Therapy For Liver Fibrosis Research Articles

Extracellular matrix-penetrating nanodrill micelles for liver fibrosis therapy

As hepatic stellate cells (HSCs) are essential for hepatic fibrogenesis, HSCs targeted nano-drug delivery system is a research hotspot in liver fibrosis therapy. However, the excessive deposition of fibrosis collagen (mainly collagen I) in the space of Disse associated with hepatic fibrogenesis would significantly hinder nano-formulation delivery to HSCs. Here, we have prepared a collagenase I and retinol co-decorated polymeric micelle that possess nanodrill-like and HSCs-target function based on poly-(lactic-co-glycolic)-b-poly (ethylene glycol)-maleimide (PLGA-PEG-Mal) (named CRM) for liver fibrosis therapy. Upon encountering collagen I barrier, CRM exerted a nanodrill-like function, efficiently degrading pericellular collagen I and showing greater uptake by human HSCs than other micelle formulations. Besides, CRM could realize excellent accumulation in the fibrotic liver and accurate targeting to activated HSCs in mouse hepatic fibrosis model. Moreover, CRM loaded with nilotinib (CRM/NIL), a second-generation tyrosine kinase inhibitor used in the treatment of liver fibrosis, showed optimal antifibrotic activity. This work suggests that CRM with dual function is an efficient carrier for liver fibrosis drug delivery and collagenase I decorating could be a new strategy for building more efficient HSCs targeted nano-drug delivery system.

Mechanisms Underlying Cell Therapy in Liver Fibrosis: An Overview.

Fibrosis is a common feature in most pathogenetic processes in the liver, and usually results from a chronic insult that depletes the regenerative capacity of hepatocytes and activates multiple inflammatory pathways, recruiting resident and circulating immune cells, endothelial cells, non-parenchymal hepatic stellate cells, and fibroblasts, which become activated and lead to excessive extracellular matrix accumulation. The ongoing development of liver fibrosis results in a clinically silent and progressive loss of hepatocyte function, demanding the constant need for liver transplantation in clinical practice, and motivating the search for other treatments as the chances of obtaining compatible viable livers become scarcer. Although initially cell therapy has emerged as a plausible alternative to organ transplantation, many factors still challenge the establishment of this technique as a main or even additional therapeutic tool. Herein, the authors discuss the most recent advances and point out the corners and some controversies over several protocols and models that have shown promising results as potential candidates for cell therapy for liver fibrosis, presenting the respective mechanisms proposed for liver regeneration in each case.

ROLE OF SERIN/ THREONINE KINASE INHIBITOR IN THERAPY NON-ALCOHOLIC STEATOHEPATITIS AND ALCOHOLIC HEPATITIS

Liver fibrosis is a reversible response to a wound healing with marked accumulation of extracellular matrix which caused by injury to the liver. Liver fibrosis can be caused by various factors including alcohol and non-alcohol steatohepatitis. The process of fibrosis serves to localize the inflammation during chronic exposure. The hepatic stem cell (HSC) has a key role in the pathogenesis of liver fibrosis. The HSC activation is characterized by increased profibrogenic mediators including members of the TGF-? superfamily. In order to enable signal transduction, the mediator needs to bind to its receptors. The serine/ threonine kinase receptor is a receptor that binds to the TGF-? superfamily ligand, including TGF-?, BMP, activin and other mediators. The ligand receptor-binding activity will stimulate signal transduction that will translocate into the nucleus and phosphorylate various transcription factors that play a role in cell proliferation, differentiation, or apoptosis. There is currently no standard therapy for liver fibrosis. Based on the central role of the serine/ threonine kinase receptor in the pathogenesis of liver fibrosis, it is thought that the use of serine/ threonine kinase inhibitors is a promising therapy.

Human Amnion Epithelial Cell Therapy for Chronic Liver Disease.

Liver fibrosis is a common consequence of chronic liver disease. Over time, liver fibrosis can develop into liver cirrhosis. Current therapies for liver fibrosis are limited, and liver transplant is the only curative therapy for patients who progress to end-stage disease. A potential approach to treat chronic liver disease with increasing interest is cell-based therapy. Among the multiple cell types which have been proposed for therapeutic uses, human amnion epithelial cells and amniotic fluid-derived mesenchymal cells are promising. These cells are highly abundant, and their use poses no ethical concern. Furthermore, they exert potent anti-inflammatory and antifibrotic effects in animal models of liver injury. This review highlights the therapeutic characteristics and discusses how human amnion epithelial cells can be utilised as a therapeutic tool for chronic liver disease.

Wogonin attenuates liver fibrosis via regulating hepatic stellate cell activation and apoptosis

Liver fibrosis is the representative features of liver chronic inflammation and the characteristic of early cirrhosis. To date, effective therapy for liver fibrosis is lacking. Recently, Traditional Chinese Medicine (TCM) has attracted increasing attention due to its wide pharmacological effects and more uses in clinical. Wogonin, as one major active constituent of Scutellaria radix, has been reported it plays an important role in anti-inflammatory, anti-cancer, anti-viral, anti-angiogenesis, anti-oxidant and neuro-protective effects. However, the anti-fibrotic effect of wogonin is never covered in liver. In this study, we evaluated the protect effect of wogonin in liver fibrosis. Wogonin significantly attenuated liver fibrosis both in CCl4-induced mice and TGF-β1 activated HSCs. Meanwhile, wogonin can enhances apoptosis of TGF-β1 activated HSC-T6 cell from rat and LX-2 cell from human detected by flow cytometry. Additionally, wogonin can largely enhances cle-caspase3, cle-caspase9 expression and the ratio of Bax/Bcl-2 in T6 cells. Pro-apoptosis effect of wogonin in vivo was further verified in situ. In conclusion, wogonin can attenuate liver fibrosis via regulating the activation and apoptosis of hepatic stellate cells, and may be an effective drug to treat and prevent liver fibrosis.

Protective effect of RNA interference targeting Ikkβ on hepatic fibrosis in rats.

Nuclear factor-κB (NF-κB) is an important regulatory factor in cells. NF-κB has a wide range of biological activities. After activation, it participates in the transcription and regulation of many genes and plays a role in infection, inflammatory response, oxidative stress, cell multiplication, and apoptosis. The activation of the NF-κB signal pathway is dependent on the degradation of the IκB kinase β (IKKβ) complex. IKK β is the key kinase in the NF-κB activation pathway. After inhibition, it can block the activation of NF-κB. IKKβ is a key regulator of NF-κB activation, also an early regulator of inflammation in all stages of the immune response. This study aimed to investigate the effect of IKKβ-siRNA lentivirus vector treatment for hepatic fibrosis of rats. An IKKβ-siRNA expression plasmid was constructed and injected in the tail vein of rats. Then, IKKβ-siRNA distribution in the liver was observed by immunofluorescence, and the quantitative polymerase chain reaction was used to detect inflammation-related and fibrosis-related factors. IKKβ-siRNA lentiviruses could be delivered to the liver and significantly decrease carbon tetrachloride-induced hepatic fibrosis. Furthermore, serum transaminase levels significantly decreased, and inflammation-related and fibrosis-related factors decreased. IKKβ-siRNA can be an effective method of anti-fibrosis gene therapy for liver fibrosis.

Liver Fibrosis: A Clinical Update

Liver fibrosis is a disease that affects patients with hepatitis B virus or hepatitis C virus, harmful alcohol consumption levels, and nonalcoholic fatty liver disease. It is important to assess the cause, disease severity, and prognosis at the time of presentation to determine suitable treatment. The aim of this review article is to outline the recent advances in the diagnosis, management, and treatment of liver fibrosis. A PubMed review was performed encompassing the years 1982–2019 using the following search terms: ‘liver fibrosis’, ‘hepatitis C virus’, ‘hepatitis B virus’, ‘non-alcoholic fatty liver disease’, and ‘alcoholic liver disease’. Results showed that the cornerstone therapy for liver fibrosis is to remove the offending agent and treat the underlying disease. The gold standard method of diagnosis is liver biopsy; however, this procedure is invasive and thus multiple laboratory and radiologic tests are used to help determine the degree of fibrosis. There are few pharmacological agents known to treat fibrosis and they are disease specific. For example, the only proven therapy for fibrosis improvement in alcoholic liver disease is abstinence. The authors concluded that liver fibrosis carries a high morbidity and mortality risk with few therapeutic options depending on the cause and degree of fibrosis. Larger multicentre prospective studies are needed to examine effective agents to prevent, stop, or reduce fibrosis.

Human Adipose Derived Stem Cells Exhibit Enhanced Liver Regeneration in Acute Liver Injury by Controlled Releasing Hepatocyte Growth Factor.

Although mesenchymal stem cells (MSCs) provide effective therapy for liver fibrosis, there are conflicting data regarding their marginal therapeutic effects. This study aimed to enhance the potential of hepatocyte regeneration in human adipose mesenchymal stem cells (ASCs) and investigate whether they have robust therapeutic efficacy in experimental liver fibrosis. ASCs were cultured with four cytokines (ASC-C), the expression of hepatogenic factors was detected by microarray, and the effects of conditioned medium (CM) from ASC-C on the activation of hepatic stellate cells were analyzed. The therapeutic effects and mechanism of liver fibrosis induced by thioacetamide (TAA) were determined after cell transplantation. ASC-C exhibited high levels of hepatogenic (HGF, G-CSF), anti-apoptotic (IGFBP-2), and chemokine (IL-8) genes and increased expression of hepatocyte specific proteins. ASC-C CM inhibited the activation of hepatic stellate cells in vitro, and injection of ASC-C significantly delayed TAA-induced liver fibrosis and improved liver function and regeneration in vivo. In addition, human albumin-expressing ASC-C were observed in the livers of recipient animals. High levels of expression of HGF and its downstream signaling molecules, including p-38, were detected in the ASC-C-injected livers. Transplantation of ASC-C exerts anti-fibrotic effects and accelerates liver regeneration. Thus, ASC-C may be a novel candidate for the enhanced treatment of liver cirrhosis in clinical settings.

Multitranscriptome analyses reveal prioritized genes specifically associated with liver fibrosis progression independent of etiology.

Elimination or suppression of causative factors can raise the possibility of liver fibrosis regression. However, different injurious stimuli will give fibrosis from somewhat different etiologies, which, in turn, may hamper the discovery of liver fibrosis-specific therapeutic drugs. Therefore, the analogical cellular and molecular events shared by various etiology-evoked liver fibrosis should be clarified. Our present study systematically integrated five publicly available transcriptomic data sets regarding liver fibrosis with different etiologies from the Gene Expression Omnibus database and performed a series of bioinformatics analyses and experimental verifications. A total of 111 significantly upregulated and 16 downregulated genes were identified specific to liver fibrosis independent of any etiology. These genes were predominately enriched in some Kyoto Encyclopedia of Genes and Genomes pathways, including the "PI3K-AKT signaling pathway," "Focal adhesion," and "ECM-receptor interaction." Subsequently, five prioritized liver fibrosis-specific genes, including COL4A2, THBS2, ITGAV, LAMB1, and PDGFRA, were screened. These genes were positively associated with each other and liver fibrosis progression. In addition, they could robustly separate all stages of samples in both training and validation data sets with diverse etiologies when they were regarded as observed variables applied to principal component analysis plots. Expressions of all five genes were confirmed in activated primary mouse hepatic stellate cells (HSCs) and transforming growth factor β1-treated LX-2 cells. Moreover, THBS2 protein was enhanced in liver fibrosis rodent models, which could promote HSC activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs. Overall, our current study may provide potential targets for liver fibrosis therapy and aid to a deeper understanding of the molecular underpinnings of liver fibrosis. NEW & NOTEWORTHY Prioritized liver fibrosis-specific genes THBS2, COL4A2, ITGAV, LAMB1, and PDGFRA were identified and significantly associated with liver fibrosis progression and could be combined to discriminate liver fibrosis stages regardless of any etiology. Among the identified prioritized liver fibrosis-specific targets, THBS2 protein was confirmed to be enhanced in liver fibrosis rodent models, which could promote hepatic stellate cell (HSC) activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs.

Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/\u03b2-catenin pathway

BackgroundMesenchymal stem cells (MSCs) are increasingly being applied as a therapy for liver fibrosis. Exosomes possess similar functions to their parent cells; however, they are safe and effective cell-free reagents with controllable and predictable outcomes. In this study, we investigated the therapeutic potential and underlying molecular mechanism for human bone mesenchymal stem cells-derived exosomes (hBM-MSCs-Ex) in the treatment of liver fibrosis.MethodsWe established an 8-week CCl4-induced rat liver fibrosis model, after which, we administered hBM-MSCs-Ex in vivo for 4 weeks. The resulting histopathology, liver function, and inflammatory cytokines were analyzed. In addition, we investigated the anti-fibrotic mechanism of hBM-MSCs-Ex in hepatic stellate cells (HSCs) and liver fibrosis tissue, by western blotting for the expression of Wnt/β-catenin signaling pathway-related genes.ResultsIn vivo administration of hBM-MSCs-Ex effectively alleviated liver fibrosis, including a reduction in collagen accumulation, enhanced liver functionality, inhibition of inflammation, and increased hepatocyte regeneration. Moreover, based on measurement of the collagen area, Ishak fibrosis score, MDA levels, IL-1, and IL-6, the therapeutic effect of hBM-MSCs-Ex against liver fibrosis was significantly greater than that of hBM-MSCs. In addition, we found that hBM-MSCs-Ex inhibited the expression of Wnt/β-catenin pathway components (PPARγ, Wnt3a, Wnt10b, β-catenin, WISP1, Cyclin D1), α-SMA, and Collagen I, in both HSCs and liver fibrosis tissue.ConclusionsThese results suggest that hBM-MSCs-Ex treatment could ameliorate CCl4-induced liver fibrosis via inhibition of HSC activation through the Wnt/β-catenin pathway.

Targeted Drug Delivery to Hepatic Stellate Cells for the Treatment of Liver Fibrosis.

Liver fibrosis is caused by excessive accumulation of extracellular matrix during chronic liver injuries. Although clinical evidence suggests that liver fibrosis can be reversed, there is no standard therapy for liver fibrosis. Moreover, there is a lack of diagnostic tools to detect early-stage liver fibrosis. Activation of hepatic stellate cells (HSCs) is the key step during liver fibrogenesis, and its mechanism has been extensively studied by various cell culture and animal models. Targeted delivery of therapeutic agents to activated HSCs is therefore critical for the successful treatment of liver fibrosis. A number of protein markers have been found to be overexpressed in activated HSCs, and their ligands have been used to specifically deliver various antifibrotic agents. In this review, we summarize these HSC-specific protein markers and their ligands for targeted delivery of antifibrotic agents.

Studies on the protective effect of total flavonoids from <i>Cichorium glandulosum</i> roots against carbon tetrachloride-induced liver fibrosis in rats

Purpose: To study the protective influence of total flavonoids from Cichorium glandulosum roots (TFCG) against carbon tetrachloride-mediated hepatic fibrosis in rats, and the probable mechanism of action involved. Methods: Rats with liver fibrosis were orally administered TFCG (50, 100 or 200 mg/kg) once a day for 13 weeks. Liver index and liver injury indices in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), lactate dehydrogenase (LDH), γ-glutamyl transpeptidase (γ-GT), hydroxyproline (HYP), albumin (ALB) and malondialdehyde (MDA) were determined using electronic balance or corresponding assay kits, as appropriate. Following staining with hematoxylin and eosin and Van Gieson, histopathological changes in liver tissues were examined by light microscopy. TGF-β/Smad pathway-related protein expressions in liver tissues, viz, transforming growth factor-β1 (TGF-β1), mothers against decapentaplegic homolog 3 (Smad3), Smad7, toll-like receptor 4 (TLR4) and α-smooth muscle actin (α-SMA) were determined using immunohistochemical techniques. Results: Exposure to TFCG significantly reversed abnormal serum levels of ALT, AST, AKP, LDH, γ- GT, HYP, ALB and MDA rats with liver fibrosis to normal levels, and also decreased their liver index values ( p < 0.01). Moreover, TFCG improved histopathological changes in the liver tissues of fibrotic rats, and significantly reversed abnormal TGF-β1, Smad3, Smad7, TLR4 and α-SMA protein expressions in the liver tissues of fibrotic rats to normal levels ( p < 0.05 or 0.01). Conclusion: T hese results indicate that TFCG exerts protective effect against liver fibrosis via a mechanism related to inactivation of TGF-β/Smad pathway. Thus, TFCG may find application in liver fibrosis therapy. Keywords: Cichorium glandulosum , Flavonoids, Liver, Fibrosis, TGF-β/Smad pathway

Alogliptin alleviates liver fibrosis via suppression of activated hepatic stellate cell

Liver fibrosis occurs in most types of chronic liver diseases. The understanding of the pathogenesis of liver fibrosis has grown considerably, but the effective treatments are still lacking. Alogliptin, a classical Dipeptidyl peptidase-4 (DPP4) inhibitor with great effects on type 2 diabetes, has shown the potential to protect liver, but its effects on the progression of liver fibrosis have not been clarified. Herein, we explored the anti-fibrosis effects of alogliptin. In vitro, we demonstrated that alogliptin suppressed the activation of LX-2 upon transforming growth factor-β (TGF-β) challenge. In vivo, chronic treatment with alogliptin alleviated hepatic steatosis and protected from the liver injury in ob/ob mice, which delayed the progression of liver fibrosis. Furthermore, alogliptin significantly relieved the hepatic fibrosis in CCl4-induced liver fibrosis mouse model. In conclusion, our results demonstrate that negatively modulation of alogliptin on hepatic stellate cell (HSC) activation might contribute to liver fibrosis alleviation. Our research provides the potential possibility of alogliptin on the application for liver fibrosis therapy and suggests that DPP4 may be a novel target for liver fibrosis therapy.

Antifibrotic effects of total or partial application of amniotic membrane in hepatic fibrosis.

Liver fibrosis is the final common pathway of chronic liver diseases, having cirrhosis as a possible progression, which has liver transplantation as the only effective treatment. Human amniotic membrane represents a potential strategy as a therapy for liver fibrosis, due to its anti-inflammatory, anti-fibrotic and immunomodulatory properties. The aim of this study was to evaluate amniotic membrane effects as a treatment for hepatic fibrosis induced in rats by bile duct ligation (BDL), verifying alterations between two different forms of amniotic membrane application, around all the lobes of the liver and around only one lobe of the liver. Two weeks after inducing fibrosis, an amniotic membrane fragment was applied to the surface of the liver, covering it either totally or partially. Four weeks later, the animals were euthanized and liver samples were collected. Histopathological and quantitative analyses demonstrated fibrosis severity decrease and an extremely significant reduction in the deposition of collagen in the groups treated with amniotic membrane, particularly when the amniotic membrane was applied in only one liver lobe. It is concluded that the amniotic membrane acted on the repair of liver fibrosis in both modes of application, with the application of the amniotic membrane around only one hepatic lobe being more effective in reducing the severity / extent of fibrosis.

Antioxidant preconditioning enhances adipose tissue-derived stem cell therapy by increasing intrahepatic engraftment for liver fibrosis

Introduction: Although it has been pre-clinically suggested that adipose-derived mesenchymal stem cells (ADSC)-based therapy can effectively treat liver cirrhosis, the hepatic engraftment of ADSC is still extremely low, which affects the clinical translation of ADSC for liver cirrhosis treatment. Method: ADSCs were treated with hydrogen peroxide to induce cell stress. Antioxidants, including reduced glutathione and melatonin were co-treated to examine their protective effects and mechanisms on stem cell damage. Liver fibrosis model was also established to test the transplantation efficacy of ADSCs with or without antioxidants pre-incubation. Result: Our data showed that precondition of antioxidants synergistically enhances the anti-stress ability of ADSCs induced by hydrogen peroxide in vitro. We found that preconditioning with antioxidants significantly improves therapeutic efficacy of ADSCs transplantation in liver fibrosis mice, including ameliorating histological damage, oxidative stress, inflammation and fibrosis. In addition, we also found that preconditioned with antioxidants increases intrahepatic engraftment of ADSCs through reducing the hepatic content of NOXs and ROS both in vitro and in vivo. Conclusion: These findings suggested that antioxidant preconditioning can enhance ADSC-based therapy for liver fibrosis via in increasing hepatic engraftment of ADSCs, which may through suppressing NOXs/ROS signaling.

Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis invitro and invivo.

At present, no satisfactory anti‐liver fibrosis drugs have been used clinically due to the poor targeting ability and short half‐life period. This study aimed to explore the effects of a new TRAIL (TNF‐related apoptosis‐inducing ligand) preparation that can target aHSCs (activated hepatic stellate cells) on liver fibrosis and explain the possible underlying mechanism. Using our self‐made drug carrier pPB‐SSL that specifically targets aHSCs, recombinant human TRAIL (rhTRAIL) protein was embedded in (named as pPB‐SSL‐TRAIL) and applied to treat liver fibrotic mice as well as 3T3 fibroblast cells and aHSCs. Through in vitro and in vivo experiments, we found that, compared with the groups treated with TRAIL (free rhTRAIL) and SSL‐TRAIL (rhTRAIL capsulated within unmodified liposome), the group treated with pPB‐SSL‐TRAIL nanoparticles showed significantly lower cell viability and higher cell apoptosis in vitro. The targeting delivering system pPB‐SSL also significantly enhanced the anti‐fibrotic effect, apoptosis induction and long circulation of rhTRAIL. After the treatment with pPB‐SSL‐TRAIL, apoptosis of aHSCs was notably increased and hepatic fibrosis in mice was remarkably alleviated. In vitro, pPB‐SSL‐TRAIL nanoparticles were mainly transported and located on membrane or into cytoplasm, but the particles were distributed mainly in mouse fibrotic liver and most on the cell membrane of aHSCs. In conclusion, rhTRAIL carried by pPB‐SSL delivering system has prolonged circulation in blood, be able to target aHSCs specifically, and alleviate fibrosis both in vitro and in vivo. It presents promising prospect in the therapy of liver fibrosis, and it is worthwhile for us to develop it for clinical use.

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis

Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNFα (CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

Prevention of hepatic stellate cell activation using JQ1- and atorvastatin-loaded chitosan nanoparticles as a promising approach in therapy of liver fibrosis

Preventing hepatic stellate cell (HSC) activation represents a promising approach to resolve liver fibrosis. Several drugs have been reported to delay/prevent HSCs activation, however with limited clinical benefits. The latter may be in part attributed to the limited ability of such drugs in targeting more than one pathway of HSC activation. Added to that, is their inability of reaching their target cell in sufficient amounts to induce a therapeutic effect. In this work, chitosan NPs were loaded with JQ1 and atorvastatin, two drugs that have been reported to prevent HSCs activation, however via different mechanisms. NPs were then modified with different densities of retinol (Rt) for active targeting of HSCs. The NP HSCs targeting ability as a function of Rt density was assessed in vitro on primary HSCs and in vivo in carbon tetrachloride (CCl4) induced fibrotic mouse models. In vitro NPs modified with a low Rt density (LRt-NPs) showed ≈2 folds enhanced HSCs uptake in comparison to unmodified NPs, whereas NPs modified with a high Rt density (HRt-NPs) showed ≈0.8 folds change in uptake relative to unmodified NPs. Similarly, in vivo LRt-NPs showed higher accumulation in fibrotic livers in comparison to healthy livers whereas HRt-NPs and unmodified NPs showed lower accumulation in fibrotic livers relative to healthy controls respectively. Finally, the ability of drug-loaded NPs in preventing HSCs activation was assessed by monitoring the reduction in α-smooth muscle actin (α-SMA) expression by Western blot. NPs loaded with both JQ1 and atorvastatin showed reduction in α-SMA expression. In addition, a synergistic reduction in α-SMA was observed when cells were co-treated with JQ1 and atorvastatin loaded NPs.

Identification of a Novel Bone Marrow Cell-Derived Accelerator of Fibrotic Liver Regeneration Through Mobilization of Hepatic Progenitor Cells in Mice.

Granulocyte colony stimulating factor (G-CSF) has been reported to ameliorate impaired liver function in patients with advanced liver diseases through mobilization and proliferation of hepatic progenitor cells (HPCs). However, the underlying mechanisms remain unknown. We previously showed that G-CSF treatment increased the number of bone marrow (BM)-derived cells migrating to the fibrotic liver following repeated carbon tetrachloride (CCl4 ) injections into mice. In this study, we identified opioid growth factor receptor-like 1 (OGFRL1) as a novel BM cell-derived accelerator of fibrotic liver regeneration in response to G-CSF treatment. Endogenous Ogfrl1 was highly expressed in the hematopoietic organs such as the BM and spleen, whereas the liver contained a relatively small amount of Ogfrl1 mRNA. Among the peripheral blood cells, monocytes were the major sources of OGFRL1. Endogenous Ogfrl1 expression in both the peripheral blood monocytes and the liver was decreased following repeated CCl4 injections. An intrasplenic injection of cells overexpressing OGFRL1 into CCl4 -treated fibrotic mice increased the number of HPC and stimulated proliferation of hepatic parenchymal cells after partial resection of the fibrotic liver. Furthermore, overexpression of OGFRL1 in cultured HPC accelerated their differentiation as estimated by increased expression of liver-specific genes such as hepatocyte nuclear factor 4α, cytochrome P450, and fatty acid binding protein 1, although it did not affect the colony forming ability of HPC. These results indicate a critical role of OGFRL1 in the mobilization and differentiation of HPC in the fibrotic liver, and administration of OGFRL1-expressing cells may serve as a potential regenerative therapy for advanced liver fibrosis. Stem Cells 2019;37:89-101.

Asiatic acid ameliorates CCl4-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways.

PurposeCurrently, there are no effective therapies for liver fibrosis; hence, the development of anti-liver fibrosis agents is urgently needed. Here, we attempted to investigate the therapeutic effect and mechanism of asiatic acid (AA) on liver fibrosis, mainly focusing on the impact of AA on nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor-kappa B (NF-κB)/IκBα, and JAK1/signal transducer and activator of transcription 3 (STAT3) signaling pathways.MethodsRats were induced liver fibrosis by carbon tetrachloride (CCl4) for 6 weeks and concomitantly treated with AA (5 and 15 mg/kg) or vehicle by daily gavage. After AA treatment, the morphology of liver tissue was analyzed by H&E and Masson’s trichrome staining, and serum biochemical indicators were also assayed. Thereafter, the protein levels of Nrf2, HO-1, NQO-1, GCLC, NF-κB, IκBα, JAK1, p-JAK1, STAT3, and p-STAT3 were determined by Western blotting.ResultsOur results showed that AA treatment dramatically ameliorated CCl4-induced oxidative stress, inflammation, and fibrosis in rats. The expression of nuclear Nrf2 was increased after AA treatment, whereas cytoplasm Nrf2 levels were decreased. The protein expression of Nrf2 target proteins including HO-1, NQO-1, and GCLC was significantly increased by AA treatment. Furthermore, AA treatment decreased the levels of nuclear NF-κB to inhibit NF-κB/IκBα signaling pathway. In addition, we also found that AA treatment regulated JAK1/STAT3 signaling by decreasing the phosphorylation levels of JAK1 and STAT3.ConclusionThese results demonstrate that AA ameliorates CCl4-induced liver fibrosis in rats by regulating Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways, which suggests that AA might be a new antifibrosis agent that improves liver fibrosis.