Treatment Of Hepatic Injury Research Articles

Luteolin attenuates CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11.

Luteolin (3,4,5,7-tetrahydroxy flavone) is reported to strongly protect from acute carbon tetrachloride (CCl4) -induced liver injury or fibrosis. Ferroptosis can be induced by hepatic injury, and contributes to liver fibrosis development. The exact functional mechanism underlying luteolin inhibition of hepatic injury and whether ferroptosis is involved are unclear. Mice model and cell model of liver injury were constructed or induced to explore the effect and molecular mechanisms of Luteolin in the treatment of hepatic injury using CCl4. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to evaluate HepG2 cell viability and apoptosis. The differential expressed genes involved in liver injury were scanned using RNA-seq and confirmed using functional study. Western blot was used to detect the indicators related to ferroptosis. Luteolin attenuated hepatic injury by alleviating cell morphology and decreasing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels in vivo mice models, and increasing cell viability, downregulating arachidonate 12-lipoxygenase (ALOX12), cyclooxygenase-2 (COX-2) and P21 protein expression, suppressing apoptosis in vitro cell models. Luteolin also inhibited ferroptosis by stimulating glutathione peroxidase 4 (GPX4) and mitochondrial ferritin (FTMT) protein expression, increasing glutathione (GSH) content, and minimizing Fe2+ and malondialdehyde (MDA) levels. Solute carrier family 7a member 11 (SLC7A11) was identified to be a key regulatory gene that participated in luteolin attenuation of CCl4-induced hepatic injuries in HepG2 cells using Microarray assay. Functional study showed that SLC7A11 can alleviate hepatic injury and ferroptosis. Luteolin attenuated CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11. SLC7A11 may serve as a novel alternative therapeutic target for hepatic injury.

Mechanisms of Ardisia japonica in the Treatment of Hepatic Injury in Rats Based on LC-MS Metabolomics.

The mechanism of action of Ardisia japonica in the treatment of immune liver injury was systematically analyzed from the perspective of the biological metabolic network by using non-targeted metabolomics combined with biological network analysis tools. A rat model of acute immune hepatic injury was established by Concanavalin A (Con A) and the efficacy of the treatment of acute immune liver injury was judged by gavage of A. japonica. Liquid chromatography-mass spectrometry (LC-MS)-based plasma metabolomics was used to identify the key metabolites and metabolic pathways for the hepatoprotective effects of A. japonica. The results demonstrated that A. japonica reduced the levels of inflammatory parameters, decreased hepatic malondialdehyde levels, and enhanced hepatic antioxidant enzyme activity in animal experiments. The clustering of metabolomic samples showed significant separation in principal component analysis plots and the three groups in PLS-DA and OPLS-DA models could be clearly distinguished in multivariate statistical analysis. Among the 937 total metabolites, 445 metabolites were significantly different between the control and model groups, while 144 metabolites were identified as metabolites with differences between the model and administration groups, and a total of 39 differential metabolites were identified to affect the metabolic levels of the three groups. The differential metabolites were principally involved in the citric acid cycle, glutathione metabolism, vitamin B6 metabolism, and steroid hormone biosynthesis. This study found that A. japonica can significantly inhibit acute liver injury in rats, and exert a hepatoprotective effect through anti-inflammatory effect, inhibition of lipid peroxidation, improvement of the antioxidant defense system, and regulation of metabolites and related metabolic pathways. This study will provide a theoretical basis for the application of A. japonica in the treatment of the liver injury.

Accident-related hepatic trauma in a medical clinical center in eastern China: a cross-sectional study

BackgroundThe treatment of hepatic injury can be complex. Medical clinical centers are often the first line hospitals for the diagnosis and treatment of hepatic trauma in China. The aim of the study is to summarize the experience in the diagnosis and treatment of hepatic trauma in one medical clinical center in China.MethodsThis retrospective study included patients with hepatic trauma admitted between January 2002 and December 2019 at the Xishan People’s Hospital of Wuxi. The outcomes were cure rate and death within 14 days post-discharge.ResultsAmong the 318 patients with hepatic trauma, 146 patients underwent surgical treatment, and 172 received conservative treatment; three patients were transferred to other hospitals for further treatment; 283 patients were cured, and 35 died. Severe hepatic trauma occurred in 74 patients, with a mortality rate of 31.1% and accounting for 65.7% of total mortality. American Association for the Surgery of Trauma (AAST) grading ≥ III (OR = 3.51, 95%CI: 1.32–9.37, P = 0.012) and multiple organ injury (OR = 7.51, 95%CI: 2.51–22.46, P < 0.001) were independently associated with death. Among patients with AAST grading ≥ III, surgery was an independent protective factor for death (OR = 0.08, 95%CI: 0.01–0.45, P = 0.004). Among patients with ASST ≥ III and who underwent surgery, age (OR = 5.29, 95%CI: 1.37–20.33, P = 0.015) and peri-hepatic packing (PHP) (OR = 5.54, 95%CI: 1.43–21.487, P = 0.013) were independently associated with death.ConclusionsAAST grading ≥ III and multiple organ injury were independently associated with death. Among patients with AAST grading ≥ III, surgery was an independent protective factor for death. Among patients with ASST ≥ III and who underwent surgery, age and PHP were independently associated with death.

Metabolomics study on the therapeutic mechanism of Schisandra chinensis polysaccharides on concanavalin A-induced immunological liver injury in mice

Background: Schisandra chinensis is a traditional Chinese herbal medicine which protects hepatic function. Its primary component is polysaccharides which is used in the treatment of hepatic injury, but the mechanism of action of S. chinensis polysaccharides (SCP) in immunological liver injury induced by concavalin A (Con A) is still not clear. Aim: In this study, we aimed to evaluate the hepatoprotective mechanism of SCP in immunological liver injury. Subjects and Methods: In this study, we performed rapid-resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry-based serum metabolomics approach to investigate the hepatoprotective effects of SCP against Con A-induced immunological liver injury in mice. Results: According to our results, SCP significantly increased the activity of superoxide dismutase in the liver; decreased the level of serum aspartate aminotransaminase (AST), serum alanine aminotransaminase (ALT), tumor necrosis factor-α, interferon-γ, interleukin (IL)-1 β, and IL-6 in the serum, and decreased the level of malondialdehyde and nitric oxide in the liver of mice with immunological liver injury induced by Con A. In this study, we identified 17 biomarkers through metabolomic analysis, and after the administration of SCP, 16 of them were found to return to the normal levels. Our analysis suggested that some metabolic pathways are involved in the mechanisms of action of SCP for the treatment of the immunological liver injury, including energy metabolism, amino acid metabolism, taurine metabolism, amino saccharide and nucleotide metabolism, arachidonic acid metabolism, and lipid metabolism. Conclusion: SCP could alleviate the oxidative stress and inflammatory reaction in the immunological liver injury and recover the metabolic dysfunction caused by Con A.

Gandou decoction, a Chinese medicinal formula, in the treatment of hepatic injury by Wnt/β-catenin pathway regulation in models of Wilson disease.

Gandou decoction (GDD) has been widely used in the treatment of Wilson disease (WD) for decades. It is optimized from the Dahuanghuanglianxiexin decoction, Yinchenhao decoction, and Huanglianjiedu decoction. It was first reported in the Treatise on Febrile and Miscellaneous Diseases and A Handbook of Prescriptions for Emergencies published in the Eastern Han Dynasty and the Eastern Jin Dynasty respectively. Hepatic injury is one of the most severe complications of WD. The current study aimed to explore the hepatic-protection effects of GDD and its exact therapeutic target, with a particular focus on the expression of oxidative stress and the Wnt/β-catenin pathway. Hepatic injury was induced in a copper-loaded rat model using the intragastric administration of copper(II) sulfate pentahydrate (CuSO4·5H2O). The water extract of GDD (0.4 g/kg/d) was administered twice a day for 4 weeks. Copper content and alanine aminotransferase (ALT) level, structural observation under the microscope, and immunohistochemical analysis of liver tissue were performed after the final administration. Moreover, the expression of β-catenin, GSK3β, Dishevelled-3, c-Myc, and p-GSK3β of liver tissue were detected to explore the relationship between the hepatic protection of GDD and the Wnt/ β-catenin signal pathway of GDD. We also stimulated the rat hepatic cell line BRL-3A with CuSO4·5H2O to establish a hepatic injury cytomodel. GDD serum at a concentration of 20% was administered into the model cell for 24 h. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry were performed to detect cell viability, mitochondrial membrane potential (MMP), and the expression of reactive oxygen species (ROS). Meanwhile, the expression of the Wnt/β-catenin signal pathway-related proteins was evaluated. GDD reduced copper and ALT while inhibiting oxidative stress and the degeneration and necrosis of liver tissue and hepatocytes. Treatment with GDD improved cell viability and MMP while suppressing the ROS level. Furthermore, GDD rectified the expression of Wnt/β-catenin signal pathway-related proteins in both livers of the copper-loaded and copper-stimulated BRL-3A cell lines. GDD had apparent therapeutic effects on the hepatic injury of copper-loaded rats and copper-stimulated BRL-3A cells. Its mechanism is related to its regulatory effect on the Wnt/β-catenin pathway rectification and oxidative stress antagonism.

Effect of L-arginine on methotrexate induced hepatotoxicity in albino rats.

Methotrexate (MTX) is commonly used in the treatment of many different types of cancer and inflammatory diseases. Its cytotoxic nature also lends a substantial risk of life-threatening side effects. L-arginine is beneficial in the treatment of hepatic injury, hepatic cirrhosis and fatty liver degeneration. The present work aims to study the effect of L-arginine on hepatotoxicity of methotrexate in albino rats. Five groups of albino rats were used. Group I: control. Group II: rats were administered (MTX) in a daily oral dose of 0.45 mg/kg, for 28 days. Group III: rats were administered L-arginine in a daily oral dose of 300 mg/kg, for 28 days. Group IV: rats were received L- arginine 2 hrs before (MTX). Group V: rats were received L-arginine 2 hrs after (MTX). The results revealed different histopathological changes in liver of MTX-treated rats such as focal areas of necrosis and increased numbers of activated Kupffer cells, an apparent increase in the amount of collagen fibers and strong immunoreactive expression of α- SMA. Biochemical results revealed a significant increase in the serum levels of ALT, AST, bilirubin and decreasing the level of antioxidant enzymes. L-agrinine minimized the hepatotoxicity of MTX by decreasing the level of ALT, AST and bilirubin, MDA and increasing the antioxidant enzymes. It is concluded that L-arginine protects liver from hepatotoxicity of methotrexate and this due to its antioxidant activity.

Protective Effects of Quercetin and Quercetin-5',8-Disulfonate against Carbon Tetrachloride-Caused Oxidative Liver Injury in Mice

Oxidative stress is one of the major factors in the pathogenesis of liver disease. Quercetin is a plant-based antioxidant traditionally used as a treatment for hepatic injury, but its poor solubility affects its bioavailability. We here report the regulative effects on hepatoprotection and absorption in mice of quercetin sulfation to form quercetin-5',8-disulfonate (QS), a novel synthetic compound. Oral administration of both QS and the parent quercetin at 100, 200 and 500 mg/kg·bw prior to acute CCl4 oxidative damage in mice, effectively attenuated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities and hepatic malondialdehyde (MDA) levels (p < 0.05), and suppressed the CCl4-induced depletion of glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD). Selective 5',8-sulfation of quercetin increased the hepatoprotective effect, and its relative absorption relative to quercetin (p < 0.05) as indicated by an improved 24-hour urinary excretion and a decreased fecal excretion determined by HPLC. These results and histopathological observations collectively demonstrate that quercetin sulfation increases its hepatoprotective effects and absorption in mice, and QS has potential as a chemopreventive and chemotherapeutic agent for liver diseases.

Autologous bone marrow stem cell transplantation attenuates hepatocyte apoptosis in a rat model of ex vivo liver resection and liver autotransplantation

BackgroundTo investigate the efficacy of autologous bone marrow stem cell (BMSC) transplantation in the treatment of hepatic injury in ex vivo liver resection and liver autotransplantation (ELRLA). Materials and methodsRat hepatic fibrosis was induced by intraperitoneal injection of 50% CCl4–olive oil solution at a dose of 2 mL/kg twice weekly for 4 wk. ELRLA was performed 3 d post the last injection of CCl4. Six rats in each group were killed 12, 24, 48, 72, and 168 h after the operation. Hepatocyte apoptosis was determined by TUNEL assay. The expression of Bcl-2, Bax, transforming growth factor (TGF) β1, TGFβ1 receptor1/2, and phosphorylated p38 MAPK were determined by Western blot. ResultsAutologous BMSC transplantation significantly inhibited the increase of alanine aminotransferease and aspartate aminotransferase at 12, 24, and 48 h post operation and attenuated ELRLA-induced hepatocyte apoptosis. In BMSC-treated rats, the expression of Bcl-2 was significantly upregulated, whereas there were no obvious changes in Bax level. The expression of TGFβ1 was significantly upregulated in the rat liver after the surgery. Autologous BMSC transplantation significantly downregulated the TGFβ1 levels at 48, 72, and 168 h post surgery. However, autologous BMSC transplantation showed little effect on the levels of TGFβ receptor 1/2 at all the time points observed. Furthermore, autologous BMSC transplantation significantly inhibited the activation of p38 MAPK. ConclusionAutologous BMSC transplantation may reduce ELRLA-induced liver injury and improve survival rates in hepatic fibrosis rats. Autologous BMSC transplantation may be useful to improve the outcome of patients who undergo ELRLA.

Hepatoprotective effects of an active part from Artemisia sacrorum Ledeb. against acetaminophen-induced toxicity in mice

Aims of study Although Artemisia sacrorum Ledeb. (Compositae) has long been used as one kind of oriental folk medicine to treat some liver diseases, the underlying mechanism(s) by which these effects are induced remains to be defined. This study was designed to investigate the hepatoprotective effects of 50% ethanol eluate precipitation of Artemisia sacrorum Ledeb. (EEP) on acetaminophen (APAP)-induced toxicity in mice. Materials and methods The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-α (TNF-α) levels in mouse sera, and glutathione (GSH), malondialdehyde (MDA) in mouse liver tissues were measured. In addition, apoptosis and necrosis were evaluated by liver histopathological analysis and DNA laddering. Moreover, caspase-3 and -8 protein expressions in mouse livers were observed by Western blot analysis. Results Pretreated with EEP prior to the administration of APAP significantly prevented the increases of AST, ALT, and TNF-α levels in sera, and suppressed the GSH depletion, MDA accumulation in liver tissues markedly. In addition, EEP prevented APAP-induced apoptosis and necrosis, as indicated by liver histopathological analysis, immunohistochemical analysis, and DNA laddering. Furthermore, according to the results from Western blot analysis, EEP decreased APAP-induced caspase-3 and caspase-8 protein expressions in mouse livers markedly. Conclusion All these results suggest that the protective effects of EEP against APAP-induced liver injury may involve mechanisms associated with its inhibitive effects of lipid peroxidation and the down-regulation of TNF-α mediated apoptosis. In a word, EEP could be a valuable candidate for further development for prevention and treatment of hepatic injury.

Biliary Fistulas Resulting from Blunt Hepatic Injury Treated by Endoscopic Diversion of the Bile Flow

Biliary fistula is a fairly uncommon complication of blunt liver injury, but with more liberal use of a nonoperative approach to the treatment of hepatic injury, the incidence is rising. If present, it becomes evident with physical examination aided by common diagnostic modalities (ultrasonography, computed tomography, cholangiography). The treatment, though, still presents a significant dilemma and often results in high morbidity with prolonged hospital stay and unnecessary expenses.Information was collected prospectively on a group of 26 consecutive patients with blunt hepatic trauma. Three cases of biliary fistulas were diagnosed, all after bile peritonitis ensued, or after a continuous discharge of bile through a postoperative drain took place. In one case, the diagnosis was confirmed by ultrasonography and computed tomography. Endoscopic retrograde cholangiopancreatography was used in all cases for diagnostic work-up and therapy. Endoscopic placement of a nasobiliary catheter was the definitive treatment in all cases. In all three patients, abdominal drains were removed two days after placement of a nasobiliary catheter. Diversion of the bile flow was discontinued after 6–7 days with no recurrent bile leak. No mortality due to hepatic injury or its complications was observed. Conclusions: Posttraumatic bile fistulas are relatively easy to diagnose and their management with endoscopic drainage of the biliary tree through a nasobiliary tube is safe and effective. Adequate perihepatic drainage prevents relaparotomy for bile peritonitis. The possibility of biliary leakage does not reduce the relative safety of non-operative treatment of injury to solid organs.

Validity of microporous polysaccharide hemispheres as a hemostatic agent in hepatic injuries: an experimental study in rats

In the treatment of hepatic injuries, there is not always adequate and secure hemostasis. A hepatic biopsy is indispensable in the evolution of focal or diffuse liver cell disease, being necessary for candidates for liver transplant and post-transplant treatment. Many patients suffer blood clotting that increases the risk of bleeding. For this reason, it is necessary to seek for substances capable of bringing about hemostasis quickly and effectively. The aim of this study was to recognize the validity of the use of microporous polysaccharide hemispheres (MPH) as a hemostatic agent for hepatic injuries. Thirty Wistar rats were used, split into three groups. Under anaesthetic, a laparotomy was done and resulted in a standard liver injury that was treated in Group A with MPH, in Group B with n-butyl-2-cyanoacrylate and in Group C with fibrin adhesive. Immediate hemostasis, delayed bleeding and histological evolution were timed. The MPH took on average six minutes to promote hemostasis and also resulted in re-bleeding, which required reapplication; the n-butyl-2-cyanoacrylate took twenty seconds and the fibrin adhesive took one minute. The cyanoacrylate resulted in more intense adherence. The three adhesives mainly showed a chronic inflammatory reaction. The injuries treated with cyanoacrylate showed a larger area of injury (p=0,0164). The density of the collagen was similar in all groups. The MPH, despite achieving hemostasis, proved to be no more favorable than n-butyl-cyanoacrylate and the fibrin adhesive, the latter resulting in the lowest tissue reaction.

Lipo-PGE 1, prostaglandin E 1 incorporated in lipid microspheres, protects injury of the liver caused by warm ischemia reperfusion

Effects of Lipo-PGE 1, prostaglandin E 1 incorporated in lipid microspheres on liver injury caused by ischemia reperfusion were investigated. Lipo-PGE 1 (10μg/kg or 3 μg/kg) or vehicle was gradually injected twice via portal vein 5 min prior to induction of ischemia and reperfusion. Rats died within 2 d after liver ischemia of 90 min from the group receiving injection of vehicle alone. Lipo-PGE 1 had its most profound effect on the survival of animals subjected to liver ischemia followed by reperfusion when given in two doses, one prior to ischemia, and another prior to reperfusion. Lipo-PGE 1 markedly suppressed both the increases in plasma PCOOH (phosphatidylcholine hydroperoxide) levels and the leakage of GOT, GPT, and LDH from the liver during the ischemia reperfusion. These findings suggest that Lipo-PGE 1 may have therapeutic applications in treatment of hepatic injury.

Liver Trauma: New Management Trends

Several significant advances in the treatment of hepatic injuries have evolved over the past decade. These trends have been incorporated into the overall treatment strategy of hepatic injuries and are reflected in experiences with 411 consecutive patients. Two hundred and fifty-eight patients (63%) with minor injuries (grades I to II) were treated by simple suture or hemostatic agents with a mortality rate of 6%. One hundred and twenty-eight patients (31%) sustained complex hepatic injuries (grades III to V). One hundred seven patients (83.5%) with grades III or IV injury underwent portal triad occlusion and finger fracture of hepatic parenchyma alone. Seventy-three surviving patients (73%) required portal triad occlusion, with ischemia times varying from 10 to 75 minutes (mean, 30 minutes). The mortality rate in this group was 6.5% (seven patients) and was accompanied by a morbidity rate of 15%. Fourteen patients (11%) with grade V injury (retro-hepatic cava or hepatic veins) were managed by prolonged portal triad occlusion (mean cross-clamp time, 46 minutes) and extensive finger fracture to the site of injury. In four of these patients an atrial caval shunt was additionally used. Two of these patients survived, whereas six of the 10 patients managed without a shunt survived, for an overall mortality rate of 43%. Over the past 4 years, six patients (4.7%) with ongoing coagulopathies were managed by packing and planned re-exploration, with four patients (67%) surviving and one (25%) developing an intra-abdominal abscess. One additional patient (0.8%) was managed by resectional debridement alone and survived. During the past 5 years, 25 hemodynamically stable and alert adult patients (6%) sustaining blunt trauma were evaluated by computed tomography scan and found to have grade I to III injuries. All were managed nonoperatively with uniform success. The combination of portal triad occlusion (up to 75 minutes), finger fracture technique, and the use of a viable omental pack is a safe, reliable, and effective method of managing complex hepatic injuries (grade III to IV). Juxtahepatic venous injuries continue to carry a prohibitive mortality rate, but nonshunting approaches seem to result in the ?? cumulative mortality rate. Packing and planned reexploration has a definitive life-saving role when used adjunctively.

Significant trends in the treatment of hepatic trauma. Experience with 411 injuries.

Several significant advances in the treatment of hepatic injuries have evolved over the past decade. These trends have been incorporated into the overall treatment strategy of hepatic injuries and are reflected in experiences with 411 consecutive patients. Two hundred fifty-eight patients (63%) with minor injuries (grades I to II) were treated by simple suture or hemostatic agents with a mortality rate of 6%. One hundred twenty-eight patients (31%) sustained complex hepatic injuries (grades III to V). One hundred seven patients (83.5%) with grades III or IV injury underwent portal triad occlusion and finger fracture of hepatic parenchyma alone. Seventy-three surviving patients (73%) required portal triad occlusion, with ischemia times varying from 10 to 75 minutes (mean, 30 minutes). The mortality rate in this group was 6.5% (seven patients) and was accompanied by a morbidity rate of 15%. Fourteen patients (11%) with grade V injury (retrohepatic cava or hepatic veins) were managed by prolonged protal triad occlusion (mean cross-clamp time, 46 minutes) and extensive finger fracture to the site of injury. In four of these patients an atrial caval shunt was additionally used. Two of these patients survived, whereas six of the 10 patients managed without a shunt survived, for an overall mortality rate of 43%. Over the past 4 years, six patients (4.7%) with ongoing coagulopathies were managed by packing and planned re-exploration, with four patients (67%) surviving and one (25%) developing an intra-abdominal abscess. One additional patient (0.8%) was managed by resectional debridement alone and survived. During the past 5 years, 25 hemodynamically stable and alert adult patients (6%) sustaining blunt trauma were evaluated by computed tomography scan and found to have grade I to III injuries. All were managed nonoperatively with uniform success. The combination of portal triad occlusion (up to 75 minutes), finger fracture technique, and the use of a viable omental pack is a safe, reliable, and effective method of managing complex hepatic injuries (grade III to IV). Juxtahepatic venous injuries continue to carry a prohibitive mortality rate, but nonshunting approaches seem to result in the lowest cumulative mortality rate. Packing and planned reexploration has a definitive life-saving role when used adjunctively in the presence of a coagulopathy. Nonoperative management of select hemodynamically stable adult patients, identified by serial computed tomography scans after sustaining blunt trauma is highly successful (95-97%).

Treatment of Hepatic Injury

Treatment of Hepatic Injury