In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: Therapeutic effect on liver fibrosis/cirrhosis

AIM To investigate the hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells(h UC-MSCs) and to evaluate their therapeutic effect on liver fibrosis/cirrhosis.METHODS A CCl4-induced liver fibrotic/cirrhotic rat model was used to assess the effect of h UC-MSCs. Histopathology was assessed by hematoxylin and eosin(H&E), Masson trichrome and Sirius red staining. The liver biochemical profile was measured using a Beckman Coulter analyzer. Expression analysis was performed using immunofluorescent staining, immunohistochemistry, Western blot, and real-time PCR.RESULTS We demonstrated that the infused h UC-MSCs could differentiate into hepatocytes in vivo. Functionally, the transplantation of h UC-MSCs to CCl4-treated rats improved liver transaminases and synthetic function, reduced liver histopathology and reversed hepatobiliary fibrosis. The reversal of hepatobiliary fibrosis was likely due to the reduced activation state of hepatic stellate cells, decreased collagen deposition, and enhanced extracellular matrix remodeling via the up-regulation of MMP-13 and down-regulation of TIMP-1. CONCLUSION Transplanted h UC-MSCs could differentiate into functional hepatocytes that improved both the biochemical and histopathologic changes in a CCl4-induced rat liver fibrosis model. h UC-MSCs may offer therapeutic opportunities for treating hepatobiliary diseases, including cirrhosis.

Hepatocellular carcinoma incidence post direct-acting antivirals in hepatitis C-related advanced fibrosis/cirrhosis patients in Australia

Background:Despite efficacy in HCV eradication,direct-acting antiviral(DAA)therapy has raised controversies around their impact on hepatocellular carcinoma(HCC)incidence.Herein we reported the first Australian data on HCC incidence in DAA-treated HCV patients with advanced fibrosis/cirrhosis.Methods:We conducted a retrospective single center study of DAA-treated HCV patients with advanced fibrosis/cirrhosis from April 2015 to December 2017.Patients with prior HCC were included if they had complete response to HCC treatment.Results:Among 138 patients who completed DAA therapy,133(96.4%)achieved sustained virologic response(median follow-up 23.8 months).Ten had prior HCC and 5/10(50.0%)developed recurrence,while de novo HCC developed in 7/128(5.5%).Median time from DAA to HCC diagnosis was 34 weeks in recurrent HCC vs.de novo 52 weeks(P=0.159).In patients with prior HCC,those with recurrence(vs.without)had shorter median time between last HCC treatment and DAA(12 vs.164 weeks,P<0.001).On bivariate analysis,failed sustained virologic response at 12 weeks(SVR12)(P=0.011),platelets(P=0.005),model for end-stage liver disease(MELD)score(P=0.029),alpha fetoprotein(AFP)(P=0.013),and prior HCC(P<0.001)were associated with HCC post-DAA.On multivariate analysis,significant factors were prior HCC(OR=4.80;95%CI:1.47–48.50;P=0.010),failed SVR12(OR=2.83;95%CI:1.71–16.30;P=0.016)and platelets(OR=0.97;95%CI:0.95–0.99;P=0.009).Conclusions:Our study demonstrates a high incidence of recurrent HCC in HCV patients with advanced fibrosis/cirrhosis treated with DAA.Factors associated with HCC development post-DAA were more advanced liver disease,failed SVR12 and prior HCC,with higher rates of recurrence in those who started DAA earlier.

Boceprevir early-access for advanced-fibrosis/cirrhosis in Asia-pacific hepatitis C virus genotype 1 non-responders/relapsers

AIM:To examined the efficacy and safety of treatment with boceprevir,PEGylated-interferon and ribavirin(PR)in hepatitis C virus genotype 1(HCVGT1) PR treatmentfailures in Asia.METHODS:The Boceprevir Named-Patient Program provided boceprevir to HCVGT1 PR treatment-failures.Participating physicians were invited to contribute data from their patients:baseline characteristics,ontreatment responses,sustained virological response at week 12(SVR12),and safety were collected and analysed.Multivariate analysis was performed to determine predictors of response.RESULTS:150 patients were enrolled from Australia,Malaysia,Singapore and Thailand(Asians = 86,Caucasians = 63).Overall SVR12 was 61%(Asians= 59.3%,Caucasians = 63.5%).SVR12 was higher in relapsers(78%) compared with non-responders(34%).On-treatment responses predicted SVR,with undetectable HCVRNA at week 4,8 and 12 leading to SVR12 s of 100%,87%,and 82%respectively,and detectable HCVRNA at week 4,8 and 12,leading to SVR12 s of 58%,22%and 6%respectively.Asian patients were similar to Caucasian patients with regards to on-treatment responses.Patients with cirrhosis(n= 69) also behaved in the same manner with regards to on-treatment responses.Those with the IL28 B CC genotype(80%) had higher SVRs than those with the CT/TT(56%) genotype(P = 0.010).Multivariate analysis showed that TW8 and TW12 responses were independent predictors of SVR.Serious adverse events occurred in 18.6%:sepsis(2%),decompensation(2.7%) and blood transfusion(14%).Discontinuations occurred in 30.7%,with 18.6%fulfilling stopping rules.CONCLUSION:Boceprevir can be used successfully in PR treatment failures with a SVR12 > 80%if they have good on-treatment responses;however,discontinuations occurred in 30%because of virological failure or adverse events.

Hotspots and trends in stem cell therapy for liver fibrosis and cirrhosis: A bibliometric analysis

BACKGROUND Liver fibrosis and cirrhosis are global medical challenges that require safe and effective treatments.In the past two decades,there has been a surge in research on stem cell therapy for liver fibrosis and cirrhosis.This study aimed to conduct a comprehensive analysis of the research hotspots and trends in this field through bibliometrics.sters was conducted.RESULTS As of September 20,2024,a total of 1935 documents were retrieved dating from 2004 to 2024,with 1186 strongly relevant publications obtained after screening.China,the United States,and Japan were the major contributors in this field.Cairo University,Zhejiang University and Yamaguchi University were the major institution in this field.The journal Stem Cell Research&Therapy published the most papers.There were 686 authors,with Shuji Terai,Isao Sakaida,Soon Koo Baik,and Lanjuan Li publishing the most papers.The research focused on alcoholic cirrhosis and nonalcoholic fatty liver disease.The emerging areas of interest were extracellular vesicles,exosomes,and their enriched microRNAs.The field is experiencing rapid growth due to the changing research trends and increasing literature.CONCLUSION These findings provide a thorough overview of stem cell therapy in the field of liver fibrosis and cirrhosis.

Unraveling the Impact of Direct-Acting Antivirals on Hepatitis-Linked Cirrhosis: A Comprehensive Analysis of Fibrosis, Child Score, and Disease Progression

The treatment of hepatitis C has undergone a significant boom since the advent of direct acting antivirals (DAA). Indeed, the interferon-ribavirin combination that has been used to treat hepatitis C has a virological response in only 45% of cases with significant side effects. The advent of direct-acting antivirals has changed the prognosis of cirrhotic patients with hepatitis C. DAAs have ensured a sustained viral response in the majority of patients. Our work aims to see the evolution of hepatitis C patients at the cirrhosis stage under DAA. We conducted a retrospective study over 15 years (January 2009, January 2024) including all patients with post-viral cirrhosis C, whom we divided into two groups: group A, cirrhotic patients who received ribavirin and interferon, and group B, patients on DAA. From January 2009 to January 2024, we conducted a study of 182 patients with viral hepatitis C, including 102 cirrhotic patients. The mean age was 55 years. 66% of patients were initially treated with the ribavirin interferon combination, while 34% received direct-acting antivirals (DAAs). Since the introduction of DAAs, the most commonly used regimens have been sofosbuvir/daclatasvir with or without ribavirin and sofosbuvir/ledipasvir with or without ribavirin. Group A achieved sustained virological response (SVR) in 60% of cases, with notable side effects. In Group B, SVR was 98.18%, with improved tolerability and fewer side effects than previous treatments. Fifteen patients developed hepatocellular carcinoma (HCC), with a significantly lower mortality rate in those treated with DAAs compared with pegylated dual therapy (p: 0.001).

Mesenchymal stromal cells in hepatic fibrosis/cirrhosis:from pathogenesis to treatment

Hepatic fibrosis/cirrhosis is a significant health burden worldwide,resulting in liver failure or hepatocellular carcinoma(HCC)and accounting for many deaths each year.The pathogenesis of hepatic fibrosis/cirrhosis is very complex,which makes treatment challenging.Endogenous mesenchymal stromal cells(MsCs)have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis.Paradoxically,exogenous MsCs have also been used in clinical trials for liver cirrhosis,and their effectiveness has been observed in most completed clinical trials.There are still many issues to be resolved to promote the use of MsCs in the clinic in the future.In this review,we will examine the controversial role of MsCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis.We also investigated the clinical trials involving MsCs in liver cirrhosis,summarized the parameters that need to be standardized,and discussed how to promote the use of MsCs from a clinical perspective.

Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Procalcitonin and presepsin for detecting bacterial infection and spontaneous bacterial peritonitis in cirrhosis:A systematic review and meta-analysis

BACKGROUND Diagnosing bacterial infections(BI)in patients with cirrhosis can be challenging because of unclear symptoms,low diagnostic accuracy,and lengthy culture testing times.Various biomarkers have been studied,including serum procal-citonin(PCT)and presepsin.However,the diagnostic performance of these markers remains unclear,requiring further informative studies to ascertain their diagnostic value.AIM To evaluate the pooled diagnostic performance of PCT and presepsin in detecting BI among patients with cirrhosis.INTRODUCTION Bacterial infections(BI)commonly occur in patients with cirrhosis,resulting in poor outcomes,including the development of cirrhotic complications,septic shock,acute-on-chronic liver failure(ACLF),multiple organ failures,and mortality[1,2].BI is observed in 20%-30%of hospitalized patients,with and without ACLF[3].Patients with cirrhosis are susceptible to BI because of internal and external factors.The major internal factors are changes in gut microbial composition and function,bacterial translocation,and cirrhosis-associated immune dysfunction syndrome[4,5].External factors include alcohol use,proton-pump inhibitor use,frailty,readmission,and invasive procedures.Spontaneous bacterial peritonitis(SBP),urinary tract infection,pneumonia,and primary bacteremia are the common BIs in hospit-alized patients with cirrhosis[6].Early diagnosis and adequate empirical antibiotic therapy are two critical factors that improve the prognosis of BI in patients with cirrhosis.However,early detection of BI in cirrhosis is challenging due to subtle clinical signs and symptoms,low sensitivity and specificity of systemic inflammatory response syndrome criteria,and low sensitivity of bacterial cultures.Thus,effective biomarkers need to be identified for the early detection of BI.Several biomarkers have been evaluated,but their efficacy in detecting BI is unclear.Procalcitonin(PCT)is a precursor of the hormone calcitonin,which is secreted by parafollicular cells of the thyroid gland[7].In the presence of BI,PCT gene expression increases in extrathyroidal tissues,causing a subsequent increase in serum PCT level[8].Changes in serum PCT are detectable as early as 4 hours after infection onset and peaks between 8 and 24 hours,making it a valuable diagnostic biomarker for BI.Several studies have demonstrated the favorable diagnostic accuracy of PCT in the diagnosis of BI in individuals with cirrhosis[9-13]and without cirrhosis[14-16].Since 2014,two meta-analyses have been published on the diagnostic value of PCT for SBP and BI in patients with cirrhosis[17,18].Other related studies have been conducted since then[10-12,19-33].Serum presepsin has recently emerged as a promising biomarker for diagnosing BI.This biomarker is the N-terminal fraction protein of the soluble CD14 g-negative bacterial lipopolysaccharide–lipopolysaccharide binding protein(sCD14-LPS-LBP)complex,which is cleaved by inflammatory serum protease in response to BI[34].Presepsin levels increase within 2 hours and peaks in 3 hours[35].This is useful for detecting BI since presepsin levels increase earlier than serum Our systematic review and meta-analysis was performed with adherence to PRISMA guidelines[37].

Gut microbiome composition in patients with liver cirrhosis with and without hepatic encephalopathy: A systematic review and metaanalysis

BACKGROUND The gut microbiome is associated with hepatic encephalopathy(HE),but research results on the gut microbiome characteristics of patients with liver cirrhosis with and without HE are inconsistent.AIM To study the gut microbiota characteristics of patients with liver cirrhosis with and without HE.METHODS We searched the PubMed,Web of Science,EMBASE,and Cochrane databases using two keywords,HE,and gut microbiome.According to the inclusion and exclusion criteria,suitable literature was screened to extract data on the diversity and composition of the fecal microbiota in patients with liver cirrhosis with and without HE.The data were analyzed using RevMan and STATA.RESULTS Seventeen studies were included:(1)A meta-analysis of 7 studies revealed that the Shannon index in liver cirrhosis patients with HE was significantly lower than that in patients without HE[-0.20,95%confidence interval(CI):-0.28 to-0.13,I2=20%];(2)The relative abundances of Lachnospiraceae(-2.73,95%CI:-4.58 to-0.87,I2=38%)and Ruminococcaceae(-2.93,95%CI:-4.29 to-1.56,I2=0%)in liver cirrhosis patients with HE was significantly lower than those in patients without HE;(3)In patients with HE,Enterococcus,Proteobacteria,Enterococcaceae,and Enterobacteriaceae proportions increased,but Ruminococcaceae,Lachnospiraceae,Prevotellaceae,and Bacteroidetes proportions decreased;(4)Differences in the fecal metabolome between liver cirrhosis patients with and without HE were detected;and(5)Differential gut microbiomes may serve as diagnostic and prognostic tools.CONCLUSION The gut microbiomes of patients with liver cirrhosis with and without HE differ.Some gut microbiomes may distinguish liver cirrhosis patients with or without HE and determine patient prognosis.

Impact of liver cirrhosis on morbidity and mortality of patients admitted to the hospital with necrotizing fasciitis

BACKGROUND Necrotizing fasciitis(NF)is a potentially fatal bacterial infection of the soft tissues.Liver cirrhosis appears to be a contributing factor to higher morbidity and mor-tality in patients with NF.This research article explores the relationship between these two conditions.AIM To evaluate whether liver cirrhosis increases morbidity and mortality in patients with NF,focusing on inpatient mortality,septic shock,length of stay,and hospital costs.METHODS This retrospective cohort study utilized data from the Healthcare Cost and Utilization Project 2019 National Inpatient Sample.Cases were identified as pa-tients with both NF and cirrhosis,while controls were non-cirrhotic.The study focused on inpatient mortality as the primary outcome,with secondary outcomes including surgical limb amputation,mechanical ventilation rates,septic shock,length of stay,and hospital costs.RESULTS A total of 14920 patients were admitted to the hospital for management of NF,of which 2.11%had liver cirrhosis.Inpatient mortality was higher in cirrhotic patients(9.5%vs 3%;adjusted odds ratio=3.78;P value=0.02).Cirrhotic patients also had higher rates of septic shock(10.5%vs 4.9%,P value<0.01).Length of hospital stay,total charges,and rates of mechanical ventilation were not statistically different between groups.CONCLUSION Liver cirrhosis is an independent risk factor of in-hospital mortality and morbidity in patients with NF.Clinicians should be aware of this association to ensure better clinical outcomes and spare healthcare expenditure.

Preoperative serum total bilirubin-albumin ratio as a prognostic indicator in patients with hepatitis-related cirrhosis after splenectomy

BACKGROUND Splenectomy is an effective yet invasive intervention for alleviating portal pressure in patients with hepatitis cirrhosis.However,the current prognostic indicators for predicting long-term overall survival of these patients have several limitations.AIM To assess the potential of preoperative total bilirubin-albumin(B/A)ratio as a prognostic indicator for patients with hepatitis cirrhosis undergoing splenectomy.METHODS A total of 257 patients diagnosed with hepatitis cirrhosis were retrospectively enrolled in the study.Normality test,t-test,Wilcoxon test,χ2 test,or Fisher’s exact test was employed to analyze the intraoperative and postoperative conditions of the patients.Receiver operating characteristic(ROC)curve analysis was utilized to depict the 10-year overall survival rate.RESULTS During the follow-up period,85.99%of the patients survived,with a median survival time of 64.6 months.Multivariate analysis revealed that total serum B/A ratio was an independent risk factor for overall survival(P=0.037).ROC curve analysis demonstrated that a B/A ratio of 0.87 was the optimal cut-off value.Consequently,the patients were categorized into two groups:High B/A group(n=64)and low B/A group(n=193).The median follow-up time for the high B/A group and low B/A group was 56.8 months and 67.2 months,respectively(P=0.045).Notably,the high B/A group exhibited a significantly lower 10-year overall survival compared to the low B/A group(P<0.001).Patients with hepatocellular carcinoma(HCC)had lower overall survival rates.Patients with a high B/A ratio exhibited a lower overall survival than those with a low B/A rate in the overall cohort and the subgroups of patients with HCC or not,early Child-Pugh grade,low albumin-bilirubin grade,and model for end-stage liver disease score≥10(log-rank test,P<0.001 for all).CONCLUSION The B/A ratio can serve as an effective prognostic indicator for overall survival in patients with hepatitis B virusrelated cirrhosis following splenectomy,and a higher B/A ratio may suggest a poorer prognosis.

Innovative diagnostic tool aids screening for minimal hepatic encephalopathy in non-alcoholic cirrhosis patients

In this editorial we comment on the article by Jiang et al.We focus on the Ence-phalApp Stroop test which is an innovative,smartphone-based tool specifically designed for screening minimal hepatic encephalopathy(MHE)in cirrhosis patients.Traditional MHE screening methods,while highly sensitive and specific,are often complex,time-consuming,and require controlled environmental con-ditions,limiting their widespread clinical use.The EncephalApp Stroop test si-mplifies the screening process,enhances diagnostic efficiency,and is applicable across diverse cultural contexts.However,the combination of additional bio-markers could further improve diagnostic accuracy.Despite its promising po-tential,more multicenter clinical studies are required to validate its effectiveness and applicability on a global scale.

Transition from acute kidney injury to chronic kidney disease in liver cirrhosis patients:Current perspective

In liver cirrhosis patients,acute kidney injury(AKI)is a common and severe complication associated with significant morbidity and mortality,often leading to chronic kidney disease(CKD).This progression reflects a complex interplay of renal and hepatic pathophysiology,with AKI acting as an initiator through maladaptive repair mechanisms.These mechanisms—such as tubular cell cycle arrest,inflammatory cascades,and fibrotic processes—are exacerbated by the hemodynamic and neurohormonal disturbances characteristic of cirrhosis.Following AKI episodes,persistent kidney dysfunction or acute kidney disease(AKD)often serves as a bridge to CKD.AKD represents a critical phase in renal deterioration,characterized by prolonged kidney injury that does not fully meet CKD criteria but exceeds the temporal scope of AKI.The progression from AKD to CKD is further influenced by recurrent AKI episodes,impaired renal autoregu-lation,and systemic comorbidities such as diabetes and metabolic dysfunction-associated steatotic liver disease,which compound kidney damage.The clinical management of AKI and CKD in cirrhotic patients requires a multidimensional approach that includes early identification of kidney injury,the application of novel biomarkers,and precision interventions.Recent evidence underscores the inadequacy of traditional biomarkers in predicting the AKI-to-CKD progression,necessitating novel biomarkers for early detection and intervention.

Management of chylous ascites after liver cirrhosis: A case report

BACKGROUND Chylous ascites is an uncommon condition,occurring in less than 1%of ascites cases.It results from traumatic or obstructive disruption of the lymphatic system,causing the leakage of thoracic or intestinal lymph into the abdominal cavity.This leads to the accumulation of a milky,triglyceride-rich fluid.In adults,malignancy and cirrhosis are the primary causes of chylous ascites.Notably,chylous ascites accounts for only 0.5%to 1%of all cirrhosis-related ascites cases.At present,there is a limited understanding of this condition,and effective timely management in clinical practice remains challenging.CASE SUMMARY This case report presents a patient with hepatic cirrhosis complicated by chylous ascites,who had experienced multiple hospitalizations due to abdominal distension.Upon admission,comprehensive examinations and assessments were conducted.The treatment strategy focused on nutritional optimization through a low-sodium,low-fat,and high-protein diet supplemented with medium-chain triglycerides,therapeutic paracentesis,and diuretics.Following a multidiscip-linary discussion and thorough evaluation of the patient’s condition,surgical indications were confirmed.After informing the patient about the benefits and risks,and obtaining consent,a transjugular intrahepatic portosystemic shunt procedure was performed,successfully alleviating the abdominal swelling symptoms.This article details the clinical characteristics and treatment approach for this uncommon case,summarizing current management methods for hepatic cirrhosis complicated by chylous ascites.The aim is to provide valuable insights for clinicians encountering similar situations.CONCLUSION Optimizing nutrition and addressing the underlying cause are essential in the treatment of chylous ascites.When conservative approaches prove ineffective,alternative interventions such as transjugular intrahepatic portosystemic shunt may be considered.

Do Child–Turcotte–Pugh and nutritional assessments predict survival in cirrhosis: A longitudinal study

BACKGROUND Cirrhotic patients face heightened energy demands,leading to rapid glycogen depletion,protein degradation,oxidative stress,and inflammation,which drive disease progression and complications.These disruptions cause cellular damage and parenchymal changes,resulting in vascular alterations,portal hypertension,and liver dysfunction,significantly affecting patient prognosis.AIM To analyze the association between Child–Turcotte–Pugh(CTP)scores and di-fferent nutritional indicators with survival in a 15-year follow-up cohort.METHODS This was a retrospective cohort study with 129 cirrhotic patients of both sexes aged>18 years.Diagnosis of cirrhosis was made by liver biopsy.The first year of data collection was 2007,and data regarding outcomes were collected in 2023.Data were gathered from medical records,and grouped by different methods,including CTP,handgrip strength,and triceps skinfold cutoffs.The prognostic values for mortality were assessed using Kaplan–Meier curves and multivariate binary logistic regression models.RESULTS The coefficient for CTP was the only statistically significant variable(Wald=5.193,P=0.023).This suggests that with a negative change in CTP classification score,the odds of survival decrease 52.6%.The other evaluated variables did not significantly predict survival outcomes in the model.Kaplan–Meier survival curves also indicated that CTP classification was the only significant predictor.CONCLUSION Although different classifications showed specific differences in stratification,only CTP showed significant predictive potential.CTP score remains a simple and effective predictive tool for cirrhotic patients even after longer follow-up.

Insight into the efficacy and safety of pirfenidone: The treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis(IPF)has a poor prognosis if left untreated;therefore,early treatment with pirfenidone is crucial.Lei et al conducted a retrospective analysis to evaluate the effectiveness of early pirfenidone treatment on lung function in 113 patients with IPF.In addition to other research,pirfeni-done has demonstrated efficacy in patients at all stages of IPF once correct diagnosis has been made.In advanced IPF,we include the requirement for pirfenidone.Therefore,it is essential to choose an appropriate method of adminis-tration method,such as inhalation.This may circumvent the drawbacks of the high cost and possible adverse effects of this drug.

NR4A1 silencing alleviates high-glucose-stimulated HK-2 cells pyroptosis and fibrosis via hindering NLRP3 activation and PI3K/AKT pathway

BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.

Non-invasive diagnosis of liver fibrosis and cirrhosis

The evaluation and follow up of liver fibrosis and cirrhosis have been traditionally performed by liver biopsy. However, during the last 20 years, it has become evident that this "gold-standard" is imperfect; even according to its proponents, it is only "the best" among available methods. Attempts at uncovering non-invasive diagnostic tools have yielded multiple scores, formulae, and imaging modalities. All are better tolerated, safer, more acceptable to the patient, and can be repeated essentially as often as required. Most are much less expensive than liver biopsy. Consequently, their use is growing, and in some countries the number of biopsies performed, at least for routine evaluation of hepatitis B and C, has declined sharply. However, the accuracy and diagnostic value of most, if not all, of these methods remains controversial. In this review for the practicing physician, we analyze established and novel biomarkers and physical techniques. We may be witnessing in recent years the beginning of the end of the first phase for the development of non-invasive markers. Early evidence suggests that they might be at least as good as liver biopsy. Novel experimental markers and imaging techniques could produce a dramatic change in diagnosis in the near future.

Microvesicles derived from mesenchymal stem cells: A promising therapeutic strategy for acute respiratory distress syndrome-related pulmonary fibrosis?

Pulmonary fibrosis significantly contributes to the pathogenesis of acute respiratory distress syndrome(ARDS),markedly increasing patient mortality.Despite the established anti-fibrotic effects of mesenchymal stem cells(MSCs),numerous challenges hinder their clinical application.A recent study demon-strated that microvesicles(MVs)from MSCs(MSC-MVs)could attenuate ARDS-related pulmonary fibrosis and enhance lung function via hepatocyte growth factor mRNA transcription.This discovery presents a promising strategy for managing ARDS-associated pulmonary fibrosis.This article initially examines the safety and efficacy of MSCs from both basic science and clinical perspectives,subsequently exploring the potential and obstacles of employing MSC-MVs as a novel therapeutic approach.Additionally,it provides perspectives on future research into the application of MSC-MVs in ARDS-associated pulmonary fi-brosis.

Non-invasive diagnosis of advanced fibrosis and cirrhosis

Liver cirrhosis is a common and growing public health problem globally.The diagnosis of cirrhosis portends an increased risk of morbidity and mortality.Liver biopsy is considered the gold standard for diagnosis of cirrhosis and staging of fibrosis.However,despite its universal use,liver biopsy is an invasive and inaccurate gold standard with numerous drawbacks.In order to overcome the limitations of liver biopsy,a number of non-invasive techniques have been investigated for the assessment of cirrhosis.This review will focus on currently available non-invasive markers of cirrhosis.The evidence behind the use of these markers will be highlighted,along with an assessment of diagnostic accuracy and performance characteristics of each test.Non-invasive markers of cirrhosis can be radiologic or serum-based.Radiologic techniques based on ultrasound,magnetic resonance imaging and elastography have been used to assess liver fibrosis.Serum-based biomarkers of cirrhosis have also been developed.These are broadly classified into indirect and direct markers.Indirect biomarkers reflect liver function,which may decline with the onset of cirrhosis.Direct biomarkers,reflect extracellular matrix turnover,and include molecules involved in hepatic fibrogenesis.On the whole,radiologic and serum markers of fibrosis correlate well with biopsy scores,especially when excluding cirrhosis or excluding fibrosis.This feature is certainly clinically useful,and avoids liver biopsy in many cases.