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.

Elafibranor:A promising therapeutic approach for liver fibrosis and gut barrier dysfunction in alcohol-associated liver disease

This article discusses the recent study written by Koizumi et al.Alcohol-associated liver disease(ALD)is a major cause of liver-related morbidity and mortality,which is driven by complex mechanisms,including lipid accumulation,apoptosis,and inflammatory responses exacerbated by gut barrier dysfunction.The study explored the therapeutic potential of elafibranor,a dual peroxisome proliferatoractivated receptor alpha/delta agonist.In clinical trials,elafibranor has shown promise for the treatment of other liver conditions;however,its effects on ALD remain unclear.The authors’findings indicate that elafibranor significantly reduced liver fibrosis and enhanced gut barrier integrity in patients with ALD.These positive effects of elafibranor are mediated through multiple pathways.Elafibranor promotes lipid metabolism,reduces oxidative stress,and inhibits inflammatory responses by restoring gut barrier function.Specifically,it improves hepatocyte function by enhancing autophagic and antioxidant capacity,and it mitigates inflammation by suppressing the lipopolysaccharide/toll-like receptor 4/nuclear factor kappa B signaling pathway.These findings indicate that elafibranor has promising clinical applications.In addition,the study highlights elafibranor’s potential as a therapeutic agent for liver diseases,particularly ALD.This article underscores the importance of understanding the mechanistic pathways underlying ALD and suggests directions for future research aimed at elucidating the benefits and limitations of elafibranor.

Importance of neonatal screening:A case study of sickle cell disease and cystic fibrosis coexistence

BACKGROUND Neonatal screening(NS)is a public health policy to identify genetic pathologies such as cystic fibrosis(CF),sickle cell disease,and other diseases.Sickle cell disea-se is the comprehensive term for a group of hemoglobinopathies characterized by the presence of hemoglobin S.CF is an autosomal recessive multisystemic disease with pathophysiology involving deleterious mutations in the transmembrane re-gulatory gene that encodes a protein that regulates the activity of chloride and sodium channels in the cell surface epithelium.NS is crucial for early diagnosis and management,which ensures a better quality of life.AIM To report a case of the coexistence of sickle cell anemia(SCA)and CF and perform an integrative literature review.METHODS This is an observational study and a review of the literature focusing on two rare genetic pathologies identified simultaneously in NS from the perspective of a clinical case.The authors identified only 5 cases of SCA associated with CF.No clinical trials or review articles were identified considering the rarity of the coexistence of these two pathologies.RESULTS Herein,the authors reported the case of a girl who after undergoing NS on day 8 of life was diagnosed with SCA with an alteration in the dosage of immunoreactive trypsin.The diagnosis of CF was confirmed by the Coulometry Sweat Test.The rarity of the co-occurrence of these two severe genetic pathologies(CF and SCA)is a challenge for medical science.CONCLUSION This study adds to the few case reports present in the literature that highlight the identification of two severe diseases via NS.

基于深度强化学习的恶意ELF文件检测对抗方法

近年来,基于深度学习的恶意可执行与可链接格式(executable and linkable format,ELF)文件检测研究取得了显著进展。同时,关于模型对抗性攻击的研究也得到了广泛关注,攻击者可以通过生成对抗样本误导神经网络,使恶意软件被错误归类为良性软件,从而逃逸检测。尽管已有多种生成对抗样本的方法被提出,但它们通常不适合对ELF文件进行修改,或缺乏在不同检测模型之间迁移的能力。为克服现有方法的局限性,提出了一种基于深度强化学习的恶意ELF文件检测对抗方法,该方法通过构造目标检测模型的最优扰动字节序列,能够在保留ELF文件原有功能的前提下生成对抗样本,而无须依赖目标模型的内部实现细节。实验结果表明,该方法生成的对抗样本针对目标检测模型的逃逸成功率达到76.80%,并能通过对抗训练提升目标检测模型的鲁棒性。

猪源和犬源ELF4蛋白的亚细胞定位比较研究

本研究旨在对比分析猪E74样因子4(sELF4)和犬E74样因子4(cELF4)的亚细胞定位,为深入开展二者功能研究提供依据。利用PCR截短扩增sELF4和cELF4,分别克隆至真核表达载体pEGFP-C1中,构建17个sELF4重组真核表达载体和13个cELF4重组真核表达质粒,转染HeLa细胞、Hoechst33342染色,荧光倒置显微镜观察亚细胞定位,运用生物信息学软件分析其编码氨基酸序列特征。结果表明,sELF4和cELF4蛋白全长均定位在细胞核中,sELF4 196~291 aa(586~873 bp)之间有可能存在两个细胞质核定位信号肽,cELF4的核定位信号肽分布在203~291 aa(607~873 bp),cELF4 292~663 aa(874~1 992 bp)、sELF4 292~662 aa(874~1 989 bp)在细胞中发生聚集现象。cELF4与sELF4氨基酸序列在第169~303位氨基酸之间均高度保守,其他区段均存在不同程度的差异。综上,sELF4蛋白全长和cELF4蛋白全长均定位在细胞核中,截短表达的羧基端功能区有聚集现象,二者的核定位信号肽分布有一定差异。

Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease

BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis.Peroxisome proliferator activated receptor(PPAR)α and δ play a key role in lipid metabolism and intestinal barrier homeostasis,which are major contributors to the pathological progression of ALD.Meanwhile,elafibranor(EFN),which is a dual PPARαand PPARδagonist,has reached a phase III clinical trial for the treatment of metabolic dysfunctionassociated steatotic liver disease and primary biliary cholangitis.However,the benefits of EFN for ALD treatment is unknown.AIM To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model.METHODS ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol(EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly(1 mL/kg)for 8 weeks.EFN(3 and 10 mg/kg/day)was orally administered during the experimental period.Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis,fibrosis,and intestinal barrier integrity.The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays.RESULTS The hepatic steatosis,apoptosis,and fibrosis in the ALD mice model were significantly attenuated by EFN treatment.EFN promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells,primarily through PPARαactivation.Moreover,EFN inhibited the Kupffer cell-mediated inflammatory response,with blunted hepatic exposure to lipopolysaccharide(LPS)and toll like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)signaling.EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses.The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation.CONCLUSION EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis,enhancing hepatocyte autophagic and antioxidant capacities,and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.

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.

Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway

BACKGROUND Development of end-stage renal disease is predominantly attributed to diabetic nephropathy(DN).Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue.Never-theless,the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.AIM To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.METHODS Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk.Subsequently,blood and urine indexes were assessed,along with examination of renal tissue pathology.Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin,periodic acid–Schiff,Masson’s trichrome,and Sirius-red.Additionally,high-glucose culturing was conducted on the RAW 264.7 cell line,treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h.In both in vivo and in vitro settings,quantification of inflammation factor levels was conducted using western blotting,real-time qPCR and ELISA.RESULTS In db/db mice,administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis.Notably,we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin,along with a decrease in expressions of inflammatory cytokine-related factors.Furthermore,myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha,interleukin-6,and interluekin-1βinduced by high glucose in RAW 264.7 cells.Additionally,myricetin modulated the M1-type polarization of the RAW 264.7 cells.Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin.The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.CONCLUSION This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

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.

Study on the efficacy of early treatment with pirfenidone on the lung function of patients with idiopathic pulmonary fibrosis

BACKGROUND Idiopathic pulmonary fibrosis(IPF)is classified under fibrotic interstitial pneumonia,characterized by a chronic and progressive course.The predominant clinical features of IPF include dyspnea and pulmonary dysfunction.AIM To assess the effects of pirfenidone in the early treatment of IPF on lung function in patients.METHODS A retrospective analysis was performed on 113 patients with IPF who were treated in our hospital from November 2017 to January 2023.These patients were divided into two groups:control group(n=53)and observation group(n=60).In the control group,patients received routine therapy in combination with methylprednisolone tablets,while those in the observation group received routine therapy together with pirfenidone.After applying these distinct treatment approaches to the two groups,we assessed several parameters,including the overall effectiveness of clinical therapy,the occurrence of adverse reactions(e.g.,nausea,vomiting,and anorexia),symptom severity scores,pulmonary function index levels,inflammatory marker levels,and the 6-min walk distance before and after treatment in both groups.RESULTS The observation group exhibited significantly higher rates than the control group after therapy,with a clear distinction(P<0.05).After treatment,the observation group experienced significantly fewer adverse reactions than the control group,with a noticeable difference(P<0.05).When analyzing the symptom severity scores between the two groups of patients after treatment,the observation group had significantly lower scores than the control group,with a distinct difference(P<0.05).When comparing the pulmonary function index levels between the two groups of patients after therapy,the observation group displayed significantly higher levels than the control group,with a noticeable difference(P<0.05).Evaluating the inflammatory marker data(C-reactive protein,interleukin-2[IL-2],and IL-8)between the two groups of patients after therapy,the observation group exhibited significantly lower levels than the control group,with significant disparities(P<0.05).Comparison of the 6-min walking distance data between the two groups of patients after treatment showed that the observation group achieved significantly greater distances than the control group,with a marked difference(P<0.05).CONCLUSION Prompt initiation of pirfenidone treatment in individuals diagnosed with IPF can enhance pulmonary function,elevate inflammatory factor levels,and increase the distance covered in the 6-min walk test.This intervention is conducive to effectively decreasing the occurrence of adverse reactions in patients.

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.

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.

MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage patients.Human placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease.Here,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC patients.The results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in vitro.Furthermore,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids.Thus,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

Tanshinone IIA ameliorates energy metabolism dysfunction of pulmonary fibrosis using 13C metabolic flux analysis

Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U-13C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of transforming growth factor-β1 (TGF-β1)-dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro. We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan IIA in treating PF using 13C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.

Echinacoside attenuates glandular fibrosis in benign prostatic hyperplasia via inhibiting MKK6/MK2 signaling pathway

Background:Lower urinary tract symptoms commonly occur in the elderly population and seriously constrain the quality of life.Glandular fibrosis is an important pathobiological process in benign prostatic hyperplasia and is also a main inducing factor for benign prostatic hyperplasia-associated lower urinary tract symptoms.Cistanches species is an important herbal medicine resource and is traditionally used in ameliorating renal and prostatic defects.Methods:This study was to investigate the potential protective function of echinacoside(a bioactive compound from Cistanches)against prostatic fibrosis in mice and human benign prostatic hyperplasia epithelial-1 cell models.Results:It was found that echinacoside attenuated testosterone-induced prostatic hyperplasia and collagen deposition in mice,relieved prostate local inflammation and oxidative damage,and ameliorated prostatic epithelial-mesenchymal transition.Additionally,echinacoside inhibited the activation of the MKK6/MK2 signaling pathway both in vivo and in vitro.Conclusion:This study added new evidence for the anti-fibrotic function of echinacoside on the prostate and provided new insights for understanding its possible pharmacological mechanisms.

Spatially resolved metabolomics visualizes heterogeneous distribution of metabolites in lung tissue and the anti-pulmonary fibrosis effect of Prismatomeris connate extract

Pulmonary fibrosis (PF) is a chronic progressive end-stage lung disease. However, the mechanisms underlying the progression of this disease remain elusive. Presently, clinically employed drugs are scarce for the treatment of PF. Hence, there is an urgent need for developing novel drugs to address such diseases. Our study found for the first time that a natural source of Prismatomeris connata Y. Z. Ruan (Huang Gen, HG) ethyl acetate extract (HG-2) had a significant anti-PF effect by inhibiting the expression of the transforming growth factor beta 1/suppressor of mothers against decapentaplegic (TGF-β1/Smad) pathway. Network pharmacological analysis suggested that HG-2 had effects on tyrosine kinase phosphorylation, cellular response to reactive oxygen species, and extracellular matrix (ECM) disassembly. Moreover, mass spectrometry imaging (MSI) was used to visualize the heterogeneous distribution of endogenous metabolites in lung tissue and reveal the anti-PF metabolic mechanism of HG-2, which was related to arginine biosynthesis and alanine, asparate and glutamate metabolism, the downregulation of arachidonic acid metabolism, and the upregulation of glycerophospholipid metabolism. In conclusion, we elaborated on the relationship between metabolite distribution and the progression of PF, constructed the regulatory metabolic network of HG-2, and discovered the multi-target therapeutic effect of HG-2, which might be conducive to the development of new drugs for PF.

BMSC-derived Exosomes Ameliorate Peritoneal Dialysis-associated Peritoneal Fibrosis via the Mir-27a-3p/TP53 Pathway

Objective:Peritoneal fibrosis(PF)is the main cause of declining efficiency and ultrafiltration failure of the peritoneum,which restricts the long-term application of peritoneal dialysis(PD).This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes(BMSC-Exos)on PF in response to PD.Methods:Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing.C57BL/6J mice were infused with 4.25%glucose-based peritoneal dialysis fluid(PDF)for 6 consecutive weeks to establish a PF model.A total of 36 mice were randomly divided into 6 groups:control group,1.5%PDF group,2.5%PDF group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Reverse transcription quantitative polymerase chain reaction(RT-qPCR)was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF.HE and Masson staining were performed to evaluate the extent of PF.The therapeutic potential of BMSC-Exos for PF was examined through pathological examination,RT-qPCR,Western blotting,and peritoneal function analyses.Epithelial-mesenchymal transition(EMT)of HMrSV5 was induced with 4.25%PDF.Cells were divided into control group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Cell Counting Kit-8 assay was used to measure cell viability,and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells.Results:Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs.The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos,but decreased in PD mice.We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice.Compared with the control mice,the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response,with markedly increased peritoneal thickness and higher expression ofα-SMA,collagen-I,fibronectin,and ECM1.The mice with PD showed decreased miR-27a-3p.Peritoneal structural and functional damage was significantly attenuated after BMSC-Exos treatment,while PF and mesothelial damage were significantly ameliorated.Additionally,markers of fibrosis(α-SMA,collagen-I,fibronectin,ECM1)and profibrotic cytokines(TGF-β1,PDGF)were downregulated at the mRNA and protein levels after BMSC-Exos treatment.In HMrSV5 cells,BMSC-Exos reversed the decrease in cell viability and the increase in cell migratory capacity caused by high-glucose PDF.Western blotting and RT-qPCR analysis revealed that BMSC-Exos treatment resulted in increased expression of E-cadherin(epithelial marker)and decreased expression ofα-SMA,Snail,and vimentin(mesenchymal markers)compared to those of the 4.25%PDF-treated cells.Importantly,a dual-luciferase reporter assay showed that TP53 was a target gene of miR-27a-3p.TP53 overexpression significantly reversed the decreases in PF and EMT progression induced by BMSC-Exos.Conclusion:The present results demonstrate that BMSC-Exos showed an obvious protective effect on PD-related PF and suggest that BMSC-derived exosomal miR-27a-3p may exert its inhibitory effect on PF and EMT progression by targeting TP53.

Microvesicles derived from mesenchymal stem cells inhibit acute respiratory distress syndrome-related pulmonary fibrosis in mouse partly through hepatocyte growth factor

BACKGROUND Pulmonary fibrosis is one of the main reasons for the high mortality rate among acute respiratory distress syndrome(ARDS)patients.Mesenchymal stromal cell-derived microvesicles(MSC-MVs)have been shown to exert antifibrotic effects in lung diseases.AIM To investigate the effects and mechanisms of MSC-MVs on pulmonary fibrosis in ARDS mouse models.METHODS MSC-MVs with low hepatocyte growth factor(HGF)expression(siHGF-MSC-MVs)were obtained via lentivirus transfection and used to establish the ARDS pulmonary fibrosis mouse model.Following intubation,respiratory mechanics-related indicators were measured via an experimental small animal lung function tester.Homing of MSC-MVs in lung tissues was investigated by near-infrared live imaging.Immunohistochemical,western blotting,ELISA and other methods were used to detect expression of pulmonary fibrosis-related proteins and to compare effects on pulmonary fibrosis and fibrosis-related indicators.RESULTS The MSC-MVs gradually migrated and homed to damaged lung tissues in the ARDS model mice.Treatment with MSC-MVs significantly reduced lung injury and pulmonary fibrosis scores.However,low expression of HGF(siHGF-MSC-MVs)significantly inhibited the effects of MSC-MVs(P<0.05).Compared with the ARDS pulmonary fibrosis group,the MSC-MVs group exhibited suppressed expression of type I collagen antigen,type III collagen antigen,and the proteins transforming growth factor-βandα-smooth muscle actin,whereas the siHGF-MVs group exhibited significantly increased expression of these proteins.In addition,pulmonary compliance and the pressure of oxygen/oxygen inhalation ratio were significantly lower in the MSC-MVs group,and the effects of the MSC-MVs were significantly inhibited by low HGF expression(all P<0.05).CONCLUSION MSC-MVs improved lung ventilation functions and inhibited pulmonary fibrosis in ARDS mice partly via HGF mRNA transfer.

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.

Assessment of Liver Fibrosis in HBsAg-Negative and Anti HBc Positive Patients

Background: Surface antigen (HBsAg) is the mean marker of hepatitis B virus infection. During the course of the infection, some patients lose the HBsAg and only the presence of anti-HBc antibody indicates previous contact with the virus. Among these patients, some have detectable viral load (occult infection) but most without viral replication. There is no guideline regarding these patients. The aim of this study was to assess hepatic fibrosis in patients with only the hepatitis B virus contact marker “total anti-HBc”. Patients and methods: it was a descriptive and analytical cross-sectional study, conducted in three private hospitals from January to August 2022. Were included HBsAg-negative and HBc-positive patients, consulting in Gastroenterology departments. Noninvasive methods (APRI, FIB-4 and FIBROSCAN) were used to evaluate liver stiffness because of their easy accessibility and low-cost. The hepatic fibrosis was considered significant when the score determined by APRI, FIB-4 and FIBROSCAN® tests was respectively greater than 1.5;2.67 and 8 kPa corresponding to fibrosis level 2 (F2). Results: A total of 63 HBsAg-negative/total HBcAg-positive patients were included. The mean age was 49.9 ± 13.4 years. The male/female sex ratio was 1.78. Of the 63 patients, 19 had significant liver fibrosis (30.1%) among which 9 patients had HCC. The FIB-4 score outperformed the APRI score in assessing liver fibrosis, with a sensitivity of 84.2%, a specificity of 100% and a negative predictive value of 93.6%. In univariate analysis, there was a significant association between the occurrence of significant liver fibrosis and age over 40 years, dyslipidaemia, obesity, alcohol consumption, smoking, herbal medicine, negative anti-HBs immunological status and detectable viral load. Conclusion: Our study revealed a high prevalence of significant to severe hepatic fibrosis in anti-HBc positive patients. In most of the cases, the fibrosis was severe. Progression to HCC has also been possible. There is no consensus on the follow-up strategy for those patients. However, screening for hepatic fibrosis using noninvasive methods should be recommended for patients aged over 40 years, alcohol or herbal medicine users, patients with metabolic syndrome or occult hepatitis B. In HBsAg-negative/anti-HBc-positive patients, liver stiffness should be evaluated and if it is greater than F2, HCC screening should be started.