Comparative Assessment of Melatonin-Afforded Protection in Liver, Kidney and Heart of Male Mice against Doxorubicin Induced Toxicity

Melatonin (MEL) was investigated for protection against the anthracycline antibiotic doxorubicin (Dox) that is well known for its oxidative damage to various body organs. It was aimed to have a comparison of this protection to heart, liver and kidney in the treated subjects. In this study, groups of mice were treated with Dox and melatonin and their individual or combined effects were evaluated by assessing lipidperoxidation, non-protein sulfhydryls (NP-SH) and nitrate/nitrite (NO) contents in these tissues. Plasma aminotransferases, LDH and CK-MB enzyme activities were measured. Moreover, these tissues were subject to histopathological assessment. MEL co-treatment significantly prevented any rise in lipidperoxides more significantly in heart and liver as compared to kidney. In tandem, MEL prevented a decline in GSH that was observed by Dox alone in liver and kidney. Dox significantly increased total NO levels in all the tissues. Melatonin at both dose levels could not afford protection against nitrosative stress. MEL in combination treatment provided significant

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.

Bidirectional associations among gallstone disease,non-alcoholic fatty liver disease,kidney stone disease

BACKGROUND A body of evidence has suggested bidirectional relationships among gallstone disease(GSD),non-alcoholic fatty liver disease(NAFLD),and kidney stone disease(KSD).However,the results are inconsistent,and studies on this topic in China are relatively few.Our goal is to explore the bidirectional associations among these three diseases through a multicenter study,systematic review,and meta-analysis.AIM To explore the bidirectional associations among these three diseases through a multicenter study,systematic review,and meta-analysis.The results may help to investigate the etiology of these diseases and shed light on the individualized prevention of these three diseases.METHODS Subjects who participated in physical examinations in Beijing,Tianjin,Chongqing in China were recruited.Multivariable logistic regression was employed to explore the bidirectional relationships among GSD,KSD,and NAFLD.Systematic review and meta-analysis were initiated to confirm the epidemiologic evidence from previous observational studies.Furthermore,trial sequential analysis(TSA)was conducted to evaluate whether the evidence was sufficient and conclusive.RESULTS Significant bidirectional associations were detected among the three diseases,independent of potential confounding factors.The pooled results of the systematic review and meta-analysis also corroborated the aforementioned results.The combined evidence from the multicenter study and meta-analysis was significant[pooled odds ratio(OR)=1.42,95%CI:1.16-1.75,KSD→GSD;pooled OR=1.48,95%CI:1.31-1.67,GSD→KSD;pooled OR=1.31,95%CI:1.17-1.47,GSD→NAFLD;pooled OR=1.37,95%CI:1.26-1.50,NAFLD→GSD;pooled OR=1.28,95%CI:1.08-1.51,NAFLD→KSD;pooled OR=1.21,95%CI:1.16-1.25,KSD→NAFLD].TSA indicated that the evidence was sufficient and conclusive.CONCLUSION The present study presents relatively sufficient evidence for the positive bidirectional associations among GSD,KSD,and NAFLD.The results may provide clues for investigating the etiology of these three diseases and offer a guideline for identifying high-risk patients.

Protecting liver health with microbial-derived succinylated bile acids

The gut microbiome produces a plethora of metabolites that influence host metabolism.In a recent article published in Cell,Nie and colleagues reveal that 3-succinylated cholic acid,a microbe-derived bile acid,protects against metabolic dysfunction-associated liver disease.The authors show that an increased abundance of the beneficial commensal microbe Akkermansia muciniphila,rather than enhanced bile acid signaling,drives this protective phenotype.

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.

Protecting kidneys in liver transplant patients:A pathway to preventive interventions

Acute kidney injury(AKI) is a frequent postoperative complication after liver transplantation. The etiology is multifactorial,including perioperative renal status,surgery related events,and postoperative immunosuppression therapy. The role of renal hypoperfusion and hepatic ischemia-reperfusion injury as causes of early AKI are now being increasingly recognized. Further studies should focus on therapies that would attenuate this injury.

Insights from exploring the interrelated dynamics of gallstone disease,non-alcoholic fatty liver disease,and kidney stone disease

This article delved into the comprehensive study by Jiang et al,which meticulously examined the bidirectional relationships among gallstone disease,nonalcoholic fatty liver disease,and kidney stone disease through a multicenter study,systematic review,and meta-analysis.The study provides significant evidence supporting these associations,offering valuable insights into the etiology and potential prevention strategies for these interconnected conditions.The clinical significance of these bidirectional relationships is profound,as they underscore the importance of recognizing these conditions not only as isolated diseases but as part of a complex network that can influence each other.These results highlight the critical need for thorough screening and personalized prevention strategies for individuals with these interconnected conditions.Explicit implications for prevention strategies and early screening practices are crucial,as they can lead to early detection and intervention,significantly altering disease progression and outcomes.Furthermore,identifying potential therapeutic targets within these shared pathways may enhance treatment efficacy and patient outcomes,making this research highly relevant to clinical practice.By comprehending the common pathophysiological mechanisms and applying specific interventions,healthcare professionals can greatly enhance patient care and lessen the impact of these widespread diseases on global health.

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.

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.

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.

Cystatin C is a biomarker for predicting acute kidney injury in patients with acute-on-chronic liver failure

AIM:To investigate serum cystatin C level as an early biomarker for predicting acute kidney injury(AKI)in patients with acute-on-chronic liver failure(ACLF).METHODS:Fifty-six consecutive patients with hepatitis B virus-related ACLF who had normal serum creatinine(Cr)level(<1.2 mg/dL in men,or<1.1 mg/dL in women)were enrolled in the Liver Failure Treatment and Research Center of Beijing 302 Hospital between August 2011 and October 2012.Thirty patients with chronic hepatitis B(CHB)and 30 healthy controls in the same study period were also included.Measurement of serum cystatin C(CysC)was performed by a particle-enhanced immunonephelometry assay using the BN Prospec nephelometer system.The ACLF patients were followed during their hospitalization period.RESULTS:In the ACLF group,serum level of CysC was 1.1±0.4 mg/L,which was significantly higher(P<0.01)than those in the healthy controls(0.6±0.3mg/L)and CHB patients(0.7±0.2 mg/L).During the hospitalization period,eight ACLF patients developed AKI.Logistic regression analysis indicated that CysC level was an independent risk factor for AKI development(odds ratio=1.8;95%CI:1.4-2.3,P=0.021).The cutoff value of serum CysC for prediction of AKI in ACLF patients was 1.21 mg/L.The baseline CysC-based estimated glomerular filtration rate(eGFR CysC)was significantly lower than the creatinine-based eGFR(eGFR CG and eGFR MDRD)in ACLF patients with AKI,suggesting that baseline eGFR CysC represented early renal function in ACLF patients while the Cr levels were still within the normal ranges.CONCLUSION:Serum CysC provides early prediction of renal dysfunction in ACLF patients with a normal serum Cr level.

Acute kidney injury in acute-on-chronic liver failure is different from in decompensated cirrhosis

AIM To evaluate the differences in acute kidney injury(AKI) between acute-on-chronic liver failure(ACLF) and decompensated cirrhosis(DC) patients. METHODS During the period from December 2015 to July 2017, 280 patients with hepatitis B virus(HBV)-related ACLF(HBV-ACLF) and 132 patients with HBV-related DC(HBV-DC) who were admitted to our center were recruited consecutively into an observational study. Urine specimens were collected from all subjects and the levels of five urinary tubular injury biomarkers were detected,including neutrophil gelatinase-associated lipocalin(NGAL), interleukin-18(IL-18), liver-type fatty acid binding protein(L-FABP), cystatin C(CysC), and kidney injury molecule-1(KIM-1). Simultaneously, the patient demographics, occurrence and progression of AKI, and response to terlipressin therapy were recorded. All patients were followed up for 3 mo or until death after enrollment. RESULTS AKI occurred in 71 and 28 of HBV-ACLF and HBV-DC patients, respectively(25.4% vs 21.2%, P = 0.358). Among all patients, the levels of four urinary biomarkers(NGAL, CysC, L-FABP, IL-18) were significantly elevated in patients with HBV-ACLF and AKI(ACLF-AKI), compared with that in patients with HBV-DC and AKI(DC-AKI) or those without AKI. There was a higher proportion of patients with AKI progression in ACLF-AKI patients than in DC-AKI patients(49.3% vs 17.9%, P = 0.013). Fortythree patients with ACLF-AKI and 19 patients with DC-AKI were treated with terlipressin. The response rate of ACLFAKI patients was significantly lower than that of patients with DC-AKI(32.6% vs 57.9%, P = 0.018). Furthermore, patients with ACLF-AKI had the lowest 90 d survival rates among all groups(P < 0.001).CONCLUSION AKI in ACLF patients is more likely associated with structural kidney injury, and is more progressive, with a poorer response to terlipressin treatment and a worse prognosis than that in DC patients.

Acute kidney injury and post-reperfusion syndrome in liver transplantation

In the past decades liver transplantation(LT) has become the treatment of choice for patients with end stage liver disease(ESLD). The chronic shortage of cadaveric organs for transplantation led to the utilization of a greater number of marginal donors such as older donors or donors after circulatory death(DCD). The improved survival of transplanted patients has increased the frequency of long-term complications, in particular chronic kidney disease(CKD). Acute kidney injury(AKI) post-LT has been recently recognized as an important risk factor for the occurrence of denovo CKD in the long-term outcome. The onset of AKI post-LT is multifactorial, with pre-LT risk factors involved, including higher Model for End-stage Liver Disease score, more sever ESLD and pre-existing renal dysfunction, either with intra-operative conditions, in particular ischaemia reperfusion injury responsible for post-reperfusion syndrome(PRS) that can influence recipient's morbidity and mortality. Post-reperfusion syndrome-induced AKI is an important complication post-LT that characterizes kidney involvement caused by PRS with mechanisms not clearly understood and implication on graft and patient survival. Since preLT risk factors may influence intra-operative events responsible for PRS-induced AKI, we aim to consider all the relevant aspects involved in PRS-induced AKI in the setting of LT and to identify all studies that better clarified the specific mechanisms linking PRS and AKI. A Pub Med search was conducted using the terms liver transplantation AND acute kidney injury; liver transplantation AND post-reperfusion syndrome; acute kidney injury AND post-reperfusion syndrome; acute kidney injury AND DCD AND liver transplantation. Five hundred seventy four articles were retrieved on Pub Med search. Results were limited to title/abstract of English-language articles published between 2000 and 2015. Twenty-three studies were identified that specifically evaluated incidence, risk factors and outcome for patients developing PRS-induced AKI in liver transplantation. In order to identify intra-operative risk factors/mechanisms specifically involved in PRSinduced AKI, avoiding confounding factors, we have limited our study to "acute kidney injury AND DCD AND liver transplantation". Accordingly, three out of five studies were selected for our purpose.

MRI-determined fat content of human liver,pancreas and kidney

AIM:To assess and correlate the lipid content of various organs in obese subjects and in persons with a normal body weight.METHODS:Magnetic resonance spectroscopy and a previously validated gradient echo magnetic resonance imaging method with Dixon's two point technique were used in this study to quantify fat in liver,pancreas as well as kidney.RESULTS:In 36 volunteers with body mass index(BMI) ranging from 20.0 to 42.9 kg/m2,the median fat content of liver,pancreas and kidney was 2.3%(interquartile range:0.2%-7.8%),2.7%(1.0%-6.5%) and 0.7%(0.1%-1.4%),respectively.BMI and subcutaneous fat correlated significantly with liver and pancreas fat content.We show for the first time the significant correlation of liver and pancreas fat content in healthy controls(r = 0.43,P < 0.01).These observations are related to body weight as measured by BMI and the amount of subcutaneous fat.Kidney fat content is very low and correlates with none of the other fat depots.CONCLUSION:Renal lipid accumulation,unlike the coupled accumulations of fat in liver and pancreas,is not observed in obese subjects.Unlike suggestions made in previous studies,renal lipid accumulation appears not to be involved in the pathogenesis of renal disease in humans.

An effective model for predicting acute kidney injury after liver transplantation

BACKGROUND: Acute kidney injury (AKI) is a common complication in the early period after liver transplantation (LT), posing an enormous obstacle to treatment efficiency and patient survival. However, the exact influencing factors of AKI are still unclear and a predictive model is desperately required in the clinic. METHODS: Data of 102 consecutive LTs were reviewed. A model for predicting AKI was established and further validated in a prospective study of 44-patients receiving LT. RESULTS: The incidence of AKI was 32.4%. AKI patients showed a significantly lower survival rate than non-AKI patients. Multivariate analysis demonstrated the independent influencing factors of AKI were preoperative serum creatinine >1.2 mg/dl, intraoperative urine output <= 60 ml/h, intraoperative hypotension status, and intraoperative use of noradrenaline. A model was then established and showed a sensitivity of 75.0%, a specificity of 93.8%, and an accuracy of 88.6% in predicting AKI. CONCLUSIONS: High preoperative serum creatinine, low intraoperative urine output, and intraoperative hypotension contribute to the development of AKI, and intraoperative use of noradrenaline serves as a protective factor. The predictive model could potentially facilitate early prediction and surveillance of AKI. (Hepatobilinty Pancreat Dis Int 2010; 9:259-263)

Prophylaxis of chronic kidney disease after liver transplantation-experience from west China

AIM： TO evaluate the prophylaxis of chronic kidney dis- ease （CKD） after liver transplantation （LT） with low-dose calcineurin inhibitor （CNI） and mycophenolate mofetil （MMF）.

Kidneys in chronic liver diseases

Acute kidney injury(AKI),defined as an abrupt increase in the serum creatinine level by at least 0.3 mg/dL,occurs in about 20% of patients hospitalized for decompensating liver cirrhosis.Patients with cirrhosis are susceptible to developing AKI because of the progressive vasodilatory state,reduced effective blood volume and stimulation of vasoconstrictor hormones.The most common causes of AKI in cirrhosis are pre-renal azotemia,hepatorenal syndrome and acute tubular necrosis.Differential diagnosis is based on analysis of circumstances of AKI development,natriuresis,urine osmolality,response to withdrawal of diuretics and volume repletion,and rarely on renal biopsy.Chronic glomerulonephritis and obstructive uropathy are rare causes of azotemia in cirrhotic patients.AKI is one of the last events in the natural history of chronic liver disease,therefore,such patients should have an expedited referral for liver transplantation.Hepatorenal syndrome(HRS) is initiated by progressive portal hypertension,and may be prematurely triggered by bacterial infections,nonbacterial systemic inflammatory reactions,excessive diuresis,gastrointestinal hemorrhage,diarrhea or nephrotoxic agents.Each type of renal disease has a specific treatment approach ranging from repletion of the vascular system to renal replacement therapy.The treatment of choice in type 1 hepatorenal syndrome is a combination of vasoconstrictor with albumin infusion,which is effective in about 50% of patients.The second-line treatment of HRS involves a transjugular intrahepatic portosystemic shunt,renal vasoprotection or systems of artificial liver support.

A successful case of combined liver and kidney transplantation for autosomal dominant polycystic liver and kidney disease

Ｗｉｔｈａｄｖａｎｃｅｓｉｎｔｒａｎｓｐｌａｎｔａｔｉｏｎ，ｍｕｌｔｉｏｒｇａｎｔｒａｎｓｐｌａｎｔａｔｉｏｎｈａｓｂｅｃｏｍｅａｔｒｅａｔｍｅｎｔｏｆｃｈｏｉｃｅｆｏｒｅｎｄｓｔａｇｅｏｒｇａｎｆａｉｌｕｒｅｗｈｉｃｈｃａｎｎｏｔｂｅｒｅｖｅｒ...