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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

허혈 재관류 손상은 기관 이식, 외과적 혈관 재개통 및 출혈 시에 발생하며 조직 및 기관 기능 장애를 유발한다. 최근 허혈 재관류 손상의 기전적 연구를 위해 간장 허혈 모델을 많이 이용하고 있다. 본 연구는 허혈 재관류 랫드 모델을 이용하여 항산화와 항염증 효과를 가진 것으로 알려진 Vanillin에 의한 간장 및 신장 손상에 대한 보호 효과를 알아보고 관련된 기전을 조사하기 위하여 실시하였다. 시험물질은 각각 100 mg/kg의 농도로 3일간 투여한 후, 60분동안 간을 결찰하여 허혈 재관류를 유도하여 관찰하였으며, 음성대조군, sham대조군 및 허혈재관류만 실시한 허혈 재관류대조군을 따로 두어, 약물투여군과 비교하였다. Vanillin 처치군에서는 AST, ALT 활성이 허혈 재관류대조군에 비해 유의하게 억제되었고, 조직병리학적 관찰에서도 염증 부분과 괴사부분이 현저하게 감소하였다. MDA와 SOD는 허혈 재관류군에 비해 유의적인 변화를 보였다. 이상의 결과를 종합하면 Vanillin은 간장 허혈 재관류에 의한 세포염증 및 세포괴사를 완화시켜 간세포 보호작용을 나타내었고, 신장의 사구체 및 원 위세뇨관에 염증 변화를 완화 시키고 있어 세포 손상을 방어하는 것으로 생각되며, 이러한 방어효과는 항산화 기능에 의한 영향으로 사료된다.

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

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

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.

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.

Instant Blood-Mediated Inflammatory Reaction (IBMIR) is a major cause of graft loss during pancreatic islet transplantation, leading to a low efficiency of this treatment method and significantly limiting its broader clinical use. Within the procedure, transplanted islets obstruct intrahepatic portal vein branches and consequently restrict blood supply of downstream lying liver tissue, resulting typically in ischemic necrosis. The extent of ischemic lesions is influenced by mechanical obstruction and inflammation, as well as subsequent recanalization and regeneration capacity of recipient liver tissue. Monitoring of immediate liver perfusion impairment, which is directly related to the intensity of post-transplant inflammation and thrombosis (IBMIR), is essential for improving therapeutic and preventive strategies to improve overall islet graft survival. In this study, we present a new experimental model enabling direct quantification of liver perfusion impairment after pancreatic islet transplantation using ligation of hepatic arteries followed by contrast-enhanced magnetic resonance imaging (MRI). The ligation of hepatic arteries prevents the contrast agent from circumventing the portal vein obstruction and enables to discriminate between well-perfused and non-perfused liver tissue. Here we demonstrate that the extent of liver ischemia reliably reflects the number of transplanted islets. This model represents a useful tool for in vivo monitoring of biological effect of IBMIR-alleviating interventions as well as other experiments related to liver ischemia. This technical paper introduces a novel technique and its first application in experimental animals.

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 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.

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...

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.