Browsing by Subject "Liver fibrosis"
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- PublicationOpen AccessChelerythrine-mediated targeting of NF-κB and Nrf2 pathways alleviates liver injury in a carbon tetrachloride-induced liver fibrosis mouse model(Universidad de Murcia, Departamento de Histología e Histopatología, 2025) Ding Yisong; Li Xiaoming; Qi Ruixing; Su Yingshi; Wang Xiaoli; Biología Celular e HistologíaBackground and Aims. This study aimed to investigate the mechanism and efficacy of chelerythrine (CHE) in treating carbon tetrachloride (CCl4)-induced liver fibrosis, with a particular focus on the nuclear factor-erythroid-related factor-2 (Nrf2) and nuclear factor-kappa-B (NF-κB) signaling pathways. Methods. Mice were induced with CCl4 for eight weeks and categorized into the control group, CCl4 model group, and CHE low (7 mg/kg/d, ig,), medium (14 mg/kg/d, ig), and high-dose (28 mg/kg/d, ig) groups with 10 animals in each group. Following CHE treatment, liver sample morphology was assessed using multiple immunohistochemistry, and serum biochemical indicators were measured. ELISA was used to determine IL-10, IL-1β, and TNF-α contents. Western blotting and RT-PCR were employed to analyze protein and mRNA levels of α-SMA, Col-I, fibronectin, Nrf2, HO-1, NQO1, GCLc, GCLm, NF-κB, p-NF-κB, IκBα, and p-IκBα. Nrf2 knockout mice were used to assess the impact of CHE on the Nrf2 signaling pathway. Results. The findings demonstrated that CHE significantly ameliorated oxidative damage, inflamma-tory response, and liver fibrosis in CCl4-induced mice. CHE treatment increased Nrf2 expression and its target proteins, including HO-1 and GCLc, an effect not observed in Nrf2 knockout mice. In addition, CHE reduced NF-κB expression levels. Conclusions. These results suggest that CHE can alleviate liver fibrosis in CCl4-induced mice by modulating NF-κB/IκBα and Nrf2 signaling pathways. These findings propose CHE as a potential novel anti-liver fibrosis drug
- PublicationOpen AccessLiver fibrosis, the hepatic stellate cell and tissue inhibitors of metalloproteinases(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) McCrudden, R.; Iredale, J. P.Liver fibrosis occurs as a consequence of net accumulation of matrix proteins (especially collagen types I and III) in response to liver injury. The pathogenesis of liver fibrosis is underpinned by the activation of hepatic stellate cells (HSC) to a myofibroblast like phenotype with a consequent increase in their synthesis of matrix proteins such as interstitial collagens that characterise fibrosis. In addition to this there is increasing evidence that liver fibrosis is a dynamic pathologic process in which altered matrix degradation may also playa major role. Extracellular degradation of matrix proteins is regulated by matrix metalloproteinases (MMPS) - produced by HSC - which in turn are regulated by several mechanisms which include regulation at the level of the gene (transcription and proenzyme synthesis), cleavage of the proenzyme to an active form and specific inhibition of activated forms by tissue inhibitors of metalloproteinases (TIMPS). Insights gained into the molecular regulation of HSC activation will lead to therapeutic approaches in treatment of hepatic fibrosis in the future , and could lead to reduced morbidity and mortality in patients with chronic liver injury .
- PublicationOpen AccessLiver fibrosis: a dynamic and potentially reversible process(Murcia : F. Hernández, 2010) Povero, Davide; Busletta, Chiara; Novo, Erica; Valfrè di Bonzo, Lorenzo; Cannito, Stefania; Paternostro, Claudia; Parola, MaurizioIn any chronic liver disease (CLDs), whatever the aetiology, reiteration of liver injury results in persisting inflammation and progressive fibrogenesis, with chronic activation of the wound healing response in CLDs, representing a major driving force for progressive accumulation of ECM components, eventually leading to liver cirrhosis. Cirrhosis is characterized by fibrous septa dividing the hepatic parenchyma into regenerative pseudo-lobules, as well as by extensive changes in vascular architecture, the development of portal hypertension and related complications. Liver fibrogenesis (i.e., the dynamic process leading to increased deposition of ECM and much more) can lead to different patterns of fibrosis and is sustained by myofibroblast-like cells (MFs) of different origin, with activated hepatic stellate cells (HSC/MFs) being the major cell type involved. Major pro-fibrogenic mechanisms also include oxidative stress, as well as derangement of epithelial-mesenchymal interactions and, as recently suggested, the process of epithelial to mesenchymal transition (EMT). Liver fibrosis has been considered traditionally as an irreversible process but experimental and clinical literature data published in the last decade have suggested that both the removal of the aetiological agent or condition, as well as an effective therapy, can result in significant regression of liver fibrosis. This is usually associated, particularly in animal models, with induction of apoptosis in MFs but, unfortunately, human HSC/MFs are much more resistant to apoptosis than murine MFs. However, clinical studies provided no unequivocal evidence for a complete reversal of cirrhosis or a significant reversal of vascular changes in conditions of established cirrhosis.
- PublicationOpen AccessNuclear localization of TRK-A in liver cells(Murcia : F. Hernández, 2008) Bonacchi, Andrea; Taddei, María Leticia; Petrai, LLaria; Efsen, Eva; DeFranco, Raffaella; Nosi, Daniele; Torcia, María; Rosini, Paolo; Formigli, Lucía; Rombouts, Krista; Zecchi, Sandra; Milani, Stefano; Pinzani, Massimo; Laffi, Giacomo; Marra, FabioThe liver represents a site of expression of neurotrophins and their receptors. We have characterized the expression and intracellular localization of the nerve growth factor (NGF) receptor, Trk-A, in liver cells in vivo and in vitro. In both normal and fibrotic liver tissue, Trk-A immunostaining was present in different cell types, including parenchymal cells and cells of the inflammatory infiltrate. In hepatocytes and activated stellate cells (HSC), Trk-A showed a predominant nuclear localization, both in the presence and absence of injury. In cultured HSC, Trk-A was found to be functional, because exposure of the cells to recombinant NGF resulted in stimulation of cell migration and activation of intracellular signaling pathways, including Ras-ERK and PI3K/Akt. Remarkably, in cultured HSC, Trk-A staining was found constitutively in the nucleus. In these cells, Trk-A could be stained only by antibodies directed against the intracellular domain but not by those recognizing the extracellular portion of Trk-A suggesting that the intracellular portion of the receptor is the major determinant of nuclear Trk-A staining. In contrast to HSC, freshly isolated hepatocytes did not show any nuclear localization of the intracellular portion of Trk-A. In pheocromocytoma cells, nuclear staining for Trk-A was not present in conditions of serum deprivation, but could be induced by exposure to NGF or to a mixture of soluble mediators. We conclude that nuclear localization of the intracellular domain of Trk-A is observed constitutively in liver cells such as HSC, while in other cell types it could be induced in response to soluble factors.
- PublicationOpen AccessPlasma Golgi protein 73 levels predict prognosis of HCV-related hepatic fibrosis(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Liu, Lingdi; Al-Dhamin, Zaid; Yuan, Xiwei; Cui, Luyao; Yang, Yang; Zhao, Wen; Zhang, Ying; Fu, NaObjectives. To explore the correlation between plasma Golgi protein 73 (GP73) and progression of hepatitis C virus (HCV)-induced hepatic fibrosis. Methods. A total of 232 subjects of chronic hepatitis C and 31 healthy controls were enrolled from the Third Hospital of Hebei Medical University from January 2010 to September 2018. The plasma GP73 levels were detected by ELISA. Liver tissue sections stained with hematoxylin and eosin and Masson-trichrome were examined under a light microscope based on the METAVIR scoring system and "Beijing classification (P- I-R)". The correlation analysis and receiver operating characteristic (ROC) curve were performed to analyze the diagnostic efficiency of plasma GP73, APRI, and FIB-4 for staging hepatic fibrosis and predicting the disease progression. Results. The plasma GP73 levels were increased with the progression of liver fibrosis, and GP73 concentrations in healthy controls, HCV patients with fibrosis stage 1, 2, 3 and 4 were 94.82, 151.3, 157.9, 181.7 and 208.5 ng/ml, respectively. According to “Beijing classification”, There was a statistically significant difference in plasma GP73 concentrations between patients in the progression and regressive / indeterminate group (177.08 vs 154.00 ng/ml , P = 0.007).The area under the ROC curves (AUCs) of GP73, APRI, and FIB-4 for diagnosis of liver cirrhosis were 0.89, 0.77, and 0.82, respectively, and GP73 for progressive fibrosis was 0.73. The plasma GP73 levels were significantly positively correlated with hepatic inflammation, serum ALT, and negatively correlated with albumin levels. Conclusion. The plasma GP73 might be a potential biomarker for staging liver fibrosis, and could predict regression or progression of HCV-related liver fibrosi
- PublicationOpen AccessProtective effect of alpha-mangostin on thioacetamide-induced liver fibrosis in rats as revealed by morpho-functional analysis(Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Rodniem, Siripa; Tiyao, Vilailak; Nilbu nga, Cheng; Poonkhum, Raksawan; Pongmayteegul, Sirinun; Pradidarcheep, WisuitLiver fibrosis is an excessive accumulation of scar tissue resulting from inflammation and cell death. Thioacetamide (TAA) is a well-known hepatotoxin that induces liver fibrosis. A marker of injured hepatocytes is transforming growth factor-beta 1 (TGF-β1), while alpha-smooth muscle actin (α-SMA) and tissue inhibitor of metalloproteinase 1 (TIMP-1) are markers of activated hepatic stellate cells. Alpha-mangostin, a major xanthone derivative from the mangosteen pericarp, has been shown to have anti-oxidant and anti-inflammatory activities. The objective of this study was to determine whether alpha-mangostin has a protective effect on TAA-induced liver fibrosis in rats. The rats were treated by intraperitoneal injection of compounds for eight weeks. For the control group a mixture of dimethyl sulfoxide and phosphate buffered saline was administered. Two hundred mg/kg BW of TAA was administered three times weekly. Alpha-mangostin was administered at 5 mg/kg BW and silymarin at 100 mg/kg BW, both twice weekly. TAA induced histologically recognizable liver damage and fibrosis, as anticipated. Furthermore, it increased immunohistochemically detectable TGF-β1, α-SMA, and TIMP-1. Coadministration of alpha-mangostin or silymarin with TAA prevented or ameliorated the effects of TAA administration alone. The anti-fibrotic effect of alphamangostin was stronger than that of silymarin.
- PublicationOpen AccessResveratrol can prevent CCl4-induced liver injury by inhibiting Notch signaling pathway(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Tanriverdi, Gamze; Kaya-Dagistanli, Fatma; Ayla, Sule; Demirci, Sibel; Eser, Mediha; Unal, Seda; Cengiz, Mujgan; Oktar, HuseyinWe investigated whether Notch signaling was increased in an experimental liver fibrosis model and examined the effects of resveratrol on Notch expression. Rats were divided into four groups: the control group, injected with physiological saline; the CCl 4 group; the CCl 4 plus resveratrol group; and the resveratrol group. After treatment, immunostaining was performed to detect Notch1, Notch3, Notch4, transforming growth factor (TGF)-beta, alpha-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and proliferating cell nuclear antigen (PCNA), and TUNEL assays were performed to evaluate apoptosis. Sirius red staining was used to detect fibrosis. Samples were also biochemically evaluated for glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), lipid peroxidation, and protein oxidation. GSH, GPx, and catalase activities were significantly decreased (p<0.001) in the CCl 4 group. Distinct collagen accumulation was detected around the central vein and portal areas, and numbers of Notch1-, Notch3-, and Notch4-positive cells were significantly increased (p<0.001) in fibrotic areas in the CCl 4 group. Increased expression of Notch proteins in fibrotic areas may support the role of Notch in mediating signaling associated with liver fibrosis through activation of hepatic stellate and progenitor cells. In contrast, resveratrol prevented liver fibrosis by decreasing lipid peroxidation and may be effective for inhibiting Notch signaling.
- PublicationOpen AccessRole of nitric oxide in the regulation of fibrogenic factors in experimental liver fibrosis in mice(Murcia: F. Hernández, 2011) Leung, Tung-Ming; Fung, Man-Lung; Liong, Emily C.; Lau, Thomas Y.H.; Nanji, Amin A.; Tipoe, George L.Previously, we have shown that an increased expression level of iNOS but a reduction in the expression of eNOS is associated with increased oxidative stress markers in CCl4-induced experimental liver fibrosis. The present study aimed to investigate the effect of L-arginine and 5-methylisothiourea hemisulfate (SMT) in the expression of profibrogenic factors in chronic liver injury. ICR mice were treated with CCl4 with or without treatment of L-arginine, an NO donor, or SMT, an iNOS inhibitor. The expression of matrix metalloptroteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), α-smooth muscle actin (α- SMA), tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) were investigated by RTPCR. The activity of the MMP-2 and MMP-9 were measured by zymography. Our results showed that CCl4- treated mice showed significant up-regulation of expression of pro-fibrogenic factors, TNF-α and COX-2. Treatment with L-arginine or SMT showed a significant reduction in CCl4-induced expression of these profibrogenic factors, TNF-α and COX-2. In conclusion, both SMT and L-arginine effectively attenuated the progression of CCl4-induced liver fibrosis. SMT suppresses iNOS mediated NO production. However, Larginine augments NO production. The similar effect of the two drugs on liver fibrosis indicates that there may be two distinct pathways of NOS mediated fibrogenesis in chronic liver injury by iNOS and eNOS. Our results suggest that eNOS-mediated liver fibrogenesis may play a more important role than that of iNOS in chronic liver injury. Taken together, these results support the contention that NO plays an active role in the progression of liver fibrosis and hepatocellular damage.
- PublicationOpen AccessTissue remodelling in liver diseases(Murcia : F. Hernández, 2003) Giannelli, G.; Quaranta, V.; Antonaci, S.Tissue remodelling is a dynamic process that occurs during fetal or adult life and involves a modification of the original organization and function of a tissue. Tissue remodelling is observed in physiological and pathological conditions such as during wound healing or in the mammary gland during the course of pregnancy. In this review we will discuss the remodelling occurring in the liver as a consequence of chronic inflammation, as observed in chronic hepatitis, or as a consequence of hepatocellular carcinoma (HCC) progression in more detail. We will consider how altered deposition and turn-over of extracellular matrix (ECM) proteins could lead to development of liver fibrosis, and how the exacerbation of fibrosis could underlie the development of cirrhosis. The involvement of inflammatory and anti-inflammatory cytokines commonly used as therapeutic agents, such as Interferon-a, is then evaluated with a particular focus on modulation of ECM proteolysis. Finally, we analyze the role of alterations of the surrounding microenvironment including ECM, growth factors, cytokines and membrane receptors for ECM ligands in the development of HCC and in its invasive behaviour.
- PublicationOpen AccessTraditional Chinese medicine Yiqi Huoxue recipe attenuates hepatic fibrosis via YAP/TAZ signaling(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Zhao, Wen; Zhang, Xiaoxiao; Hou, Mengmeng; Zhang, Yuguo; Tang, Yuhui; Li, Lu; Dong, Shiming; Liu, Lingdi; Zhao, Dandan; Li, Wencong; Nan, YueminBackground/Aims. The Yiqi Huoxue (YQHX) recipe has been shown to attenuate liver fibrosis, but precise mechanisms have not yet been elucidated. Recently, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling has been implicated in liver fibrogenesis. This study investigated whether the YAP/TAZ signaling is involved in the therapeutic effect of YQHX on hepatic fibrosis. Materials and Methods. Wistar rats were used to generate a model of carbon tetrachloride (CCl 4)-induced liver fibrosis. Chronic hepatitis B (CHB) patients with liver fibrosis were enrolled and assigned to receive either nucleoside/nucleotide analogues (NAs) or NAs plus YQHX. Histology, immunohistochemistry, qRT-PCR, and western blotting were conducted to mechanistically assess the therapeutic effects of YQHX on liver fibrosis. Results. YQHX markedly alleviated morphological alterations in CCl 4-induced liver fibrosis and decreased markers of hepatic fibrosis in rats. Furthermore, YQHX significantly suppressed CCl 4-meidated activation of the transforming growth factor-beta (TGF-β)/Smad signaling pathway. Notably, CCl 4 induced up-regulation of YAP, TAZ, and connective tissue growth factor (CTGF), which were significantly abrogated by YQHX. Consistent with the above major findings in rats, CHB patients treated with NAs plus YQHX had greater improvement in liver fibrosis than those given NAs alone (71.4% vs. 28.6%; P=0.057). In addition, hepatic and plasma levels of YAP were significantly decreased after YQHX treatment in CHB patients with liver fibrosis. Conclusion. YAP/TAZ signaling plays a role, at least in part, in the anti-fibrotic activity of YQHX. The findings may help to better understand the mechanisms of YQHX in the treatment of liver fibrosis