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1
Wang, Pei-Wen, Tung-Yi Lin, Pei-Ming Yang, Chau-Ting Yeh, and Tai-Long Pan. "Hepatic Stellate Cell Modulates the Immune Microenvironment in the Progression of Hepatocellular Carcinoma." International Journal of Molecular Sciences 23, no. 18 (September 15, 2022): 10777. http://dx.doi.org/10.3390/ijms231810777.
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Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently modulate extracellular remodeling, cell invasion, macrophage conversion, and cancer deterioration. In this regard, the tumor microenvironment created by activated HSC plays a critical role in mediating pathogenesis and immune escape during HCC progression. Herein, intermediately differentiated human liver cancer cell line (J5) cells were co-cultured with HSC-conditioned medium (HSC-CM); changes in cell phenotype and cytokine profiles were analyzed to assess the impact of HSCs on the development of hepatoma. The stage of liver fibrosis correlated significantly with tumor grade, and the administration of conditioned medium secreted by activated HSC (aHSC-CM) could induce the expression of N-cadherin, cell migration, and invasive potential, as well as the activity of matrix metalloproteinases in J5 cells, implying that aHSC-CM could trigger the epithelial-mesenchymal transition (EMT). Next, the HSC-CM was further investigated and network analysis indicated that specific cytokines and soluble proteins, such as activin A, released from activated HSCs could remarkably affect the tumor-associated immune microenvironment involved in macrophage polarization, which would, in turn, diminish a host’s immune surveillance and drive hepatoma cells into a more malignant phenotype. Together, our findings provide a novel insight into the integral roles of HSCs to enhance hepatocarcinogenesis through their immune-modulatory properties and suggest that HSC may serve as a potent target for the treatment of advanced HCC.
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Mailloux, Adam, and Pearlie Epling-Burnette. "Collagen matrix deposition by hepatic stellate cells protects hepatocellular carcinoma from NK-mediated cytotoxicity (P2013)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 53.7. http://dx.doi.org/10.4049/jimmunol.190.supp.53.7.
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Abstract Liver fibrosis (LF), a leading risk factor for hepatocellular carcinoma (HCC), is caused by collagen-producing hepatic stellate cells (HSC) activated during chronic inflammation secondary to hepatitis-C infection, or alcohol liver disease (ALD). NK cells promote disease resolution via RAE1-dependant HSC clearance. A defect in NK function by an ill-defined mechanism contributes to a pro-fibrotic response. Using an engineered bioartifical collagen matrix, the expression of inhibitory leukocyte associated IgG-like receptor-1 (LAIR-1) was increased on dividing NK cells and IL-2-induced NK proliferation was inhibited. Thus, we hypothesized that the accumulation of HSC-derived collagen directly inhibits NK activity and protects both HSC and HCC from innate clearance. We found that deposition of native collagen matrix for 72h protected HSCs from NK lysis in Cr51 cytotoxicity assays. A HCC cell line (HEPG2), which produced no collagen when cultured in the absence of HSCs, was susceptible to activated NK killing and was unaffected by collagenase. To test if HSC-derived collagen protects HEPG2 cells, the populations were differentially labeled with ipophilic dyes and co-cultured for 72h for use in flow-based assays. Collagen matrix protected both targets, while collagenase pretreatment restored NK sensitivity. These results suggest that HSC-derived collagen may contribute to NK dysfunction in LF and HCC, and identifies LAIR-1 as a potential mediator of tumor-induced immune suppression.
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Jia, Shu-Qin, Jian-Jun Ren, Pei-De Dong, and Xing-Kai Meng. "Probing the Hepatic Progenitor Cell in Human Hepatocellular Carcinoma." Gastroenterology Research and Practice 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/145253.
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Objective. The intrahepatic stem cells, also known as hepatic progenitor cells (HPCs), are able to differentiate into hepatocytes and bile duct epithelia. By exposure of different injuries and different hepatocarcinogenic regimens, the mature hepatocytes can no longer effectively regenerate; stem cells are involved in the pathogenesis of hepatocellular carcinoma.Methods. Immunohistochemistry was performed on 107 paraffin-embedded hepatocellular carcinoma specimens with the marker of hepatocyte and hepatocellular carcinoma (HepPar1), biliary differentiation (CK7,CK19), haemopoietic stem cell (HSC) (c-kit/CD117, CD34, and Thy-1/CD90), HPC specific markers (OV-6), and Ki-67, p53 protein.Results. HPCs can be identified in the tumor nodules, around the edge of tumor nodules, and in the portal tracts of the paracirrhosis nodules being positive in HepPar1, CK7, CK19, and OV-6, but they failed to immunostain with CD117, CD34, and CD90. The HPCs positive in Ki-67 are observed in the tumor and paracirrhosis tissues. In 107 specimens, 40.2% (43/107) HCC tissues expressed p53 protein, lower than that of the HPCs around the tumor nodules (46.7%, 50/107) and much higher than that of the HPCs around the paracirrhosis nodules (8.41%, 9/107).Conclusion. Human hepatocellular carcinogenesis may be based on transformation of HPCs, not HSCs, through the formation of the transitional cells (hepatocyte-like cells and bile ductal cells).
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Wu, Mengna, Huajie Miao, Rong Fu, Jie Zhang, and Wenjie Zheng. "Hepatic Stellate Cell: A Potential Target for Hepatocellular Carcinoma." Current Molecular Pharmacology 13, no. 4 (November 2, 2020): 261–72. http://dx.doi.org/10.2174/1874467213666200224102820.
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: Liver cancer is a leading cause of cancer-related death worldwide, in which hepatocellular carcinoma (HCC) accounts for the majority. Despite the progression in treatment, the prognosis remains extremely poor for HCC patients. The mechanisms of hepatocarcinogenesis are complex, of which fibrosis is acknowledged as the pre-cancerous stage of HCC. Approximately, 80-90% of HCC develops in the fibrotic or cirrhotic livers. Hepatic stellate cells (HSCs), the main effector cells of liver fibrosis, could secret various biological contents to maintain the liver inflammation. By decades, HSCs are increasingly correlated with HCC in the tumor microenvironment. : In this review, we summarized the underlying mechanisms that HSCs participated in the genesis and progression of HCC. HSCs secrete various bioactive contents and regulate tumor-related pathways, subsequently contribute to metastasis, angiogenesis, immunosuppression, chemoresistance and cancer stemness. The study indicates that HSC plays vital roles in HCC progression, suggesting it as a promising therapeutic target for HCC treatment.
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Liu, Man, Jingying Zhou, Xiaoyu Liu, Yu Feng, Weiqin Yang, Feng Wu, Otto Ka-Wing Cheung, et al. "Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma." Gut 69, no. 2 (May 10, 2019): 365–79. http://dx.doi.org/10.1136/gutjnl-2018-317257.
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ObjectiveHepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy.DesignFunctional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined.ResultsAccumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model.ConclusionOur results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.
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Subramanian, Pallavi, Jochen Hampe, Frank Tacke, and Triantafyllos Chavakis. "Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)." International Journal of Molecular Sciences 23, no. 13 (June 23, 2022): 6996. http://dx.doi.org/10.3390/ijms23136996.
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The prevalence of nonalcoholic fatty liver disease (NAFLD), recently also re-defined as metabolic dysfunction associated fatty liver disease (MAFLD), is rapidly increasing, affecting ~25% of the world population. MALFD/NAFLD represents a spectrum of liver pathologies including the more benign hepatic steatosis and the more advanced non-alcoholic steatohepatitis (NASH). NASH is associated with enhanced risk for liver fibrosis and progression to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSC) activation underlies NASH-related fibrosis. Here, we discuss the profibrogenic pathways, which lead to HSC activation and fibrogenesis, with a particular focus on the intercellular hepatocyte–HSC and macrophage–HSC crosstalk.
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Wang, Wen-Hung, Kuo-Yu Hsuan, Ling-Ya Chu, Chia-Ying Lee, Yu-Chang Tyan, Zong-Shiow Chen, and Wan-Chi Tsai. "Anticancer Effects of Salvia miltiorrhiza Alcohol Extract on Oral Squamous Carcinoma Cells." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/5364010.
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Researchers have reported significant effects from Danshen (Salvia miltiorrhiza) in terms of inhibiting tumor cell proliferation and promoting apoptosis in breast cancer, hepatocellular carcinomas, promyelocytic leukemia, and clear cell ovary carcinomas. Here we report our data indicating that Danshen extracts, especially alcohol extract, significantly inhibited the proliferation of the human oral squamous carcinoma (OSCC) cell lines HSC-3 and OC-2. We also observed that Danshen alcohol extract activated the caspase-3 apoptosis executor by impeding members of the inhibitor of apoptosis (IAP) family, but not by regulating the Bcl-2-triggered mitochondrial pathway in OSCC cells. Our data also indicate that the extract exerted promising effects in vivo, with HSC-3 tumor xenograft growth being suppressed by 40% and 69% following treatment with Danshen alcohol extract at 50 and 100 mg/kg, respectively, for 34 days. Combined, our results indicate appreciable anticancer activity and significant potential for Danshen alcohol extract as a natural antioxidant and herbal human oral cancer chemopreventive drug.
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MAN, LIU, Jingying Zhou, John Wong, Anthony W. H. Chan, Zhiwei Chen, and Alfred S. L. Cheng. "Delineating the epigenetic regulation of myeloid derived suppressor cell generation in hepatocellular carcinoma associated with cirrhosis." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 205.14. http://dx.doi.org/10.4049/jimmunol.198.supp.205.14.
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Abstract Hepatocellular carcinoma (HCC) is the most common liver tumor with dismal prognosis. Since most liver tumors arise in a context of chronic inflammation associated with fibrosis, tumor microenvironment plays a critical role in liver carcinogenesis. Myeloid derived suppressor cell (MDSC) is a population of immature myeloid cells that undermine immune surveillance and facilitate tumor immune escape. As a key driver of liver fibrosis, activated hepatic stellate cell (HSC) has been recently shown to induce MDSC generation through cell-cell contact and/or secreted soluble factors. Given the crucial role of epigenetics in cell lineage specification, we aim to elucidate the chromatin regulation of MDSC in the immunosuppressive liver tumor microenvironment. Using human PBMCs from healthy donors, we have successfully recapitulated the immunomodulatory effect of HSCs on monocytic MDSC generation. Comprehensive epigenetic drug screening and expression analysis indicated that accumulation of histone H3 lysine 27 acetylation (H3K27ac), an active enhancer histone mark, is involved in the process of HSC-induced MDSC generation. We further demonstrated that inhibitors of BET family, which disrupts BRD4 association with H3K27ac-enriched active enhancers, abrogates MDSC generation. These results highlight the importance of epigenetic regulation in MDSC accumulation in the fibrotic microenvironment. Ongoing work is directed towards the identification of HSC-activated enhancers that orchestrate MDSC identity and functions. As we showed high level of monocytic MDSC accumulation in patients with cirrhotic HCC, our study may provide novel therapeutic targets to restore effective anti-tumor immune response in this dreadful disease.
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Iwahashi, Shuichi, Mitsuo Shimada, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Yu Saito, Shinichiro Yamada, and Feng Rui. "The effect of hepatic stellate cells on hepatocellular carcinoma progression." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 265. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.265.
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265 Background: The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Some manuscripts mentioned that activated HSCs predicted prognoses of hepatocellular carcinoma. The aim of this study is to investigate the effect of HSCs and the role of IL-6 / Stat3 pathway on HCC progression. Methods: HCC cells (Hep G2 and Huh 7) were co-cultured with HSC (LX2 and Li90). The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44), TGF-b and p-STAT3 of cancer cells were evaluated. Then the IL-6 neutralization was performed during HCC cells and HSCs co-culture. The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44) and p-STAT3 of cancer cells were evaluated. Results: Co-culture with hepatic stellate cell increased cancer cell viability and migration ability. The expression of E-cadherin, EpCAM and CD44 of cancer cells also increased after co-culture with HSCs. The IL-6 expression and secretion of HSCs were elevated by cancer cell stimulation. The over-expressed IL-6 activated STAT3 of cancer cell showed as the level of phosphorylated STAT3 increased. Neutralized IL-6 during co-culture significantly decrease the viability and migration ability of cancer cells. Also, the expression of E-cadherin, EpCAM and CD44 of cancer cells decreased. Conclusions: HSCs might promote HCC progression through IL-6 / STAT3 pathway.
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Santamato, Angela, Emilia Fransvea, Francesco Dituri, Alessandra Caligiuri, Michele Quaranta, Tomoaki Niimi, Massimo Pinzani, Salvatore Antonaci, and Gianluigi Giannelli. "Hepatic stellate cells stimulate HCC cell migration via laminin-5 production." Clinical Science 121, no. 4 (April 28, 2011): 159–68. http://dx.doi.org/10.1042/cs20110002.
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Activated HSCs (hepatic stellate cells) are the main source of extracellular matrix proteins present in cirrhotic liver on which HCC (hepatocellular carcinoma) commonly develops. HCC cells behave differently according to differences in the surrounding microenvironment. In the present study, we have investigated a mechanism whereby HSCs modulate the migratory activity of HCC cells. We used primary cultures of human HSCs to investigate their effect on Hep3B, Alexander, HLE and HLF HCC cells. The expression of Ln-5 (laminin-5) was documented at transcript and protein levels both in vitro and in vivo. HCC cells strongly adhere, migrate and spread in the presence of HSC-conditioned medium and of co-culture. HSCs produce and secrete Ln-5 in the CM (conditioned medium). The electrophoretic pattern of secreted Ln-5 is consistent with that of a migratory substrate, showing the presence of the γ2x fragment. Blocking antibodies against Ln-5 inhibit HCC migration in the presence of HSC-CM. HCC cells migrate very poorly in the presence of Ln-5 immunodepleted HSC-CM. HCC migration in the presence of HSCs is dependent on the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathway, but not the PI3K (phosphoinositide 3-kinase)/Akt pathway. HSC-CM, as well as Ln-5, activates the MEK/ERK but not the PI3K/Akt pathway. In human HCC tissues, Ln-5 is mainly distributed along α-SMA (smooth muscle actin)-positive cells, whereas in peritumoural tissues, Ln-5 is absent. HSCs stimulate HCC migration via the production and secretion of Ln-5.
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Cho, Yuri, Min Ji Park, Koeun Kim, Jae-Young Park, Jihye Kim, Wonjin Kim, and Jung-Hwan Yoon. "Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drive the Progression of Hepatocellular Carcinoma." International Journal of Molecular Sciences 21, no. 2 (January 11, 2020): 472. http://dx.doi.org/10.3390/ijms21020472.
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Abstract: Background: Crosstalk between tumors and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). However, there is little existing information about the key signaling molecule that modulates tumor-stroma crosstalk. Methods: Complementary DNA (cDNA) microarray analysis was performed to identify the key molecule in tumor-stroma crosstalk. Subcutaneous xenograft in vivo murine model, immunoblotting, immunofluorescence, and real-time polymerase chain reaction using HCC cells and tissues were performed. Results: The key molecule, regenerating gene protein-3A (REG3A), was most significantly enhanced when coculturing HCC cells and activated human hepatic stellate cells (HSCs) (+8.2 log) compared with monoculturing HCC cells using cDNA microarray analysis. Downregulation of REG3A using small interfering RNA significantly decreased the proliferation of HSC-cocultured HCC cells in vitro and in vivo, and enhanced deoxycholic acid-induced HCC cell apoptosis. Crosstalk-induced REG3A upregulation was modulated by platelet-derived growth factor ββ (PDGF-ββ) in p42/44-dependent manner. REG3A mRNA levels in human HCC tissues were upregulated 1.8-fold compared with non-tumor tissues and positively correlated with PDGF-ββ levels. Conclusions: REG3A/p42/44 pathway/PDGF-ββ signaling plays a significant role in hepatocarcinogenesis via tumor-stroma crosstalk. Targeting REG3A is a potential novel therapeutic target for the management of HCCs by inhibiting crosstalk between HCC cells and HSCs.
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Dhar, Debanjan, Jacopo Baglieri, Tatiana Kisseleva, and David A. Brenner. "Mechanisms of liver fibrosis and its role in liver cancer." Experimental Biology and Medicine 245, no. 2 (January 2020): 96–108. http://dx.doi.org/10.1177/1535370219898141.
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Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic process that involves cross-talk between parenchymal cells (hepatocytes), hepatic stellate cells, sinusoidal endothelial cells and both resident and infiltrating immune cells. In this review, we focus on key cell-types that contribute to liver fibrosis, cytokines, and chemokines influencing this process and what it takes for fibrosis to regress. We discuss how mitochondria and metabolic changes in hepatic stellate cells modulate the fibrogenic process. We also briefly review how the presence of fibrosis affects development of hepatocellular carcinoma. Impact statement Advanced liver fibrosis results in cirrhosis, portal hypertension, and liver failure and often requires liver transplantation. Advanced liver fibrosis and cirrhosis are also major risk factors for hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) play a pivotal role in the pathogenesis of liver fibrosis. In this review, we summarize the basic mechanisms that influence liver fibrosis development and how oxidative stress, mitochondrial dysfunction, and metabolic remodeling modulate HSC activation and indicate areas of potential therapeutic intervention.
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Jeng, Kuo-Shyang, Ssu-Jung Lu, Chih-Hsuan Wang, and Chiung-Fang Chang. "Liver Fibrosis and Inflammation under the Control of ERK2." International Journal of Molecular Sciences 21, no. 11 (May 27, 2020): 3796. http://dx.doi.org/10.3390/ijms21113796.
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Chronic liver injury could lead the formation of liver fibrosis, eventually some would develop to hepatocellular carcinoma (HCC), one of the leading malignancies worldwide. The aim of the study is to dissect the role of extracellular signal-regulated kinase 2 (ERK2) signaling in liver fibrosis and inflammation. The choline-deficient, ethionine-supplemented (CDE) diet could lead to fatty livers and generate oval cells, activate hepatocyte stellate cell (HSC) and recruit immune cells as the liver fibrosis model mice. WT and ERK2 deficient (ERK2−/−) mice were compared in terms of liver weight/body weight, liver function, liver fibrosis markers and the differential gene expression in hepatotoxicity. ERK2−/− mice display the less degree of liver fibrosis when compared to WT mice. The protein level of alpha smooth muscle (α-SMA) was reduced and several hepatocellular carcinoma-related genes such as MMP9, FoxM1 were down-regulated. In addition, the cell proliferation and the percentages of activated T cells were reduced in ERK2−/− mice upon liver injury. Therefore, ERK2 plays an important role in regulating liver cirrhosis and inflammation.
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Fujii, Hideki, and Norifumi Kawada. "The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease." International Journal of Molecular Sciences 21, no. 11 (May 29, 2020): 3863. http://dx.doi.org/10.3390/ijms21113863.
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Nonalcoholic fatty liver disease (NAFLD) consists of the entire spectrum of fatty liver disease in patients without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to cirrhosis, with NASH recently shown as an important cause of hepatocellular carcinoma (HCC). There is a close relationship between insulin resistance (IR) and NAFLD, with a five-fold higher prevalence of NAFLD in patients with type 2 diabetes (T2DM) compared to that in patients without T2DM. IR is involved in the progression of disease conditions such as steatosis and NASH, as well as hepatic fibrosis progression. The mechanisms underlying these processes involve genetic factors, hepatic fat accumulation, alterations in energy metabolism, and inflammatory signals derived from various cell types including immune cells. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is the hepatic stellate cell (HSC). HSC activation by IR involves “direct” and “indirect” pathways. This review will describe the molecular mechanisms of inflammation and hepatic fibrosis in IR, the relationship between T2DM and hepatic fibrosis, and the relationship between T2DM and HCC in patients with NAFLD.
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Niu, Gengming, Xiaotian Zhang, Runqi Hong, Ximin Yang, Jiawei Gu, Tao Song, Zhiqing Hu, et al. "GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells." Open Medicine 16, no. 1 (January 1, 2021): 1459–71. http://dx.doi.org/10.1515/med-2021-0344.
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Abstract Introduction Gap junction protein, alpha 1 (GJA1), which is correlated with recurrences and unfavorable prognoses in hepatocellular carcinomas (HCCs), is one of the specific proteins expressed by activated hepatic stellate cells (HSCs). Methods Expression of GJA1 was compared between HCCs and nontumor tissues (NTs), between hepatic cirrhosis and NTs, and between primary and metastatic HCCs using transcriptomic datasets from the Gene Expression Omnibus and the Integrative Molecular Database of Hepatocellular Carcinoma. The in vitro activities of GJA1 were investigated in cultured HSCs and HCC cells. The underlying mechanism was characterized using Gene Set Enrichment Analysis and validated by western blotting. Results The expression of GJA1 was significantly increased in HCCs and hepatic cirrhosis compared to that in NTs. GJA1 was also overexpressed in pulmonary metastases from HCCs when compared with HCCs without metastasis. Overexpression of GJA1 promoted while knockdown of GJA1 inhibited proliferation and transforming growth factor (TGF)-β-mediated activation and migration of cultured HSCs. Overexpression of GJA1 by lentivirus infection promoted proliferation and migration, while conditioned medium from HSCs overexpressing GJA1 promoted migration but inhibited proliferation of Hep3B and PLC-PRF-5 cells. Lentivirus infection with shGJA1 or conditioned medium from shGJA1-infected HSCs inhibited the proliferation and migration of HCCLM3 cells that had a high propensity toward lung metastasis. Mechanistically, GJA1 induced the epithelial–mesenchymal transition (EMT) in HSCs and HCCLM3 cells. Conclusion GJA1 promoted HCC progression by inducing HSC activation and the EMT in HSCs. GJA1 is potentially regulated by TGF-β and thus may be a therapeutic target to inhibit HCC progression.
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Liepelt, Anke, and Frank Tacke. "Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 2 (August 1, 2016): G203—G209. http://dx.doi.org/10.1152/ajpgi.00193.2016.
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The chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is constitutively expressed in healthy liver. However, its expression increases following acute or chronic liver injury. Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and malignant hepatocytes are important sources of SDF-1/CXCL12 in liver diseases. CXCL12 is able to activate two chemokine receptors with different downstream signaling pathways, CXCR4 and CXCR7. CXCR7 expression is relevant on LSEC, while HSC, mesenchymal stem cells, and tumor cells mainly respond via CXCR4. Here, we summarize recent developments in the field of liver diseases involving this chemokine and its receptors. SDF-1-dependent signaling contributes to modulating acute liver injury and subsequent tissue regeneration. By activating HSC and recruiting mesenchymal cells from bone marrow, CXCL12 can promote liver fibrosis progression, while CXCL12-CXCR7 interactions endorse proregenerative responses in chronic injury. Moreover, the SDF-1 pathway is linked to development of hepatocellular carcinoma (HCC) by promoting tumor growth, angiogenesis, and HCC metastasis. High hepatic CXCR4 expression has been suggested as a biomarker indicating poor prognosis of HCC patients. Tumor-infiltrating myeloid-derived suppressor cells (MDSC) also express CXCR4 and migrate toward CXCL12. Thus CXCL12 inhibition might not only directly block HCC growth but also modulate the tumor microenvironment (angiogenesis, MDSC), thereby sensitizing HCC patients to conventional or emerging novel cancer therapies (e.g., sorafenib, regorafenib, nivolumab, pembrolizumab). We herein summarize the current knowledge on the complex interplay between CXCL12 and CXCR4/CXCR7 in liver diseases and discuss approaches on the therapeutic targeting of these axes in hepatitis, fibrosis, and liver cancer.
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Seo, Hye-Young, So-Hee Lee, Eugene Han, Jae Seok Hwang, Sol Han, Mi Kyung Kim, and Byoung Kuk Jang. "Evogliptin Directly Inhibits Inflammatory and Fibrotic Signaling in Isolated Liver Cells." International Journal of Molecular Sciences 23, no. 19 (October 1, 2022): 11636. http://dx.doi.org/10.3390/ijms231911636.
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Chronic liver inflammation can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Kupffer cells (KC) secrete proinflammatory and fibrogenic cytokines in response to lipopolysaccharide (LPS), and so play an important role in liver inflammation, where they induce hepatocellular damage. LPS also activates hepatic stellate cells and induces extracellular matrix deposition. In this study, we used isolated primary KC, primary hepatocytes, and primary hepatic stellate cells (HSC) to investigate whether evogliptin directly inhibits inflammatory and fibrotic signaling. We found that evogliptin inhibited LPS-induced secretion of inducible nitric oxide synthase and transforming growth factor β (TGF-β) from KC. Moreover, evogliptin inhibited inflammatory mediator release from hepatocytes and hepatic stellate cell activation that were induced by KC-secreted cytokines. In hepatocytes, evogliptin also inhibited LPS-induced expression of proinflammatory cytokines and fibrotic TGF-β. In addition, evogliptin inhibited TGF-β-induced increases in connective tissue growth factor levels and HSC activation. These findings indicate that evogliptin inhibits inflammatory and fibrotic signaling in liver cells. We also showed that the inhibitory effect of evogliptin on inflammatory and fibrotic signaling is associated with the induction of autophagy.
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Weiskirchen, Ralf, and Frank Tacke. "Relevance of Autophagy in Parenchymal and Non-Parenchymal Liver Cells for Health and Disease." Cells 8, no. 1 (January 1, 2019): 16. http://dx.doi.org/10.3390/cells8010016.
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Autophagy is a highly conserved intracellular process for the ordered degradation and recycling of cellular components in lysosomes. In the liver, parenchymal cells (i.e., mainly hepatocytes) utilize autophagy to provide amino acids, glucose, and free fatty acids as sources of energy and biosynthesis functions, but also for recycling and controlling organelles such as mitochondria. Non-parenchymal cells of the liver, including endothelial cells, macrophages (Kupffer cells), and hepatic stellate cells (HSC), also employ autophagy, either for maintaining cellular homeostasis (macrophages, endothelium) or for providing energy for their activation (stellate cells). In hepatocytes, autophagy contributes to essential homeostatic functions (e.g., gluconeogenesis, glycogenolysis, fatty acid oxidation), but is also implicated in diseases. For instance, storage disorders (alpha 1 antitrypsin deficiency, Wilson’s disease), metabolic (non-alcoholic steatohepatitis, NASH), and toxic (alcohol) liver diseases may benefit from augmenting autophagy in hepatocytes. In hepatic fibrosis, autophagy has been implicated in the fibrogenic activation of HSC to collagen-producing myofibroblasts. In hepatocellular carcinoma (HCC), autophagy may contribute to tumor surveillance as well as invasiveness, indicating a dual and stage-dependent function in cancer. As many drugs directly or indirectly modulate autophagy, it is intriguing to investigate autophagy-targeting, possibly even cell type-directed strategies for the treatment of hereditary liver diseases, NASH, fibrosis, and HCC.
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An, Lingxuan, Ulrich Wirth, Dominik Koch, Malte Schirren, Moritz Drefs, Dionysios Koliogiannis, Hanno Niess, et al. "Metabolic Role of Autophagy in the Pathogenesis and Development of NAFLD." Metabolites 13, no. 1 (January 7, 2023): 101. http://dx.doi.org/10.3390/metabo13010101.
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Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins resulting from abnormal wound repair response and metabolic disorders. Various metabolic factors play crucial roles in the progression of NAFLD, including abnormal lipid, bile acid, and endotoxin metabolism, leading to chronic inflammation and hepatic stellate cell (HSC) activation. Autophagy is a conserved process within cells that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. Accumulating evidence has shown the importance of autophagy in NAFLD and its close relation to NAFLD progression. Thus, regulation of autophagy appears to be beneficial in treating NAFLD and could become an important therapeutic target.
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Ozutsumi, Takahiro, Tadashi Namisaki, Naotaka Shimozato, Kosuke Kaji, Yuki Tsuji, Daisuke Kaya, Yukihisa Fujinaga, et al. "Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis." International Journal of Molecular Sciences 21, no. 6 (March 21, 2020): 2164. http://dx.doi.org/10.3390/ijms21062164.
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Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-β1 and α1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice; combined treatment may represent a potential strategy against NASH.
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Teng, Kun-Yu, Juan M. Barajas, Peng Hu, Samson T. Jacob, and Kalpana Ghoshal. "Role of B Cell Lymphoma 2 in the Regulation of Liver Fibrosis in miR-122 Knockout Mice." Biology 9, no. 7 (July 8, 2020): 157. http://dx.doi.org/10.3390/biology9070157.
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MicroRNA-122 (miR-122) has been identified as a marker of various liver injuries, including hepatitis- virus-infection-, alcoholic-, and non-alcoholic steatohepatitis (NASH)-induced liver fibrosis. Here, we report that the extracellular miR-122 from hepatic cells can be delivered to hepatic stellate cells (HSCs) to modulate their proliferation and gene expression. Our published Argonaute crosslinking immunoprecipitation (Ago-CLIP) data identified several pro-fibrotic genes, including Ctgf, as miR-122 targets in mice livers. However, treating Ctgf as a therapeutic target failed to rescue the fibrosis developed in the miR-122 knockout livers. Alternatively, we compared the published datasets of human cirrhotic livers and miR-122 KO livers, which revealed upregulation of BCL2, suggesting its potential role in regulating fibrosis. Notably, ectopic miR-122 expression inhibited BCL2 expression in human HSC (LX-2) cells). Publicly available ChIP-seq data in human hepatocellular cancer (HepG2) cells and mice livers suggested miR-122 could regulate BCL2 expression indirectly through c-MYC, which was confirmed by siRNA-mediated depletion of c-MYC in Hepatocellular Carcinoma (HCC) cell lines. Importantly, Venetoclax, a potent BCL2 inhibitor approved for the treatment of leukemia, showed promising anti-fibrotic effects in miR-122 knockout mice. Collectively, our data demonstrate that miR-122 suppresses liver fibrosis and implicates anti-fibrotic potential of Venetoclax.
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Hsieh, Ching-Chuan, Chien-Hui Hung, Meihua Chiang, Yu-Chin Tsai, and Jie-Teng He. "Hepatic Stellate Cells Enhance Liver Cancer Progression by Inducing Myeloid-Derived Suppressor Cells through Interleukin-6 Signaling." International Journal of Molecular Sciences 20, no. 20 (October 13, 2019): 5079. http://dx.doi.org/10.3390/ijms20205079.
Full textAbstract:
The tumor microenvironment, which consists of fibroblasts, smooth muscle cells, endothelial cells, immune cells, epithelial cells, and extracellular matrices, plays a crucial role in tumor progression. Hepatic stellate cells (HSCs), a class of unique liver stromal cells, participate in immunomodulatory activities by inducing the apoptosis of effector T-cells, generation of regulatory T-cells, and development of myeloid-derived suppressor cells (MDSCs) to achieve long-term survival of islet allografts. This study provides in vitro and in vivo evidences that HSCs induce the generation of MDSCs to promote hepatocellular carcinoma (HCC) progression through interleukin (IL)-6 secretion. HSC-induced MDSCs highly expressed inducible nitric oxide synthase (iNOS) and arginase 1 mRNA and presented potent inhibitory T-cell immune responses in the tumor environment. Wild-type HSC-induced MDSCs expressed lower levels of CD40, CD86, and MHC II, and a higher level of B7-H1 surface molecules, as well as increased the production of iNOS and arginase I compared with MDSCs induced by IL-6-deficient HSCs in vitro. A murine-transplanted model of the liver tumor showed that HCCs cotransplanted with HSCs could significantly enhance the tumor area and detect more MDSCs compared with HCCs alone or HCCs cotransplanted with HSCs lacking IL-6. In conclusion, the results indicated that MDSCs are induced mainly by HSCs through IL-6 signaling and produce inhibitory enzymes to reduce T-cell immunity and then promote HCC progression within the tumor microenvironment. Therapies targeting the pathway involved in MDSC production or its immune-modulating pathways can serve as an alternative immunotherapy for HCC.
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Ying, Hanglu, Long Li, Yufen Zhao, and Feng Ni. "Ivermectin Attenuates CCl4-Induced Liver Fibrosis in Mice by Suppressing Hepatic Stellate Cell Activation." International Journal of Molecular Sciences 23, no. 24 (December 16, 2022): 16043. http://dx.doi.org/10.3390/ijms232416043.
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Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other diseases, including antiviral and anticancer actions, as well as treating metabolic diseases. Herein, we evaluated the function of ivermectin in regulating liver fibrosis. Firstly, carbon tetrachloride (CCl4)-injected Balb/c mice were used to assess the antifibrosis effects of ivermectin in vivo. Further, CFSC, a rat hepatic stellate cell (HSC) line, was used to explore the function of ivermectin in HSC activation in vitro. The in vivo data showed that ivermectin administration alleviated histopathological changes, improved liver function, reduced collagen deposition, and downregulated the expression of profibrotic genes. Mechanistically, the ivermectin treatment inhibited intrahepatic macrophage accumulation and suppressed the production of proinflammatory factors. Importantly, the ivermectin administration significantly decreased the protein levels of α-smooth muscle actin (α-SMA) both in vivo and in vitro, suggesting that the antifibrotic effects of ivermectin are mainly due to the promotion of HSC deactivation. The present study demonstrates that ivermectin may be a potential therapeutic agent for the prevention of hepatic fibrosis.
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Koyama, Yukinori, Jun Xu, Xiao Liu, and David A. Brenner. "New Developments on the Treatment of Liver Fibrosis." Digestive Diseases 34, no. 5 (2016): 589–96. http://dx.doi.org/10.1159/000445269.
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Liver fibrosis results from many chronic injuries and often progresses to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Liver transplantation is the only treatment available for patients with advanced stages of liver fibrosis. Therefore, new strategies for anti-fibrotic therapy are required. Various kinds of hepatocyte damage result in inflammation, which leads to the activation of hepatic stellate cells (HSCs), which are the major source of myofibroblasts in the liver. Myofibroblasts proliferate in response to various kinds of cytokines, chemokines, and growth factors and produce extracellular matrix proteins, which forms the fibrous scar. Myofibroblasts undergo apoptosis and inactivation when the underlying causative etiologies are cleared. Here we describe our current knowledge of targeting the steps in HSC activation as therapeutic target for liver fibrosis.
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Lai, Chi-Yu, Kun-Yun Yeh, Chiu-Ya Lin, Yang-Wen Hsieh, Hsin-Hung Lai, Jim-Ray Chen, Chia-Chun Hsu, and Guor Mour Her. "MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling." Cancers 13, no. 5 (February 24, 2021): 940. http://dx.doi.org/10.3390/cancers13050940.
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MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.
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Dewidar, Meyer, Dooley, and Meindl-Beinker. "TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019." Cells 8, no. 11 (November 11, 2019): 1419. http://dx.doi.org/10.3390/cells8111419.
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Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.
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Ding, Ning, Nasun Hah, Ruth T. Yu, Mara H. Sherman, Chris Benner, Mathias Leblanc, Mingxiao He, Christopher Liddle, Michael Downes, and Ronald M. Evans. "BRD4 is a novel therapeutic target for liver fibrosis." Proceedings of the National Academy of Sciences 112, no. 51 (December 7, 2015): 15713–18. http://dx.doi.org/10.1073/pnas.1522163112.
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Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.
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Akter, Sharmin. "Non-alcoholic Fatty Liver Disease and Steatohepatitis: Risk Factors and Pathophysiology." Middle East Journal of Digestive Diseases 14, no. 2 (April 30, 2022): 167–81. http://dx.doi.org/10.34172/mejdd.2022.270.
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Non-alcoholic fatty liver disease (NAFLD) and its progressive subtype non-alcoholic steatohepatitis (NASH) are the most prevalent liver diseases, often leading to hepatocellular carcinoma (HCC). This review aims to describe the present knowledge of the risk factors responsible for the development of NAFLD and NASH. I performed a literature review identifying studies focusing on the complex pathogenic pathway and risk factors of NAFLD and steatohepatitis. The relationship between NAFLD and metabolic syndrome is well established and widely recognized. Obesity, dyslipidemia, type 2 diabetes, hypertension, and insulin resistance are the most common risk factors associated with NAFLD. Among the components of metabolic syndrome, current evidence strongly suggests obesity and type 2 diabetes as risk factors of NASH and HCC. However, other elements, namely gender divergences, ethnicity, genetic factors, participation of innate immune system, oxidative stress, apoptotic pathways, and adipocytokines, take a leading role in the onset and promotion of NAFLD. Pathophysiological mechanisms that are responsible for NAFLD development and subsequent progression to NASH are insulin resistance and hyperinsulinemia, oxidative stress, hepatic stellate cell (HSC) activation, cytokine/adipokine signaling pathways, and genetic and environmental factors. Major pathophysiological findings of NAFLD are dysfunction of adipose tissue through the enhanced flow of free fatty acids (FFAs) and release of adipokines, and altered gut microbiome that generate proinflammatory signals and cause NASH progression. Understanding the pathophysiology and risk factors of NAFLD and NASH; this review could provide insight into the development of therapeutic strategies and useful diagnostic tools.
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Liao, Yi-Jen, Yuan-Hsi Wang, Chao-Lien Liu, Cheng-Chieh Fang, Ming-Hua Hsu, and Fat-Moon Suk. "4-Methoxy Sulfonyl Paeonol Inhibits Hepatic Stellate Cell Activation and Liver Fibrosis by Blocking the TGF-β1/Smad, PDGF-BB/MAPK and Akt Signaling Pathways." Applied Sciences 10, no. 17 (August 27, 2020): 5941. http://dx.doi.org/10.3390/app10175941.
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Liver fibrosis initiates the progression of cirrhosis, and, finally, hepatocellular carcinoma (HCC). The increased proliferation and activation of hepatic stellate cells (HSCs) are crucial for hepatic fibrogenesis. Paeonol is the major vigorous component of Cortex Moutan, a traditional herbal medicine widely used for treating various diseases. Here, we identified a novel paeonol derivative (4-methoxy sulfonyl paeonol, 4-MSP) that inhibits TGF-β1-induced Smad2/3 phosphorylation and collagen expression in HSCs. 4-MSP pretreatment suppressed the PDGF-BB–induced phosphorylation of MAPK pathway members (MEK/ERK, p38, JNK), Akt/p70S6K, and HSC proliferation. However, 4-MSP treatment had no effect on the induction of apoptosis in HSCs. The microarray experiments showed that 4-MSP treatment affects the TGF-β signaling, MAPK cascade, and other pathways related to HSCs activation and proliferation. The administration of 4-MSP to a liver fibrosis mouse model induced by CCl4 significantly decreased the expression of hepatic fibrosis markers (α-SMA, col1A2, TGF-β, and MMP2), and attenuated hepatic collagen deposition and liver damage. In addition, no adverse effects were observed in 4-MSP exposed mice. In conclusion, this novel paeonol-phenylsulfonyl derivative prevents the progression of liver fibrosis through blocking TGF-β1/Smad, PDGF-BB/MAPK, and Akt signaling, which suggests its use as a novel therapeutic against liver fibrosis.
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Spirk, Marlen, Sebastian Zimny, Maximilian Neumann, Nichole McMullen, Christopher J. Sinal, and Christa Buechler. "Chemerin-156 is the Active Isoform in Human Hepatic Stellate Cells." International Journal of Molecular Sciences 21, no. 20 (October 13, 2020): 7555. http://dx.doi.org/10.3390/ijms21207555.
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The chemokine chemerin exists as C-terminally processed isoforms whose biological functions are mostly unknown. A highly active human chemerin variant (huChem-157) was protective in experimental hepatocellular carcinoma (HCC) models. Hepatic stellate cells (HSCs) are central mediators of hepatic fibrogenesis and carcinogenesis and express the chemerin receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). Here we aimed to analyse the effect of chemerin isoforms on the viability, proliferation and secretome of the human HSC cell line LX-2. Therefore, huChem-157, 156 and 155 were over-expressed in LX-2 cells, which have low endogenous chemerin levels. HuChem-157 produced in LX-2 cells activated CMKLR1 and GPR1, and huChem-156 modestly induced GPR1 signaling. HuChem-155 is an inactive chemerin variant. Chemerin isoforms had no effect on cell viability and proliferation. Cellular expression of the fibrotic proteins galectin-3 and alpha-smooth muscle actin was not regulated by any chemerin isoform. HuChem-156 increased IL-6, IL-8 and galectin-3 in cell media. HuChem-157 was ineffective, and accordingly, did not enhance levels of these proteins in media of primary human hepatic stellate cells when added exogenously. These analyses provide evidence that huChem-156 is the biologic active chemerin variant in hepatic stellate cells and acts as a pro-inflammatory factor.
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Claveria-Cabello, Alex, Leticia Colyn, Maria Arechederra, Jesus M. Urman, Carmen Berasain, Matias A. Avila, and Maite G. Fernandez-Barrena. "Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?" Cells 9, no. 10 (October 19, 2020): 2321. http://dx.doi.org/10.3390/cells9102321.
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Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.
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Lee, Jung Il, Jocelyn H. Wright, Melissa M. Johnson, Renay L. Bauer, Kristina Sorg, Sebastian Yuen, Brian J. Hayes, Lananh Nguyen, Kimberly J. Riehle, and Jean S. Campbell. "Role of Smad3 in platelet-derived growth factor-C-induced liver fibrosis." American Journal of Physiology-Cell Physiology 310, no. 6 (March 15, 2016): C436—C445. http://dx.doi.org/10.1152/ajpcell.00423.2014.
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Chronic liver injury leads to fibrosis and cirrhosis. Cirrhosis, the end stage of chronic liver disease, is a leading cause of death worldwide and increases the risk of developing hepatocellular carcinoma. Currently, there is a lack of effective antifibrotic therapies to treat fibrosis and cirrhosis. Development of antifibrotic therapies requires an in-depth understanding of the cellular and molecular mechanisms involved in inflammation and fibrosis after hepatic injury. Two growth factor signaling pathways that regulate liver fibrosis are transforming growth factor-β (TGFβ) and platelet-derived growth factor (PDGF). However, their specific contributions to fibrogenesis are not well understood. Using a genetic model of liver fibrosis, we investigated whether the canonical TGFβ signaling pathway was necessary for fibrogenesis. PDGF-C transgenic ( PDGF-C Tg) mice were intercrossed with mice that lack Smad3, and molecular and histological fibrosis was analyzed. PDGF-C Tg mice that also lacked Smad3 had less fibrosis and improved liver lobule architecture. Loss of Smad3 also reduced expression of collagen genes, which were induced by PDGF-C, but not the expression of genes frequently associated with hepatic stellate cell (HSC) activation. In vitro HSCs isolated from Smad3-null mice proliferated more slowly than cells from wild-type mice. Taken together, these findings indicate that PDGF-C activates TGFβ/Smad3 signaling pathways to regulate HSC proliferation, collagen production and ultimately fibrosis. In summary, these results suggest that inhibition of both PDGF and TGFβ signaling pathways may be required to effectively attenuate fibrogenesis in patients with chronic liver disease.
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Khomich, Olga, Alexander V. Ivanov, and Birke Bartosch. "Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis." Cells 9, no. 1 (December 20, 2019): 24. http://dx.doi.org/10.3390/cells9010024.
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Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.
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Rhee Chai, Ming, Padmaan Sankaran, and Lee Ming Yap. "Extrahepatic metastasis of hepatocellular carcinoma: A Malaysian case series." International Journal of Hepatobiliary and Pancreatic Diseases 12, no. 2 (December 2, 2022): 9–12. http://dx.doi.org/10.5348/100099z04mc2022cs.
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Introduction: Hepatocellular carcinoma (HCC) is a primary malignancy which arises from hepatocytes. It is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide in 2020. It predominantly metastasizes via the hematogenous route. However, there are possibility of distant metastasis via the lymphatic and bone dissemination in a few of HCC cases. Case Series: We report two atypical cases of HCC with distant metastasis to cervical lymph node and bone in Malaysia. The first case reported is a HCC case of extrahepatic metastasis to cervical lymph node and the second case is a HCC case of extrahepatic metastasis to right femur. Conclusion: The patients with atypical site of distant metastasis from HCC have poor prognosis. Overall physical examination should be done to prevent overlook for all the patients with HCC.
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Shreenivas, Aditya Varnam, Guru Subramanian Guru Murthy, Ben George, James P. Thomas, Sakti Chakrabarti, Mandana Kamgar, and Paul S. Ritch. "Impact of tumor histology and socioeconomic factors on survival of patients suffering from malignant vascular tumors of liver and hepatocellular carcinomas: A SEER database analysis." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16612-e16612. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16612.
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e16612 Background: Primary malignant vascular tumors of the liver are rare, aggressive and poorly understood subtypes of liver cancers. In this analysis, we aim to determine the impact of tumor histology and other socio economic factors on survival of these tumors and hepatocellular carcinomas. Methods: Patients with malignant histopathological diagnoses of hepatocellular carcinoma not otherwise specified (HCC NOS), hepatocellular carcinoma with spindle cell (HCC SP), fibrolamellar (HCC F), clear cell (HCC CL), scirrhous (HCC SC) and pleomorphic variants ( HCC PL), combined hepatocellular carcinoma and cholangiocarcinoma (Mixed), hepatic angiosarcoma (AS), hemangioendothelioma (HE), its epithelioid variant (EHE) and hemangiopericytoma (HP) were identified using the SEER (version 2018) database. Overall survival was studied with Kaplan–Meier with the log rank method. Multivariable analysis was performed to assess the impact of race, ethnicity, marital and insurance status on survival of these patients. Results: We analyzed de-identified data of 104502 patients from the year 1973 to 2016 with hepatocellular carcinomas and malignant vascular tumors of liver (including 101851 patients with HCCNOS, 70 with HCC SP, 378 with HCC F, 104 with HCC SC, 593 with HCC CL, 23 with HCC PL, 950 with Mixed, 367 with AS, 36 with HE, 120 with EHE and 10 with HP ) respectively. Median overall survival (OS) of HCC NOS was calculated to be 7 months. Among hepatocellular carcinoma patients HCC F had the longest median OS of 29 months and HCC SP had the shortest median OS of 3months (P < 0.001). Additionally, among patients with malignant vascular tumors, AS had the shortest median OS (1 month) while patients with EHE had the longest median OS of 81 months (P < 0.001). Overall, married and insured patients had a better overall survival than unmarried and uninsured patients (P < 0.04). Conclusions: Malignant vascular tumors of liver are rare in comparison to hepatocellular carcinomas. Spindle cell variant of HCC and liver angiosarcomas carry the worst prognosis and fibrolamellar variant of HCC, hemangioendothelioma (HE) and its epithelioid variant (EHE) have the best prognosis. Insurance and marital status has a positive impact on overall survival of liver cancer patients.
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Saputri, Kurnia Apryani, and Danang Tri Yudhono. "Manajemen Jalan Nafas Pasien Heptocellurar Carsinoma Dengan Masalah Pola Nafas Tidak Efektif." JKM : Jurnal Keperawatan Merdeka 2, no. 2 (November 30, 2022): 126–31. http://dx.doi.org/10.36086/jkm.v2i2.1226.
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Latar Belakang : Hepatocellular carcinoma (HCC) merupakan pertumbuhan sel yang berlangsung tidak normal pada bagian hati yang ditandai dengan meningkatnya jumlah sel dalam hati. Masalah Pola nafas tidak efektif dapat terjadi karena keterbatasan pengembangan diafragma, penurunan energi. Penelitian bertujuan untuk mendeskripsikan manajemen jalan nafas pada pasien Hepatocellular carcinoma dengan masalah pola nafas tidak efektif. Metode: Menggunakan study kasus pendekatan asuhan keperawatan yang mencakup pengkajian, penentuan diagnosa, penentuan intervensi keperawatan, implementasi hingga evaluasi pada tahun 2022 dengan subyek partisipan penelitian satu orang dengan diagnosa Hepatocellurar carcinoma dan mengalami pola nafas tidak efektif. Penelitian dilaksanakan 13-15 januari 2022, bertempat di RSUD Dr. Margono Soekarjo. Data dikumpulkan melalui format pengkajian, observasi, wawancara dan pemeriksasan dan data sekunder rekam medis. Analisis deskriptif digunakan dalam penelitian ini. Hasil: Hasil penelitian pasien mengalami Pola nafas tidak efektif yang disebabkan keterbatasan pengembangan diafragma dan penurunan energi. Hasil implementasi manajemen jalan nafas selama tiga hari perawatan menunjukkan terjadinya penurunan frekuensi nafas dan tidak adanya dispnea. Kesimpulan: Manajemen jalan nafas efektif diberikan untuk mengatasi masalah pola nafas tidak efektif. Penelitian menyarankan untuk penetapan standar manajemen jalan nafas bagi pasien dengan hepatocellurar carcinoma.
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Roßner, Florian, Bruno Valentin Sinn, and David Horst. "Pathology of Combined Hepatocellular Carcinoma-Cholangiocarcinoma: An Update." Cancers 15, no. 2 (January 13, 2023): 494. http://dx.doi.org/10.3390/cancers15020494.
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Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that is composed of both hepatocellular and cholangiocellular differentiated cells. It is slightly more common in men and among Asian and Pacific islanders. Overall, risk factors are similar to classic risk factors of hepatocellular carcinoma (HCC). The classification has significantly evolved over time. The last WHO classification (2019) mainly emphasized diagnosis on morphological basis with routine stainings, discarded previously recognized classifications with carcinomas with stem cell features, introduced intermediate cell carcinoma as a specific subtype and considered cholangiolocarcinoma as a subtype of cholangiocellular carcinoma. Immunohistochemical markers may be applied for further specification but have limited value for diagnosis. Recent discoveries in molecular pathway regulation may pioneer new therapeutic approaches for this poor prognostic and challenging diagnosis.
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Cao, Qinghua, Fang Liu, Ping Xiao, Min Wang, Yuan Lin, Ziyin Ye, Lihong Che, and Ling Xue. "Cytoplasmic Staining of TTF-1 Antibody in the Diagnosis of Hepatocellular Carcinoma: Study on 299 Cases Using Tissue Microarray." ISRN Pathology 2011 (July 6, 2011): 1–7. http://dx.doi.org/10.5402/2011/257352.
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The diagnosis of hepatocellular carcinoma (HCC) remains obscure in some complicated cases. Thyroid transcription factor-1 (TTF-1) was presumed to be helpful in the diagnosis of HCC. This paper aims to study the utility of TTF-1 in the diagnosis and differential diagnosis of HCC and to assign clinicopathological correlations. Immunohistochemical detection of TTF-1 is performed with tissue microarray which contains a total of 781 cases including 299 hepatocellular carcinomas (HCCs), 31 intrahepaticcholangiocarcinomas (ICCs), 86 metastatic adenocarcinomas (MACs), 5 metastatic hepatocellular carcinomas (mHCCs), 9 hepatoblastomas (HBs), 40 renal clear cell carcinomas (RCCs), 215 adjacent nonneoplastic hepatic tissue, and 96 normal hepatic tissue. The result shows that TTF-1 is positive in 55.2% (165/299) HCCs, 6.4% (2/31) ICCs, 3.5% (3/86) MACs, 60% (3/5) mHCCs, 33.3% (3/9) HBs, 0% (0/40) RCCs, 99.0% (213/215) adjacent nonneoplastic hepatic tissue, and 95.8% (93/96) normal hepatic tissue. Expression of TTF-1 is correlated with differentiation of HCC, but not with patients' age, gender, serum AFP, tumor size, number of tumor nodules, and tumor thrombus in vein or bile duct. These data suggest that TTF-1 antibody is sensitive and specific in HCC and might serve as a candidate for the diagnosis and differential diagnosis of HCC.
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Hirota, Shigeru, Minoru Nomoto, Sadahiro Hosobe, Yutaka Aoyagi, and Hitoshi Asakura. "Mucin in Primary Liver Carcinomas: Combined Hepatocellular-Cholangiocarcinoma or Variant Hepatocellular Carcinoma." Canadian Journal of Gastroenterology 10, no. 1 (1996): 12–16. http://dx.doi.org/10.1155/1996/808592.
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OBJECTIVE: To investigate whether the presence of mucin defines a combined hepatocellular-cholangiocarcinoma or merely a variant of usual hepatocellular carcinoma (HCC).METHODS: From 1979-92, 124 cases of usual HCC were studied at Niigata University Hospital, Niigata City, Japan, and several affiliated hospitals. Histological diagnoses were determined according to World Health Organization (WHO) criteria. Hematoxylin and eosin stain, periodic acid-Schiff (PAS) stain, PAS stain after diastase digestion (D-PAS) and silver stain tests were performed. Cases containing D-PAS-positive substances were also stained by Alcian blue (AB) stain, high iron diamine (HID) stain and concanavaline A paradox-3 type (ConA3) stain. The classification of mucin was determined by AB, HID and ConA3 stains.RESULTS: Mucin was recognized in the area of HCC by mucin stains in 25 of 124 cases. Two forms of mucin existence were classified: extracellular and intracellular. Mucins were classified by histochemical stains into three types: sulfomucin, sialomucin and neutral mucin.CONCLUSIONS: According to the WHO histological classification of primary carcinoma of the liver, mucin existence is characteristic of intrahepatic cholangiocarcinoma. But if mucin exists in morphologically usual HCC, it is better to diagnose it as a variant of HCC (with mucin) rather than as a combined hepatocellular-cholangiocarcinoma.
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Hossain, Md Akter, Md Saiful Haque, Md Ashikur Rahman, Zinat Nasreen, Mostaque Ahmed Bhuiya, and Abu Bakar Siddique. "Pattern of Tumour among Hepatocelluar Carcinoma Patients attended at a Tertiary Care Hospital in Dhaka City." Journal of Current and Advance Medical Research 6, no. 1 (March 27, 2019): 6–9. http://dx.doi.org/10.3329/jcamr.v6i1.40774.
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Background: The pattern of hepatocelluar carcinoma may vary in different patients.
Objective: The purpose of the present study was to see the pattern of hepatocelluar carcinoma among the patients attended at a tertiary care hospital in Dhaka city.
Methodology: This cross-sectional study was carried out in the Department of Radiology and Imaging at Dhaka Medical College, Dhaka and Banghabandhu Sheikh Mujib Medical University, Dhaka from January 2007 to May 2008 for a period of around one and half year. All the patients presented with hepatocellular carcinoma at the age group of more than 20 years with both sexes were selected as study population. The patients were undergone CT-scan examination and the confirmation was performed by histopathological examination. The details of the pattern of tumor among the hepatocellular carcinoma patients were examined and were recorded.
Result: A total number of 50 patients were recruited in this study after fulfilling the inclusion and exclusion criteria. Mean age with SD of study population was 48.78 ±12.07. Within 25 cases of HCC as diagnosed by CT scan 13(52%) had solitary lesion 7(28%) had multiple lesions and remaining 5(20%) had diffuse lesions. The tumour size of 8 cm or more was the highest which was 10 in numbers. However, 4 to 8 cm was found in 7(28.0%) cases and 3 to 4 cm was detected in 3(12.0%) cases.
Conclusion: In conclusion most of the HCC is solitary lesion with more than 8 cm in size.
Journal of Current and Advance Medical Research 2019;6(1):6-9
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Ezhilararasan, Devaraj, Thangavelu Lakshmi, and Biond Raut. "Novel Nano-Based Drug Delivery Systems Targeting Hepatic Stellate Cells in the Fibrotic Liver." Journal of Nanomaterials 2021 (October 22, 2021): 1–9. http://dx.doi.org/10.1155/2021/4674046.
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Hepatic stellate cells (HSCs) exist in the liver’s perisinusoidal space, are phenotypically activated, and acquire myofibroblast-like phenotype. This phenotypic transformation is accountable for the accumulation and production of various extracellular matrix (ECM) proteins, involving different fibril-forming collagens in the perisinusoidal space, producing altered hepatic function and portal hypertension and increased vascular resistance, fibrosis, cirrhosis, and hepatocellular carcinoma. The activated HSCs/myofibroblasts are principal collagen-producing cells in the damaged liver. Therefore, fibrosis treatments are often targeting HSCs. HSCs store most of the total body’s retinol in their cytoplasm, and hence, antifibrotic nanomedicines are often targeted with vitamin A decoration. Vitamin A-decorated nanomedicines with siRNAs for transforming growth factor-beta, collagen, and connective tissue growth factors target to inhibit fibrogenesis and the ECM-associated gene expressions, leading to fibrosis regression. Similarly, a variety of miRNAs play pro- and antifibrotic function. In the fibrotic liver, the profibrotic miRNAs are targeted with their respective antagomir and the antifibrotic miRNAs are targeted with their respective agomirs along with HSC-specific nanodecoration. These miRNA treatments reduce fibrogenesis by downregulation of ECM-related gene expressions. However, liver fibrosis is caused by the upregulation of a different type of profibrotic signaling pathways associated with ECM accumulation in the fibrotic liver. Therefore, specific gene silencing by siRNAs or targeting particularly miRNA may also not effectively reduce fibrosis to a greater extent. However, nanodecoration of a drug is useful to deliver drugs into activated HSCs in the injured liver. Therefore, the aim of this review is to focus on targeted drug delivery towards activated HSCs in the persistently damaged liver.
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Агабабян, И. Р., and Ш. Ш. Садыкова. "Pleyotropic Effects of Statins Non-Alcoholic Fat Disease of the Liver Non-Alcoholic Steatohepatitis." Рецепт, no. 2 (May 5, 2022): 194–99. http://dx.doi.org/10.34883/pi.2022.25.2.006.
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Гиполипидемические препараты и неалкогольная жировая болезнь печени (НАЖБП), неалкогольный стеатогепатит (НАСГ), патологии, связанные с липидами, имеют сложную взаимосвязь, которая приводит к повреждению печени. В последние годы появляются исследования, которые направлены на определение эффективности статинов при НАЖБП/НАСГ в лечении и профилактике связанных с ними неблагоприятных исходов. Были проведены научные наблюдения, оценивающие влияние статинов на НАЖБП/НАСГ, а затем проведен анализ их плейотропного влияния на функции печени. Несколько исследований продемонстрировали снижение НАЖБП/НАСГ-ассоциированного воспаления и фиброза при лечении статинами. Эти противовоспалительные и противофиброзные эффекты были получены за счет их плейотропных свойств, которые наблюдались в дополнение к гиполипидемическому эффекту. В различных исследованиях на животных было обнаружено, что статины уменьшают липотоксичность печени, окислительный стресс, воспалительные реакции и связанный с фиброзом НАСГ. Статины оказывают эти защитные эффекты, восстанавливая уровень экспрессии гена рецептора альфа, активируемого пероксисомальным пролифератором (PPARα), и таким образом восстанавливают митохондриальное и пероксисомальное окисление жирных кислот (ФАО). Статины также увеличивали уровень параоксоназы-1 (PON1), антиоксиданта и антиатерогенный фермент, уровень которого снижается при НАЖБП, а также проявляется липотоксичность печени путем разделения кристаллов холестерина и клеток Купфера (KC) с короноподобными структурами (CLS). Они проявляют противоопухолевые свойства, ингибируя провоспалительные цитокины и сосудистые пролиферативные факторы. Более того, они восстановили здоровые синусоидальные эндотелиальные клетки печени (LSEC) и звездчатые клетки печени (HSC) наряду с ингибированием активации HSC посредством модуляции индуцированной синтазы оксида азота (iNOS) и экспрессии эндотелиальной синтазы оксида азота (eNOS). Кроме того, они защищали от сердечно-сосудистых заболеваний (ССЗ) и смертности, гепатоцеллюлярной карциномы (ГЦК) и метаболического синдрома (МС), связанных с НАЖБП/НАСГ. НАСГ и его предшественник НАЖБП можно лечить и предотвращать с помощью статинов, благодаря плейотропным свойствам. Если бы все вышесказанное однажды было подтверждено крупными клиническими испытаниями на людях, это могло бы произвести революцию в терапии НАСГ. Hypolipidemic preparations and non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and lipid-related pathologies have a complex relationship that results in liver damage. In recent years, studies have been carried out to determine the effectiveness of statins in NAFLD/NASH in the treatment and prevention of their adverse effects. Scientific observations were made to assess the effects of statins on NAFLD/NASH, followed by an analysis of their pleyotropic effects on liver function. Several studies have shown decreases in NAFLD/NASH-associated inflammation and fibrosis in the treatment of statins. These anti-inflammatory and anti-fibrous effects were due to their pleyotropic properties, which were observed in addition to the hypolipidemic effect. In various animal studies, statins have been found to reduce liver lipotoxicity, oxidative stress, inflammatory reactions, and associated with fibrosis with NHA in several ways. Statins provide these protective effects by restoring the expression of the alpha receptor gene activated by peroxysomal proliferator (PPARα) and thus reducing mitochondrial and peroxysomal oxidation of fatty acids (FAO). Statins also increased paraoxonase 1 (PON1), antioxidant, and antiatherogenic enzyme, which decreases with NAVBP, as well as liver lipotoxicity by separating cholesterol crystals and Kupfer cells (KC) from coronogenic structures (CLS). They exhibit anti-tumor properties by inhibiting inflammatory cytokines and vascular proliferative factors. Moreover, they have restored healthy sinusoidal liver endothelial cells (LSEC) and stellated liver cells (HSC), along with inhibiting HSC activation by modulating the induced synthase of nitrogen oxide (iNOS) and expressing the endothelial synthase of nitrogen oxide (eNOS). In addition, they protected against cardiovascular disease (GCC) and mortality, hepatocellular carcinoma (GCC) and metabolic syndrome (MS) associated with NHA/NHA. NHA and its predecessor, NHA, can be treated and prevented with statins, due to its pleyotropic properties. This study helps to prove and successfully explain the substance. Once confirmed by major human clinical trials, this could revolutionize NASG therapy.
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Ferenci, Peter, Michael Fried, Douglas Labrecque, Jordi Bruix, Morris Sherman, Masao Omata, Jenny Heathcote, et al. "Hepatocellular Carcinoma (HCC)." Journal of Clinical Gastroenterology 44, no. 4 (April 2010): 239–45. http://dx.doi.org/10.1097/mcg.0b013e3181d46ef2.
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Villanueva, A. "Hepatocellular Carcinoma (Hcc)." Annals of Oncology 25 (September 2014): iv14. http://dx.doi.org/10.1093/annonc/mdu297.2.
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Shah, Moushmi, Chinnammal C. Kandaswamy, Chris Cho, Tom Weichle, Diely A. Pichardo, and Divyesh G. Mehta. "Hepatocellular Carcinoma (HCC)." American Journal of Gastroenterology 100 (September 2005): S126. http://dx.doi.org/10.14309/00000434-200509001-00312.
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Shah, Moushmi, Chinnammal Kandaswamy, Chris Cho, Tom Weichle, Divyesh G. Mehta, and Diely A. Pichardo. "Hepatocellular Carcinoma (HCC)." American Journal of Gastroenterology 100 (September 2005): S127. http://dx.doi.org/10.14309/00000434-200509001-00314.
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Atiq, Muhammad, Muhammad Haroon, Muhammad Imran Khan, Ahmed Siddique Ammar, Warda Khalid, and Faisal Hanif. "A Case Report of Fibrolamellar Hepatocellular Carcinoma in a Young Adult." Annals of King Edward Medical University 28, no. 2 (August 4, 2022): 213–15. http://dx.doi.org/10.21649/akemu.v28i2.5095.
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Among the four histopathological variants of hepatocellular carcinoma, Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC). It occurs in less than 1 % cases of hepatocellular carcinoma with distinct features as compared to classical HCC. It differs from typical HCC in terms of epidemiology, etiology, clinical presentation and prognosis. In this case report we are going to present a case of fibrolamellar variety of HCC in a 20-year young male with no history of previous liver disease and no characteristics features on Computed Tomography (CT) scan when compared with typical HCC. After discussing in multidisciplinary meeting, he underwent non anatomical liver resection which remained uneventful. Histopathology of the biopsy sample revealed FLHCC. No neoadjuvant therapy was given. Patient was kept on 1 year follow-up and no recurrence or metastasis occurred.
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Fahim, Amin, Mohammad Ahmed Azmi, Muhammad Hanif, and Anila Qureshi. "HEPATOCELLULAR CARCINOMA." Professional Medical Journal 23, no. 04 (April 10, 2016): 415–21. http://dx.doi.org/10.29309/tpmj/2016.23.04.1499.
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Objectives: To determine the expression of miR-92-1 in HCC patients and correlatethem with clinicopathological data. Study Design: A Cross sectional study. Place of Study:Samples were collected from Jinnah Postgraduate Medical Center Karachi, Civil HospitalKarachi and Asian Institute of Medical Sciences Hyderabad. Duration of Study: January2014 to December 2014. Materials and Methods: 150 patients of hepatocellular carcinomawere divided into two groups on the basis of etiologic agent. HCC patients with chronic viralhepatitis B were labeled as group-I, whereas those with chronic viral hepatitis C in group-II,compared with 75 healthy control individuals in group-III. Results: The results showed thatmiR-92-1 expression was decreased in patients with HCC when compared with controls. Downregulation was seen more pronounced in HCC cases with chronic viral hepatitis C. A significantcorrelation was found between the expression of miR-92-1 and AFP level 20-200 ng/ml andChild Pugh score B. However no correlation was found between the expression of miR-92-1and age, gender, fibro scan, tumor distribution, tumor size, tumor metastasis and BCLC stage.Conclusion: miR-92-1 is down regulated in HCC patients with significant correlation with serumAFP level between 20-200 ng/ml.
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Zakka, Katerina Mary, Renjian Jiang, Olatunji B. Alese, Walid Labib Shaib, Christina Wu, Joel Wedd, Marty T. Sellers, Madhusmita Behera, Bassel F. El-Rayes, and Mehmet Akce. "Clinical outcomes of hepatocellular carcinoma variants compared to hepatocellular carcinoma." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 435. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.435.
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435 Background: There is no consensus regarding treatment for HCC variants. Clinical outcomes of HCC variants differ from pure HCC. The aim of this study is to compare clinicopathological characteristics, treatment, and outcomes of HCC variants with pure HCC. Methods: Patients with HCC and variants with 8170/3-8175/3 and 8180/3 ICD-O-3 codes were identified from National Cancer Database between 2004 and 2013. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results: 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. The mean age was similar in all except FLHCC (37.9 vs. 60.9-64.1 years, p < 0.001). Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p < 0.001). Pure HCC (10.57%) underwent surgical resection less often than variants; FLHCC (54.8%), clear cell (34.5%), mixed HCC (29.8%), spindle cell (33.3%), pleomorphic (34.8%), and scirrhous (9.9%) (p < 0.001). Ablation was performed in 9.8% of pure HCC, and in up to 8.7% of HCC variants. More than a third of all patients received chemotherapy; pure HCC (42.3%), mixed HCC (38.5%), scirrhous (31.1%), spindle cell (36.1%), clear cell (35.5%), pleomorphic (34.8%), and FLHCC (41.3%). FLHCC had the best 5-year OS (38.7%), spindle cell and pleomorphic had the worst (9.6% and 13.0%). In univariate and multivariate analyses, fibrolamellar histology, female sex, diagnosis between 2009 and 2013, treatment at academic center, well/moderately differentiated histology, early stage, and chemotherapy was associated with better OS compared to pure HCC, male sex, diagnosis between 2004 and 2008, treatment at community cancer program, poorly differentiated, late stage, and no chemotherapy (p < 0.001). Conclusions: HCC variants underwent surgical resection more often than HCC. FLHCC had the best 5-year OS. Liver transplant is commonly performed in HCC variants.
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Rehman, Khalil ur, Dr Muhammad Samiullah, Sidra Sharif, and Saira Farhat. "HEPATOCELLULAR CARCINOMA." Professional Medical Journal 23, no. 02 (February 10, 2016): 209–12. http://dx.doi.org/10.29309/tpmj/2016.23.02.1072.
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Background: Hepatocellular carcinoma (HCC) also known as malignanthepatoma, accounts for most of the liver cancers. Alpha fetoprotein (AFP) has been undoubtedlywidely used as a marker for the detection and monitoring of HCC. This study aimed to find thecorrelation of serum alpha fetoprotein and tumor size in HCC in the tertiary care hospital. StudyDesign: This cross sectional descriptive study. Setting: Pathology Department of Allama IqbalMedical College, Lahore (AIMC). Materials and Methods: The study was carried out on 45HCC patients (13 females and 32 males) came to Jinnah Hospital Lahore. Five ml of venousblood was drawn aseptically from anterior cubital vein of patients and added into plain vial toclot. The samples were centrifuged, to get the plasma separated from blood cells. Serum AFPwas measured by using Enzyme linked Immunosorbent Assay technique (ELISA). Results:There were 10 (22.2%), 19 (42.2%), 16 (35.6) cases in AFP group 1,2,3 respectively. While10 (22.2%), 13 (28.8%), 22 (48.8%) cases in tumor size groups A,B,C. Group C with largetumor size got 48.8% raised AFP levels as compared to group B (28.8%) and group A (10%).Conclusion: This study shows there is significant correlation between serum AFP and tumorsize in HCC (r=0.668). Serum AFP progressively increases with tumor size especially in largersize. Although AFP have suboptimal sensitivity but it is still proves a beneficial in early diagnosisand screening of HCC, when used in combination of USG/Imaging technique.