Establishment and validation of a nomogram for predicting the risk of liver inflammation in chronic HBV infection

Objective:To establish a non-invasive quantitative and visual predictive model for assessing the occurrence of significant inflammation in chronic HBV infection,and to present nomogram to validate the efficacy.Methods:A total of 180 patients with chronic HBV infection that were admitted to the Department of Infectious Liver Diseases of the First Affiliated Hospital of Hainan Medical College from January 2019 to December 2021 with informed consent and underwent liver biopsy puncture were selected,and to prevent overfitting of the model,131 patients and 49 patients were randomly divided into a model group and a validation group according to randomization,to collect the clinic information,serological examination,liver elastography and liver histopathology results.The patients were divided into non-significant inflammation and significant inflammation groups in the modeling group.The R 4.1.1 package and the rms package were used to build the column line graph model,while the Bootstrap method was applied to repeat the sampling 1000 times for internal and external validation,and the H-L goodness of fit test and ROC curve were used to assess the calibration and discrimination of the column line graph model respectively.Results:A total of 180 patients with chronic HBV infection were included,and 92 patients(51.1%)had significant inflammation.In the modeling set,67 patients(51.1%)had significant inflammation.In the modeled group,comparison of HBV DNA,PLT,ALT,AST,ALP,GGT,PAB,H.A,PⅢP,CⅣ,L.N,IL-6,LSM and HBeAg for non-significant inflammation and significant inflammation showed statistically significant differences(P<0.05).Nomogram were obtained using stepwise regression analysis to establish a predictive model for the risk of significant inflammation following chronic HBV infection.The χ^(2) values of the H-L goodness-of-fit test for the modelling and validation groups were 0.279 and 2.098,respectively,corresponding to P values of 0.87 and 0.35,suggesting that the nomogram has good predictive accuracy;the area under the ROC curve of the column line plot predicting the occurrence of significant inflammation after HBV infection for the modelling and validation groups was 0.895[95%CI(0.843-0.948)]and 0.760[95%CI(0.622-0.897)],suggesting that the column line plot model has good discrimination.Conclusion:After stepwise regression analysis,it was established that PLT,Ln(HBV-DNA),AST,C桇and LSM were more closely associated with the occurrence of significant inflammation after HBV infection,and a visualization of the occurrence of significant inflammation nomogram was established by comprehensive assessment,and the effectiveness was good.

Effect of liver inflammation on accuracy of FibroScan device in assessing liver fibrosis stage in patients with chronic hepatitis B virus infection

BACKGROUND Transient elastography(FibroScan)is a new and non-invasive test,which has been widely recommended by the guidelines of chronic hepatitis B virus(HBV)management for assessing hepatic fibrosis staging.However,some confounders may affect the diagnostic accuracy of the FibroScan device in fibrosis staging.AIM To evaluate the diagnostic value of the FibroScan device and the effect of hepatic inflammation on the accuracy of FibroScan in assessing the stage of liver fibrosis in patients with HBV infection.METHODS The data of 416 patients with chronic HBV infection who accepted FibroScan,liver biopsy,clinical,and biological examination were collected from two hospitals retrospectively.Receiver operating characteristic(ROC)curves were used to analyze the diagnostic performance of FibroScan for assessing the stage of liver fibrosis.Any discordance in fibrosis staging by FibroScan and pathological scores was statistically analyzed.Logistic regression and ROC analyses were used to analyze the accuracy of FibroScan in assessing the stage of fibrosis in patients with different degrees of liver inflammation.A non-invasive model was constructed to predict the risk of misdiagnosis of fibrosis stage using FibroScan.RESULTS In the overall cohort,the optimal diagnostic values of liver stiffness measurement(LSM)using FibroScan for significant fibrosis(≥F2),severe fibrosis(≥F3),and cirrhosis(F4)were 7.3 kPa[area under the curve(AUC)=0.863],9.7 kPa(AUC=0.911),and 11.3 kPa(AUC=0.918),respectively.The rate of misdiagnosis of fibrosis stage using FibroScan was 34.1%(142/416 patients).The group of patients who showed discordance between fibrosis staging using FibroScan and pathological scores had significantly higher alanine aminotransferase and aspartate aminotransferase levels,and a higher proportion of moderate to severe hepatic inflammation,compared with the group of patients who showed concordance in fibrosis staging between the two methods.Liver inflammation activity over 2(OR=3.53)was an independent risk factor for misdiagnosis of fibrosis stage using FibroScan.Patients with liver inflammation activity≥2 showed higher LSM values using FibroScan and higher rates of misdiagnosis of fibrosis stage,whereas the diagnostic performance of FibroScan for different fibrosis stages was significantly lower than that in patients with inflammation activity<2(all P<0.05).A non-invasive prediction model was established to assess the risk of misdiagnosis of fibrosis stage using FibroScan,and the AUC was 0.701.CONCLUSION Liver inflammation was an independent risk factor affecting the diagnostic accuracy of FibroScan for fibrosis stage.A combination of other related noninvasive factors can predict the risk of misdiagnosis of fibrosis staging using FibroScan.

AstragalosideⅣplays a role in reducing radiation-induced liver inflammation in mice by inhibiting thioredoxin-interacting protein/nod-like receptor protein 3 signaling pathway

OBJECTIVE:To investigate the efficacy of Astragaloside IV(AS-IV)on radiation-induced liver inflammation in mice.METHODS:The mice were divided into normal group,dimethyl sulfoxide solvent group,irradiation group(IR),irradiation+AS-IV(20 mg/kg)group(IR+AS-20)and irradiation+AS-IV(40 mg/kg)group(IR+AS-40).One month after intraperitoneal injection of AS-IV,the mice were irradiated with 8Gry Co60γ,the blood was collected for biochemical analysis,and the liver was collected for hematoxylin-eosin staining,immunofluorescence and electron microscopic observation,oxidative stress,and Western blot analysis.RESULTS:The AS-IV treatment significantly ameliorated the pathological morphology of liver and reduced the alanine aminotransferase and aspertate aminotransferase levels in serum induced by radiation;AS-IV treatment also significantly reduced the expression of inflammatory factors tumor necrosis factor alpha and interleukin 6 and antagonized malonaldehyde content and superoxide dismutase activity in liver caused by radiation;in addition,AS-IV treatment can significantly inhibited the positive expression of thioredoxin-interacting protein(TXNIP)and nod-like receptor protein 3(NLRP3)inflammasome in liver tissue after radiation;The expression of TXNIP,NLRP3 inflammasome,apoptosisassociated speck-like protein containing a CARD,cysteinyl aspartate-specific proteinase 1 and interleukin 1beta in the AS-IV prevention group decreased significantly compared to the radiation group.CONCLUSIONS:These findings suggested that Co60γradiation can cause structural and functional damage to the liver,which may be related to the NLRP3 mediated inflammatory pathway;AS-IV may play a protective role by inhibiting the TXNIP/NLRP3 inflammasome signaling pathway in the radiation-induced liver injury model.

Liver Stiffness Measurement can Predict Liver Inflammation in Chronic Hepatitis B Patients with Normal Alanine Transaminase

Background and Aims:To determine whether liver stiffness measurement(LSM)indicates liver inflammation in chronic hepatitis B(CHB)with different upper limits of normal(ULNs)for alanine aminotransferase(ALT).Methods:We grouped 439 CHB patients using different ULNs for ALT:cohort I,≤40 U/L(439 subjects);cohort II,≤35/25 U/L(males/females;330 subjects);and cohort III,≤30/19 U/L(males/females;231 subjects).Furthermore,84 and 96 CHB patients with normal ALT(≤40 U/L)formed the external and prospective validation groups,respectively We evaluated the correlation between LSM and biopsy-confirmed liver inflammation,and determined diagnostic accuracy using area under the curve(AUC).A noninvasive LSM-based model was developed using multivariate logistic regression.Results:Fibrosis-adjusted LSM values significantly increased with increasing inflammation.The AUCs of LSM in cohorts I,II,and III were 0.799,0.796,and 0.814,respectively,for significant inflammation(A≥2)and 0.779,0.767,and 0.770,respectively,for severe inflammation(A=3).Cutoff LSM values in all cohorts for A≥2and A=3 were 6.3 and 7.5 kPa,respectively.Internal,external,and prospective validations showed high diagnostic accuracy of LSM for A≥2 and A=3,and no significant differences in AUCs among the four groups.LSM and globulin independently predicted A≥2.The AUC of an LSM-globulin model for A≥2 exceeded those of globulin,ALT,and AST,but was similar to that of LSM.Conclusions:LSM predicted liver inflammation and guided the indication of antiviral therapy for CHB in patients with normal ALT.

Inflammation and fibrosis in chronic liver diseases including nonalcoholic fatty liver disease and hepatitis C

At present chronic liver disease(CLD),the third commonest cause of premature death in the United Kingdom is detected late,when interventions are ineffective,resulting in considerable morbidity and mortality.Injury to the liver,the largest solid organ in the body,leads to a cascade of inflammatory events.Chronic inflammation leads to the activation of hepatic stellate cells that undergo transdifferentiation to become myofibroblasts,the main extra-cellular matrix producing cells in the liver;over time increased extra-cellular matrix production results in the formation of liver fibrosis.Although fibrogenesis may be viewed as having evolved as a“wound healing”process that preserves tissue integrity,sustained chronic fibrosis can become pathogenic culminating in CLD,cirrhosis and its associated complications.As the reference standard for detecting liver fibrosis,liver biopsy,is invasive and has an associated morbidity,the diagnostic assessment of CLD by non-invasive testing is attractive.Accordingly,in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice.Due to differing disease prevalence and treatment efficacy,disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection.To facilitate this,a review of the pathogenesis of both conditions is also conducted.Finally,the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed,including the current use of antifibrotic therapy.

Combined deficiency of SLAMF8 and SLAMF9 prevents endotoxin-induced liver inflammation by downregulating TLR4 expression on macrophages

Classical signaling lymphocyte activating molecule(SLAM)family receptors are abundant within many types of immune cells,whereas the nonclassical SLAM family receptors SLAMF8 and SLAMF9,which uniquely lack cytoplasmic signaling motifs,are highly expressed by myeloid cells.Due to the potential redundancy,whether these two receptors regulate macrophage function remains largely unknown.Here,we show that SLAMF8 and SLAMF9 co-regulate macrophage-mediated liver inflammation.To overcome the redundancy,we generated mice that simultaneously lacked SLAMF8 and SLAMF9 using CRISPR-Cas9 technology.Although macrophage differentiation was not altered by the combined deficiency of SLAMF8 and SLAMF9,the loss of these two receptors significantly protected against lipopolysaccharide(LPS)-induced liver injury.SLAMF8 and SLAMF9 double-deficient mice had a prolonged survival rate and less infiltration of inflammatory cells.The depletion of macrophages using clodronate liposomes abolished the effects of SLAMF8 and SLAMF9 deficiencies on LPS-induced liver injury,which demonstrates that these receptors are required for macrophage activation following LPS challenge.Moreover,the deficiency of SLAMF8 and SLAMF9 suppressed the secretion of inflammatory cytokines by downregulating the expression of Toll-like receptor-4(TLR4),a receptor that specifically binds LPS,which led to decreased mitogen-activated protein kinases(MAPK)signaling activation.Notably,combined injections of truncated extracellular SLAMF8 and SLAMF9 proteins significantly alleviated LPS-induced liver injury.Thus,our findings provide insights into the role of SLAMF8 and SLAMF9 in endotoxin-induced liver injury and suggest that SLAMF8 and SLAMF9 are potential therapeutic targets for acute hepatic injury.

Machine learning insights concerning inflammatory and liver-related risk comorbidities in non-communicable and viral diseases

The liver is a key organ involved in a wide range of functions,whose damage can lead to chronic liver disease(CLD).CLD accounts for more than two million deaths worldwide,becoming a social and economic burden for most countries.Among the different factors that can cause CLD,alcohol abuse,viruses,drug treatments,and unhealthy dietary patterns top the list.These conditions prompt and perpetuate an inflammatory environment and oxidative stress imbalance that favor the development of hepatic fibrogenesis.High stages of fibrosis can eventually lead to cirrhosis or hepatocellular carcinoma(HCC).Despite the advances achieved in this field,new approaches are needed for the prevention,diagnosis,treatment,and prognosis of CLD.In this context,the scientific community is using machine learning(ML)algorithms to integrate and process vast amounts of data with unprecedented performance.ML techniques allow the integration of anthropometric,genetic,clinical,biochemical,dietary,lifestyle and omics data,giving new insights to tackle CLD and bringing personalized medicine a step closer.This review summarizes the investigations where ML techniques have been applied to study new approaches that could be used in inflammatoryrelated,hepatitis viruses-induced,and coronavirus disease 2019-induced liver damage and enlighten the factors involved in CLD development.

Beneficial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease

BACKGROUND：Non-alcoholic fatty liver disease（NAFLD）refers to any fatty liver disease that is not due to excessive use of alcohol.NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance.Aerobic exercise is shown to improve NAFLD.This review aimed to evaluate the molecular mechanisms involved in the beneficial effects of aerobic exercise on NAFLD.DATA SOURCE：We searched articles in English on the role of aerobic exercise in NAFLD therapy in Pub Med.RESULTS： The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include： （i） reducing in- trahepatic fat content by down-regulating sterol regulatory element-binding protein-lc and up-regulating peroxisome proliferator-activated receptor y expression levels; （ii） decreas- ing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; （iii） ameliorating hepatic inflammation via the inhibition of pro-inflammatory media- tors such as tumor necrosis factor-alpha and interleukin-1 beta; （iv） attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and （v） inducing hepato-protective autophagy. CONCLUSION： Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

Dysregulation of apoptosis in hepatocellular carcinoma cells

Hepatocellular carcinoma （HCC） is a major health prob- lem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in hu- man hepatocarcinogenesis. This review updates the recent relevant contributions reporting molecular altera- tions for HCC that induce an imbalance in the regulation of apoptosis. Alterations in the expression and/or activation of p53 are frequent in HCC cells, which confer on them resistance to chemotherapeutic drugs. Many HCCs are also insensitive to apoptosis induced either by death receptor ligands, such as FasL or TRAIL, or by transforming growth factor-beta （TGF-β）. Although the expression of some pro-apoptotic genes is decreased, the balance between death and survival is dysregulated in HCC mainly due to overactivation of anti-apoptotic pathways. Indeed, some molecules involved in counter- acting apoptosis, such as Bcl-X1, Mcl-1, c-IAP1, XIAP or survivin are over-expressed in HCC cells. Furthermore, some growth factors that mediate cell survival are upregulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their pro- forms to an active peptide. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs path- ways are enhanced in many HCC cells, conferring on them resistance to apoptotic stimuli. Finally, recent evi- dence indicates that inflammatory processes, as well as the epithelial-mesenchymal transitions that occur in HCC cells to facilitate their dissemination, are related to cell survival. Therefore, therapeutic strategies to selectively inhibit anti-apoptotic signals in liver tumor cells have the potential to provide powerful tools to treat HCC.

Negative Correlation of Serum Hepatitis B Surface Antigen and Hepatitis B e Antigen Levels with the Severity of Liver Inflammation in Treatment-naive Patients with Chronic Hepatitis B Virus Infection

Background： Estimating the grades of liver inflammation is critical in the determination ofantiviral therapy in patients chronically infected with hepatitis B virus （HBV）. The aim of this study was to investigate the correlation ofserum levels of hepatitis B surface antigen （HBsAg） and hepatitis B e antigen （HBeAg） with the liver inflammation grades in treatment-naTve patients with chronic HBV infection. Methods： We retrospectively enrolled 584 treatment-na＇l＇ve HBeAg-positive patients who underwent liver biopsy in Ditan Hospital from January 2008 to January 2016. Based on the severity of liver inflammation, the patients were divided into minimal, mild, and moderate groups. SPSS software was used lbr statistical analysis of all relevant data. Results： The liver histological examinations showed that 324, 194, and 66 patients had minimal, mild, and moderate liver inflammation, respectively. The median age of the three groups was 30, 33, and 38 years, respectively （X2 =26.00, P 〈 0.001 ）. The median HBsAg levels in minimal, mild, and moderate inflammation groups were 4.40, 4.16, and 3.67 log U/ml, respectively, and the median HBeAg levels in the three groups were 3.12, 2.99, and 1.86 log sample/cutoff. respectively; both antigens tended to decrease as the grade of inflammation increased （X2 = 99.68 and X2 =99.23, respectively; both P 〈 0.001 ）. The cutoff values of receiver operating characteristic curve in the age, HBsAg and HBeAg levels were 36 years, 4.31 log U/ml, and 2.86 Iog S/CO, respectively, 1 to distinguish minimal grade and other grades of treatment-naTve HBeAg-positive patients with chronic HBV infection. Conclusions： Serum HBsAg and HBeAg quantitation might gradually decrease with aggravated liver inflammation and the corresponding cutoff values rnight help us to distinguish rninimal grades and other grades and detect those who do not need antiviral therapy in treatment-naive HBeAg-positive patients with chronic HBV infection.

Investigation of an inflammatory viral disease HBV in cardiac patients through polymerase chain reaction

In the present study 100 cardiac patients were randomly selected from the cardiology ward, Allied Hospital Faisalabad, Pakistan. All the selected cases were analysed for different parameters like Hepatitis B surface Antigen (HbsAg), Bilirubin, Alkaline phosphatase, serum glutamic pyruvic transaminase, and serum glutamic-oxaloacetic transaminase. Out of total 16% patients were lying in the age of 21-30 year, 25% in the age of 31-40 year, 35% in the age of 41-50 year, 19% in the age of 51-60 years and 5% patients in the age of 61-70 years. No subject was found positive in age group 21-30 years patients. 35% patients have higher value of SGPT while, other 26% were with higher value of SGOT. Rest of the 32 and 24% have higher ALP and Bilirubin levels, respectively. Assay profile revealed that ALP level was increased with increasing age, body mass index, Creactive protein, diabetes, smoking, sex, serum uric acid, lead, cadmium, hypercholesterolemia, lesion of liver and cardiovascular disease. The serum of the eight HbsAg positive cases were tested for the presence of HBV through PCR and no sample was found positive. At the end of the study, PCR amplified samples were run on 1.5% agarose gel to confirm the case.

Novel insights into the impact of liver inflammatory responses on primary liver cancer development

Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context.This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process(initiation steps)and the impact of the immune response favoring tumor cell expansion(progression steps).Several cytokines,namely interleukin(IL)-6,IL-17,IL-1beta,and tumor necrosis factor-alpha,have been described to play a prominent role in the initiation of liver cancers.Additionally,inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response,angiogenesis,and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation.These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation.These strategies are based on the use of anti-inflammatory agents,antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors,metastasis key factors,and microRNAs involved in tumor development.This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.

Hepatic macrophages in liver homeostasis and diseasesdiversity,plasticity and therapeutic opportunities

Macrophages,which are key cellular components of the liver,have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases.Upon liver injury,resident Kupffer cells(KCs)sense disturbances in homeostasis,interact with hepatic cell populations and release chemokines to recruit circulating leukocytes,including monocytes,which subsequently differentiate into monocyte-derived macrophages(MoMφs)in the liver.Both KCs and MoMφs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases.The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases.In this review,we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.

Gut-liver axis:gut microbiota in shaping hepatic innate immunity

Gut microbiota play an essential role in shaping immune cell responses. The liver was continuously exposed to metabolic products of intestinal commensal bacterial through portal vein and alteration of gut commensal bateria was always associated with increased risk of liver inflammation and autoimmune disease. Considered as a unique immunological organ, the liver is enriched with a large number of innate immune cells. Herein, we summarize the available literature of gut microbiota in shaping the response of hepatic innate immune cells including NKT cells, NK ceils, 78 T cells and Kupffer cells during health and disease. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of innate immune cell-related liver disease.

Dietary rumen-protected L-arginine or N-carbamylglutamate attenuated fetal hepatic inflammation in undernourished ewes suffering from intrauterine growth restriction

This study aimed to explore whether dietary rumen-protected L-arginine(RP-Arg)or N-carbamylglutamate(NCG)supplementation to feed-restricted pregnant ewes counteracts fetal hepatic inflammation and innate immune dysfunction associated with intrauterine growth retardation(IUGR)in ovine fetuses.On d 35 of pregnancy,twin-bearing Hu ewes(n=32)were randomly assigned to 4 treatment groups(8 ewes and 16 fetuses per group)and fed diets containing 100%of the NRC requirements(CON),50%of the NRC requirements(RES),RES+RP-Arg(20 g/d)(RESA),or RES+NCG(5 g/d)(RESN).At 08:00 on d 110 of gestation,fetal blood and liver tissue samples were collected.The levels of triglyceride,free fatty acid,cholesterol andβ-hydroxybutyrate in the fetal blood of RESA and RESN groups were lower(P<0.05)than those of the RES group,but were higher(P<0.05)than those of the CON group.The interleukin(IL)-6 and IL-1 levels in fetal blood and liver tissue as well as the myeloid differentiation primary response 88(MyD88),transforming growth factorβ(TGFβ),and nuclear factor kappa B(NF-κB)mRNA levels in the fetal liver were decreased(P<0.05)by the NCG or RP-Arg supplementation compared to the RES treatment.Similarly,the toll-like receptor(TLR)-4,MyD88,TGFβ,and p-c-Jun N-terminal kinase(JNK)protein levels in the fetal liver were reduced(P<0.05)in the NCG and RP-Arg-supplemented groups compared to the RES group.These results showed that dietary supplementation of RP-Arg or NCG to underfed pregnant ewes could protect against IUGR fetal hepatic inflammation via improving lipid metabolism,down-regulating the TLR-4 and the inflammatory JNK and NF-icB signaling pathways,and decreasing cytokine production in ovine fetal blood and liver tissue.

Noncanonical NF-κB Signaling Pathway in Liver Diseases

The noncanonical NF-κB signaling pathway is an important branch of NF-κB signaling.It is involved in regulating multiple important biological processes,including inflammation and host immune response.A central adaptor protein of the noncanonical NF-κB pathway is NF-κB-inducing kinase(NIK),which activates the downstream kinase IKKαto process p100 to p52,thereby forming the RelB/p52 heterodimer to initiate the expression of target genes.Currently,many specific inhibitors and monoclonal antibodies targeting or triggering this pathway are being developed and tested for various diseases,including cancers,autoimmune diseases,and virus infection.Given that aberrant activation of the noncanonical NF-κB pathway is frequently observed in various liver diseases,targeting this pathway may be a promising therapeutic strategy to alleviate liver inflammation.Moreover,activation of this pathway may contribute to the antiviral immune response and promote the clearance of persistent hepatotropic virus infection.Here,we review the role of the noncanonical NF-κB pathway in the occurrence and development of different liver diseases,and discuss the potency and application of modulating the noncanonical NF-κB pathway for treatment of these liver diseases.

Gama-aminobutyric acid(GABA)alleviates hepatic inflammation via GABA receptors/TLR4/NF-kB pathways in growing-finishing pigs generated by super-multiparous sows

The offspring of super-multiparous sows face problems such as decreased growth performance,poor meat quality and even diseases in animal husbandry.Gama-aminobutyric acid(GABA)has long been known to promote growth and suppress inflammation,but little is known about the mechanisms.A total of 72 growing-finishing pigs from the 8th generation were randomly allotted to 2 groups with 6 replicates per treatment to receive a cornesoybean basal diet or the basal diet supplemented 20 mg/kg GABA for 60 d.After the animal-trial period,samples of serum and liver were collected for further analysis.Additionally,a lipopolysaccharide(LPS)-induced inflammatory model using HepG2 cells was established to explore the role of GABA on regulating hepatic inflammation.The results indicated that inflammatory cell infiltration occurs in the liver of progeny of super-multiparous sows,and dietary supplementation with GABA influenced liver morphology,increased activities of antioxidant enzymes and decreased the expression abundance of pro-inflammatory cytokines,including tumor necrosis factor-α(TNFα)and interleukin(IL)-1β,in the liver of growing-finishing pigs(P<0.05).In addition,GABA supplementation increased mRNA expressions of peroxisome proliferator-activated receptor g(PPARg)and GABA receptors(GABARs),and reduced the expression of toll-like receptor 4(TLR4)/nuclear factor-kB(NF-kB)signaling(P<0.05).Additionally,an in vitro experiment demonstrated that GABA decreased the expressions of hepatic TLR4/NF-kB signaling via activating GABARs under LPS-stress(P<0.05).In summary,liver injury may affect the growth performance of growing-finishing pigs by changing hepatic mitochondrial metabolism,the expression of pro-inflammatory cytokines and TLR4/NF-kB pathway and that GABA supplementation has a restorative effect by acting on GABARs.

Correlation of effective hepatic blood flow with liver pathology in patients with hepatitis B virus

Background and aims:Effective hepatic blood flow(EHBF)decreases with liver disease progression,and identifying liver pathology is critical for patients with liver disease.This study was designed to elucidate the correlation between EHBF and liver pathology and explore the potential of EHBF for predicting the degree of liver pathology.Methods:In this study,207 patients with hepatitis B virus(HBV)who underwent liver biopsy and indocyanine green(ICG)clearance tests were enrolled.EHBF was measured using the ICG clearance test,and liver tissue was histologically analyzed to determine the pathological stage according to the Scheuer scoring system.Demographic data,biochemical indexes,and FibroScan data were collected for statistical analysis.Results:EHBF levels decreased as the liver histological stages of inflammation and fibrosis increased(P<0.01).EHBF was significantly negatively associated with the levels of alanine aminotransferase,aspartate aminotransferase,gamma-glutamyl transpeptidase,alkaline phosphatase,aspartate aminotransferase-to-platelet ratio index,fibrosis index based on the four factors,and liver stiffness measurement(P<0.05).The EHBF levels of patients without liver inflammation(G0)were significantly higher than those of patients with liver inflammation(G1e4)(P<0.001).The area under the receiver operating characteristic curve(AUROC)value for discriminating patients without liver inflammation was 0.827,and the optimal cutoff value was 0.936 L/min.The EHBF levels of patients with severe liver inflammation(G4)were significantly lower than those of patients with G0e3 liver inflammation(P<0.001).The AUROC value for discriminating patients with severe liver inflammation was 0.792,and the optimal cutoff value was 0.552 L/min.The EHBF levels of patients without liver fibrosis(S0)were significantly higher than those of patients with liver fibrosis(S1e4)(P<0.001).The AUROC value for discriminating patients without liver fibrosis was 0.633,and the optimal cutoff value was 1.173 L/min.The EHBF levels of patients with liver cirrhosis(S4)were significantly lower than those of patients with S0e3 liver fibrosis(P<0.001).The AUROC value for discriminating patients with liver cirrhosis(S4)was 0.630,and the optimal cutoff value was 0.562 L/min.Conclusions:EHBF levels and liver pathology are significantly correlated.EHBF could effectively reflect liver inflammation and fibrosis in patients infected with HBV,especially for patients without liver inflammation or liver fibrosis.

Erythroid Lineage Cells in the Liver:Novel Immune Regulators and Beyond

The lineage of the erythroid cell has been revisited in recent years. Instead of being classified as simply inert oxygen carriers, emerging evidence has shown that they are a tightly regulated in immune potent population with potential devel-opmental plasticity for lineage crossing. Erythroid cells have been reported to exert immune regulatory function through secreted cytokines, or cell-cell contact, depending on the conditions of the microenvironment and disease models. In this review, we explain the natural history of erythroid cells in the liver through a developmental lens, as it offers perspec-tives into newly recognized roles of this lineage in liver biology. Here, we review the known immune roles of erythroid cells and discuss the mechanisms in the context of disease models and stages. Then, we explore the capability of erythroid lineage as a cell source for regenerative medicine. We propose that the versatile lineage of erythroid cells provides an underappreciated and potentially promising area for basic and translational research in the field of liver disease.

The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis(NASH)have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated.Inactive rhomboid protein 2(IRHOM2),a promising target for treatment of inflammation-related diseases,contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis(NASH)progression.However,the molecular mechanism underlying Irhom2 regulation is still not completely understood.In this work,we identify the ubiquitin-specific protease 13(USP13)as a critical and novel endogenous blocker of IRHOM2,and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes.Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis,followed by glycometabolic disorder,lipid deposition,increased inflammation,and markedly promotes NASH development.Conversely,transgenic mice with Usp13 overexpression,lentivirus(LV)-or adeno-associated virus(AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent.Mechanistically,in response to metabolic stresses,USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N(UBC13),a ubiquitin E2 conjugating enzyme,and thus prevents its activation of downstream cascade pathway.USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.