Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways

Background:G-protein coupled receptors(GPCRs)are recognized as attractive targets for drug therapy.However,it remains poorly understood how GPCRs,except for a few chemokine receptors,regulate the progression of liver fibrosis.Here,we aimed to reveal the role of GPR65,a proton-sensing receptor,in liver fibrosis and to elucidate the underlying mechanism.Methods:The expression level of GPR65 was evaluated in both human and mouse fibrotic livers.Furthermore,Gpr65-deficient mice were treated with either bile duct ligation(BDL)for 21 d or carbon tetrachloride(CCl4)for 8 weeks to investigate the role of GPR65 in liver fibrosis.A combination of experimental approaches,including Western blotting,quantitative real-time reverse transcription-polymerase chain reaction(qRT-PCR),and enzyme-linked immunosorbent assay(ELISA),confocal microscopy and rescue studies,were used to explore the underlying mechanisms of GPR65’s action in liver fibrosis.Additionally,the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated.Results:We found that hepatic macrophage(HM)-enriched GPR65 was upregulated in both human and mouse fibrotic livers.Moreover,knockout of Gpr65 significantly alleviated BDL-and CCl4-induced liver inflammation,injury and fibrosis in vivo,and mouse bone marrow transplantation(BMT)experiments further demonstrated that the protective effect of Gpr65knockout is primarily mediated by bone marrow-derived macrophages(BMMs).Additionally,in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited,while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and transforming growth factor-β(TGF-β),all of which subsequently promoted the activation of hepatic stellate cells(HSCs)and the damage of hepatocytes(HCs).Mechanistically,GPR65 overexpression,the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-αand IL-6 via the Gαq-Ca^(2+)-JNK/NF-κB pathways,while promoted the expression of TGF-βthrough the Gαq-Ca^(2+)-MLK3-MKK7-JNK pathway.Notably,pharmacological GPR65 inhibition retarded the development of inflammation,HCs injury and fibrosis invivo.Conclusions:GPR65 is a major regulator that modulates the progression of liver fibrosis.Thus,targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis.

Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis

Liver fibrosis is primarily driven by the activation of hepatic stellate cells(HSCs),a process associated with ferroptosis.Ginsenoside Rb1(GRb1),a major active component extracted from Panax ginseng,inhibits HSC activation.However,the potential role of GRb1 in mediating HSC ferroptosis remains unclear.This study examined the effect of GRb1 on liver fibrosis both in vivo and in vitro,using CCl4-induced liver fibrosis mouse model and primary HSCs,LX-2 cells.The findings revealed that GRb1 effectively inactivated HSCs in vitro,reducing alpha-smooth muscle actin(a-SMA)and type I collagen(Col1A1)levels.Moreover,GRb1 significantly alleviated CCl4-induced liver fibrosis in vivo.From a mechanistic standpoint,the ferroptosis pathway appeared to be central to the antifibrotic effects of GRb1.Specifically,GRb1 promoted HSC ferroptosis both in vivo and in vitro,characterized by increased glutathione depletion,malondialdehyde production,iron overload,and accumulation of reactive oxygen species(ROS).Intriguingly,GRb1 increased Beclin 1(BECN1)levels and decreased the System Xc-key subunit SLC7A11.Further experiments showed that BECN1 silencing inhibited GRb1-induced effects on HSC ferroptosis and mitigated the reduction of SLC7A11 caused by GRb1.Moreover,BECN1 could directly interact with SLC7A11,initiating HSC ferroptosis.In conclusion,the suppression of BECN1 counteracted the effects of GRb1 on HSC inactivation both in vivo and in vitro.Overall,this study highlights the novel role of GRb1 in inducing HSC ferroptosis and promoting HSC inactivation,at least partly through its modulation of BECN1 and SLC7A11.

Engineered SPIONs functionalized with endothelin a receptor antagonist ameliorate liver fibrosis by inhibiting hepatic stellate cell activation

Endothelin-1/endothelin A receptor(ET-1/ETAR)pathway plays an important role in the progression of liver fibrosis by activating hepatic stellate cells(HSCs)-a key cell type involved in the pathogenesis of liver fibrosis.Inactivating HSCs by blocking the ET-1/ETAR pathway using a selective ETAR antagonist(ERA)represents a promising therapeutic approach for liver fibrosis.Unfortunately,small-molecule ERAs possess limited clinical potential due to poor bioavailability,short half-life,and rapid renal clearance.To improve the clinical applicability,we conjugated ERA to superparamagnetic iron-oxide nanoparticles(SPIONs)and investigated the therapeutic efficacy of ERA and ERA-SPIONs in vitro and in vivo and analyzed liver uptake by in vivo and ex vivo magnetic resonance imaging(MRI),HSCs-specific localization,and ET-1/ETAR-pathway antagonism in vivo.In murine and human liver fibrosis/cirrhosis,we observed overexpression of ET-1 and ETAR that correlated with HSC activation,and HSC-specific localization of ETAR.ERA and successfully synthesized ERA-SPIONs demonstrated significant attenuation in TGFβ-induced HSC activation,ECM production,migration,and contractility.In an acute CCl4-induced liver fibrosis mouse model,ERA-SPIONs exhibited higher liver uptake,HSC-specific localization,and ET-1/ETAR pathway antagonism.This resulted in significantly reduced liver-to-body weight ratio,plasma ALT levels,andα-SMA and collagen-I expression,indicating attenuation of liver fibrosis.In conclusion,our study demonstrates that the delivery of ERA using SPIONs enhances the therapeutic efficacy of ERA in vivo.This approach holds promise as a theranostic strategy for the MRI-based diagnosis and treatment of liver fibrosis.

Evaluation of Hepatic Fibrosis and Hepatic Steatosis by Pulse Elastography (FIBROSCAN/CAP) in Asymptomatic Patients about 170 Cases at the Donka CHU National Hospital in Conakry

Introduction: Fibroscan is a recent, non-invasive and non-irradiating diagnostic method. It is based on the principle of ultrasound, which enables liver tissue elasticity to be quantified using a probe, and fibrosis to be assessed. Fibroscan measures both elasticity correlated with hepatic fibrosis and CAP correlated with steatosis. The aim of this study was to evaluate hepatic fibrosis and steatosis using pulse elastometry (Fibroscan/CAP). Methods: This was a descriptive and analytical cross-sectional study in which 170 patients were included. It was conducted from October 1 2021 to December 31 2023, i.e. 27 months, in an outpatient clinic in the hepato-gastroenterology department of the Donka national hospital of the CHU Conakry. Results: Of the 170 patients identified, 87 were male (51%) and 83 female (49%), giving a M/F sex ratio of 1.04. The average age of our patients was 40. The 30 - 50 age group was the most affected, with a frequency of 58.23% (n = 99), followed by the 50 age group with a frequency of 29.41% (n = 50). Hepatomegaly, steatotic liver on ultrasonography, transaminase elevation and obesity were the main indications, respectively: (21.76%), (17.65%), (14.71%), and (13.53%). The examinations were requested by hepatogastroenterologists (47.06%), diabetologists (35.88%) and general practitioners (29%). Of the 170 patients, 100 patients (58.82%) had no significant fibrosis F0F1, 39 (22.94%) had moderate fibrosis F2, 20 patients (11.76%) had severe fibrosis F3 and 11 patients (6.47%) had fibrosis F4. Hepatic steatosis: 62 patients (36.47%) had no S0 steatosis;29.41% had S1 steatosis, 20% had S2 steatosis and 24 patients (14.11%) had S3 steatosis. Abdominal ultrasound revealed a normal liver in 67.05% of patients, hepatic steatosis in 29.41% and non-decompensated cirrhosis in 6 cases. Thus, 108 patients had the parameters required to calculate the Fatty Liver Index (FLI), steatosis was present in 20% of our patients, while 29.41% had an undetermined status and 24 14.11% had a normal FLI. Conclusion: Identifying subjects at risk of metabolic steatopathy, diagnosing and managing these patients is a public health issue and one of the future challenges of hepato-gastroenterology. Fibroscan is an increasingly popular screening tool for hepatic fibrosis and steatosis. The fight against obesity must be a priority.

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.

Improvement of hepatic fibrosis after tenofovir disoproxil fumarate switching to tenofovir alafenamide for three years

BACKGROUND Both tenofovir alafenamide(TAF)and tenofovir disoproxil fumarate(TDF)are the first-line treatments for chronic hepatitis B(CHB).We have showed switching from TDF to TAF for 96 weeks resulted in further alanine aminotransferase(ALT)improvement,but data remain lacking on the long-term benefits of TDF switching to TAF on hepatic fibrosis.AIM To assess the benefits of TDF switching to TAF for 3 years on ALT,aspartate aminotransferase(AST),and hepatic fibrosis improvement in patients with CHB.METHODS A single center retrospective study on 53 patients with CHB who were initially treated with TDF,then switched to TAF to determine dynamic patterns of ALT,AST,AST to platelet ratio index(APRI),fibrosis-4(FIB-4)scores,and shear wave elastography(SWE)reading improvement at switching week 144,and the associated factors.RESULTS The mean age was 55(28-80);45.3%,males;15.1%,clinical cirrhosis;mean baseline ALT,24.8;AST,25.7 U/L;APRI,0.37;and FIB-4,1.66.After 144 weeks TDF switching to TAF,mean ALT and AST were reduced to 19.7 and 21,respectively.From baseline to switching week 144,the rates of ALT and AST<35(male)/25(female)and<30(male)/19(female)were persistently increased;hepatic fibrosis was also improved by APRI<0.5,from 79.2%to 96.2%;FIB-4<1.45,from 52.8%to 58.5%,respectively;mean APRI was reduced to 0.27;FIB-4,to 1.38;and mean SWE reading,from 7.05 to 6.30 kPa after a mean of 109 weeks switching.The renal function was stable and the frequency of patients with glomerular filtration rate>60 mL/min was increased from 86.5%at baseline to 88.2%at switching week 144.CONCLUSION Our data confirmed that switching from TDF to TAF for 3 years results in not only persistent ALT/AST improvement,but also hepatic fibrosis improvement by APRI,FIB-4 scores,as well as SWE reading,the important clinical benefits of long-term hepatitis B virus antiviral treatment with TAF.

Evaluating short-term and long-term liver fibrosis improvement in hepatitis C patients after DAA treatment

Despite achieving a high cure rate with the direct-acting antivirals(DAAs)in hepatitis C treatment,further research is needed to identify additional benefits of the DAA therapy.The current study evaluated liver fibrosis improvement in 848 hepatitis C patients treated with DAAs,who also achieved sustained virologic response.By the fibrosis-4(FIB-4)index,patients were categorized based on their baseline fibrosis levels,and the improvement in fibrosis was analyzed in both short-term(9-26 weeks)and long-term(≥36 weeks)follow-up.The results showed a significant decrease in the FIB-4 index,indicating an improvement in liver fibrosis,in 63.0%and 67.6%of the patients during the short-term and long-term follow-up,respectively.Short-term improvement was associated with factors including ribavirin usage,blood cholinesterase levels,alanine transaminase levels,albumin levels,and the baseline FIB-4 index,while long-term improvement was associated with factors such as aspartate transaminase levels,total protein level,and the baseline FIB-4 index.The current study emphasizes the importance of continuous assessment and post-treatment monitoring of liver fibrosis,which will provide crucial insights for enhancing patient care in hepatitis C management.

New markers of fibrosis in hepatitis C:A step towards the Holy Grail?

In the present issue of the World Journal of Hepatology,Ferrassi et al examine the problem of liver fibrosis staging in chronic hepatitis C.They identify novel biomarkers in an effort to predict accurate fibrosis staging with the aid of the metabolome of Hepatitis C patients.Overall I think Ferrassi et al took a different approach in identifying fibrosis biomarkers,by looking at the patients’metabolome.Their biomarkers clearly separate patients from controls.They can also separate out,patients with minimal fibrosis(F0-F1 stage)and patients with cirrhosis(F4 stage).Obviously,if these biomarkers were to be widely used,tests for all the important metabolites would need to be readily available for use in hospitals or outpatient setting and that may prove difficult and above all,costly.Nevertheless,this step could eventually lead to a metabolomic approach for novel biomarkers of Fibrosis.Obviously,it would need to be validated,but could represent a step towards the Holy Grail of Hepatology.

Ensemble for evaluating diagnostic efficacy of non-invasive indices in predicting liver fibrosis in untreated hepatitis C virus population

BACKGROUND Hepatitis C virus(HCV)infection progresses through various phases,starting with inflammation and ending with hepatocellular carcinoma.There are several invasive and non-invasive methods to diagnose chronic HCV infection.The invasive methods have their benefits but are linked to morbidity and complications.Thus,it is important to analyze the potential of non-invasive methods as an alternative.Shear wave elastography(SWE)is a non-invasive imaging tool widely validated in clinical and research studies as a surrogate marker of liver fibrosis.Liver fibrosis determination by invasive liver biopsy and non-invasive SWE agree closely in clinical studies and therefore both are gold standards.AIM To analyzed the diagnostic efficacy of non-invasive indices[serum fibronectin,aspartate aminotransferase to platelet ratio index(APRI),alanine aminotransferase ratio(AAR),and fibrosis-4(FIB-4)]in relation to SWE.We have used an Artificial Intelligence method to predict the severity of liver fibrosis and uncover the complex relationship between non-invasive indices and fibrosis severity.METHODS We have conducted a hospital-based study considering 100 untreated patients detected as HCV positive using a quantitative Real-Time Polymerase Chain Reaction assay.We performed statistical and probabilistic analyses to determine the relationship between non-invasive indices and the severity of fibrosis.We also used standard diagnostic methods to measure the diagnostic accuracy for all the subjects.RESULTS The results of our study showed that fibronectin is a highly accurate diagnostic tool for predicting fibrosis stages(mild,moderate,and severe).This was based on its sensitivity(100%,92.2%,96.2%),specificity(96%,100%,98.6%),Youden’s index(0.960,0.922,0.948),area under receiver operating characteristic curve(0.999,0.993,0.922),and Likelihood test(LR+>10 and LR-<0.1).Additionally,our Bayesian Network analysis revealed that fibronectin(>200),AAR(>1),APRI(>3),and FIB-4(>4)were all strongly associated with patients who had severe fibrosis,with a 100% probability.CONCLUSION We have found a strong correlation between fibronectin and liver fibrosis progression in HCV patients.Additionally,we observed that the severity of liver fibrosis increases with an increase in the non-invasive indices that we investigated.

Transient elastography and diffusion-weighted magnetic resonance imaging for assessment of liver fibrosis in children with chronic hepatitis C

BACKGROUND Chronic hepatitis C(CHC)is a health burden with consequent morbidity and mortality.Liver biopsy is the gold standard for evaluating fibrosis and assessing disease severity and prognostic purposes post-treatment.Noninvasive altern-atives for liver biopsy such as transient elastography(TE)and diffusion-weighted magnetic resonance imaging(DW-MRI)are critical needs.AIM To evaluate TE and DW-MRI as noninvasive tools for predicting liver fibrosis in children with CHC.METHODS This prospective cross-sectional study initially recruited 100 children with CHC virus infection.Sixty-four children completed the full set of investigations including liver stiffness measurement(LSM)using TE and measurement of apparent diffusion coefficient(ADC)of the liver and spleen using DW-MRI.Liver biopsies were evaluated for fibrosis using Ishak scoring system.LSM and liver and spleen ADC were compared in different fibrosis stages and correlation analysis was performed with histopathological findings and other laboratory parameters.RESULTS Most patients had moderate fibrosis(73.5%)while 26.5%had mild fibrosis.None had severe fibrosis or cirrhosis.The majority(68.8%)had mild activity,while only 7.8%had moderate activity.Ishak scores had a significant direct correlation with LSM(P=0.008)and were negatively correlated with both liver and spleen ADC but with no statistical significance(P=0.086 and P=0.145,respectively).Similarly,histopatho-logical activity correlated significantly with LSM(P=0.002)but not with liver or spleen ADC(P=0.84 and 0.98 respectively).LSM and liver ADC were able to significantly discriminate F3 from lower fibrosis stages(area under the curve=0.700 and 0.747,respectively)with a better performance of liver ADC.CONCLUSION TE and liver ADC were helpful in predicting significant fibrosis in children with chronic hepatitis C virus infection with a better performance of liver ADC.

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.

Progress on traditional Chinese medicine in improving hepatic fibrosis through inhibiting oxidative stress

Hepatic fibrosis is a common pathological process that occurs in the development of various chronic liver diseases into cirrhosis and liver cancer,characterized by excessive deposition of the extracellular matrix.In the past,hepatic fibrosis was thought to be a static and irreversible pathological process.In recent years,with the rapid development of molecular biology and the continuous in-depth study of the liver at the microscopic level,more and more evidence has shown that hepatic fibrosis is a dynamic and reversible process.Therefore,it is particularly important to find an effective,simple,and inexpensive method for its prevention and treatment.Traditional Chinese medicine(TCM)occupies an important position in the treatment of hepatic fibrosis due to its advantages of low adverse reactions,low cost,and multi-target effectiveness.A large number of research results have shown that TCM monomers,single herbal extracts,and TCM formulas play important roles in the prevention and treatment of hepatic fibrosis.Oxidative stress(OS)is one of the key factors in the occurrence and development of hepatic fibrosis.Therefore,this article reviews the progress in the understanding of the mechanisms of TCM monomers,single herbal extracts,and TCM formulas in preventing and treating hepatic fibrosis by inhibiting OS in recent years,in order to provide a reference and basis for drug therapy of hepatic fibrosis.

Hydroxysafflor yellow A protects against thioacetamide-induced liver fibrosis in rats via suppressing proinflammatory/fibrogenic mediators and promoting hepatic stellate cell senescence and apoptosis

Objective:To evaluate the effect of hydroxysafflor yellow A(HSYA)on thioacetamide-induced liver fibrosis.Methods:Thioacetamide was administered to rats intraperitoneally in doses of 200 mg/kg twice a week for 12 weeks.Thioacetamide-intoxicated rats were given silymarin(50 mg/kg)or HSYA(5 mg/kg)orally every day for 8 weeks.Liver enzymes,fibrosis markers,histological changes as well as immunohistochemistry of TNF-α,IL-6,p21,α-SMA,and caspase-3 were examined.The effect of HSYA on HSC-T6 activation/proliferation and apoptosis was also determined in vitro.Results:HSYA decreased liver enzymes,TNF-α,IL-6,and p21 expressions,hepatic PDGF-B,TIMP-1,TGF-β1,and hydroxyproline levels,as well as fibrosis score(S2 vs.S4)compared to the thioacetamide group.HSYA also downregulatedα-SMA while increasing caspase-3 expression.Surprisingly,at 500μg/mL,HSYA had only a slightly suppressive effect on HSC proliferation,with a 9.5%reduction.However,it significantly reduced TGF-β1,inhibitedα-SMA expression,induced caspase-3 expression,and promoted cell senescence.Conclusions:HSYA may be a potential therapeutic agent for delaying and reversing the progression of liver fibrosis.More research on HSYA at higher doses and for a longer period is warranted.

Anti-Fibrotic Effects of Calotropis procera (Ait.) R.Br Roots Barks against Diethylnitrosamine-Induced Hepatic Fibrosis in Rats

Background: Liver diseases including chronic hepatitis, steatosis, fibrosis, cirrhosis and liver cancer are now a public health problem. In 2002, cirrhosis accounted for 27.63% of hepatobiliary diseases in Burkina Faso. In Africa and more particularly in Burkina Faso, the majority of the population (about 80%) uses medicinal plants for their primary health care. Calotropis procera (Ait.) R.Br (Apocynaceae) is a medicinal plant used in Burkina Faso in the treatment of liver problems. This work aims to evaluate the anti-fibrotic properties of Calotropis procera roots barks. Methods: The anti-fibrotic activity of the ethanolic extract of Calotropis procera roots barks was evaluated using diethylnitrosamine (DEN) to induce liver fibrosis in male Wistar rats. Serum biomarkers, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), Total protein, Albumin, Υ-Glutamyl transferase (GGT) were evaluated and the activities of antioxidant enzymes (Superoxide dismutase and catalase) as well as the level of malonedialdehyde (MDA) and that of nitric oxide (NO) were determined in the liver homogenate. Results: The treatment of rats suffering from hepatic fibrosis with the ethanolic extract leads to a significant restoration of the biomarkers of the hepatic function in particular, AST, ALP, GGT, Albumin. The extract also causes a reduction in oxidative stress in the liver through a significant increase in the activity rate of the antioxidant enzymes Superoxide dismutase (SOD) and catalase accompanied by a significant drop in the rate of MDA and NO suggesting the anti-oxidant effect of extract. Conclusion: The results of the study show that the ethanolic extract of the roots barks of Calotropis procera has anti-fibrotic properties.

A Discussion on the Relationship among Hepatic Stellate Cells,Hepatic Sinusoidal Endothelial Cells and Hepatic Sinusoidal Capillarization in the Development of Hepatic Fibrosis

Hepatic stellate cells,hepatic sinusoidal endothelial cells and hepatic sinusoidal capllarization are closely related to the occurrence and progression of hepatic fibrosis.The pathological activation of hepatic stellate cels is the central link of hepatic fibrosis,and hepatic sinusoidal capillarization also promotes the occurrence and development of liver diseases.In the course of hepatic fibrosis,there is always a mutually reinforcing relationship between the activation of hepatic stellate cells and the capillarization of hepatic sinusoids.This paper strives to find an effective way to intervene or even reverse this vicious cycle by deeply investigating the effect of hepatic stellate cells and hepatic sinusoidal capillarization on hepatic fibrosis and their mutual promotion,and provide a new idea for the treatment of hepatic fibrosis,which is of great significance for relieving and reversing hepatic fibrosis.

Exploration of the mechanism of action of Xiayuxue Tang against hepatic fibrosis based on GEO data mining,network pharmacology and molecular docking technology

Objective:To study the mechanism of action of Xiayuxue Tang in treating hepatic fibrosis by combining GEO data mining,network pharmacology,and molecular docking technology,and provide new research directions for the treatment of hepatic fibrosis.Method:Utilizing multiple databases,we aim to identify the relevant targets of various components in Xiayuxue Tang and their associations with hepatic fibrosis.After pinpointing the key targets through interaction analysis,we will construct both the compound-target network and the protein interaction network for Xiayuxue Tang.Conclusively,we will conduct GO and KEGG enrichment analyses on these key targets,followed by molecular docking verification.Result:Through mining the GEO database,171 related targets were identified.When combined with other databases,a total of 2,343 hepatic fibrosis-related targets were obtained.Xiayuxue Tang comprises 82 related components,which include 26 active components from rhubarb,1 from ground beetle worm,46 from peach kernels,with a total of 314 predicted targets.The GO enrichment analysis revealed 748 biological processes,32 cellular components,and 73 molecular functions,while the KEGG enrichment analysis identified 222 pathways.Molecular docking verification confirmed that effective compounds can bind stably to key proteins,exhibiting strong binding activity.This underscores the potential efficacy of Xiayuxue Tang in addressing hepatic fibrosis.Conclusion:Xiayuxue Tang exerts regulatory effects on hepatic fibrosis through different targets and pathways,suggesting that the herbal compound has the characteristics of multiple pathways and targets.

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells(HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.

Pathological mechanisms of alcohol-induced hepatic portal hypertension in early stage fibrosis rat model

AIM： To study the role of hepatic sinusoidal capillarization and perisinusoidal fibrosis in rats with alcohol-induced portal hypertension and to discuss the pathological mechanisms of alcohol-induced hepatic portal hypertension. METHODS： Fifty SD rats were divided into control group （n=20） and model group （n=30）. Alcoholic liver fibrosis rat model was induced by intragastric infusion of a mixture containing alcohol, corn oil and pyrazole （1 000：250：3）. Fifteen rats in each group were killed at wk 16. The diameter and pressure of portal vein were measured. Plasma hyaluronic acid （HA）, type IV collagen （COW） and laminin （LN） were determined by radioimmunoassay. Liver tissue was fixed in formalin （10%） and 6-μm thick sections were routinely stained with Mallory and Sirius Red. Liver tissue was treated with rabbit polydonal antibody against LN and ColⅣ. Hepatic non-parenchymal cells were isolated, total protein was extracted and separated by SDS-PAGE. MMP-2 and TIMP-1 protein expression was estimated by Western blotting. RESULTS： The diameter （2.207 ± 0.096 vs 1.528±0.054 mm, P〈0.01） and pressure （11.014±0.395 vs 8.533±0.274 mmHg, P〈0.01） of portal vein were significantly higher in model group than those in the control group. Plasma HA （129.97±16.10 vs 73.09±2.38 ng/mL, P〈0.01）, ColⅣ （210.49±4.36 vs 89.65±4.42 ng/mL, P〈0.01） and LN （105.00±7.29 vs 55.70±4.32 ng/mL, P〈0.01） were upregulated in model group. Abundant collagen deposited around the central vein of Iobules, hepatic sinusoids and hepatocytes in model group. ColⅠ and ColⅢ increased remarkably and perisinusoids were almost surrounded by ColⅢ. Immunohistochemical staining showed that ColⅣ protein level （0.130±0.007 vs 0.032±0.004, P〈0.01） and LN protein level （0.152±0.005 vs 0.029±0.005, P〈0.01） were up-regulated remarkably in model group. MMP-2 protein expression （2.306±1.089 vs 0.612±0.081, P〈0.01） and TIMP-1 protein expression （3.015±1.364 vs 0.446±0.009, P〈0.01） in freshly isolated hepatic nonparenchymal cells were up-regulated in model group and TIMP-1 protein expression was evidently higher than MMP-2 protein expression （2.669±0.170 vs 1.695±0.008, P〈0.05）. CONCLUSION： Hepatic sinusoidal capillarization and peri-sinusoidal fibrosis are responsible for alcoholinduced portal hypertension in rats,

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.

Hepatic Elastometry in the Management of Hepatitis B at National Hospital of Niamey

Introduction: Viral hepatitis B is a public health problem in Niger which is classified as a high endemicity area with a prevalence ranging from 8 to 17% depending on the studies [1] and that of HBV-related cirrhosis is about 40.26% in 2024. The decision to treat is based on a combination of three parameters: viral load, ALT values and the degree of hepatic fibrosis [2]. The latter is assessed by hepatic elastography (Fibroscan), which is a decisive factor in treatment. In Niger, until 2024, the decision to treat or not to treat a patient with HBV was based on the determination of viral load B and transaminases, and no work evaluating the contribution of this third element, liver elasticity, has been done, hence the interest of our study. Objective: To study the contribution of Fibroscan in measuring hepatic elasticity in the management of patients with HBV. Methodology: This was a prospective descriptive study conducted from January 05 to November 30, i.e. a period of 11 months, on clinically asymptomatic HBsAg-positive patients who had undergone FibroScan liver elasticity measurement. The examination was carried out by a hepatogastroenterologist who had received training in the Fibroscan. The median of ten measures of liver elasticity at the same point with an IQR of less than 30% was considered the valid measure and no or minimal fibrosis was defined as a value ˂7 Kpa, moderate fibrosis as a value between 7 and 10 kpa, severe fibrosis as a value greater than 10 Kpa, and the existence of cirrhosis as a value greater than 14 Kpa were analyzed using SPSS version 20 software. Results: Out of 398 patients monitored for HBV, 60 cases met the inclusion criteria, i.e., a frequency of 15.07%. The mean age of the patients was 35.63 years, with extremes of 18 and 70 years. They were predominantly male, with a sex ratio of 3.2. Married patients accounted for 61.67% (n = 37). Jaundice was absent in 91.67% (n = 55). The circumstances of discovery of HBV were the routine health check-up, followed by blood donation with 50% and 46.67%, respectively. The viral load was >2000 UI/ml in 32.7% (n = 17). HBeAg was negative in 93.33% of cases (n = 56). ALT levels were normal in 47 patients (78.33%). Mean liver elasticity was 6.7 KPa. Fibrosis was classified as F0 - F1 in 75% (n = 45), F1 - F2 in 18.33% (n = 11) and F3 - F4 in 6.67% (n = 4) of patients. There was no significant relationship between viremia value, liver activity, degree of fibrosis and quantitative HBsAg. Conclusion: Measurement of hepatic elasticity has made it possible to diagnose cases of compensated cirrhosis and significant fibrosis in patients considered to be inactive carriers (viral load ˂2000 IU/ml and normal transaminases) in asymptomatic HBV+ patients. This made it possible to put these patients on Tenofovir in order to avoid decompensation for the first group and for the second the progression to cirrhosis. It is an excellent tool to aid in the decision to start treatment.