Therapy For Liver Fibrosis Research Articles

Yangyinghuoxue decoction exerts a treatment effect on hepatic fibrosis by PI3K/AKT pathway in rat model: based on the network pharmacology and molecular docking.

Yangyinghuoxue decoction (YYHXD) is a Traditional Chinese medicine (TCM) compound with satisfactory clinical efficacy in the treatment of hepatic fibrosis (HF). However, the pharmacological molecular mechanisms of YYHXD in the treatment of hepatic fibrosis have not yet been clarified. To determine the pharmacological mechanisms of YYHXD for the treatment of hepatic fibrosis via network pharmacology analysis combined with experimental verification. First, the bioactive ingredients and potential targets of YYHXD and HF-related targets were retrieved from the online databases and literatures. Next, the "herb-ingredient-target-disease" network and PPI network were constructed for topological analyses and key active compounds and targets screening. Enrichment analyses were performed to identify the critical biological processes and signaling pathways. Then, the molecular docking experiment was performed to initially validate the network pharmacology prediction results. Finally, the antifibrotic effect and pharmacological mechanisms of YYHXD were investigated in CCl4 induced liver fibrosis in rats. In total, 141 active compounds in YYHXD, 637 YYHXD-related targets and 1598 liver fibrosis-related targets were identified. Among them, 69 overlapped targets were finally obtained. Network analysis screened 5 critical bioactive components and 34 key targets. Functional enrichment analysis indicated that YYHXD obviously influenced biological processes such as oxidative stress, cellular inflammation and hepatocyte apoptosis and signaling pathways such as PI3K-Akt, Apoptosis, and JAK-STAT in the treatment of HF. The molecular docking results suggested that the YYHXD may have a direct impact on the PI3K-Akt signaling pathway. Further, in vivo experiment indicated that YYHXD treatment not only reduced liver injury and protected liver function, but also decrease the apoptosis of hepatic parenchyma cells, reducing inflammatory and attenuating oxidative stress. Moreover, YYHXD significantly attenuated the upregulation of target proteins enriched in PI3K signaling pathway, including P-PI3K, P-Akt1, HSP90, MYC, p53. The mechanisms of YYHXD against liver fibrosis were involved in multiple ingredients, multiple targets and multiple signaling pathways. The PI3K/Akt pathway could be the most important pharmacological mechanism of YYHXD therapy for liver fibrosis.

Self-Healing Hydrogel Containing Decellularized Liver Matrix and Endothelial Cell-Covered Hepatocyte Spheroids for Rescue of Injured Hepatocytes.

Liver fibrosis occurs in many chronic liver diseases, while severe fibrosis can lead to liver failure. A chitosan-phenol based self-healing hydrogel (CP) integrated with decellularized liver matrix (DLM) is proposed in this study as a 3D gel matrix to carry hepatocytes for possible therapy of liver fibrosis. To mimic the physiological liver microenvironment, DLM is extracted from pigs and mixed with CP hydrogel to generate DLM-CP self-healing hydrogel. Hepatocyte spheroids coated with endothelial cells (ECs) are fabricated using a customized method and embedded in the hydrogel. Hepatocytes injured by exposure to CCl4-containing medium are used as the in vitro toxin-mediated liver fibrosis model, where the EC-covered hepatocyte spheroids embedded in the hydrogel are co-cultured with the injured hepatocytes. The urea synthesis of the injured hepatocytes reaches 91% of the normal level after 7 days of co-culture, indicating that the hepatic function of injured hepatocytes is rescued by the hybrid spheroid-laden DLM-CP hydrogel. Moreover, the relative lactate dehydrogenase activity of the injured hepatocytes is decreased 49% by the hybrid spheroid-laden DLM-CP hydrogel after 7 days of co-culture, suggesting reduced damage in the injured hepatocytes. The combination of hepatocyte/EC hybrid spheroids and DLM-CP hydrogel presents a promising therapeutic strategy for hepatic fibrosis.

Treatment of chronic viral hepatitis c in perm Krai

Objective. To analyze the effectiveness of etiotropic antiviral therapy with direct antiviral drugs against chronic viral hepatitis C in the adult population of the Perm Krai.
 Materials and methods. In the regional register of Perm Krai, 20095 patients with chronic viral hepatitis C were registered. In 2019–2021, antiviral therapy with direct antiviral drugs, registered in the Russian Federation, and included in the list of vital and essential medicines for medical use was prescribed to 282 patients with chronic hepatitis C. There were 137 men (48.6 %), 145 (51.4 %) – women. The age of the patients ranged from 26 to 82 years, the duration of the disease – from 3 to 25 years.
 Results. All the therapy regimes we used showed 100 % effectiveness in the population of patients suffering from chronic hepatitis C associated with mild liver fibrosis regardless of genotype, whereas in the population of patients with grade 3 fibrosis or liver cirrhosis, 100 % effectiveness was achieved only after the use of sofosbuvir-containing schemes. The pangenotypic schemes resulted in 100 % achievement of a stable virological response among patients with genotype 1 regardless of the stage of liver fibrosis and previous therapy experience. In the treatment of patients infected with genotype 3 of hepatitis C virus with severe fibrosis, the effectiveness of 100 % was noted after the use of sofosbuvir-containing regimes.
 Conclusions. Among the adult population of Perm Krai, the overall effectiveness of therapy in patients with chronic hepatitis C, who used direct antiviral drugs, was 97.8 %.

Protozoan-Derived Cytokine-Transgenic Macrophages Reverse Hepatic Fibrosis.

Macrophage therapy for liver fibrosis is on the cusp of meaningful clinical utility. Due to the heterogeneities of macrophages, it is urgent to develop safer macrophages with a more stable and defined phenotype for the treatment of liver fibrosis. Herein, a new macrophage-based immunotherapy using macrophages stably expressing a pivotal cytokine from Toxoplasma gondii, a parasite that infects ≈ 2 billion people is developed. It is found that Toxoplasma gondii macrophage migration inhibitory factor-transgenic macrophage (Mφtgmif) shows stable fibrinolysis and strong chemotactic capacity. Mφtgmif effectively ameliorates liver fibrosis and deactivates aHSCs by recruiting Ly6Chi macrophages via paracrine CCL2 and polarizing them into the restorative Ly6Clo macrophage through the secretion of CX3CL1. Remarkably, Mφtgmif exhibits even higher chemotactic potential, lower grade of inflammation, and better therapeutic effects than LPS/IFN-γ-treated macrophages, making macrophage-based immune therapy more efficient and safer. Mechanistically, TgMIF promotes CCL2 expression by activating the ERK/HMGB1/NF-κB pathway, and this event is associated with recruiting endogenous macrophages into the fibrosis liver. The findings do not merely identify viable immunotherapy for liver fibrosis but also suggest a therapeutic strategy based on the evolutionarily designed immunomodulator to treat human diseases by modifying the immune microenvironment.

Phomopsterone B Alleviates Liver Fibrosis through mTOR-Mediated Autophagy and Apoptosis Pathway.

Liver fibrosis is the initial pathological process of many chronic liver diseases. Targeting hepatic stellate cell (HSC) activation is an available strategy for the therapy of liver fibrosis. We aimed to explore the anti-liver fibrosis activity and potential mechanism of phomopsterone B (PB) in human HSCs. The results showed that PB effectively attenuated the proliferation of TGF-β1-stimulated LX-2 cells in a concentration-dependent manner at doses of 1, 2, and 4 μM. Quantitative real-time PCR and Western blot assays displayed that PB significantly reduced the expression levels of α-SMA and collagen I/III. AO/EB and Hoechst33342 staining and flow cytometry assays exhibited that PB promoted the cells' apoptosis. Meanwhile, PB diminished the number of autophagic vesicles and vacuolated structures, and the LC3B fluorescent spots indicated that PB could effectively inhibit the accretion of autophagosomes in LX-2 cells. Moreover, rapamycin and MHY1485 were utilized to further investigate the effect of mTOR in autophagy and apoptosis. The results demonstrated that PB regulated autophagy and apoptosis via the mTOR-dependent pathway in LX-2 cells. In summary, this is the first evidence that PB effectively alleviates liver fibrosis in TGF-β1-stimulated LX-2 cells, and PB may be a promising candidate for the prevention of liver fibrosis.

Therapeutic potential of natural products in schistosomiasis-associated liver fibrosis.

Schistosomiasis is a parasitic disease that endangers human health and social development. The granulomatous reaction of Schistosoma eggs in the liver is the main cause of hepatosplenomegaly and fibrotic lesions. Anti liver fibrosis therapy is crucial for patients with chronic schistosomiasis. Although Praziquantel is the only clinical drug used, it is limited in insecticide treatment and has a long-term large-scale use, which is forcing the search for cost-effective alternatives. Previous research has demonstrated that plant metabolites and extracts have effective therapeutic effects on liver fibrosis associated with schistosomiasis. This paper summarizes the mechanisms of action of metabolites and some plant extracts in alleviating schistosomiasis-associated liver fibrosis. The analysis was conducted using databases such as PubMed, Google Scholar, and China National Knowledge Infrastructure (CNKI) databases. Some plant metabolites and extracts ameliorate liver fibrosis by targeting multiple signaling pathways, including reducing inflammatory infiltration, oxidative stress, inhibiting alternate macrophage activation, suppressing hepatic stellate cell activation, and reducing worm egg load. Natural products improve liver fibrosis associated with schistosomiasis, but further research is needed to elucidate the effectiveness of natural products in treating liver fibrosis caused by schistosomiasis, as there is no reported data from clinical trials in the literature.

Structural characterization of an inulin neoseries-type fructan from Ophiopogonis Radix and the therapeutic effect on liver fibrosis in vivo

Ophiopogonis Radix is a well-known Traditional Chinese Medicine and functional food that is rich in polysaccharides and has fructan as a characteristic component. In this study, an inulin neoseries-type fructan designated as OJP-W2 was obtained and characterized from Ophiopogonis Radix, and its potential therapeutic effect on liver fibrosis in vivo were investigated. Structural studies revealed that OJP-W2 had a molecular weight of 5.76 kDa and was composed of glucose and fructose with a molar ratio of 1.00:30.87. Further analysis revealed OJP-W2 has a predominantly lineal (1–2)-linked β-D-fructosyl units linked to the glucose moiety of the sucrose molecule with (2–6)-linked β-D-fructosyl side chains. Pharmacological studies revealed that OJP-W2 exerted a marked hepatoprotective effect against liver fibrosis, the mechanism of action was involved in regulating collagen deposition (α-SMA, COL1A1 and liver Hyp contents) and TGF-β/Smads signaling pathway, alleviating liver inflammation (IL-1β, IL-6, CCL5 and F4/80) and MAPK signaling pathway, and inhibiting hepatic apoptosis (Bax, Bcl-2, ATF4 and Caspase 3). These data provide evidence for expanding Ophiopogonis Radix-acquired fructan types and advancing our understanding of the specific role of inulin neoseries-type fructan in liver fibrosis therapy.

The combination of tetracyclines effectively ameliorates liver fibrosis via inhibition of EphB1/2

Eph receptor tyrosine kinase EphB1/2 contributes to the development of liver fibrosis, suggesting the rationale that EphB1/2 inhibitors may be effective in liver fibrosis therapy. Since tetracycline antibiotics were recently demonstrated as EphB kinase inhibitors, in present study we investigated their therapeutic potential against liver fibrosis. Our results showed that the tetracycline combination of demeclocycline (D), chlortetracycline (C), and minocycline (M) inhibited the activation of hepatic stellate cells (HSCs) in vitro and alleviated CCl4-induced animal model of liver fibrosis in vivo. Mechanistically, DCM combination inhibited EphB1/2 phosphorylation and subsequent activation of the MAPK signaling. Moreover, we found that short-term and low-dose DCM combination treatment decreased tissue inflammation and improved liver fibrosis in mice. Thus, our study indicates that tetracyclines may be repurposed for the treatment of liver fibrosis.

Two-Membrane Hybrid Nanobiomimetic Delivery System for Targeted Autophagy Inhibition of Activated Hepatic Stellate Cells To Synergistically Treat Liver Fibrosis.

Liver fibrosis is one of the most common and highly prevalent chronic liver diseases caused by multiple pathogenic factors, and there is still no effective therapeutic drugs up to now. The activated hepatic stellate cells (aHSCs) are the main executor in liver fibrosis, and the autophagy plays a key role in the proliferation and differentiation of aHSCs, which promotes the development of liver fibrosis. However, autophagy has the opposite effect on the different kinds of liver cells in the development of liver fibrosis, and the clinical treatment has been limited by the poor selectivity and inefficient drug delivery to aHSCs. Therefore, in this study, a liposome (Lip) and exosome (Exo) two-membrane hybrid nanobiomimetic delivery system HCQ@VA-Lip-Exo was designed, which was modified by vitamin A (VA) to target the aHSCs and carried the autophagy inhibitor hydroxychloroquine (HCQ). The experimental results in vitro and in vivo revealed that the constructed aHSC-targeted hybrid delivery system HCQ@VA-Lip-Exo combined with the benefits of HCQ and exosomes derived from bone marrow mesenchymal stem cells. HCQ@VA-Lip-Exo had good aHSC-targeted delivery ability, effective autophagy inhibition, and synergistical anti-liver fibrosis performance, thus reducing the production and deposition of the extracellular matrix to inhibit the liver fibrosis. This combined strategy provided a potential idea for the construction and clinical application of a two-membrane hybrid delivery system as an effective targeted therapy of liver fibrosis.

Thyroid hormone receptor alpha modulates fibrogenesis in hepatic stellate cells.

Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells(HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or β (TRα/β). Here, we evaluated the influence of TH in hepatic fibrogenesis. Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFβ in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR. TRα and TRβ expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFβ-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFβ signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis. These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFβ signalling pathway. Thus, the TH-TR axis may be a valuable target for future therapy of liver fibrosis.

Viscoelastic Multiscale Mechanical Indexes for Assessing Liver Fibrosis and Treatment Outcomes.

Understanding liver tissue mechanics, particularly in the context of liver pathologies like fibrosis, cirrhosis, and carcinoma, holds pivotal significance for assessing disease severity and prognosis. Although the static mechanical properties of livers have been gradually studied, the intricacies of their dynamic mechanics remain enigmatic. Here, we characterize the dynamic creep responses of healthy, fibrotic, and mesenchymal stem cells (MSCs)-treated fibrotic lives. Strikingly, we unearth a ubiquitous two-stage power-law rheology of livers across different time scales with the exponents and their distribution profiles highly correlated to liver status. Moreover, our self-similar hierarchical theory effectively captures the delicate changes in the dynamical mechanics of livers. Notably, the viscoelastic multiscale mechanical indexes (i.e., power-law exponents and elastic stiffnesses of different hierarchies) and their distribution characteristics prominently vary with liver fibrosis and MSCs therapy. This study unveils the viscoelastic characteristics of livers and underscores the potential of proposed mechanical criteria for assessing disease evolution and prognosis.

NIR-II emissive nanoprobe for non-invasive monitoring of liver fibrosis and in-situ ratiometric visualization of NO gas-based therapy process

Timely detecting the progression and therapeutic effect of non-alcoholic liver disease is a great challenge due to lacking suitable non-invasive imaging methods. Herein, a novel theranostic nanoplatform based on lanthanide nanorods integrated with photo-triggered NO releasing molecule (NaYF4:Gd/Yb/Er@mSiO2-RBS) is designed for simultaneous diagnosis of liver fibrosis and second near infrared (NIR-II) ratiometric fluorescence imaging of the NO gas-based therapy of liver fibrosis. The mice with liver fibrosis present bright NIR-II emission (1000–1400 nm) via endogenous pigment secreted in liver fibrosis area under 808 nm laser excitation, enabling non-invasive diagnosis of liver fibrosis. In addition, the nanoplatform presents efficient NO gas release for therapy of liver fibrosis and 1532 nm emission activated by 980 nm laser. Importantly, after NO gas therapy, NIR-II fluorescent signal of the endogenous pigment was decreased, while the fluorescent signal around 1532 nm was increased, leading to the specific ratiometric NIR-II imaging of the therapy process with high specificity. Thus, the developed theranostic nanoprobe provided a powerful tool for timely NIR-II ratiometric detecting the progression and therapeutic effect of liver disease.

Nano-calcipotriol as a potent anti-hepatic fibrosis agent.

Calcipotriol (CAL) has been widely studied as a fibrosis inhibitor and used to treat plaque psoriasis via transdermal administration. The clinical application of CAL to treat liver fibrosis is bottlenecked by its unsatisfactory pharmacokinetics, biodistribution, and side effects, such as hypercalcemia in patients. The exploration of CAL as a safe and effective antifibrotic agent remains a major challenge. Therefore, we rationally designed and synthesized a self-assembled drug nanoparticle encapsulating CAL in its internal hydrophobic core for systematic injection (termed NPs/CAL) and further investigated the beneficial effect of the nanomaterial on liver fibrosis. C57BL/6 mice were used as the animal model, and human hepatic stellate cell line LX-2 was used as the cellular model of hepatic fibrogenesis. Immunofluorescence staining, flow cytometry, western blotting, immunohistochemical staining, and in vitro imaging were used for evaluating the efficacy of NPs/CAL treatment. We found NPs/CAL can be quickly internalized in vitro, thus potently deactivating LX-2 cells. In addition, NPs/CAL improved blood circulation and the accumulation of CAL in liver tissue. Importantly, NPs/CAL strongly contributed to the remission of liver fibrosis without inducing hypercalcemia. Overall, our work identifies a promising paradigm for the development of nanomaterial-based agents for liver fibrosis therapy.

9-POHSA prevents NF-kB activation and ameliorates LPS-induced inflammation in rat hepatocytes.

Liver inflammation has become increasingly prevalent in recent years, leading to the development of diseases like hepatitis, alcoholic liver disease, and fatty liver disease. One factor that has been linked to liver inflammation is increased levels of lipopolysaccharides (LPS), which can be caused by poor diets and sedentary lifestyles that contribute to liver inflammation. There is promising research on a new class of lipids called fatty acid esters of hydroxy fatty acids (FAHFAs), which have been shown to potentiate insulin release and exert an anti-inflammatory effect. Specifically, one type of FAHFA called 9-POHSA (palmitoleic acid ester of 9-hydroxy stearic acid) has been studied for its potential to attenuate inflammation-related indexes induced by LPS in hepatocytes, which play a critical role in the progression of liver inflammation. This study found that following LPS treatment, tumor necrosis factor- α, interleukin-6, and connective tissue growth factor (CTGF) were upregulated and increased cell migration, but 9-POHSA pre-treatment attenuated the upregulation of these markers and prevented cell migration induced by LPS. Using flowcytometry analysis, intracellular reactive oxygen species (ROS) was found to be responsible for CTGF upregulation. In addition, the effects of 9-POHSA were likely associated with its inhibition of the activation of the NF-kB. These results suggest that 9-POHSA has potential as a therapy for liver inflammation and fibrosis by attenuating inflammation-related indexes induced by LPS in hepatocytes. This study provides important insight into the mechanisms of liver inflammation and the potential for new treatments to address liver diseases.

Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

Fibrosis Development Linked to Alterations in Glucose and Energy Metabolism and Prooxidant-Antioxidant Balance in Experimental Models of Liver Injury.

The development of liver fibrosis is one of the most severe and life-threatening outcomes of chronic liver disease (CLD). For targeted therapy of CLD, it is highly needed to reveal molecular targets for normalizing metabolic processes impaired in damaged liver and associated with fibrosis. In this study, we investigated the morphological and biochemical changes in rat liver models of fibrosis induced by chronic administration of thioacetamide, carbon tetrachloride, bile duct ligation (BDL), and ischemia/reperfusion (I/R), with a specific focus on carbohydrate and energy metabolism. Changes in the levels of substrates and products, as well as enzyme activities of the major glucose metabolic pathways (glycolysis, glucuronidation, and pentose phosphate pathway) were examined in rat liver tissue after injury. We examined key markers of oxidative energy metabolism, such as the activity of the Krebs cycle enzymes, and assessed mitochondrial respiratory activity. In addition, pro- and anti-oxidative status was assessed in fibrotic liver tissue. We found that 6 weeks of exposure to thioacetamide, carbon tetrachloride, BDL or I/R resulted in a decrease in the activity of glycolytic enzymes, retardation of mitochondrial respiration, elevation of glucuronidation, and activation of pentose phosphate pathways, accompanied by a decrease in antioxidant activity and the onset of oxidative stress in rat liver. Resemblance and differences in the changes in the fibrosis models used are described, including energy metabolism alterations and antioxidant status in the used fibrosis models. The least pronounced changes in glucose metabolism and mitochondrial functions in the I/R and thioacetamide models were associated with the least advanced fibrosis. Ultimately, liver fibrosis significantly altered the metabolic profile in liver tissue and the flux of glucose metabolic pathways, which could be the basis for targeted therapy of liver fibrosis in CLD caused by toxic, cholestatic, or I/R liver injury.

Traditional Chinese medicine invigorating the spleen and kidney promotes HBsAg seroclearance in the mouse model.

Traditional Chinese medicine (TCM) is often used as an adjuvant or alternative therapy for abnormal liver biochemistry or liver fibrosis associated with chronic hepatitis B (CHB). However, the role of TCM in HBsAg seroclearance remains unclear. We aimed at exploring the role and possible mechanisms of TCM in HBsAg seroclearance. Fifteen widely used TCM granules invigorating the spleen and kidneys were screened. C57BL/6J mice were administered daily with TCM granules by gavage for 1 week. The effect of TCM on the M1 polarization of macrophages was measured using a CD86 assay. According to the principles of formulating prescriptions, three single TCM with the most noticeable effect on M1 polarization, accompanied by two other TCM granules, were used to develop a TCM formula. The hepatitis B virus-expressing mouse model was constructed by hydrodynamic injection of the pAAV/HBV1.2 plasmid. Hepatitis B virus-expressing mice were gavaged daily with phosphate-buffered saline (PBS), TCM formula, or Codonopsis Radix, for 1 week. HBsAg, HBeAg, and hepatitis B virus DNA levels were measured. In addition, gut microbiota was profiled using 16S rDNA sequencing. Several TCM granules showed significant effects on M1 polarization. The TCM formula accelerated HBsAg seroclearance compared with the Codonopsis Radix and PBS groups. Intrahepatic M1 polarization, as indicated by flow cytometry and immunohistochemistry, was induced in the TCM formula and Codonopsis Radix groups. The abundance of Alloprevotella significantly increased in the TCM formula and Codonopsis Radix groups. These results demonstrate that the TCM formula for invigorating the spleen and kidney can accelerate HBsAg seroclearance. This effect can be attributed, at least in part, to M1 polarization of intrahepatic macrophages.

Administration of AG490 decreases the senescence of umbilical cord-mesenchymal stem cells and promotes the cytotherapeutic effect in liver fibrosis

The therapeutic potential of umbilical cord-mesenchymal stem cell (UC-MSC) transplantation in liver fibrosis has been highlighted. However, the fate of transplanted MSCs in the fibrotic microenvironment remains unclear. In this study, we aim to uncover the fate of transplanted MSCs and develop targeting strategies that could enhance the therapeutic efficacy of MSC therapy in liver fibrosis. We used human UC-MSCs as the study object. For in vitro experiments, we stimulated UC-MSCs with several fibrotic-related factors (Liver fibrotic Factors, LF), including TGFβ, TNFα and IFNγ for downstream investigations. We co-cultured LF-treated UC-MSCs with hepatic stellate cell line LX-2 to assess the anti-fibrotic effect. We showed that upon LF stimulation, UC-MSCs exhibited reduced anti-fibrotic activity and underwent rapid senescence. Pathway analysis showed that JAK/STAT3 signaling was highly activated upon LF stimulation, which significantly elevated senescence-associated secretory phenotype (SASP) and senescence in UC-MSCs and could be reversed by a specific JAK inhibitor AG490. Moreover, using both carbon tetrachloride (CCl4) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induce fibrosis models, we demonstrated that AG490 pretreatment promoted UC-MSCs survival within the fibrotic liver microenvironment and exhibited enhance therapeutic efficacy. Overall, we showed that targeting MSC senescence in vivo through AG490 pretreatment could enhance the anti-fibrotic activities of UC-MSCs.

Carbon Nitride-Based siRNA Vectors with Self-Produced O2 Effects for Targeting Combination Therapy of Liver Fibrosis via HIF-1α-Mediated TGF-β1/Smad Pathway.

Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, a safe and effective method is established to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA can be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger the water splitting process to produce O2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy can inhibit the activation of HSCs via HIF-1α-mediated TGF-β1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site.

Mesoporous polydopamine based biominetic nanodrug ameliorates liver fibrosis via antioxidation and TGF-β/SMADS pathway

Early intervention of liver fibrosis can prevent its further irreversible progression. Both excess reactive oxygen species (ROS) and transforming growth factor beta(TGF-β)/drosophila mothers against decapentaplegic protein (SMADS) pathway balance disorder promote the progression of hepatic stellate cell (HSC) activation, but existing therapeutic strategies failed to focus on those two problems. A new biomimetic mesoporous polydopamine nandrug (MPO) was constructed for liver fibrosis therapy with multiple targets and reliable biosafety. The MPO was formed by mesoporous polydopamine (mPDA) which has the effect of ROS elimination and encapsulated with anti-fibrotic drug -oxymatrine (OMT) which can intervene liver fibrosis targeting TGF-β/SMADSpathway. Particularly, the nanodrug was completed by macrophage-derived exosome covering. The MPO was confirmed to possess a desired size distribution with negative zeta potential and exhibite strong ROS scavenger ability. Besides, in vitro studies, MPO showed efficient endocytosis and superior intracellular ROS scavenging without cytotoxicity; in vivo studies, MPO effectively cleared the excessive ROS in liver tissue and balanced the TGF-β/SMADS pathways, which in turn inhibited HSC activation and showed superior anti-liver fibrosis therapeutic efficiency with good biological safety. Taken together, this work showed highlights the great potential of the MPO for ameliorating liver fibrosis via ROS elimination and TGF-β/SMADS balancing.