as a solvent. Ischemia was determined as 1 h, and reperfusion was identified as 6 h in animals. Results Increased levels of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase, malondialdehyde, myeloperoxidase, and decreased levels of superoxide dismutase, and glutathione related enzymes caused by I/R application have been converged to healthy group level with Liv-52 treatment and the damage in liver tissue has been improved histopathologically. Conclusions Liv-52 may be beneficial for preventing liver I/R damage in pre-surgery application.

Background/Objectives Celiac axis stenosis (CAS) represents an uncommon and typically innocuous condition. However, when a pancreatic resection is required, a high risk for upper abdominal organs ischemia is observed. In presence of collaterals, such a risk is minimized if their preservation is realized. The aim of the present study is to systematically review the literature with the intent to address the routine management of collateral arteries in the case of CAS patients requiring pancreatoduodenectomy. Methods A systematic search was done in accordance with the PRISMA guidelines, using “celiac axis stenosis” AND “pancreatoduodenectomy” as MeSH terms. Seventy-four articles were initially screened: eventually, 30 articles were identified (n = 87). Results The main cause of CAS was median arcuate ligament (MAL) (n = 31; 35.6%), followed by atherosclerosis (n = 20; 23.0%). CAS was occasionally discovered during the Whipple procedure in 15 (17.2%) cases. Typically, MAL was divided during surgery (n = 24/31; 77.4%). In the great majority of cases (n = 83; 95.4%), vascular abnormalities involved the pancreatoduodenal arteries (i.e., dilatation, arcade, channels, aneurysms). Collateral arteries were typically preserved, being divided or reconstructed in only 14 (16.1%) cases, respectively. Severe ischemic complications were reported in six (6.9%) patients, 20.0% of whom were reported in patients with preoperatively unknown CAS (p-value 0.06). Conclusions A correct pre-operative evaluation of anatomical conditions as well as a correct surgical planning represent the paramount targets in CAS patients with arterial collaterals. Vascular flow must be always safeguarded preserving/reconstructing the collaterals or resolving the CAS, with the final intent to avoid dreadful intra- and post-operative complications.

Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH, required for glutathione (GSH)-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx) and glutathione reductase (GR). Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR)-associated mitochondrial injury using Idh2-knockout (Idh2-/-) mice and wild-type (Idh2+/+) littermates. Mice were subjected to either 60 min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant). HIR induced severe histological and functional damages of liver in both Idh2+/+ mice and Idh2-/- mice and those damages were more severe in Idh2-/- mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2-/- mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2-/- mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure., Graphical abstract fx1, Highlights • HIR induces dysfunction of IDH2, a producer of mitochondrial NADPH. • HIR impairs mitochondrial NADPH-GSH antioxidant system with mitochondrial injury. • IDH2 deletion augments HIR-induced mitochondrial oxidative injury and dysfunction. • A mitochondria-targeting antioxidant prevents the effects of IDH2 deficiency. • IDH2 plays a critical role on mitochondrial antioxidant system.

Background: As the criteria for liver donation have been extended to include marginal donors, liver grafts are becoming particularly vulnerable to hepatic ischemia-reperfusion injury (IRI). However, no specific measures have been validated to ameliorate hepatic IRI. Objective: To investigate the effect of ischemic preconditioning on hepatic ischemia/reperfusion (IR) injury in aged rats. Materials and Methods: The present study was performed on 45 aged male Wistar rats, weighing at the start of the study between 350-550 g. Animals were randomly divided into the following equal groups: Group I (Sham-operated control group), Group II (Liver ischemia reperfusion group): Rats were subjected to 1-hour partial liver ischemia followed by 24-hour reperfusion and Group III (ischemic preconditioned group): Rats were subjected to brief period of ischemia and reperfusion, then were subjected to hepatic IR as group II. Blood samples were collected and were subjected to measurement of Liver function tests, i.e. serum ALT, AST, liver malondialdehyde and glutathione peroxidase. Also, histopathological study of rat livers was performed. Results: There were significant decrease in liver weight and liver weight to body weight percent in IR group compared to the sham-operated rats. Upon preconditioning before IR, the liver weights still decreased compared to the sham-operated rats. Liver weight to body weight ratio ameliorated or less decreased in the ratio compared to sham-operated, and significantly increased in the ratio compared to the IR rats. There were significant increases in serum levels of liver enzymes (ALT and AST), at two time points, especially 24 hours after reperfusion as well as significant increase in hepatic MDA level in IR rats. In addition, IR has induced marked liver damage as shown by histopathological examination. Ischemic preconditioning ameliorated liver ischemia reperfusion injury as indicated by marked reduction in the liver enzymes although their levels did not match the levels recorded in the sham-operated rats and hepatic MDA. Hepatic level of GPx showed a significant increase compared to both the sham-operated and IR rats and that was associated with significant improvement of the histopathological examination compared to IR rats. Conclusion: Ischemic preconditioning ameliorated the hepatic injury associated with ischemia reperfusion. However, future work is needed to explain the mechanism by which IPC ameliorate liver IRI.

Introduction: We glad to introduce several variants of pharmacological correction of ischemic hepatic injury by imidazoline I2 receptor agonistС7070. Materials and methods: The experiment was carried out on 70 rats of both sexes, divided into 7 groups (n = 10): an intact group; Pseudo-operated animals (autopsy of the abdominal wall without ligation of the liver vessels); Ischemia / reperfusion group without drug correction; Animals undergoing ischemia / liver reperfusion + Metformin (50 mg / kg); Animals undergoing ischemia / liver reperfusion + Moxonidine (1 μg / kg); Animals undergoing ischemia / liver reperfusion + C7070 (1 mg / kg). For the evaluation, the coefficients calculated from the level of hepatic transaminases (ALT, AST), as well as morphometric ratios of the area of necrosis and deep ischemia of the liver, were used for the evaluation according to the histological examination. Results and discussion: The indicated agonists of peripheral imidazoline I2receptors (C7070) significantly reducesischemically-reperfusion injury of the liver, in comparison with the preparations of moxonidine and metformine. Indirect sign of imidazoline activating mechanism of C7070 is decreasing of the hepatoprotective effect of C7070 by the preliminary administration of imidazoline receptor blocker BU-224. The coefficients for ALT / AST for C7070, moxonidine and metformin were 72.8 / 62.13, respectively; 44.99 / 34.20 and 36.88 / 21.02. The coefficients of the morphological hepatoprotective activity of the preparations were: С7070 – 82.61, moxonidine – 72.33, metformin – 38.96. Conclusions: The imidazoline receptor agonists significantly and significantly reduce the functional and morphological manifestations of liver ischemia / reperfusion.

Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction and liver failure post-transplantation. To date, ischemia-reperfusion injury is an unsolved problem in clinical practice. In this context, inflammasome activation, recently described during ischemia-reperfusion injury, might be a potential therapeutic target to mitigate the clinical problems associated with liver transplantation and hepatic resections. The present review aims to summarize the current knowledge in inflammasome-mediated inflammation, describing the experimental models used to understand the molecular mechanisms of inflammasome in liver ischemia-reperfusion injury. In addition, a clear distinction between steatotic and non-steatotic livers and between warm and cold ischemia-reperfusion injury will be discussed. Finally, the most updated therapeutic strategies, as well as some of the scientific controversies in the field will be described. Such information may be useful to guide the design of better experimental models, as well as the effective therapeutic strategies in liver surgery and transplantation that can succeed in achieving its clinical application.

Aim: To investigate the protective efficacy of magnesium sulphate in a model of rat liver ischemia-reperfusion (I/R) injury. Method: 32 adult female Wistar-Albino rats (250 to 350 g) were used in this experimental study. Rats were divided into 4 groups according to liver ischemia and magnesium sulfate application methods. Group 1 (C); control, group 2 (M); magnesium sulphate, group 3 (I/R); liver I/R, group 4 (I/R+M); I/R + magnesium sulphate treated. The blood samples were centrifuged for the study of aspartate aminotransferase (AST), alanine aminotransferase, prothrombin time (PT), international normalized ratio (INR) troponin I, total antioxidant status (TAS), total oxidant status (TOS) assays. The livers of the animals were removed at the end of the study and samples were taken for histopathological examination. Results: AST and INR values were significantly decreased in I/R+M group compared to I/R group. There was no significant difference in ALT values of the groups. Although not statistically significant, the TAS values were increased in I/R + M group compared to I/R group rats. In addition, the value of TOS was found to be lower in I/R + M group rats. In the histopathological examination, the mean values of apoptosis and necrosis were lower in the IR+M group compared to the IR group. Conclusion: The main finding of the present study suggested that magnesium sulphate pretreatment moderately decreased the liver damage through its anti-inflammatory and anti-oxidant effects in a rat model of liver I/R.

The present study aimed to investigate the effects of intestinal remote ischemic preconditioning (iRIC) on ischemia-reperfusion injury (IRI) and gut barrier integrity in a rat model of total hepatic ischemia (THI). Male Wistar rats (n = 50, 250&ndash, 300 g) were randomly allocated into two experimental groups: RIC/Control. Thirty minutes of THI was induced by clamping the hepatoduodenal ligament. iRIC was applied as 4-min of ischemia followed by 11-min of reperfusion by clamping the superior mesenteric artery. Animals were sacrificed at 1, 2, 6, 24 h post-reperfusion (n = 5/group/timepoint). RIC of the gut significantly improved microcirculation of the ileum and the liver. Tissue ATP-levels were higher following iRIC (Liver: 1.34 &plusmn, 0.12 vs. 0.97 &plusmn, 0.20 &mu, mol/g, p = 0.04) and hepatocellular injury was reduced significantly (ALT: 2409 &plusmn, 447 vs. 6613 &plusmn, 1117 IU/L, p = 0.003). Systemic- and portal venous IL-6 and TNF-alpha levels were markedly lower following iRIC, demonstrating a reduced inflammatory response. iRIC led to a structural and functional preservation of the intestinal barrier. These results suggest that iRIC might confer a potent protection against the detrimental effects of THI in rats via reducing IRI and systemic inflammatory responses and at the same time by mitigating the dramatic consequences of severe intestinal congestion and bacterial translocation.

Introduction and objectives The omega-3 fatty acids (ω3), EPA and DHA, have been described for their beneficial effects on metabolism and inflammation. In addition, they are interesting tools in the treatment of acute liver disease. This investigation was conducted to assess the effect of EPA + DHA administration before partial ischemia (IR) on survival and liver injury. Materials and methods Male Sprague-Dawley rats were supplemented for 7 days with ω3 [EPA (270 mg/kg) and DHA (180 mg/kg)]; controls received saline solution. After EPA + DHA supplementation, liver IR was induced by temporarily occluding the blood supply for 1 h, followed up by 48 h of reperfusion. Control animals were subjected to sham laparotomy. Results Previous to IR, the EPA + DHA administration improved the rate and prolonged the survival time by decreasing the AST and ALT levels and improving liver degenerative changes generated by the IR, which decreased TNF-α and IL-1β. In addition, IL-10 increased at 20 h with a tendency to normalize at 48 h. The IR group had no differences in the IL-10 levels compared to controls. Conclusions The ω3 supplementation could prevent and promote the restoration of the liver tissue and significantly improve the survival rate in rats at 48 h.

Increased inflammatory responses and enhanced reactive oxygen species contribute to hepatic ischemia/reperfusion (I/R) injury, however the modulatory mechanisms haven't been completely unveiled. Here, we report that genetic deficiency of MAPK-activated protein kinase 2 (MK2) protected against hepatic I/R injury and decreased hepatic neutrophil accumulation in MK2-/- mice. Depletion of neutrophil attenuated hepatic I/R injury in wide type mice. In response to C5a stimulation, MK2-/- neutrophils generated less superoxide in which both NADPH oxidase activation and p47phox phosphorylation were decreased. Furthermore, Ser329 of p47phox was identified for enhancement of superoxide production. The Ser329 phosphorylation was reduced in MK2-/- neutrophils. To determine whether MK2 modulates hepatic I/R injury via activating neutrophils, we generated myeloid-specific MK2 deletion mice (MK2Lyz2-KO) and liver I/R injury was reduced in MK2Lyz2-KO mice. Our results indicate that MK2 augments hepatic I/R injury and induces ROS production with increased p47phox phosphorylation and MK2 is a potential drug target for treating hepatic I/R injury.

Background and Aim: Our previous studies have shown that regulatory T cells (Tregs) are reduced and Th17 cells are elevated in liver insults. Recent studies have indicated the critical role of endoplasmic reticulum (ER) stress of Kupffer cells (KCs) in evoking liver inflammation following reperfusion. The objective of this study was to investigate the role of ER stress of KCs in the conversion of Tregs to Th17 cells and the effect on liver ischemia-reperfusion injury. Methods: The partial warm liver ischemia-reperfusion injury mouse model was adopted. ER stress of KCs and the frequency of Tregs and Th17 cells following reperfusion were analyzed. Apart from depletion and adoptive transfer of KCs, KCs were isolated from ischemic lobes and co-cultured with Tregs to study the effect of KCs on Tregs and Th17 cells. Results: It was found that KCs induced ER stress, decreased natural Tregs (nTregs), and increased Th17 cells after reperfusion. Depletion of KCs modulated the reduction of nTregs and elevation of Th17 cells. Co-culture with stressed KCs led to the reduction in nTregs and elevation of Th17 cells. This effect was suppressed by anti-interleukin-6. Adoptive transfer of these stressed KCs resulted in the reduction in nTregs and elevation of Th17 cells and caused liver injury. Conclusion: Endoplasmic reticulum stress of KCs contributed to the conversion of nTregs to Th17 cells due to interleukin-6, resulting in the worsening of liver insult.

Objectives The purpose of our study was to evaluate the potential of x-ray propagation-based phase-contrast imaging (PCI) computed tomography (CT) for the detection and characterization of early changes after ischemia-reperfusion (IR) in a standardized rat liver transplantation (LTx) model. Materials and Methods Syngeneic orthotopic liver transplantation was performed in male Lewis rats. Ischemia-reperfusion injury (IRI)-induced changes of liver parenchyma were investigated in a time-dependent manner (2, 16, 24, and 32 hours). X-ray phase-contrast images of formalin-fixated liver specimens were acquired in CT mode by using a voxel size of 8 x 8 x 8 mu m(3). Necrapoptotic cell death was visualized with the TdT-mediated dUTP-biotin nick end labeling technique, and alterations of liver graft microhemodynamics, that is, acinar and sinusoidal perfusion failure, were evaluated by in vivo fluorescence microscopy. Results Acquired and reconstructed PCI-CT images showed an increase in necrotic liver parenchyma dependent on cold storage time, measuring 5.7% +/- 1.6% after 2 hours (comparable to 2.6% +/- 0.4% for sham livers), 11.5% +/- 2.1% (16 hours;P < 0.05 vs control), 23.0% +/- 0.5% (24 hours;P < 0.001 vs control), and 31.3% +/- 2.2% (32 hours;P < 0.001 vs control). There were a significant lower number of perfused acini in dependence on increasing cold storage time. The acinar perfusion index reached 0.970 +/- 0.006 after 2 hours of cold ischemia (comparable to 0.960 +/- 0.009 for sham livers) and declined continuously after 16, 24, and 32 hours cold ischemia (0.58 +/- 0.03, 0.49 +/- 0.02, 0.41 +/- 0.03, each P < 0.0001 vs controls). Comparable results were found for sinusoidal perfusion, reaching 1.8% +/- 0.4% of nonperfused sinusoids for 2 hours of cold ischemia and 8.2% +/- 0.8% after 16 hours, 18.8% +/- 1.4% after 24 hours, and 39.0% +/- 2.4% after 32 hours (each P < 0.0001 vs controls). Prolonged cold ischemia was associated with an increasing number of TdT-mediated dUTP-biotin nick end labeling-positive cells (hepatocytes and sinusoidal lining cells), reaching 0.4 +/- 0.1 (sham), 0.7 +/- 0.4 (2 hours), 6.4 +/- 1.1 (16 hours), 2.1 +/- 0.3 (24 hours), and 14.7 +/- 3.5 (32 hours;P = 0.002) for hepatocytes. Conclusions X-ray PCI of histological liver specimens can detect IR-induced tissue necrosis and can provide detailed complementary 3-dimensional information to standard histopathologic findings.

Background Aggravated liver ischemia and reperfusion (IR) injury has been reported in aged mice. Although necroptosis inhibition showed no crucial effect on hepatic IR injury in young mice, whether and how necroptosis affects liver IR injury in aged mice remains unclear. Methods Young and aged mice were subjected to liver IR modeling. Liver injury, hepatocyte necroptosis and endoplasmic reticulum (ER) stress were analyzed in different groups. Results Significantly increased liver necroptosis was found in aged mice post IR compared with young mice. Necroptosis inhibition by necrostatin-1 (Nec-1) decreased hepatocyte necroptosis and liver injury post IR in aged mice, with no significant effects on young mice. Furthermore, IR induced ER stress in both young and aged mice, and enhanced ER stress was observed in aged mice post IR. Administration of 4-phenylbutyrate (4-PBA), an ER stress antagonist, alleviated liver IR injury in both young and aged mice. However, ER stress inhibition reduced hepatocyte necroptosis in aged mice but not in young mice. Conclusions Aging increased ER stress in IR-stressed hepatocytes, leading to aggravated necroptosis and liver IR injury. Our study demonstrated a novel mechanism of ER stress in the regulation of hepatocyte necroptosis in aged livers post IR, which would be a potential therapeutic target to reduce liver IR injury in elderly patients.

The total hepatic ischemia/reperfusion injury (IRI) involves the fact that both liver and gut are subjected to warm ischemia, which is a complex unavoidable process encountered during liver transplantation and a serious threat to graft outcome. The ways to improve hepatic IRI are currently limited. The aim of the present study was to explore the protective effect of simvastatin on total hepatic IRI and examine the underlying mechanisms.Male Sprague Dawley rats were subjected to total (100%) hepatic warm ischemia to induce hepatic IRI. Thirty-six male rats (250-300 g) were randomly divided into three groups: sham, IRI control and simvastatin (1 mg/kg) pretreatment 0.5 h before surgery. Serum samples and liver tissues were collected after reperfusion at 6 and 24 h for further studies.Simvastatin pretreatment significantly decreased the values of the transaminases alanine aminotransferase and aspartate aminotransferase and improved histological alterations according to improved Suzuki's Score (P 0.05). Moreover, simvastatin upregulated the expression of Kruppel-like factor 2 (KLF2), phosphorylated endothelial nitric oxide synthase and thrombomodulin (P 0.05). Furthermore, simvastatin pretreatment affected superoxide dismutase and malondialdehyde activities (P 0.05) to reduce oxidative stress, and inhibited levels of high-mobility group box-1, CD68, toll-like receptor 4, tumor necrosis factor α, interleukin-1β and interleukin-6 (P 0.05) to suppress inflammatory response.Simvastatin pretreatment ameliorates total hepatic IRI via a KLF2-mediated protective mechanism. Simvastatin may be used as a potential prophylactic treatment strategy for clinical trials against hepatic IRI.

Background Remote ischemic preconditioning (RIPC) can be protective against the damage. However, there is no consensus on the optimal amount of tissue, the number and duration of the ischemic cycles, and the timing of the preconditioning. The hemorheological background of the process is also unknown. Objective To investigate the effects of remote organ ischemic preconditioning on micro-rheological parameters during liver ischemia-reperfusion in rats. Methods In anesthetized rats 60-minute partial liver ischemia was induced with 120-minute reperfusion (Control, n = 7). In the preconditioned groups a tourniquet was applied on the left thigh for 3×10 minutes 1 hour (RIPC-1, n = 7) or 24 hours (RIPC-24, n = 7) prior to the liver ischemia. Blood samples were taken before the operation and during the reperfusion. Acid-base, hematological parameters, erythrocyte aggregation and deformability were tested. Results Lactate concentration significantly increased by the end of the reperfusion. Erythrocyte deformability was improved in the RIPC-1 group, erythrocyte aggregation increased during the reperfusion, particularly in the RIPC-24 group. Conclusions RIPC alleviated several hemorheological changes caused by the liver I/R. However, the optimal timing of the RIPC cannot be defined based on these results.

Ischemia reperfusion injury (IRI) is a complex pathophysiologic process that occurs during liver transplantation and liver resection. It is a significant cause of morbidity and mortality in liver s...

Hepatic ischemia/reperfusion (I/R) describes the paradox of additional tissue injury caused by reperfusion. The aim of this survey was to investigate the mRNA expression of genes exerting their inflammatory and regenerative reaction in a porcine model of I/R and extended hepatectomy.Twelve pigs were used, weighing 30-35 kg in average, which were allocated in two groups: the I/R group with eight pigs and the sham-operated (control) one with four pigs. The I/R group underwent portacaval anastomosis and Pringle maneuver followed by extended hepatectomy. The hepatoduodenal ligament was occluded for 150 min and the liver remnant was reperfused for 24 hours. Blood samples were steadily received throughout the surgical procedure, where hepatic biopsies were taken for pathological evaluation. Animals were sacrificed in 24 hours after the onset of reperfusion.Between the two groups, statistically significant differences were noticed in serum values of AST, ALT, ALP, and total bilirubin in the early and late phase of reperfusion. The mRNA expression of iNOS, IL-1b, and TGF-a did not increase significantly in the I/R group. Conversely, the mRNA modification of IL-6, STAT-3, and E-selectin demonstrated significantly increased expression in I/R animals.In the present survey, a new I/R swine model was proposed and specific parameters were analyzed, revealing differences between the study groups.

Aim: Ischemic preconditioning (IPC) protects tissue against ischemia and reperfusion (I/R) injury. The aim of this study was to examine the impact of IPC on protection of hepatocytes after prolonged I/R injury. Methods: Twenty-four Wistar rats were randomly divided into ischemic preconditioning group (IP), ischemia/reperfusion group (IR) and sham operation group (SO). A model of partial liver ischemia/reperfusion was used, in which rats were subjected to liver ischemia for 90 min prior to reperfusion. The animals in the IP group underwent ischemic preconditioning for 10 min prior to the ischemia/reperfusion challenge. After 3 h of reperfusion, serum and liver tissue in each group were collected to detect the level of serum ALT, AST, HA, MDA and liver histopathology. Results: Compared with IR group, IP group showed a significantly lower ALT, AST, HA and MDA level in 3 h. Proliferation index (PI) was significantly increased in IP group compared with IR group. Conclusion: Ischemic preconditioning can protect liver cells against ischemia/reperfusion injury, which may be related to cell proliferation during early ischemic reperfusion.

Ischemic preconditioning exerts a protective effect in hepatic ischemia/reperfusion injury. The exact mechanism of ischemic preconditioning action remains largely unknown. Recent studies suggest that autophagy plays an important role in protecting against ischemia/reperfusion injury. However, the role of autophagy in ischemic preconditioning-afforded protection and its regulatory mechanisms in liver ischemia/reperfusion injury remain poorly understood. This study was designed to determine whether ischemic preconditioning could protect against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy.Laboratory investigation.University animal research laboratory.Male inbred Lewis rats and C57BL/6 mice.Ischemic preconditioning was produced by 10 minutes of ischemia followed by 10 minutes of reperfusion prior to 60 minutes of ischemia. In a rat model of hepatic ischemia/reperfusion injury, rats were pretreated with wortmannin or rapamycin to evaluate the contribution of autophagy to the protective effects of ischemic preconditioning. Heme oxygenase-1 was inhibited with tin protoporphyrin IX. In a mouse model of hepatic ischemia/reperfusion injury, autophagy or heme oxygenase-1 was inhibited with vacuolar protein sorting 34 small interfering RNA or heme oxygenase-1 small interfering RNA, respectively.Ischemic preconditioning ameliorated liver ischemia/reperfusion injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines, and less severe ischemia/reperfusion-associated histopathologic changes. Ischemic preconditioning treatment induced autophagy activation, as indicated by an increase of LC3-II, degradation of p62, and accumulation of autophagic vacuoles in response to ischemia/reperfusion injury. When ischemic preconditioning-induced autophagy was inhibited with wortmannin in rats or vacuolar protein sorting 34-specific small interfering RNA in mice, liver ischemia/reperfusion injury was worsened, whereas rapamycin treatment increased autophagy and mimicked the protective effects of ischemic preconditioning. Furthermore, ischemic preconditioning increased heme oxygenase-1 expression. The inhibition of heme oxygenase-1 with tin protoporphyrin IX in rats or heme oxygenase-1-specific small interfering RNA in mice decreased ischemic preconditioning-induced autophagy and diminished the protective effects of ischemic preconditioning against ischemia/reperfusion injury.Ischemic preconditioning protects against liver ischemia/reperfusion injury, at least in part, via heme oxygenase-1-mediated autophagy.

We investigated the hepatoprotective effect of Silibinin (SLB) to ischemia-reperfusion (I/R) rat model, by evaluating the histological expression of the tissue markers Fas/FasL, HMGB-1 and CD45, and SLB pharmacokinetics.Seventy-three Wistar-type male rats were randomized in 11 groups: Sham control group (open-close laparotomy); four I/R control groups (laparotomy, 45 min vascular occlusion, reperfusion, euthanasia after 60, 120, 180, and 240 min); four SLB (Si) groups (laparotomy, 45 min vascular occlusion, IV administration of SLB, reperfusion, euthanasia after 60, 120, 180, and 240 min); two SLB pharmacokinetics (PK) groups (IV administration of SLB, euthanasia after 45 and 240 min).Fas/FasL increased with reperfusion time in I/R control groups and decreased in the Si groups, reaching, respectively, the highest and lowest values at 240 min of reperfusion (p.0001). HMGB1 and CD45 increased with time in the I/R control groups up to 240 min and decreased in the Si groups, approaching zero expression after 180 and 60 min, respectively. Pharmacokinetic data showed higher liver accumulation and slower plasma elimination of SLB in ischemic animals.The hepatoprotective effect of SLB was demonstrated through the reduction of the expression of Fas/FasL, HMGB-1 and CD45 in liver tissue under I/R conditions, and in the pharmacokinetic study. The results document the efficacy of silibinin in the protection of the liver, and are particularly encouraging for its use in hepatic surgery.

Previous studies have revealed the activation of neutral sphingomyelinase (N-SMase)/ceramide pathway in hepatic tissue following warm liver ischemia reperfusion (IR) injury. Excessive ceramide accumulation is known to potentiate apoptotic stimuli and a link between apoptosis and endoplasmic reticulum (ER) stress has been established in hepatic IR injury. Thus, this study determined the role of selective N-SMase inhibition on ER stress and apoptotic markers in a rat model of liver IR injury. Selective N-SMase inhibitor was administered via intraperitoneal injections. Liver IR injury was created by clamping blood vessels supplying the median and left lateral hepatic lobes for 60 min, followed by 60 min reperfusion. Levels of sphingmyelin and ceramide in liver tissue were determined by an optimized multiple reactions monitoring (MRM) method using ultrafast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Spingomyelin levels were significantly increased in all IR groups compared with controls. Treatment with a specific N-SMase inhibitor significantly decreased all measured ceramides in IR injury. A significant increase was observed in ER stress markers C/EBP-homologous protein (CHOP) and 78 kDa glucose-regulated protein (GRP78) in IR injury, which was not significantly altered by N-SMase inhibition. Inhibition of N-SMase caused a significant reduction in phospho-NF-kB levels, hepatic TUNEL staining, cytosolic cytochrome c, and caspase-3, -8, and -9 activities which were significantly increased in IR injury. Data herein confirm the role of ceramide in increased apoptotic cell death and highlight the protective effect of N-SMase inhibition in down-regulation of apoptotic stimuli responses occurring in hepatic IR injury.

The present review discusses strategies for minimizing the ischemia/reperfusion injury (IRI) experienced during liver surgery and transplantation. We present the experimental models used to study the complexity of hepatic IRI and new surgical and pharmacologic strategies for manipulating and improving liver function after liver surgery and transplantation. This would be of clinical interest to reduce the prevalence of IRI and improve patient management and outcomes. The ongoing effort to expand the pool of usable liver grafts has made it clear that a better understanding of the mechanisms of IRI and other consequences of using expanded criteria donor (ECD) liver allografts are critical to improving results with these grafts.

Our previous study indicated that adoptive transferred regulatory T cells (Tregs) attenuated liver ischemia reperfusion injury (IRI). Recent studies demonstrated that hepatic stellate cells (HSCs) were producers of induced Tregs (iTregs) via retinoic acid. This study aimed to investigate the role of adoptive transferred HSCs in liver IRI. Mice were treated with gradient doses of HSCs before surgery at 24 h or 72 h. The levels of serum aminotransferases and hepatic cytokines were evaluated after reperfusion. Meanwhile, hepatic Tregs and their subsets were analyzed by flow cytometry. We found that adoptive transferred HSCs attenuated liver IRI. Administration of HSCs expanded the number of hepatic iTregs and natural Tregs (nTregs) after reperfusion. In addition, we found that the increased Tregs were almost Helios-Tregs before surgery. These Helios-Tregs were considered as iTregs and protected liver from IRI partially. Furthermore, adoptive transferred HSCs stabilized nTregs and prevented nTregs from reducing after reperfusion. These nTregs also attenuated liver IRI partially. Depletion of Tregs abolished the protective effect of HSCs. Thus, we conclude that adoptive transferred HSCs ameliorate liver IRI in Tregs-dependent manner.

The aim of this study was to assess the classification accuracy of an e-Nose in detecting acute liver failure (ALF) in rats. Exhaled breath from 14 rats was repeatedly sampled by e-Nose (8 sensors) and an additional external CO2 sensor at three stages: healthy period; portacaval shunt; and during the development of ALF due to surgically induced complete liver ischemia. We performed principal component analysis (PCA) on the (grouped) sensor data in each stage and the classification accuracy of the first two principal components was assessed by the leave-one-out approach. In addition we performed gas chromatography–mass spectrometry (GC–MS) analysis of the exhaled breath from three rats. The first and second principal components from the PCA analysis of e-Nose data accounted for more than 95% variance in the data. Measurements in the ALF stage were contrasted with the measurements in the control stage. Leave-one-out validation showed classification accuracy of 96%. This accuracy was reached after 3 h of ALF development, and was reached already after 2 h when data of an external CO2 sensor were also included. GC–MS identified 2-butanol, 2-butanone, 2-pentanone and 1-propanol to be possibly elevated in the ALF stage. This is the first study to demonstrate that ALF in rats can be detected by e-Nose data analysis of the exhaled breath. Confirmation of these results in humans will be an important step forward in the non-invasive diagnosis of ALF.

Liver ischemia-reperfusion injury (IRI) represents a risk factor for early graft dysfunction and an obstacle to expanding donor pool in orthotopic liver transplantation (OLT). We have reported on the crucial role of macrophage Notch1 signaling in mouse warm hepatic IRI model. However, its clinical relevance or therapeutic potential remain unknown. Here, we used Serelaxin (SER), to verify Notch1 induction and putative hepatoprotective function in IR-stressed OLT. C57BL/6 mouse livers subjected to extended (18hr) cold storage were transplanted to syngeneic recipients. SER treatment at reperfusion ameliorated IRI, improved post-OLT survival, decreased neutrophil/macrophage infiltration, suppressed pro-inflammatory cytokine programs, while simultaneously increasing Notch1 intracellular domain (NICD) and hairy and enhancer of split-1 (Hes1) target genes. In bone marrow-derived macrophage cultures, SER suppressed pro-inflammatory while enhancing anti-inflammatory gene expressions concomitantly with increased NICD and Hes1. Hepatic biopsies from twenty-one adult primary liver transplant patients (2h post-reperfusion) were divided into low-NICD (n=11) and high-NICD (n=10) expression groups (Western blots). Consistent with our murine findings, human livers characterized by high-NICD were relatively IRI resistant, as shown by sALT levels at day 1 post-OLT. Our study documents the efficacy of SER – Notch1 signaling in mouse OLT and highlights the protective function of Notch1 in liver transplant patients.