Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis:Should we consider further implications?

This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology.The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis.Here,we recapitulated the complexity of the renin-angiotensin system,discussed the role of hepatic stellate cell(HSC)autophagy in liver fibrogenesis,and analyzed the possible implications in the development of hepatocarcinoma(HCC).Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis,whereas their involvement in HCC is more evident in experimental conditions than in human studies.Angiotensin-converting enzyme 2(ACE2),and its product Angiotensin(Ang)1-7,not only regulate HSC autophagy and liver fibrosis,but they also represent potential targets for unexplored applications in the field of HCC.Finally,ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase(AMPK)/mammalian target of rapamycin(mTOR)pathway.In this case,Ang 1-7 acts binding to the MasR,and its agonists could modulate this pathway.However,since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively,we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.

Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system

The present letter to the editor is related to the study titled‘Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells’.Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

Screening for metabolic dysfunction-associated fatty liver disease:Time to discard the emperor’s clothes of normal liver enzymes?

Metabolic dysfunction-associated fatty liver disease(MAFLD)is the most prevalent chronic liver condition worldwide.Current liver enzyme-based screening methods have limitations that may missed diagnoses and treatment delays.Regarding Chen et al,the risk of developing MAFLD remains elevated even when alanine aminotransferase levels fall within the normal range.Therefore,there is an urgent need for advanced diagnostic techniques and updated algorithms to enhance the accuracy of MAFLD diagnosis and enable early intervention.This paper proposes two potential screening methods for identifying individuals who may be at risk of developing MAFLD:Lowering these thresholds and promoting the use of noninvasive liver fibrosis scores.

HepG2.2.15-derived exosomes facilitate the activation and fibrosis of hepatic stellate cells

BACKGROUND The role of exosomes derived from HepG2.2.15 cells,which express hepatitis B virus(HBV)-related proteins,in triggering the activation of LX2 liver stellate cells and promoting liver fibrosis and cell proliferation remains elusive.The focus was on comprehending the relationship and influence of differentially expressed microRNAs(DE-miRNAs)within these exosomes.AIM To elucidate the effect of exosomes derived from HepG2.2.15 cells on the activation of hepatic stellate cell(HSC)LX2 and the progression of liver fibrosis.METHODS Exosomes from HepG2.2.15 cells,which express HBV-related proteins,were isolated from parental HepG2 and WRL68 cells.Western blotting was used to confirm the presence of the exosomal marker protein CD9.The activation of HSCs was assessed using oil red staining,whereas DiI staining facilitated the observation of exosomal uptake by LX2 cells.Additionally,we evaluated LX2 cell proliferation and fibrosis marker expression using 5-ethynyl-2′-deoxyuracil staining and western blotting,respectively.DE-miRNAs were analyzed using DESeq2.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways were used to annotate the target genes of DE-miRNAs.RESULTS Exosomes from HepG2.2.15 cells were found to induced activation and enhanced proliferation and fibrosis in LX2 cells.A total of 27 miRNAs were differentially expressed in exosomes from HepG2.2.15 cells.GO analysis indicated that these DE-miRNA target genes were associated with cell differentiation,intracellular signal transduction,negative regulation of apoptosis,extracellular exosomes,and RNA binding.KEGG pathway analysis highlighted ubiquitin-mediated proteolysis,the MAPK signaling pathway,viral carcinogenesis,and the toll-like receptor signaling pathway,among others,as enriched in these targets.CONCLUSION These findings suggest that exosomes from HepG2.2.15 cells play a substantial role in the activation,proliferation,and fibrosis of LX2 cells and that DE-miRNAs within these exosomes contribute to the underlying mechanisms.

Liver disease in patients with transfusion-dependentβ-thalassemia:The emerging role of metabolism dysfunction-associated steatotic liver disease

In this Editorial,we highlight the possible role that metabolism dysfunction-associated steatotic liver disease(MASLD)may play in the future,regarding liver disease in patients with transfusion-dependent β-thalassemia(TDBT).MASLD is characterized by excessive accumulation of fat in the liver(hepatic steatosis),in the presence of cardiometabolic factors.There is a strong correlation between the occurrence of MASLD and insulin resistance,while its increased prevalence parallels the global epidemic of diabetes mellitus(DM)and obesity.Patients with TDBT need regular transfusions for life to ensure their survival.Through these transfusions,a large amount of iron is accumulated,which causes saturation of transferrin and leads to the circulation of free iron molecules,which cause damage to vital organs(primarily the liver and myocardium).Over the past,the main mechanisms for the development of liver disease in these patients have been the toxic effect of iron on the liver and chronic hepatitis C,for which modern and effective treatments have been found,resulting in successful treatment.Additional advances in the treatment and monitoring of these patients have led to a reduction in deaths,and an increase in their life expectancy.This increased survival makes them vulnerable to the onset of diseases,which until recently were mainly related to the non-thalassemic general population,such as obesity and DM.There is insufficient data in the literature regarding the prevalence of MASLD in this population or on the risk factors for its occurrence.However,it was recently shown by a study of 45 heavily transfused patients with beta-thalassemia(Padeniya et al,BJH),that the presence of steatosis is a factor influencing the value of liver elastography and thus liver fibrosis.These findings suggest that future research in the field of liver disease in patients with TDBT should be focused on the occurrence,the risk factors,and the effect of MASLD on these patients.

Quantitative Assessment of Liver Fibrosis by Elastography in Patients with Chronic Liver Disease: A Cross-Sectional Study in Lomé (Togo)

Aim: To describe the two-dimensional elastographic profile according to the Shearwave (2D-SWE) technique in patients with chronic liver disease in Lom. Materials and method: Cross-sectional, descriptive study conducted over seven month at the Autel dElie Clinic in Lom, from January to August 2022, on adult patients with chronic liver disease who underwent abdominal ultrasound coupled with two-dimensional elastography. Results: The sample size was 54 patients. The mean age of the patients was 33 12 years, with extremes of 18 and 66 years. Patients aged 30 years or less accounted for 48.1% (n = 26). All patients (n = 54) had at least one transaminase assay with a mean of 69.3 78.3 IU/l (AST) and 59.3 82.8 IU/l (ALT). There was no statistically significant association between the biological parameters and the presence of fibrosis. Viral liver disease was the main cause, accounting for 81.5% (n = 44) of cases, with no significant association with the degree of fibrosis. Ultrasound revealed a dysmorphic liver (57.4%;n = 31) and portal hypertension (18.5%, n = 10). Fibrosis stages F1, F2 and F4 accounted for (48.1%, n = 26), (24.1%, n = 13) and (13%, n = 7) of cases respectively. Liver dysmorphia was significantly associated with the presence of fibrosis (p = 0.012) and portal hypertension was significantly associated with the degree of fibrosis (p = 0.0063). Conclusion: Assessment of liver fibrosis in patients with chronic liver disease using 2D-SWE elastography is essential for patient follow-up.

Correlation of image textures of a polarization feature parameter and the microstructures of liver fibrosis tissues

Mueller matrix imaging is emerging for the quantitative characterization of pathological microstructures and is especially sensitive to fibrous structures.Liver fibrosis is a characteristic of many types of chronic liver diseases.The clinical diagnosis of liver fibrosis requires time-consuming multiple staining processes that specifically target on fibrous structures.The staining proficiency of technicians and the subjective visualization of pathologists may bring inconsistency to clinical diagnosis.Mueller matrix imaging can reduce the multiple staining processes and provide quantitative diagnostic indicators to characterize liver fibrosis tissues.In this study,a fibersensitive polarization feature parameter(PFP)was derived through the forward sequential feature selection(SFS)and linear discriminant analysis(LDA)to target on the identification of fibrous structures.Then,the Pearson correlation coeffcients and the statistical T-tests between the fiber-sensitive PFP image textures and the liver fibrosis tissues were calculated.The results show the gray level run length matrix(GLRLM)-based run entropy that measures the heterogeneity of the PFP image was most correlated to the changes of liver fibrosis tissues at four stages with a Pearson correlation of 0.6919.The results also indicate the highest Pearson correlation of 0.9996 was achieved through the linear regression predictions of the combination of the PFP image textures.This study demonstrates the potential of deriving a fiber-sensitive PFP to reduce the multiple staining process and provide textures-based quantitative diagnostic indicators for the staging of liver fibrosis.

Intervention effect of Zhuangfang Rugan Huaxian Granules on CCl_(4)compound factor‑induced liver fibrosis rat model and its effect on the expression ofα‑SMA and E‑Cadherin

Objective:To study the intervention effect of Zhuangfang Soft Liver and Fibrous Granules on CCl_(4)compound factor-induced liver fibrosis rat model and its effect onα-SMA and E-Cadherin protein expression.Methods:Forty-eight male Wistar rats were randomly divided into a blank group,a pathological model group and a group of 16 rats in each group.The rats in the pathological model group and the pellet group were injected subcutaneously with 40%carbon tetrachloride(CCl_(4))oil combined with peanut oil to establish an animal model of rat liver fibrosis,and the pellets were administered by gavage three times a week for 8 weeks from the 5th week.The expression of oxidative stress oxidase dismutase(SOD)and malondialdehyde(MDA)was detected by enzyme-linked immunoassay(ELISA),and the expression ofα-smooth muscle actin(α-SMA)and E-calmodulin(E-Cadherin)was detected by RT-PCR andWestern Blot.expression.Results:Compared with the blank group,the serum ALT and AST levels of the rats in the pathological model group were significantly increased,and the serum ALT and AST levels of the rats in the soft liver and fibrous pellet group were significantly decreased(P<0.001).In the pathological model group,the lobular structure of liver tissue was mutilated and numerous liver fibrous tissues were abnormally proliferated,and the collagen fibers formed by the proliferation were confluent into dense fibrous intervals,thus turning into pseudolobular structure,and a large number of fatty degenerated hepatocytes of different shapes and sizes appeared inside the pseudolobular structure,and the diffuse infiltration of inflammatory cells was significant.Compared with the pathological model group,the degree of destruction of hepatic lobular structure was significantly reduced in the LBP group,and there were different degrees of proliferation of collagen fibrous tissue concentrated in the area from the central vein to the confluent area,and the fibrous septum was relatively loose,with a small amount of inflammatory cell infiltration,and the degree of infiltration was reduced compared with the pathological model group.Compared with the pathological model group,the SOD level was significantly higher in the group of liver softener and fibrous pellets compared with the pathological model group and the blank group(P<0.001),the MDA level was significantly lower in the group of liver softener and fibrous pellets compared with the pathological model group(P<0.001),the expression level ofα-SMA was significantly lower in the group of liver softener and fibrous pellets(P<0.001),and the expression level of E-Cadherin was significantly higher in the group of liver softener and fibrous pellets(P<0.001).Conclusion:Soft Liver Fibro Pellets can effectively inhibit liver fibrous tissue proliferation and reduce the serum ALT and AST levels in rats with CCl_(4)combined with peanut oil compound solution induced liver fibrosis,and its anti-liver fibrosis mechanism may be through protecting liver function,reducing the level of oxidative stress,down-regulating the expression ofα-SMA protein,up-regulating the expression of E-cadherin protein,and inhibiting epithelial-mesenchymal transition epithelial mesenchymal transformation(EMT)and thus exerting therapeutic effects on CCl_(4)compound-induced hepatic fibrosis in rats.

The diagnostic value of transient elastography combined with serum SAA and IL-6 in the degree of hepatitis B liver fibrosis

Objective:To investigat the diagnostic value of transient elastography combined with serum amyloid A and interleukin-6 in the degree of hepatitis B liver fibrosis.Methods:A total of 334 patients with chronic HBV infection that were admitted to the Department of Infectious Diseases of the First Affiliated Hospital of Hainan Medical College from January 2020 to May 2022 with informed consent and underwent liver biopsy puncture were selected.According to the pathological results,they were divided into no obvious fibrosis group,obvious fibrosis group and liver cirrhosis group.Comparison of liver stiffness measurement(LSM),serum amyloid A(SAA0,IL-6 levels between different groups.This study drawed was conducted draw the receiver operating characteristic(ROC)curve of each index to diagnose significant liver fibrosis and liver cirrhosis,and compared the area under the ROC curve(AUC)and diagnostic efficacy of each non-invasive fibrosis diagnostic model.The diagnostic performance of the combined assay was superior to that of APRI and FIB-4 In different degrees of liver fibrosis.Results:According to the degree of liver fibrosis,the levels of SAA,IL-6,and LSM in the no significant fibrosis group(n=140),the significant fibrosis group(n=134),and the cirrhosis group(n=60)were statistically significant difference(All P<0.001).SAA,IL-6 and LSM were significantly correlated with the degree of liver fibrosis(rs=0.456,rs=0.482,rs=0.602,All P<0.001).The AUC of SAA and IL-6 for the diagnosis of significant fibrosis in hepatitis B were 0.738 and 0.809,respectively.And the AUC for the diagnosis of liver cirrhosis were 0.813 and 0.823,respectively.The AUC for the combined diagnosis of significant fibrosis and cirrhosis were 0.930 and 0.964,respectively.The diagnostic performance of the combined assay was superior to that of APRI and FIB-4 in different degrees of liver fibrosis(All P<0.001).Conclusion:LSM combined with serum SAA and IL-6 has great diagnostic value for different degrees of hepatitis B liver fibrosis.

Correlation between the triglyceride glucose index and the degree of steatosis and liver fibrosis in nonalcoholic fatty liver disease

Objective:To investigate the relationship between triglyceride glucose index(TyG)and the degree of steatosis and liver fibrosis in patients with nonalcoholic fatty liver disease(NAFLD).Methods:Totally 2054 patients hospitalized in the second affiliated hospital of Xinjiang Medical University from September 2020 to September 2021 were retrospectively selected.According to abdominal ultrasound were divided into NAFLD group and non-NAFLD group.In accordance with the degree of steatosis,NAFLD patients were separated into mild group,moderate group and severe group.According to the liver stiffness,NAFLD patients were divided into liver fibrosis group and non-liver fibrosis group.We used the logistic regression to examine the correlation between TyG index and the the degree of steatosis and liver fibrosis.ROC curve was drawn to evaluate the diagnostic value of TyG index for NAFLD and liver fibrosis.Results:The prevalence of NAFLD increased with the increase of the interquartile of TyG index(Q_(1)44.1%,Q_(2)58.7%,Q_(3)71.9%,Q_(4)84.6%,P<0.001);The prevalence of liver fibrosis increased with the increase of the interquartile of TyG index(Q_(1)25.8%,Q_(2)30.2%,Q_(3)38.6%,Q_(4)44.3%,P<0.001).After adjusting for confounders,there was a correlation between TyG index and the degree of steatosis in NAFLD patients(the OR values of mild,moderate and severe groups were 1.383,2.450 and 3.070,P<0.001).TyG index was associated with liver fibrosis(OR=1.132,P<0.001).The ROC curve of TyG index predicted NAFLD was 0.701,with an optimal cutoff value of TyG is 8.57.However,the ROC curve of TyG index predicted liver fibrosis was 0.595.TyG index may not be a reliable predictor of liver fibrosis.Conclusion:TyG index was positively correlated with the degree of steatosis and liver fibrosis in NAFLD.

Application of ARFI technology to explore the clinical study of Gandou Tang in treating liver fibrosis of wilson's disease with damp-heat accumulation

Objective:Acoustic radiation force impulse(ARFI)was applied to measure Shear wave velocity(SWV)of liver in patients with Wilson's disease(WD).To investigate the relationship between SWV and the serological indexes of liver fibrosis,such as type Ⅳ collagen(CⅣ),hyaluronic acid(HA),type Ⅲ procollagen peptide(PⅢNP),laminin(LN),APRI score(Asparate Aminotransfer to Platelet Ratio Index),and FIB-4 index(FIB-4 index).The clinical efficacy of GandouTang(GDT)in the treatment of liver fibrosis in WD with damp-heat internalization was also observed.Methods:80 cases of WD patients who met the inclusion criteria were randomly divided into the treatment group and the control group,with 40 cases in each group.The control group was treated with Sodium Dimercaptopropylsulfonate(DMPS)and the treatment group was additionally treated with the traditional Chinese medicine GDT.One course for 8 days,a total of 6 courses.The levels of SwV and four serological indicators of liver fibrosis(PⅢNP,HA,CⅣ,LN),APRI score and FIB-4 index were compared before and after treatment.Pearson correlation test was used to analyze the correlation between SWV and HA,CⅣ,LN,PⅢNP,APRI score and FIB-4 index.The effects of GDT on SWV,liver fiber,APRI and FIB-4 were evaluated according to the treatment plan.Results:①The SWV was positively correlated with FIB-4(r=0.83),APRI(r=0.82),HA(r=0.87),CⅣ(r=0.71),LN(r=0.85)and PINP(r=0.77).②Before treatment,there were no significant differences in SWV level,PⅢNP,HA,CⅣ,LN,APRI and FIB-4 levels between two groups(P>0.05).After treatment,the levels of PⅢNP,HA,LN,SWV,APRI and FIB-4 in both groups were significantly decreased(P<0.05,P<0.01),and the levels in the treatment group were lower than those in the control group.There were no significant specific changes in CⅣ level(P>0.05).Conclusion:SWV value can reflect the degree of WD liver fibrosis,and is positively correlated with HA,PⅢNP,CⅣ,LN,FIB-4 index and APRI score.On the basis of the treatment of protecting liver and expelling copper with western medicine,plus the treatment of traditional Chinese medicine GDT can effectively improve the degree of liver fibrosis in WD patients with damp-heat accumulation.

Evaluation of the diagnostic value of total bile acids/platelets in HBV related liver fibrosis

Objective:Explore the diagnostic value of total bile acids/platelets in HBV related liver fibrosis.Methods:160 patients with chronic HBV infection admitted to the Infection Department of the First Affiliated Hospital of Hainan Medical College from February 2021 to December 2022 were selected.They were divided into two groups based on the degree of liver fibrosis detected by liver biopsy:significant liver fibrosis group and non-significant liver fibrosis group.The total bile acid/blood platelet levels and their correlation with liver fibrosis in the two groups were compared and observed,and the efficacy of other non-invasive liver fibrosis diagnostic models was evaluated.Results:(1)Compared with the non-significant liver fibrosis group,the significant liver fibrosis group showed an increase in total bile acid levels,a decrease in platelet levels,and a significant increase in total bile acid/platelet levels(P<0.05).(2)Platelets decrease with the increase of liver fibrosis degree,total bile acids increase with the increase of liver fibrosis degree,and total bile acids/platelets increase with the increase of liver fibrosis degree.(3)The area under the curve(AUC)of total bile acid/platelet,APRI,FIB-4,and elastography in diagnosing the degree of liver fibrosis were 0.69,0.57,0.56,and 0.68,respectively.Conclusions:The diagnostic efficacy of total bile acids/platelets in diagnosing HBV related liver fibrosis is no less than that of other liver fibrosis diagnostic methods,and it is non-invasive,simple,and convenient,which is worthy of further clinical promotion and validation.

The diagnostic value of liver stiffness measurement combined with S index in the degree of hepatitis B liver fibrosis

Objective:To investigate the value of liver stiffness measurement(LSM)combined with S index in predicting the degree of liver fibrosis in hepatitis B patients.Methods:A total of 187 chronic hepatitis B patients who were admitted to the Department of Infection,the First Affiliated Hospital of Hainan Medical College from January 2019 to December 2021 were selected.General data were collected,blood routine,liver function,liver fibrosis and liver stiffness measurement were tested,and S index,APRI and FIB-4 index were calculated,and liver biopsy was performed.Results:According to the pathological results of liver puncture,The patients were divided into no significant fibrosis group(n=86),significant fibrosis group(n=71)and cirrhosis group(n=30).There were significant differences in age,PLT,GGT,ALB,S index,HA,LN and LSM levels among the three groups(P<0.05).There was a good correlation between S index and the degree of hepatic fibrosis(rs=0.738,P<0.001).The AUC of S index and LSM for the diagnosis of significant fibrosis in hepatitis B were 0.873 and 0.792,respectively.And the AUC of S index and LSM for the diagnosis of liver cirrhosis were 0.966 and 0.879,respectively.The AUC for the combined diagnosis of significant fibrosis and cirrhosis were 0.908 and 0.988,respectively.The AUROC of combined detection in the diagnosis of cirrhosis was higher than that of LSM,APRI and FIB-4(P<0.05).Conclusion:LSM combined with S index has certain application value in the diagnosis of liver fibrosis/cirrhosis in hepatitis B patients.

Mechanism of FXR alleviating the liver fibrosis by regulating perilipin 5

Objective:To investigate the regulatory mechanism in liver fibrosis progression by nuclear receptor of farnesoid X receptor(FXR)and the lipid droplet-associated protein of perilipin 5(PLIN5).Methods:FXR response element(FXRE)upstream of PLIN5 gene was found by bioinformatics,and confirmed by a dual luciferase reporter gene system;a hepatic fibrosis model based on human hepatic stellate cell LX-2 was established by induction of transforming growth factor-β1(TGF-β1);mRNA and protein levels ofα-smooth muscle actin(α-SMA)and collagen栺were measured by qPCR and Western blot after transient overexpression of FXR or PLIN5;Oil red O staining was used to study the formation of lipid droplets.Results:The promoter region of the PLIN5 gene contained a known reverse repeats-1(IR-1);the gene expression of PLIN5 in LX-2 cells was up-regulated after FXR activation(P<0.01);overexpression of PLIN5 promoted the formation of lipid droplets and significantly reduced the TGF-β1 induced fibrosis gene expression(P<0.05);FXR activation showed no effects on the inhibition of LX-2 cells activation.Conclusion:Overexpression of PLIN5 promotes the formation of lipid droplets and inhibits activation of LX-2 cells.FXR might bind to the FXRE site upstream of PLIN5 gene and regulate its gene expression.In summary,FXR may prevent liver fibrosis progression partially by regulating lipid droplet-associated protein of PLIN5.

Staging liver fibrosis with various diffusion-weighted magnetic resonance imaging models

BACKGROUND Diffusion-weighted imaging(DWI)has been developed to stage liver fibrosis.However,its diagnostic performance is inconsistent among studies.Therefore,it is worth studying the diagnostic value of various diffusion models for liver fibrosis in one cohort.AIM To evaluate the clinical potential of six diffusion-weighted models in liver fibrosis staging and compare their diagnostic performances.METHODS This prospective study enrolled 59 patients suspected of liver disease and scheduled for liver biopsy and 17 healthy participants.All participants underwent multi-b value DWI.The main DWI-derived parameters included Mono-apparent diffusion coefficient(ADC)from mono-exponential DWI,intravoxel incoherent motion model-derived true diffusion coefficient(IVIM-D),diffusion kurtosis imaging-derived apparent diffusivity(DKI-MD),stretched exponential model-derived distributed diffusion coefficient(SEM-DDC),fractional order calculus(FROC)model-derived diffusion coefficient(FROC-D)and FROC model-derived microstructural quantity(FROC-μ),and continuous-time random-walk(CTRW)model-derived anomalous diffusion coefficient(CTRW-D)and CTRW model-derived temporal diffusion heterogeneity index(CTRW-α).The correlations between DWI-derived parameters and fibrosis stages and the parameters’diagnostic efficacy in detecting significant fibrosis(SF)were assessed and compared.RESULTS CTRW-D(r=-0.356),CTRW-α(r=-0.297),DKI-MD(r=-0.297),FROC-D(r=-0.350),FROC-μ(r=-0.321),IVIM-D(r=-0.251),Mono-ADC(r=-0.362),and SEM-DDC(r=-0.263)were significantly correlated with fibrosis stages.The areas under the ROC curves(AUCs)of the combined index of the six models for distinguishing SF(0.697-0.747)were higher than each of the parameters alone(0.524-0.719).The DWI models’ability to detect SF was similar.The combined index of CTRW model parameters had the highest AUC(0.747).CONCLUSION The DWI models were similarly valuable in distinguishing SF in patients with liver disease.The combined index of CTRW parameters had the highest AUC.

Current remarks and future directions on the interactions between metabolic dysfunction-associated fatty liver disease and COVID-19

During the outbreak of the coronavirus disease 2019(COVID-19)pandemic,particular interest rose regarding the interaction between metabolic dysfunctionassociated fatty liver disease(MAFLD)and the COVID-19 infection.Several studies highlighted the fact that individuals with MAFLD had higher probability of severe acute respiratory syndrome coronavirus 2 infection and more severe adverse clinical outcomes.One of the proposed mechanisms is the inflammatory response pathway,especially the one involving cytokines,such as interleukin 6,which appeared particularly elevated in those patients and was deemed responsible for additional insult to the already damaged liver.This should increase our vigilance in terms of early detection,close follow up and early treatment for individuals with MAFLD and COVID-19 infection.In the direction of early diagnosis,biomarkers such as cytokeratin-18 and scoring systems such as Fibrosis-4 index score are proposed.COVID-19 is a newly described entity,expected to be of concern for the years to come,and MAFLD is a condition with an ever-increasing impact.Delineating the interaction between these two entities should be brought into the focus of research.Reducing morbidity and mortality of patients with COVID-19 and MAFLD should be the ultimate objective,and the optimal way to achieve this is by designing evidence-based prevention and treatment policies.

Association between Serum Ferritin Levels and Metabolic-associated Fatty Liver Disease in Adults:a Cross-sectional Study Based on the NHANES

Objective Ferritin,initially acting as an iron-storage protein,was found to be associated with metabolic diseases.Our study was designed to investigate the association between serum ferritin and metabolic-associated fatty liver disease(MAFLD)using data from the National Health and Nutrition Examination Survey(NHANES)of the United State of America.Methods A cross-sectional study was conducted,enrolling a total of 2145 participants from the NHANES in the 2017–2018 cycles.Hepatic steatosis and liver fibrosis were assessed by ultrasound images and several non-invasive indexes.Multiple regression analysis was conducted to determine the associations between serum ferritin concentration and MAFLD and liver fibrosis.Results The analysis revealed that participants with higher serum ferritin levels(Q3 and Q4 groups)had a higher prevalence of MAFLD than those with the lowest serum ferritin levels[Q3 vs.Q1:OR=2.17(1.33,3.53),P<0.05 in fatty liver index(FLI);Q4 vs.Q1:OR=3.13(1.91,5.13),P<0.05 in FLI].Additionally,participants with the highest serum ferritin levels(Q4 group)displayed a higher prevalence of liver fibrosis[Q4 vs.Q1:OR=2.59(1.19,5.62),P<0.05 in liver stiffness measurement;OR=5.06(1.12,22.94),P<0.05 in fibrosis-4 index],with significantly increased risk observed in participants with concomitant diabetes[OR=7.45(1.55,35.72),P=0.012].Conclusion Our study revealed that elevated serum ferritin levels are associated with a higher prevalence of MAFLD and advanced liver fibrosis in patients.Elevated serum ferritin levels combined with diabetes are important risk factors for liver fibrosis.

Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells

BACKGROUND Liver fibrosis is the common pathological process associated with the occurrence and development of various chronic liver diseases.At present,there is still a lack of effective prevention and treatment methods in clinical practice.Hepatic stellate cell(HSC)plays a key role in liver fibrogenesis.In recent years,the study of liver fibrosis targeting HSC autophagy has become a hot spot in this research field.Angiotensin-converting enzyme 2(ACE2)is a key negative regulator of reninangiotensin system,and its specific molecular mechanism on autophagy and liver fibrosis needs to be further explored.AIM To investigate the effect of ACE2 on hepatic fibrosis in mice by regulating HSC autophagy through the Adenosine monophosphate activates protein kinases(AMPK)/mammalian target of rapamycin(mTOR)pathway.METHODS Overexpression of ACE2 in a mouse liver fibrosis model was induced by injection of liver-specific recombinant adeno-associated virus ACE2 vector(rAAV2/8-ACE2).The degree of liver fibrosis was assessed by histopathological staining and the biomarkers in mouse serum were measured by Luminex multifactor analysis.The number of apoptotic HSCs was assessed by terminal deoxynucleoitidyl transferase-mediated dUTP nick-end labeling(TUNEL)and immunofluorescence staining.Transmission electron microscopy was used to identify the changes in the number of HSC autophagosomes.The effect of ACE2 overexpression on Wu Y et al.ACE2 improves liver fibrosis through autophagy WJG https://www.wjgnet.com 4976 September 7,2023 Volume 29 Issue 33 autophagy-related proteins was evaluated by multicolor immunofluorescence staining.The expression of autophagy-related indicators and AMPK pathway-related proteins was measured by western blotting.RESULTS A mouse model of liver fibrosis was successfully established after 8 wk of intraperitoneal injection of carbon tetrachloride(CCl4).rAAV2/8-ACE2 administration reduced collagen deposition and alleviated the degree of liver fibrosis in mice.The serum levels of platelet-derived growth factor,angiopoietin-2,vascular endothelial growth factor and angiotensin II were decreased,while the levels of interleukin(IL)-10 and angiotensin-(1-7)were increased in the rAAV2/8-ACE2 group.In addition,the expression of alpha-smooth muscle actin,fibronectin,and CD31 was down-regulated in the rAAV2/8-ACE2 group.TUNEL and immunofluorescence staining showed that rAAV2/8-ACE2 injection increased HSC apoptosis.Moreover,rAAV2/8-ACE2 injection notably decreased the number of autophagosomes and the expression of autophagy-related proteins(LC3I,LC3II,Beclin-1),and affected the expression of AMPK pathway-related proteins(AMPK,p-AMPK,p-mTOR).CONCLUSION ACE2 overexpression can inhibit HSC activation and promote cell apoptosis by regulating HSC autophagy through the AMPK/mTOR pathway,thereby alleviating liver fibrosis and hepatic sinusoidal remodeling.

KLF4 Inhibits the Activation of Human Hepatic Stellate Cell In Vitro

Objective Hepatic stellate cells(HSCs)play a crucial role in liver fibrosis.Early-stage liver fibrosis is reversible and intimately associated with the state of HSCs.Kruppel-like factor 4(KLF4)plays a pivotal role in a wide array of physiological and pathological processes.This study aimed to investigate the effect of KLF4 on the proliferation,apoptosis and phenotype of quiescent HSCs Methods We designed a KLF4 lentiviral vector and a KLF4 siRNA lentiviral vector,to upregulate and silence KLF4 expression in human HSC LX-2 cells via transfection.Cell proliferation was assessed using the CCK-8 assay.Flow cytometry was used to detect the cell cycle distribution and apoptosis rate.Western blotting was used to determine the levels of some quiescence and activation markers of HSCs Results Overexpression of KLF4 significantly increased the levels of E-cadherin and ZO-1,which are quiescent HSC markers,while significantly decreased the levels of N-cadherin and a-SMA,known activated HSC markers.In contrast,cell proliferation and apoptosis rates were elevated in LX-2 cells in which KLF4 expression was silenced Conclusion KLF4 inhibits the proliferation and activation of human LX-2 HSCs.It might be a key regulatory protein in the maintenance of HSC quiescence and may serve as a target for the inhibition of hepatic fibrosis.

Protective mechanism of Paeoniae Radix Alba against chemical liver injury based on network pharmacology,molecular docking,and in vitro experiments

Objective:To explore and validate the potential targets of Paeoniae Radix Alba(P.Radix,Bai Shao)in protecting against chemical liver injury through network pharmacology,molecular docking technology,and in vitro cell experiments.Methods:Network pharmacology was used to identify the common potential targets of P.Radix and chemical liver injury.Molecular docking was used to fit the components,which were subsequently verified in vitro.A cell model of hepatic fibrosis was established by activating hepatic stellate cell(HSC)-LX2 cells with 10 ng/mL transforming growth factor-β1.The cells were exposed to different concentrations of total glucosides of paeony(TGP),the active substance of P.Radix,and then evaluated using the cell counting kit-8 assay,enzyme-linked immunosorbent assay,and western blot.Results:Analysis through network pharmacology revealed 13 key compounds of P.Radix,and the potential targets for preventing chemical liver injury were IL-6,AKT serine/threonine kinase 1,jun protooncogene,heat shock protein 90 alpha family class A member 1(HSP90AA1),peroxisome proliferator activated receptor gamma(PPARG),PTGS2,and CASP3.Gene Ontology(GO)enrichment analysis indicated the involvement of response to drugs,membrane rafts,and peptide binding.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis revealed that the main pathways involved lipid and atherosclerosis and chemical carcinogenesis-receptor activation.Paeoniflorin and albiflorin exhibited strong affinity for HSP90AA1,PTGS2,PPARG,and CASP3.Different concentrations of TGP can inhibit the expression of COL-I,COL-III,IL-6,TNF-a,IL-1β,HSP-90a,and PTGS2 while increasing the expression of PPAR-γand CASP3 in activated HSC-LX2 cells.Conclusion:P.Radix primarily can regulate targets such as HSP90AA1,PTGS2,PPARG,CASP3.TGP,the main active compound of P.Radix,protects against chemical liver injury by reducing the inflammatory response,activating apoptotic proteins,and promoting the apoptosis of activated HSCs.