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Hepatic fibrosis is an over-accumulation of extracellular matrix (ECM). It is a result of an imbalance between collagen synthesis and degradation. Matrix metalloproteinase (MMP) has degradative activity against collagen, but tissue inhibitors of metalloproteinase (TIMP) control the active forms of MMP by blocking the active site of MMP. In our study, we established the bile duct ligated model (BDL) in rats to evaluate anti-fibrotic potential of Chinese medicine sho-saiko-to (TJ-9). We assessed the drug's potential in inhibiting collagen accumulation, suppressing procollagen α1 types (I) and (III), and TIMP-1 mRNA expression. After administration of TJ-9, hyperbilirubinemia reduced approximately four-fold when compared with BDL-untreated group. TJ-9 also significantly reduced the collagen content and fibrogenic score, as well as downregulated elevated procollagen α1 types (I) and (III) and TIMP-1 mRNA level. Finally, we concluded that (1) TJ-9 significantly reduced cholestasis in rats with BDL, (2) TJ-9 markedly reduced the collagen content by 50%, and (3) TJ-9 exerted its antifibrogenic effect by downregulation of the mRNA expression of procollagen α1 types (I) and (III), and TIMP-1 in liver tissue.

The purpose of this study was to evaluate the hepatoprotective and anti-fibrotic actions of crude extracts of Ganoderma tsugae (GTE) on chronic liver injury induced by carbon tetrachloride (CCl₄) in rats. CCl₄ (20%, 0.5 ml/rat) was given twice a week for 8 weeks, and animals received GTE through the whole experimental period. GTE showed obvious reducing actions on the elevated levels of glutamate-oxalate-transaminase (GOT) and glutamate-pyruvate-transaminase (GPT) caused by CCl₄ at weeks 3, 6 and 8. Liver fibrosis in rats induced by CCl₄ led to the drop of serum albumin and hepatic protein concentrations, while GTE increased serum albumin and hepatic protein concentrations. The CCl₄-induced liver fibrosis may prolong the prothrombine time and increase albumin/globulin (A/G) ratio. GTE significantly decreased the prothrombine time and A/G ratio. Liver fibrosis induced by CCl₄ markedly increased the weight of the spleen, hepatic water and hydroxyproline contents in rats, while GTE decreased the rat's spleen weights, hepatic water and hydroxyproline contents. All these results clearly demonstrated that GTE has hepatoprotective and anti-fibrotic activities.

Oxidative stress can be implicated as a cause of liver fibrosis. In this sense, Ginkgo Biloba Extract (EGB), an antioxidant, may be beneficial in restraining liver fibrosis. The aim of this study was to evaluate the effects of EGB on experimental liver fibrosis. Rat liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl₄) twice a week for 8 weeks. Three groups of rats received EGB (0.25, 0.5 and 1.0 g/kg, respectively) by stomach everyday. CCl₄ administration induced liver fibrosis, which was inhibited by EGB in a dose-dependent manner. The histopathologic score of fibrosis, liver function and the levels of plasma hyaluronic acid (HA) and laminin (LN) were significantly improved in rats treated with CCl₄ + EGB, compared with those treated with CCl₄ only (p < 0.01 or p < 0.05). The activities of superoxide dismutase (SOD) and glutathione pero xidase (GSH-Px) were notably elevated, while malondialdehyde (MDA) content was significantly decreased in the rats treated with CCl₄ + EGB (p < 0.01 or p < 0.05). Inhibition of hepatic stellate cell (HSC) activation and nuclear factor kappaBP₆₅ (NF-κBP₆₅) expression was demonstrated in the livers of EGB-treated rats. The activation of NF-κB was significantly suppressed in EGB-treated rats determined by electrophoretic mobility shift assay (EMSA). Furthermore, EGB reduced expressions of transforming growth factor-β₁ (TGF-β₁) and collagen I mRNA. In conclusion, EGB is able to ameliorate liver injury and prevent rats from CCl₄-induced liver fibrosis by suppressing oxidative stress. This process may be related to inhibiting the induction of NF-κB on HSC activation and the expression of TGF-β₁.

The purpose of this study was to evaluate the antioxidant activity and hepatoprotective effect of ethanol extracts of Actinidia rubricaulis (AR) on chronic liver injury induced by carbon tetrachloride (CCl₄) in rats. CCl₄ (20%, 0.5 ml/rat) was given twice a week for 8 weeks, and animals received AR throughout the entire experimental period. AR reduced the elevated levels of serum glutamate-oxalate-transaminase (sGOT) and glutamate-pyruvate-transaminase (sGPT) caused by CCl₄ at weeks 1,3,6, and 8. The biochemical data were consistent with those of the histological observations. The AR extract recovered the CCl₄-induced liver injury and showed antioxidant effect in assays of antioxidant enzyme activity, such as SOD, GSH-Px and GSH-Rd. Based on these results, we suggest that the hepatoprotective effect of the AR is related to its antioxidant activity.

Curcumin and saikosaponin A as antioxidants improve antioxidant status. This study investigated the anti-inflammatory and antifibrotic actions of curcumin and saikosaponin A on CCl₄-induced liver damage. Sprague-Dawley rats were randomly divided into control, CCl₄, CCl₄+ curcumin (0.005%; CU), CCl₄ + saikosaponin A (0.004%; SS), and CCl₄ + curcumin + saikosaponin A (0.005% + 0.004%; CU + SS) groups. Carbon tetrachloride (40% in olive oil) at a dose of 0.75 ml/kg was injected intraperitoneally once a week. Curcumin and saikosaponin A were supplemented alone or in combination with diet 1 week before CCl₄ injection for 8 weeks. After 8-week supplementation, histopathological results showed hepatic collagen deposition was significantly reduced in the CU and SS groups, and activated nuclear factor-κ B expression induced by CCl₄ in the liver was significantly inhibited by curcumin and/or saikosaponin A. Hepatic proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 were significantly inhibited, and anti-inflammatory cytokine interleukin-10 was significantly increased by supplementation with curcumin and/or saikosaponin A. Additionally, curcumin and/or saikosaponin A significantly reduced the increased levels of hepatic transforming growth factor-β1 and hydroxyproline after CCl₄ treatment. Therefore, supplementation with curcumin and/or saikosaponin A suppress inflammation and fibrogenesis in rats with CCl₄-induced liver injury. However, the combination has no additive effects on anti-inflammation and antifibrosis.

Acremoniumterricola milleretal mycelium (AMM) is one of the most precious traditional Chinese medicines. It has numerous protective effects on organs, and has been used in Chinese herb prescription to treat refractory diseases. Our preliminary studies demonstrated that AMM had hepatoprotective activity in acute liver injury. We further investigated the effects of AMM on liver fibrosis in rats induced by carbon tetrachloride (CCl₄) and explore its possible mechanisms. The animal model was established by injection with 50% CCl₄ subcutaneously in male Sprague-Dawley rats twice a week for eight weeks. Meanwhile, AMM (175, 350 and 700 mg/kg) was administered intragastrically per day until sacrifice. We found that treatment with AMM (175, 350 and 700 mg/kg) decreased CCl₄-induced elevation of serum transaminase activities, hyaluronic acid, laminin and procollagen type III levels, and contents of hydroxyproline in liver tissues. It also restored the decreased SOD and GSH-Px activities and inhibited the formation of lipid peroxidative products during CCl₄ treatment. Moreover, AMM (350 and 700 mg/kg) decreased the elevation of TGF-β1 by 19.6% and 34.3%, respectively. In the pathological study, liver injury and the formation of liver fibrosis in rates treated by AMM were improved significantly. Immunoblot analysis showed that AMM (175, 350 and 700 mg/kg) inhibited Smad 2/3 phosphorylation, and elevated inhibitor Smad 7 expression. These results suggested that AMM could protect liver damage and inhibit the progression of hepatic fibrosis induced by CCl₄, and its mechanisms might be associated with its ability to scavenge free radicals, decrease the level of TGF-β1 and block TGF-β/Smad signaling pathway.

Ocimum gratissimum is a traditional herb commonly found in tropical regions, which prevents free radical damage and protects the liver from oxidative stress. In this study, we tested in vivo and in vitro the effectiveness of O. gratissimum extracts (OGEs) in anti-hepatic fibrosis in rats. Male Wistar rats were administered with carbon tetrachloride (CCl₄) by intraperitoneal injection and varying amounts of oral injection of OGE doses (0–40 mg/kg body weight) for 8 weeks. Our experiments showed that OGE significantly reduced liver damage, including steatosis and fibrosis, in a dose-dependent manner, as well as significantly decreased the elevation in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT). It also inhibited the formation of lipid peroxidative products during CCl₄ treatment. Moreover, OGE-inhibited CCl₄-induced liver collagen accumulation and promoted the expression of catalase, an anti-oxidative enzyme. The inhibition of fibrosis factors α-SMA expression was also observed. In primary cultures, OGE significantly inhibited the serum-induced activation of hepatic stellate cells (HSCs), and the expression of α-SMA and collagen α (I). These data suggest that O. gratissimum possesses anti-hepatic fibrosis properties via its anti-oxidative components.

Notch signaling has been demonstrated to be involved in ductular reactions and fibrosis. Previous studies have shown that Huang Qi Decoction (HQD) can prevent the progression of cholestatic liver fibrosis (CLF). However, whether HQD affects the Notch signaling pathway is unclear. In this study, CLF was established by common bile duct ligation (BDL) in rats. At the end of the first week, the rats were randomly divided into a model group (i.e., BDL), an HQD group, and a sorafenib positive control group (SORA) and were treated for 3 weeks. Bile duct proliferation and liver fibrosis were determined by tissue staining. Activation of the Notch signaling pathway was evaluated by analyzing expressions of Notch-1, -2, -3, and -4, Jagged (JAG) 1, and Delta like (DLL)-1, -3, and -4. The results showed that HQD significantly reduced the deposition of collagen and the Hyp content of liver tissue and inhibited the activation of HSCs compared with the BDL group. In addition, HQD significantly decreased the protein and mRNA expressions of TGF-$\text{β}$1 and $\alpha$-SMA. In contrast, HQD significantly enhanced expression of the Smad 7 protein. HQD also reduced biliary epithelial cell proliferation, and reduced the mRNA levels of CK7, CK8, CK18, SRY-related high mobility group-box gene (SOX) 9, epithelial cell adhesion molecule (EpCAM) and the positive areas of CK19 and OV6. In addition, the mRNA and protein expressions of Notch-3, -4, JAG1, and DLL-1, -3 were significantly reduced in the HQD compared to the BDL group. These results demonstrated that HQD may prevent biliary liver fibrosis through inhibition of the Notch signaling pathway, and it may be a potential treatment for cholestatic liver disease.

Gypenosides (GPs), the predominant components of Gynostemma pentaphyllum, exert antifibrotic effects; however, the mechanisms underlying their ability to ameliorate liver fibrosis are unclear. Liver fibrosis was induced in C57BL/6 mice via subcutaneous injection of 10% carbon tetrachloride (CCl${}_4)$ three times a week for two weeks. Then, CCl₄ was administered in conjunction with intragastric GPs for another three weeks. For in vitro analyses, WB-F344, hepatatic progenitor cells (HPCs) were treated with transforming growth factor beta 1 (TGF-$\beta$1) with or without GPs for 48h. The results showed that alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, deposition of collagen, hydroxyproline content, and expression of alpha-smooth muscle actin ($\alpha$-SMA) and collagen type I (Col I) were significantly decreased after treatment with GPs ($p<0.01$, $p<0.05$, $p<0.05$, $p<0.05$). In the 5M CCl₄ group, the expression of HPC markers, Sox9 and cytokeratin 19 (CK19), was significantly increased compared with the normal or GPs-treated group ($p<0.05$, $p<0.01$). Immunostaining showed that the number of Sox9 and $\alpha$-SMA double-positive cells was higher in the 5M CCl₄ group than in the normal group, but the addition of GPs caused this cell number to decrease. In WB-F344 cells, the expression of $\alpha$-SMA and Col I was significantly increased after treatment with TGF-$\beta 1$, whereas in the GPs treatment group, expression was markedly decreased ($p<0.05$). The levels of TGF-$\beta 1$ and TGF-$\beta$R1 were markedly reduced after GPs treatment both in vivo and in vitro. In conclusion, GPs ameliorated CCl₄-induced liver fibrosis via the inhibition of TGF-$\beta$ signaling, consequently inhibiting the differentiation of HPCs into myofibroblasts.

Liver fibrosis is a worldwide clinical issue that generally causes hepatic cirrhosis. Lonicerae Japonicae Flos (dried flower buds of Lonicera japonica Thunb) is a traditional heat-clearing and detoxifying herbal medicine in China. This study aims to observe the protection of the water extract of Lonicerae Japonicae Flos (FL) from carbon tetrachloride (CCl₄)-induced liver fibrosis in mice. Liver fibrosis was induced in mice by intraperitoneal injection of 2ml/kg CCl₄ twice a week for 4 weeks. FL’s attenuation of CCl₄-induced liver fibrosis in mice was evidenced by the results of Masson’s trichrome and Sirius red staining, liver hydroxyproline content and serum amount of collagen IV. FL reduced hepatic stellate cells (HSCs) activation and reversed the epithelial-mesenchymal transition (EMT) process in mice treated with CCl₄. FL also alleviated liver oxidative stress injury and enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant signaling pathway in mice treated with CCl₄. Additionally, the main phenolic acids in FL including chlorogenic acid (CGA) and caffeic acid (CA) both reduced HSCs activation in vitro. In summary, FL attenuates CCl₄-induced liver fibrosis in mice by inhibiting HSCs activation, reversing EMT and reducing liver oxidative stress injury via inducing Nrf2 activation. CGA may be the main active compound contributing to the antifibrotic activity of FL.

Corilagin is a polyphenol that can be extracted from many medicinal plants and shows multiple pharmacological effects. We aimed to investigate the role of corilagin on miR-21-regulated hepatic fibrosis, especially miR-21-regulated TGF-$\beta$1/Smad signaling pathway, in hepatic stellate LX2 cell line and Sprague–Dawley rats. The mRNA or protein levels of miR-21, Smad7, connective tissue growth factor (CTGF), $\alpha$-smooth muscle actin ($\alpha$-SMA), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), collagen type I alpha 1 (COL1A1), Smad2, Smad3, Smad2/3, p-Smad2, p-Smad3, p-Smad2/3, and transforming growth factor-$\beta$1 (TGF-$\beta$1) in LX2 cells and liver tissues were determined. Furthermore, gain-of and loss-of function of miR-21 in miR-21-regulated TGF-$\beta$1/Smad signaling pathway were analyzed in LX2 cells. Liver tissues and serum were collected for pathological analysis, immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Corilagin treatment reduced mRNA or protein levels of miR-21, CTGF, $\alpha$-SMA, TIMP-1, TGF-$\beta$1, COL1A1, p-Smad2, p-Smad3, and p-Smad2/3 both in vitro and in vivo. While corilagin increased mRNA and protein levels of Smad7 and MMP-9. After gain-of and loss-of function of miR-21, the downstream effectors of miR-21-regulated TGF-$\beta$1/Smad signaling pathway in LX2 cells changed accordingly, and the changes were inhibited by corilagin. Simultaneously, administration of corilagin not only ameliorated pathological manifestation of liver fibrosis but also reduced levels of $\alpha$-SMA and COL1A1 in liver tissues and TGF-$\beta$1, ALT levels in serum. Corilagin is able to potentially prevent liver fibrosis by blocking the miR-21-regulated TGF-$\beta$1/Smad signaling pathway in LX2 cells and CCl₄-induced liver fibrosis rats, which may provide a novel therapeutic strategy for liver fibrosis.

Activation of the hepatic stellate cell is implicated in pathological vascularization during development of liver fibrosis. MAPK signaling is involved in the activation of hepatic stellate cell. Oxidative stress and inflammation are also involved in the pathogenesis of liver fibrosis. Notoginsenoside R1 is an effective saponin isolated from the roots of Panax notoginseng (Burk) F. H. Chen and exerts anti-oxidant, anti-inflammatory and anti-fibrotic roles in various diseases. However, the role of Notoginsenoside R1 in liver fibrosis has not been investigated yet. First, a rat model with liver fibrosis was established through oral gavage administration with carbon tetrachloride. Data from hematoxylin and eosin (H&E) and Masson’s trichrome stainings showed that carbon tetrachloride induced severe hepatic damages, including inflammatory cell infiltration, lipid droplets deposition in hepatocytes and liver centrilobular necrosis. Meanwhile, the rats were also intraperitoneal injected with different concentrations of Notoginsenoside R1. Results demonstrated that Notoginsenoside R1 treatment suppressed the pathological changes in the livers with enhanced levels of ALB and TP, and reduced levels of ALP, AST and ALT. Second, Notoginsenoside R1 also significantly attenuated carbon tetrachloride-induced decrease in PPAR-$\gamma$ and increase in Coll-a1, $\alpha$-SMA and TIMP1 in liver tissues ($p$$<$ 0.001). Third, the decrease in GSH, SOD and GST and increase in MDA, IL-1$\beta$, IL-6 and TNF-$\alpha$ induced by carbon tetrachloride were markedly restored by Notoginsenoside R1 ($p$$<$ 0.001). Lastly, Notoginsenoside R1 counteracted with the promotive effects of carbon tetrachloride on levels of proteins involved in MAPK signaling, including phosphorylated p65 (p-p65), p-ERK, p-JNK and p-p38. In conclusion, Notoginsenoside R1 suppressed the activation of hepatic stellate cells and exerted anti- oxidant and anti-inflammatory to attenuate carbon tetrachloride-induced liver fibrosis through inactivation of NF-$\kappa$B and MAPK signaling.

Liver fibrosis is a disease largely driven by resident and recruited macrophages. The phenotypic switch of hepatic macrophages can be achieved by chemo-attractants and cytokines. During a screening of plants traditionally used to treat liver diseases in China, paeoniflorin was identified as a potential drug that affects the polarization of macrophages. The aim of this study was to evaluate the therapeutic effects of paeoniflorin in an animal model of liver fibrosis and explore its underlying mechanisms. Liver fibrosis was induced in Wistar rats via an intraperitoneal injection of CCl₄. In addition, the RAW264.7 macrophages were cultured in the presence of CoCl₂ to simulate a hypoxic microenvironment of fibrotic livers in vitro. The modeled rats were treated daily with either paeoniflorin (100, 150, and 200mg/kg) or YC-1 (2mg/kg) for 8 weeks. Hepatic function, inflammation and fibrosis, activation of hepatic stellate cells (HSC), and extracellular matrix (ECM) deposition were assessed in the in vivo and in vitro models. The expression levels of M1 and M2 macrophage markers and the NF-$\kappa$B/HIF-1$\alpha$ pathway factors were measured using standard assays. Paeoniflorin significantly alleviated hepatic inflammation and fibrosis, as well as hepatocyte necrosis in the CCl₄-induced fibrosis model. Furthermore, paeoniflorin also inhibited HSC activation and reduced ECM deposition both in vivo and in vitro. Mechanistically, paeoniflorin restrained M1 macrophage polarization and induced M2 polarization in the fibrotic liver tissues as well as in the RAW264.7 cells grown under hypoxic conditions by inactivating the NF-$\kappa$B/HIF-1$\alpha$ signaling pathway. In conclusion, paeoniflorin exerts its anti-inflammatory and anti-fibrotic effects in the liver by coordinating macrophage polarization through the NF-$\kappa$B/HIF-1$\alpha$ pathway.

Liver fibrosis is a common complication of chronic liver disease, significantly affecting patients’ quality of life and potentially leading to cirrhosis and hepatocellular carcinoma. Despite advancements in modern medicine, the treatment of liver fibrosis remains limited and challenging. Thus, identifying new therapeutic strategies is of great clinical importance. Signaling pathways related to liver fibrosis play a crucial regulatory role in immune response and inflammation. Aberrant activation of specific pathways, such as the NF-κB signaling pathway, results in the overexpression of genes associated with liver inflammation and fibrosis, thereby promoting the progression of liver fibrosis. Chinese medicine offers unique potential advantages as a therapeutic approach. Recent studies have increasingly demonstrated that certain Chinese medicines can effectively treat liver fibrosis by regulating relevant signaling pathways. The active ingredients in these medicines can inhibit hepatic inflammatory responses and fibrotic processes by interfering with these pathways, thus reducing the severity of liver fibrosis. This paper aims to investigate the mechanisms of Chinese medicine in treating liver fibrosis and its modulation of related signaling pathways. Additionally, it discusses the prospects of the clinical application of these treatments and provides valuable references for further research and clinical practice.

At present, percutaneous liver biopsy is the gold standard in assessing liver fibrosis such as hepatitis and cirrhosis, but there could be sampling error, and specimens might not represent the state of the whole liver accurately because only about 0.002% of the organ is sampled. In this research, we propose the three-dimensional fiber structure extraction echo filter to realize a quantitative ultrasonic diagnosis. The filter is designed based on a statistical theory, and it is possible to reduce the noise contained in a back scattered ultrasonic echo signal, and to visualize the structure of a fiber.

Viscoelastic mechanical characteristics of the liver play a crucial role in fibrosis and cancer progression. Despite the evolution of liver fibrosis, as a pivotal step toward cirrhosis and hepatoma, originates from molecular dysfunctions and further extends to cellular and tissue levels, current clinical assessment is still largely based on tissue level stiffness. This study introduces a novel multiscale viscoelastic signature-based machine learning model for liver fibrosis evaluation. Utilizing a hybrid hierarchical theory-microrheology approach, we unveil a universal two-stage power-law rheology capturing dynamic mechanical variations in diverse liver conditions. Our analysis of multiscale viscoelastic disparities through a self-similar hierarchical theoretical framework enhances our understanding of fibrosis evolution. Distinct mechanical signatures observed across liver states provide valuable insights for assessing fibrotic individuals and treatment responses at different spatial scales. Furthermore, we propose a series of threshold values for each marker in the diagnosis of liver fibrosis. Notably, based on these new viscoelastic signatures, we eventually propose a Light Gradient Boosting Machine (LightGBM) diagnostic model that outperforms conventional stiffness-based classification, offering superior diagnostic precision for fibrotic treatment. This research contributes to the growing knowledge of viscoelastic characteristics in soft tissues and holds promise for innovative diagnostic strategies in various diseases and cancers.

Mueller matrix imaging is emerging for the quantitative characterization of pathological microstructures and is especially sensitive to fibrous structures. Liver fibrosis is a characteristic of many types of chronic liver diseases. The clinical diagnosis of liver fibrosis requires time-consuming multiple staining processes that specifically target on fibrous structures. The staining proficiency of technicians and the subjective visualization of pathologists may bring inconsistency to clinical diagnosis. Mueller matrix imaging can reduce the multiple staining processes and provide quantitative diagnostic indicators to characterize liver fibrosis tissues. In this study, a fiber-sensitive polarization feature parameter (PFP) was derived through the forward sequential feature selection (SFS) and linear discriminant analysis (LDA) to target on the identification of fibrous structures. Then, the Pearson correlation coefficients and the statistical T-tests between the fiber-sensitive PFP image textures and the liver fibrosis tissues were calculated. The results show the gray level run length matrix (GLRLM)-based run entropy that measures the heterogeneity of the PFP image was most correlated to the changes of liver fibrosis tissues at four stages with a Pearson correlation of 0.6919. The results also indicate the highest Pearson correlation of 0.9996 was achieved through the linear regression predictions of the combination of the PFP image textures. This study demonstrates the potential of deriving a fiber-sensitive PFP to reduce the multiple staining process and provide textures-based quantitative diagnostic indicators for the staging of liver fibrosis.