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Immunohistochemistry (IHC) of mouse liver samples from wide type (WT) and hepatitis B virus X protein transgenic (HBx) mice. Samples were stained with antibodies of HBx. The scale bars indicate 30 μm.
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Hepatocellular carcinoma (HCC) is among the ten most commonly diagnosed cancers and the fourth leading cause of cancer-related death. Patients with hepatitis B virus (HBV) infection are prone to developing chronic liver diseases (i.e., fibrosis and cirrhosis), and the HBV X antigen plays an important role in the development of HCC. The difficulty i...
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Simple Summary
Infections with Hepatitis B and Hepatitis C viruses are usually asymptomatic and although some patients undergo resolution of infection, the majority do not. Chronic hepatitis leads to continuous cycles of inflammation that can cause complications including liver fibrosis, cirrhosis, and eventually liver cancer. This review summarize...
Background: Hepatitis B virus (HBV) is a causative agent of hepatocellular carcinoma (HCC). Until now, the mechanism behind the progress of hepatitis B fibrosis to HCC remains largely unknown. This study aims to examine the candidate biomarkers and pathways involved in HBV-associated HCC.
Methods: Gene expression profiles were retrieved from the Ge...
Citations
... 85 The altered expression of GDF11 in HCC models suggested that GDF11 might contribute to HCC development. 86 Also, genetic mutations in TGFβ core genes, including GDF11, play an important role in HCC pathogenesis. 87,88 Previous studies discovered tumour suppressive roles of GDF11 in HCC by reducing HCC cell proliferation, clonogenic capacity, cellular function, and aggressiveness, as well as causing dysregulation of cancer cell metabolism. ...
Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti‐aging properties, others have documented its senescence‐inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non‐alcoholic fatty liver disease (NAFLD), non‐alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.
... The difficulty of the early detection of HCC causes the increase in the death rates. Annually, HCC affects approximately one million individuals worldwide (Yang et al. 2020). ...
... Note that most hepatocytes in GIV appeared with normal architecture the liver cytosol into the blood. This facilitates its measurement as a marker of liver damage (Yang et al. 2020). Elevated values of the liver functions' parameters serve as useful prognostic factors in advanced cancer patients (Tsai et al. 2014). ...
... HBx is recognized as a therapeutic target due to its potential carcinogenic role in HCC and transactivation activity (Yang et al., 2020). Since current anti-HBV treatment cannot eliminate or permanently silence HBV ccDNA therefore rarely lead to cure, it has been suggested that transcriptional inhibition of ccDNA may lead to functional cure for HBV. ...
The host structural maintenance of chromosomes 5/6 complex (Smc5/6) is a restriction factor of hepatitis B virus (HBV) that inhibits the transcription of viral ccDNA. HBV antagonizes this restriction by expressing the regulatory X protein (HBx) which targets Smc5/6 for degradation via DNA damage-binding protein 1 (DDB1) E3 ubiquitin ligase. However, the molecular insights into how Smc5/6 interacts with HBx remain elusive. In this study, we systematically investigated the interaction between Smc5/6 and HBx. Smc5/6 interacts with HBx through multiple sites in the absence of DDB1 in the pull-down assay. HBx C-terminal is sufficient for the interaction. Most importantly, residue Phe132, which is strictly conserved in all HBV subtypes, is critical for interaction with Smc5/6 both in vitro and in vivo. Mutation of this site (F132A) results in defect in Smc5/6 interaction, extrachromosomal reporter transcription, and HBV production both in cells and in mouse model. Collectively, our data identifies a key residue on HBx for Smc5/6 interaction and viral production. These results provide valuable information for both basic research and therapeutic drugs targeting HBx.
... HBx suppresses the expression of the natural TGFβ inhibitor, alpha-2 macroglobulin (α2M), by (i) activation of NF-κB, which in turn blocks the expression of the α2M gene normally activated by STAT3, and/or (ii) by the HBx activation of PI3K, which then suppresses α2M expression [70]. Activation of TGFβ signaling and additional markers associated with fibrosis was seen by proteomics analysis of HBx transgenic mice that developed mild fibrosis [80]. For example, HBx transcriptionally promotes the expression of fibronectin via activation of NF-κB and via inhibition of p53, the latter normally suppressing the fibronectin promoter [70,81]. ...
Patients who are carriers of the hepatitis B virus (HBV) are at high risk of chronic liver disease (CLD) which proceeds from hepatitis, to fibrosis, cirrhosis and to hepatocellular carcinoma (HCC). The hepatitis B-encoded X antigen, HBx, promotes virus gene expression and replication, protects infected hepatocytes from immunological destruction, and promotes the development of CLD and HCC. For virus replication, HBx regulates covalently closed circular (ccc) HBV DNA transcription, while for CLD, HBx triggers cellular oxidative stress, in part, by triggering mitochondrial damage that stimulates innate immunity. Constitutive activation of NF-κB by HBx transcriptionally activates pro-inflammatory genes, resulting in hepatocellular destruction, regeneration, and increased integration of the HBx gene into the host genome. NF-κB is also hepatoprotective, which sustains the survival of infected cells. Multiple therapeutic approaches include direct-acting anti-viral compounds and immune-stimulating drugs, but functional cures were not achieved, in part, because none were yet devised to target HBx. In addition, many patients with cirrhosis or HCC have little or no virus replication, but continue to express HBx from integrated templates, suggesting that HBx contributes to the pathogenesis of CLD. Blocking HBx activity will, therefore, impact multiple aspects of the host–virus relationship that are relevant to achieving a functional cure.
... If there has a therapeutic strategy that can balance this pathological change? Previous studies have suggested that FSTL1 attenuated pathological injury of multiple organs by alleviating fibrosis, particularly in cardiac dysfunction Hu et al., 2020;Li et al., 2021;Chen Z. et al., 2019;Yang et al., 2020). Our current findings are consistent with these aforementioned research findings that the upregulation of FSTL1 in DM compared with the control group, which was further increased in T2DM with MI. ...
The incidence of type 2 diabetes mellitus (T2DM) has been increasing globally, and T2DM patients are at an increased risk of major cardiac events such as myocardial infarction (MI). Nevertheless, the molecular mechanisms underlying MI injury in T2DM remain elusive. Ubiquitin-specific protease 10 (USP10) functions as a NICD1 (Notch1 receptor) deubiquitinase that fine-tunes the essential myocardial fibrosis regulator Notch signaling. Follistatin-like protein 1 (FSTL1) is a cardiokine with proven benefits in multiple pathological processes including cardiac fibrosis and insulin resistance. This study was designed to examine the roles of FSTL1/USP10/Notch1 signaling in MI-induced cardiac dysfunction in T2DM. High-fat-diet-treated, 8-week-old C57BL/6J mice and db/db T2DM mice were used. Intracardiac delivery of AAV9-FSTL1 was performed in T2DM mice following MI surgery with or without intraperitoneal injection of crenigacestat (LY3039478) and spautin-1. Our results demonstrated that FSTL1 improved cardiac function following MI under T2DM by reducing serum lactate dehydrogenase (LDH) and myocardial apoptosis as well as cardiac fibrosis. Further in vivo studies revealed that the protective role of FSTL1 against MI injury in T2DM was mediated by the activation of USP10/Notch1. FSTL1 protected cardiac fibroblasts (CFs) against DM-MI-induced cardiofibroblasts injury by suppressing the levels of fibrosis markers, and reducing LDH and MDA concentrations in a USP10/Notch1-dependent manner. In conclusion, FSTL1 treatment ameliorated cardiac dysfunction in MI with co-existent T2DM, possibly through inhibition of myocardial fibrosis and apoptosis by upregulating USP10/Notch1 signaling. This finding suggests the clinical relevance and therapeutic potential of FSTL1 in T2DM-associated MI and other cardiovascular diseases.
... HBV contributes to HCC development indirectly through HBV virus proteins. HBV-encoded HBx is a key regulatory protein that acts as a transcriptional coactivator and hijacks the host factor, playing a leading role in the development of HCC [11,12]. HBx interacts with the C terminal of p53, blocks nuclear import of p53 and impairs p53-mediated apoptosis [13]. ...
Hepatitis B virus (HBV) infection is closely related to hepatocellular carcinoma (HCC) development. To investigate the mechanism of HBV causing HCC, we previously analyzed the transcription of the HBV-transgenic cell line HepG2-4D14 and parental HepG2 cells and identified a subset of long noncoding RNAs (lncRNAs) differentially expressed between them. In this study, we focus on lncRNA LINC01010, as it is significantly downregulated in HepG2-4D14 cells and in liver tissues of HCC patients, and positively correlated with survival. We found that HBV-encoded HBx can reduce the transcription of LINC01010. Functional analysis showed that the overexpression of LINC01010 inhibits proliferation, migration and invasion of HepG2 cells while the knockdown of LINC01010 promotes these processes. By taking the approach of RNA immunoprecipitation (RIP) and mass spectrometry, we identified that LINC01010 can interact with vimentin. Further studies demonstrated that LINC01010 negatively affects the vimentin network extension and causes more rapid subunit exchange and lower stability of vimentin filaments. In addition, LINC01010 can reduce the amount of insoluble vimentin within cells, which suggests that LINC01010 interfers with vimentin polymerization. These data indicate that LINC01010 can inhibit the assembly of vimentin filament. Thus, we revealed that HBV HBx-downregulated LINC01010, which suppresses cell proliferation and migration by negatively regulating the formation of vimentin filament. Taken together, LINC01010 is a potential tumor suppressor that may restrain HBV-related HCC development.
... These results indicated that LL could ameliorate the severity of liver damage in db/db mice. Serum aminotransferase such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are commonly used as an indicator for liver disease (Yang, Chen et al. 2020). In the present study a signi cant elevation of serum ALT and AST activities (P < 0.05) were observed in model mice. ...
Background
Modulations on gut microbiota by traditional Chinese medicines (TCMs) and their active components are emerging as potential therapeutic agents on diabetes. Litsea glutinosa is a TCM used in clinic to treat diabetes with alkaloids as the active constituents, and the Laurolitsine is the richest one.
Purpose
Based on that, this study was designed to identify the potential capability of Laurolitsine on alleviating Type 2 diabetes and the changes of the composition of intestinal flora related to this disease.
Methods
In present study, Laurolitsine was administered to diabetic mice (db/db) by daily oral gavage at doses of 50, 100 and 200 mg/kg/day for 4 weeks. The body weight, fasting blood glucose, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT), lipid metabolism of serum and liver and liver function were measured to assess the anti-hyperglycemic and anti-hyperlipidemic effects of Laurolitsine. The liver pathological changes were observed by HE staining. Meanwhile, the effects of Laurolitsine on the changes of the composition of gut microbiota in mice were investigated via metagenomic analysis.
Results
Experimental results show that different doses of Laurolitsine have varying degrees of hypoglycemic and hypolipidemic effects. Among them, the treatment effect of 200mg·Kg⁻¹ is the most obvious. In addition, Laurolitsine changes the structure of intestinal microflora significantly at various taxonomical levels in the diabetic db/db mice.
Conclusions
These results demonstrate that Laurolitsine may regulate glucose and lipid metabolism and improve diabetes through modulating intestinal microflora of Parabacteroides and Mucispirillum, which may be acknowledged as the iconic bacteria of diabetes.
... The knockdown of circ_00004812 has been shown to lead to an increase in the mRNA and protein expression levels of IFN-α and IFN-β (37). FSTL1 and IFN-β have been reported to participate in the oncogenesis process induced by HBV infection (38). With regards to the association between HBV infection and liver fibrosis, hsa_circ_4099 enhances H 2 O 2 -mediated fibrosis, as well as exerts a sponge effect on miR-706 (39). ...
Circular RNAs (circRNAs) are a class of non‑coding RNAs with a circular, covalent structure that lack both 5' ends and 3' poly(A) tails, which are stable and specific molecules that exist in eukaryotic cells and are highly conserved. The role of circRNAs in viral infections is being increasingly acknowledged, since circRNAs have been discovered to be involved in several viral infections (such as hepatitis B virus infection and human papilloma virus infection) through a range of circRNA/microRNA/mRNA regulatory axes. These findings have prompted investigations into the potential of circRNAs as targets for the diagnosis and treatment of viral infection‑related diseases. The aim of the present review was to systematically examine and discuss the role of circRNAs in several common viral infections, as well as their potential as diagnostic markers and therapeutic targets.
... essential to the biomarker discovery [10,11]. Missing proteins are proteins not evident at the protein level due to informatics, technical issues or biological expression patterns [12]. ...
Glycine N-methyltransferase (GNMT) regulates S-adenosylmethionine (SAMe), a methyl donor in methylation. Over-expressed SAMe may cause neurogenic capacity reduction and memory impairment. GNMT knockout mice (GNMT-KO) was applied as an experimental model to evaluate its effect on neurons. In this study, proteins from brain tissues were studied using proteomic approaches, Haemotoxylin and Eosin staining, immunohistochemistry, Western blotting, and ingenuity pathway analysis. The expression of Receptor-interacting protein 1(RIPK1) and Caspase 3 were up-regulated and activity-dependent neuroprotective protein (ADNP) was down-regulated in GNMT-KO mice regardless of the age. Besides, proteins related to neuropathology, such as excitatory amino acid transporter 2, calcium/calmodulin-dependent protein kinase type II subunit alpha, and Cu-Zn superoxide dismutase were found only in the group of aged wild-type mice; 4-aminobutyrate amino transferase, limbic system-associated membrane protein, sodium- and chloride-dependent GABA transporter 3 and ProSAAS were found only in the group of young GNMT-KO mice and are related to function of neurons; serum albumin and Rho GDP dissociation inhibitor 1 were found only in the group of aged GNMT-KO mice and are connected to neurodegenerative disorders. With proteomic analyses, a pathway involving Gonadotropin-releasing hormone (GnRH) signal was found to be associated with aging. The GnRH pathway could provide additional information on the mechanism of aging and non-aging related neurodegeneration, and these protein markers may be served in developing future therapeutic treatments to ameliorate aging and prevent diseases.
... The difficulty of the early detection of HCC causes the increase in the death rates. Annually, HCC affects approximately one million individuals worldwide (Yang et al. 2020). ...
... Note that most hepatocytes in GIV appeared with normal architecture Environ Sci Pollut Res the liver cytosol into the blood. This facilitates its measurement as a marker of liver damage (Yang et al. 2020). Elevated values of the liver functions' parameters serve as useful prognostic factors in advanced cancer patients (Tsai et al. 2014). ...
Hepatocellular carcinoma (HCC) is one of the ten most commonly diagnosed cancers. Doxorubicin is an antibiotic used in cancer treatment protocols that has several side effects. L-Arginine is a non-essential amino acid that is used as immune system activation and antitumor drugs. Therefore, the current study was designed to compare using doxorubicin, L-arginine, or their combination as a prophylactic agent against hepatic carcinoma induced by hepatocellular carcinoma cells (HepG2) injection in mice. The mice were divided into five groups: normal mice and mice that received HepG2, doxorubicin and HepG2, L-arginine and HepG2, and doxorubicin, L-Arginine, and HepG2, respectively. Liver function test as, aspartate transaminase (AST) and alanine transaminase (ALT), and alpha-fetoprotein (AFP), caspase 3, interleukin 6 (IL-6), tumor necrotic factor (TNF), lipid peroxidation (NDA), and some antioxidant parameters were determined. A significant increase in AST and ALT, α-fetoprotein, TNF-α, and cytokines IL6 and MDA and a significant decrease in the serum caspase and liver catalase were determined in HepG2-injected mice. Moreover, some large hyperchromatic heptocytes were observed and the percentage of the positive area/field of HepPar-1, the most specific HCC marker, was 9.56%. Interestingly, mice that received doxorubicin, L-arginine, or their combination showed an improvement in some of the previous parameters. The improvement was more prominent with L-arginine administration.
