Acute Toxicity of Jinchuan Formula Plum Wine Extract and Its Protective Effect on Mice with Liver Injury

[Objectives]To investigate the acute toxicity and hepatoprotective effect of Jinchuan formula plum wine extract on mice,determine its safety range,and evaluate its hepatoprotective effect.[Methods]The median lethal dose(LD_(50))was determined by acute toxicity test with the toxic reaction and mortality of mice as indexes.Sixty Kunming mice were randomly divided into 6 groups:normal control group,model group(ConA-induced liver injury model),Jinchuan formula plum wine high,medium and low dose groups(1.0,0.5,0.25 g/kg)and silybin group(0.1 g/kg).The levels of ALT,AST,LDH in serum and TG,VLDL in liver were measured.After HE staining,the pathological changes of liver tissue in mice were observed,and the liver protective effect of Jinchuan formula plum wine extract was analyzed and evaluated.[Results]LD_(50)was 11.18 g/kg,and the 95%confidence limit of LD_(50)was 10.31-12.05 g/kg.The high-dose group of Jinchuan formula plum wine extract could significantly reduce the serum ALT and AST activities of ConA-induced liver injury mice(P<0.05).[Conclusions]Jinchuan formula plum wine extract is relatively safe,and also has a protective effect on liver injury.

Protective effect of Solanum Nigrum Linn green fruit ethanolic extract on alcoholic liver injury in mice

Alcoholic liver injury is a liver disease caused by excessive alcohol consumption,which can lead to chronic liver disease death.Solanum Nigrum Linn taste bitter,cold,has the effect of clearing heat and detoxification,promoting blood and detumescence.Solanum Nigrum Linn fruit contains a variety of antioxidant enzymes,can remove the body produced by aerobic metabolism harmful substances.In this paper,a model of alcohol-induced liver injury in C57BL/6 mice was established to evaluate the protective effect of Solanum Nigrum Linn green fruit(SNGF)ethanolic extract on alcohol-induced liver injury.H&E staining and oil red O(ORO)staining showed that hepatic lobules were clearly demarcated,vacuoles were significantly reduced and lipid droplets were reduced in SNGF ethanolic extract treatment group.Serum levels of TC,TG,LDH,TBA,AKP,ALT and AST were decreased in the SNGF ethanolic extract treatment group,and SNGF ethanolic extract could clear reactive oxygen species(ROS)in time.MDA content was signifi cantly decreased after SNGF ethanolic extract treatment,while superoxide dismutase(SOD)and GSH-Px contents were increased after SNGF ethanolic extract treatment.These results suggest that SNGF ethanolic extract has a protective effect on alcohol-induced liver injury.

Liver protection strategies in liver transplantation

BACKGROUND： Liver transplantation is the therapy of choice for patients with end-stage liver diseases. However, the gap between the low availability of organs and high demand is continuously increasing. Innovative strategies for organ protection are necessary to expand donor pool and to achieve better outcomes for liver transplantation. The present review analyzed and compared various strategies of liver protection.DATA SOURCES： Databases such as PubM ed, Embase and Ovid were searched for the literature related to donor liver protection strategies using following key words： ＂ischemia reperfusion injury＂, ＂graft preservation＂, ＂liver transplantation＂, ＂machine perfusion＂ and ＂conditioning＂. Of the 146 studies identified,only those with cutting edge strategies were analyzed.RESULTS： A variety of therapeutic approaches were proposed to alleviate graft ischemia/reperfusion injury, which included static cold storage, machine perfusion （hypothermic, normothermic and subnormothermic）, manual conditioning （pre,post and remote）, and pharmacological conditioning. Evidences from animal experiments and clinical trials suggested that all these strategies could potentially protect liver graft; however, their clinical applications are limited partially due to their own disadvantages.CONCLUSIONS： There are a plenty of methods suggested to decrease the degree of donor liver transplantation-related injury. However, none of these approaches is perfect in clinical practice. More translational researches （molecular and clinical studies） are needed to improve the techniques in liver graft protection.

Immune protection of auxiliary liver to other allograft: report of 3 cases

OBJECTIVE: To assess the immune status of auxiliary liver transplantation and to clarify the immune protection of auxiliary liver to other allograft. METHODS: Immunological markers and pathological changes in 3 patients undergoing auxiliary liver transplantation were analysed. RESULTS: The lower the concentration of immunosuppressive agent, the less the rejection and the milder the intensity in the 3 patients. The function of allograft after auxiliary liver transplantation was excellent. CONCLUSIONS: Patients are in a low immune reaction state after auxiliary liver transplantation. Auxiliary liver can protect other allografts by related immunological mechanisms. The side-effects of low-concentration immunosuppressive agents on auxiliary liver and other allografts are mild.

Protective Effect of Ethanol Extract from Sweet Potato Leaves on CCL_(4)-Induced Liver Injury in Mice

[Objectives]To investigate the protective effect of ethanol extract from sweet potato leaves on liver injury induced by CCl_(4)in mice.[Methods]25 ICR mice were randomly divided into blank group,model group,high-dose extract group(200 mg/kg),low-dose extract group(100 mg/kg)and positive control group(2 mg/kg colchicine),with 5 mice in each group.All groups except the blank group were given intraperitoneal injection of 20%CCl 4 olive oil solution(2 mL/kg),and the blank group was given the same dose of olive oil solution three times a week.After 4 weeks,each administration group was given the corresponding dose of drugs(10 mL/kg),and the blank group and model group were given the corresponding amount of normal saline for 2 weeks.After the last intragastric administration,fasting was required,but water was allowed,blood was taken from eyeballs,and upper serum was taken by static centrifugation.Serum AST,ALT,CRP,IL-6 and SOD levels were detected by the kit.[Results]Compared with the blank group,the serum AST and ALT levels in the model group were significantly increased;compared with the model group,the ethanol extract of sweet potato leaves could decrease the levels of ALT,AST,CRP,IL-6 and increase the level of SOD in serum.[Conclusions]The ethanol extract of sweet potato leaves had protective effect on the mice with liver injury induced by CCl_(4),and its mechanism may be to protect the liver by lowering enzymes,inhibiting inflammation and antioxidant stress.

Prostaglandin E1 administration post liver transplantation and renal outcomes:A retrospective single center experience

BACKGROUND Prostaglandin E1(PGE1),or alprostadil,is a potent vasodilator that improves hepatic blood flow and reduces ischemia-reperfusion injury post-liver transplantation(LT).However,the benefits of PGE1 on renal function after LT have not yet been well described.AIM To assess the impact of PGE1 administration on renal function in patients who underwent liver or liver-kidney transplant.METHODS This retrospective study included all patients who underwent liver or liverkidney transplant at our institution from January,2011 to December,2021.Patients were classified based on whether they received PGE1.PGE1 was administered post-LT to those with transaminases>1000 U/L in the immediate postoperative period.Demographics,post-LT treatments and/or complications,renal function,and survival were analyzed.Multivariable logistic regression analysis was performed,and a two-tailed P value<0.05 was considered statistically significant.RESULTS A total of 145 patients underwent LT,with 44(30%)receiving PGE1.Baseline patient characteristics were comparable,except the PGE1 group had significantly higher aspartate aminotransferase(AST)(1961.9 U/L±1862.3 U/L vs 878 U/L±741.4 U/L,P=0.000),alanine aminotransferase(1070.6 U/L±895 U/L vs 547.7 U/L±410 U/L,P=0.000),international normalized ratio on post-LT day 1(2±0.74 vs 1.8±0.4,P=0.03),a longer intensive care unit stay(8.1 days±11.8 days vs 3.8 days±4.6 days,P=0.003),more vasopressor use(55.53 hours±111 hours vs 16.33 hours±26.3 hours,P=0.002),and higher immediate postoperative complications(18.6%vs 4.9%,P=0.04).The PGE1 group also had a significantly higher 90-day readmission rate(29.6%vs 13.1%,P=0.02)and lower 1-year liver graft survival(87.5%vs 98.9%,P=0.005).However,30-day readmission(31.6%vs 27.4%,P=0.64),LT complications(hepatic artery thrombosis,biliary complications,rejection of liver graft,cardiomyopathy),1-year patient survival(96.9%vs 97.8%,P=0.77),overall liver graft survival,and overall patient survival were similar between the two groups(95.4%vs 93.9%,P=0.74 and 88.4%vs 86.9%,P=0.81 respectively).Although the PGE1 group had a significantly lower glomerular filtration rate(eGFR)on post-LT day 7(46.3 mL/minute±26.7 mL/minute vs 62.5 mL/minute±34 mL/minute,P=0.009),the eventual need for renal replacement therapy(13.6%vs 5.9%,P=0.09),the number of dialysis sessions(0.91 vs 0.27,P=0.13),and eGFR at 1-month(37.2 mL/minute±35.9 mL/minute vs 42 mL/minute±36.9 mL/minute,P=0.49),6-months(54.8 mL/minute±21.6 mL/minute vs 62 mL/minute±21.4 mL/minute,P=0.09),and 12-months(63.7 mL/minute±20.7 mL/minute vs 62.8 mL/minute±20.3 mL/minute,P=0.85)post-LT were similar to those in the non-PGE1 group.CONCLUSION In patients who received PGE1 for ischemia-reperfusion injury,despite immediate acute renal injury post-LT,the renal function at 1-month,6-months,and 12-months post-LT was similar compared to those without ischemiareperfusion injury.Prospective clinical trials are needed to further elucidate the benefits of PGE1 use in renal function.

Study on Protection Mechanism of Viscum coloratum (Kom.) Nakai f. lutescens kitag Fruit Polysaccharides on Mice with Acute Alcoholic Liver Injury

This study was conducted to investigate the protective mechanism of V. coloratum fruit polysaccharides（ VCFP） on mice with acute alcoholic liver injury. Acute liver injury model was built by one-time alcohol gavage. The mice were randomly divided into VCFP-treated groups（ low-,medium-,and highdose）,alcohol model group and normal control group at the same time. VCFP-treated groups were administrated polysaccharide intragastrically continuously for4 weeks; and the alcohol model group and normal control group were administrated intragastrically the same amount of normal saline. The general situation and liver tissue morphological structure changes were observed. The results showed that the levels of ALT,AST,TC,TG,MDA contents,and CAT and GSH-Px activity of mice in the model group increased significantly（ P 〈 0. 01）,while the activity of SOD and weight and liver index decreased significantly（ P 〈 0. 01） compared with the normal control group. After 4 weeks of gavage,VCFP could significantly improve weight,liver index and SOD activity,and significantly reduce ALT,AST,TC and TG levels,MDA content and CAT and GSH-Px activity. These results suggest that VCFP can improve antioxidant enzyme activity,remove oxygen free radical and reduce membrane lipid peroxidation reaction,thereby protecting liver cells.

A microbial-derived succinylated bile acid to safeguard liver health

In this issue of Cell,Nie and co-authors report that the microbe-derived bile acid(BA)3-succinylated cholic acid protects against the progression of metabolic dysfunction-associated liver disease.Intriguingly,its protective mechanism does not involve traditional BA signaling pathways but is instead linked to the proliferation of the commensal microbe Akkermansia muciniphila.

Pharmacological effects and mechanisms of polyphenols in Radix Puerariae on liver protection and anti-diabetes

In recent years,the incidence of liver diseases and diabetes is increasing year by year,and the patients are younger than before.Although the clinical medicine treatment is eff ective,but it would produce side eff ects.Radix Puerariae is the dried root of the Pueraria lobata(Willd.)Ohwi.Puerarin is an isofl avone compound with polyphenol structure.It is one of the main bioactive components of Radix Puerariae.Studies have found that the application of puerarin off ers beatifical act on liver protection,hypoglycemia,blood lipid,antioxidant,anti-osteoporosis,anti-cancer,anti-inflammatory and cardiovascular protection.Puerarin has been used in the treatment of liver disease and diabetes.In this study,the eff ect of puerarin on liver protection,diabetes treatment and the relationship between the two diseases were reviewed.The therapeutic mechanism and molecular targets of puerarin were explored in order to further improve the development of puerarin and increase its clinical application in protection against liver disease and diabetes.

Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes

AIM： To investigate the hypothesis that the protective effects of curcumin in hepatic warm ischemia/reperfusion （I/R） injury are associated with increasing heat shock protein 70 （Hsp70） expression and antioxidant enzyme activity. METHODS： Sixty Sprague-Dawley male rats were randomly divided into sham, I/R, C ＋ I/R groups. The model of reduced-size liver warm ischemia and reperfusion was used. Curcumin （50 mg/kg） was administered by injection through a branch of superior mesenteric vein at 30 min before ischemia in C ＋ I/R group. Five rats were used to investigate the survival during 1 wk after operation in each group. Blood samples and liver tissues were obtained in the remaining animals after 3, 12, and 24 h of reperfusion to assess serum alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, liver tissue NO2- ＋ NO3-, malondialdehyde （MDA） content, superoxide dismutase （SOD）, catalase （CAT）, nitricoxide synthase （NOS） and myeloperoxidase （MPO） activity, HspT0 expression and apoptosis ratio. RESULTS： Compared with I/R group, curcumin pretreatment group showed less ischemia/reperfusioninduced injury. CAT and SOD activity and Hsp70 expression increased significantly. A higher rate of apoptosis was observed in I/R group than in C ＋ I/R group, and a significant increase of MDA, NO2^- ＋ NO3^- and MPO level in liver tissues and serum transaminase concentration was also observed in I/R group compared to C ＋ I/R group. Curcumin also decreased the activity of inducible NO synthase （iNOS） in liver after reperfusion,but had no effect on the level of endothelial NO synthase （eNOS） after reperfusion in liver. The 7 d survival rate was significantly higher in C ＋ I/R group than in I/R group. CONCLUSION： Curcumin has protective effects against hepatic I/R injury. Its mechanism might be related to the overexpression of Hsp70 and antioxidant enzymes.

Hepatic organ protection:From basic science to clinical practice

Hepatic ischemia and reperfusion (I/R) injury during liver surgery is still the main cause of postoperative liver failure and the subsequent rise of mortality in these patients. During the last few years, a multitude of underlying mechanisms have been extensively characterized and many different protective approaches have been evaluated under experimental conditions. Some of them have already found their way into small sized clinical trials. In this Topic Highlight series of articles, we present recent insights into promising protective concepts including the regulation and optimization of hepatic blood flow, molecular mechanisms of preconditioning and pharmacological approaches with the aim of limiting hepatic I/R injury. Leading international experts present the latest experimental evidence in their fields stressing clinically relevant ideas, which are now on the edge of entering clinical practice.

Cerebral protective effect of nicorandil premedication on patients undergoing liver transplantation

BACKGROUND:Neurological injury is a common complication in the early period after liver transplantation,posing an enormous obstacle to treatment efficiency and patient survival.Nicorandil is a mitochondrial ATP-sensitive potassium channel(mitoK ATP) opener.It has been reported to be effective in reducing brain injury in recent studies.However,it is still unclear whether nicorandil has cerebral protective effect in patients undergoing liver transplantation.METHODS:Fifty patients scheduled for liver transplantation were randomly divided into a nicorandil group(group N)(n=25),in which patients received 10 mg nicorandil through a nasogastric tube 30 minutes before induction of anesthesia,and a control group(group C)(n=25) who received 10 mL normal saline.The Mini-Mental State Examination(MMSE) was performed before anesthesia(day 0),and on days 3 and 7 after surgery.Blood samples were obtained before induction of anesthesia(T1),and at 12(T2) and 36 hours(T3) after surgery for determination of serum neuron-specific enolase(NSE) and S100β protein(S100β) concentrations.RESULTS:During surgery,5 patients in each group were eliminated due to severe reperfusion or renal insufficiency.Therefore,20 patients remained in each group.The MMSE scores after operation were significantly lower than those before operation in group C.However,there was no difference at days 3 and 7 compared with day 0 in group N.Serum NSE concentrations after surgery were significantly higher than baseline(at T1) in both groups,except at T3 in group N.Serum S100β concentration after surgery was significantly higher than baseline(at T1) in both groups.The MMSE scores at days 3 and 7 in group N were significantly higher than those in group C.The concentrations of serum NSE and S100β at T2 and T3 in group N were significantly lower than those in group C.CONCLUSIONS:Oral nicorandil,as a premedication before liver transplantation,improves postoperative MMSE scores.It also attenuates the increase of NSE and S100β in blood,indicating its cerebral protective effect.

Protective Effect of Dimethyl-4,4'-Dimethoxy-5,6,5',6'-Dimethylene Dioxybiphenyl-2,2'-Dicarboxylate (DDB) against Carcinogen-Induced Rat Liver Nuclear DNA Damage

The protective effect of DDB against carcinogen-induced DNA damage was examined in the present investigation. Preincubation of rat liver nuclei with DDB (1 mmol.L-1) resulted in 60% inhibition of binding of 3H-benzo (a) pyrene to nuclear DNA. Unscheduled DNA synthesis (UDS) induced by aflatoxin BI (10^(-7) mol.L-1) in freshly isolated rat hepatocytes was also inhibited by DDB (10^(-6)-10^(-3)mol.L-1). Oral administration of DDB at 200 mg.kg-1 once daily for 3 d induced a significant increase of liver cytosol glutathione-S-transferase and microsomal UDPG-transferase activity in mice. These results indicate that DDB is able to directly or indirectly antagonize certain carcinogen-induced DNA damages.

Cyclosporin A protects Balb/c mice from liver damage induced by superantigen SEB and D-GaIN

AIM To investigate the pathogenic effect ofSEB and D-GalN on liver and the protection ofcyclosporin A, the relationship between hepaticapoptosis and necrosis and the possiblemechanism of acute hepatic necrosis.METHODS After staphylococcal enterotoxin B(SEB ) mixed with D--galactosamine (D-GaiN )were injected intraperitoneally into Balb/c miceand those previously treated with cyclosporin A,blood samples were collected and livers wereisolated at 2, 6, 12 and 24 h. Patterns othepatocellular death were studiedmorphologically and biochemically, circulatingcytokines (TNF-a, IFN--y ) and mice mortalitywithin 24h was assessed.RESU’LTS The SEB could induce the typicalapoptotic changes of hepatocytes, the D-GaiNcould induce hepatocytes apoptosis anddegeneration at the same time, and the micehaving received the SEB + D-GaiN injectionsdeveloped apoptosis at 2 and 6 h, but after 12 hhepatocytes were characterized by severein jury, whereas all the examinations in thecyclosporin A treated mice were normal.CONCLUSION Hepatic cell apoptosis might berelated to necrosis, and massive hepatocyteapoptosis is likely the initiating step of acutehepatic necrosis in mice. The effects induced bySEB and D--GaiN on hepatocytes might bemediated by T cells, and could be prevented bycyclosporin A.

The Extraction of Eucommia Ulmoides Oliv Polysaccharides and Its Protective Effect on Liver of Clophasphamidecy Injured Mice

Objective:To study the influenceof eucommia polysaccharide on the mice' liver damaged by clophasphamidecy (CY).Methods:Injecting CY build mice liver damage model,eucommia polysaccharide given different doses, measured blood serum ALT,AST and the liver's SOD,MDA. Results:After the injection CY,blood serum ALT,AST and the MDA of liver rise and the SOD of liver reduce comparedwith the blank group. The eucommia polysaccharide can improve these index.Conclusion:The Eucommia polysaccharide may protect the mice' liver damaged by CY.

Screening on the Pharmacodynemic Active Parts of Protecting Liver of Peristrope japonica (thunb.)Bremek

The pharmacodynamic active parts of protecting liver of Peristrope japonica (thunb.)Bremek were identified. Rat acute liver injury model was induced by D-galactosamine (D-GlaN). The active parts were identified on the whole extraction and 4 fractions. The results showed that the pharmacodynamic active parts of Peristrope japonica were the n-BuOH fraction.

Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin(C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective eff ects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglyceride(TG), total cholesterol(CHOL), low-density lipoprotein(LDL), liver homogenate malondialdehyde(MDA), superoxide dismutase(SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory eff ects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

Protective Effect of Mongolian Medicine Youning Bawei Powder on Liver Injury Induced by CCl4 in Mice

[Objectives]To study the protective effect of Mongolian medicine Youning Bawei Powder on liver injury induced by carbon tetrachloride(CCl_(4))in mice.[Methods]The experimental mice were divided into 5 groups:normal group,model group,positive control group,low-dose group and high-dose group of Mongolian medicine Youning Bawei Powder.The model group was induced by CCl_(4),the positive control group was treated with liver-protecting tablet,and the Mongolian medicine group was treated with Youning Bawei Powder for one month.The liver tissue injury of mice in each group was observed by HE staining,and the levels of serum ALT,AST,SOD and MDA were detected.[Results]Mongolian medicine Youning Bawei Powder significantly improved the pathological liver injury induced by CCl_(4),significantly decreased the content of ALT,AST and MDA in serum of mice with CCl_(4) liver injury,and significantly increased the activity of serum SOD.[Conclusions]Youning Bawei Powder,a Mongolian medicine,has a protective effect on liver injury induced by CCl_(4) in mice.

Bitter Melon Powder Protects against Obesity-associated Fatty Liver Disease by Improving Colonic Microenvironment in Rats with High-fat Diet-induced Obesity

This study explored how bitter melon powder （BMP） alters the colonic microenvironment during the development of obesity-associated fatty liver in rats. We observed that BMP effectively inhibited the body weight gain and lipid accumulation in the liver, ameliorated glucose intolerance, and increased the colon weight after an 8-week treatment compared to that in the high-fat diet （HFD） group. BMP significantly decreased fecal water toxicity towards HT-29 cells, as revealed by the cell counting kit （CCK）-8 assay results, and the mRNA expression of Toll-like receptor 4 （TLR4） in colon mucosa. Additionally, gut permeability in the BMP group was restored to normal levels. Finally, BMP alleviated the inflammatory state of the rat colon mucosa and liver tissues as well as the systemic inflammation.

Late Protective Effects of the Anticalmodulin Drug Fluphenazine on Carbon Tetrachloride-induced Liver Necrosis

Fluphenazine (FP) treatment (50mg/kg bw, ip in saline) 30 min before or 6 or 10 h after CCl4 administration (1 ml/kg ip in olive oil) significantly prevented the liver necrosis produced by the hepatotoxin at 24 h. FP had enhancing effects on the covalent binding of CCl4 reactive metabolites to cellular constituents and on CCl4 induced lipid peroaldation.FP lowered bOdy temperature of the CCl4-poisoned animals during the 24 h observation period. The obtained results are compatible but do not prove the hypothesis that calmodulin (CaM) had participation in late occurring events preceding necrosis. FP lowering action on body temperature, however, might also play a role in the effects of this drug on the onset of CCl4 induced liver necrosis. FP levels in liver tissue as determined by gas chromatography-mass spectrometry evidenced the presence of the drug in amounts suffi cient to inhibit CaM and that suggests that not all preventive effects of FP are due to its indirect actions on the central nervous system via decreased body temperature