PubMed Health⌕ Search

Biomedical subjects

Bin Gao

Publications and source records attributed to Bin Gao.

At least 19 recordsLinked to original sources
PubMed2026

Genetic regulation of AIF1 shapes immune and liver injury profiles in chronic alcohol use.

BACKGROUNDIn chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver disease (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express allograft inflammatory factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation.METHODSUsing serum and urine samples from 868 individuals classified as having alcohol use disorder or not, based on DSM-IV/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the AIF1 promoter single-nucleotide polymorphism (SNP) (rs3132451; C/C, C/G, G/G) on liver function markers and immune cell profiles.RESULTSAIF1 transcript levels were genotype dependent: C/C homozygotes expressed 5.2% of the levels observed in G/G individuals, while C/G heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the G/G genotype is highly prevalent, present in about 70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than 3-fold increase in hepatic immune cells, including infiltrating AIF1+ macrophages and neutrophils. Despite similar durations of alcohol misuse, G/G individuals had higher Model for End-Stage Liver Disease scores compared with C/G individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in G/G males even after alcohol abstinence.CONCLUSIONThese findings suggest that functional genetic variation in AIF1 may contribute to the severity and persistence of ALD.TRIAL REGISTRATIONClinicalTrials.gov NCT02231840.FUNDINGResearch support was provided from the National Institute on Alcohol Abuse and Alcoholism of the NIH under grants 1ZIAAA000440-02 and R24AA025017.

Humans↗
PubMed2025

Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy.

Hepatocellular carcinoma (HCC) is an increasingly prevalent and deadly disease that is initiated by different etiological factors, such as alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatohepatitis (MASH), viral hepatitis, and other hepatotoxic and hepatocarcinogenic agents. The tumor microenvironment (TME) of HCC is characterized by several different fibroblastic and immune cell types, all of which affect the initiation, progression and metastasis of this malignant cancer. This complex immune TME can be divided into an innate component that includes macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, mucosal-associated invariant T cells, natural killer cells, natural killer T cells, and innate lymphoid cells, as well as an adaptive component that includes CD4+ T cells, CD8+ T cells, regulatory T cells, and B cells. In this review, we discuss the latest findings shedding light on the direct or indirect roles of these immune cells (and fibroblastic-like cells such as hepatic stellate cells) in the pathogenesis of HCC. Henceforth, further characterization of this heterogeneous TME is highly important for studying the progression of HCC and developing novel immunotherapeutic treatment options. In line with this, we also review novel groundbreaking experimental techniques and animal models aimed at specifically elucidating this complex TME and discuss emerging immune-based therapeutic strategies intended to treat HCC and predict the efficacy of these immunotherapies.

Humans↗
PubMed2007

First glimpse of the peptide presentation by rhesus macaque MHC class I: crystal structures of Mamu-A*01 complexed with two immunogenic SIV epitopes and insights into CTL escape.

The infection of rhesus macaques (Macaca mulatta) by the SIV is the best animal model for studying HIV infection and for AIDS vaccine development. A prevalent MHC class I allele, Mamu-A*01, is known to correlate with containment of SIV, which has been extensively explored in studies of CTL-based vaccination concepts. We determined the crystal structures of Mamu-A*01 complexed with two immunodominant SIV epitopes: the nonamer CM9 of group-specific Ag (Gag, 181-189; CTPYDINQM) and the octamer TL8 of transcription activator (Tat, 28-35; TTPESANL). The overall structures of the two Mamu-A*01 complexes are similar to other MHC class I molecules. Both structures confirm the presence of an absolutely conserved proline anchor residue in the P3 position of the Ag, bound to a D pocket of the Mamu-A*01 H chain with optimal surface complementarity. Like other MHC/peptide complex structures, the P2 and C-terminal residues of the epitopes are also important for anchoring to the MHC molecule, whereas the middle residues form an arch and their side chains are directed into solvent. These two structures reveal details of how Mamu-A*01 interacts with two well-studied epitopes at the atomic level. We discuss the structural basis of CTL escape, based on molecular models made possible by these two structures. The results we present in this study are most relevant for the rational design of Mamu-A*01-restricted CTL epitopes with improved binding, as a step toward development of AIDS vaccines.

Amino Acid Sequence↗
PubMed2006

AICAR potentiates ROS production induced by chronic high glucose: roles of AMPK in pancreatic beta-cell apoptosis.

We previously demonstrated that chronic high glucose (33.3 mM) induced beta-cell dysfunction and apoptosis through glucokinase (GCK) downregulation, but the exact mechanisms involved remain unclear. Here, we show that prolonged exposure of 5-aminoimidazole-4-carboxamide (AICA)-riboside potentiated apoptosis induced by high glucose in MIN6N8 pancreatic beta-cells, correlating with enhanced GCK downregulation and decreased production of ATP and insulin. These events are potentiated in AMPK-overexpressing cells, but are prevented in cells transfected with mutant dominant-negative AMPK (AMPK-K45R). Furthermore, AMPK activation increases production of reactive oxygen species (ROS) and loss of mitochondria membrane potential induced by high glucose, which is significantly inhibited by treatment with compound C or by AMPK-K45R overexpression. Overexpression of GCK prevents apoptosis; decreased cellular ATP and insulin secretion, and ROS production enhanced by AICAR, but does not affect AMPK activation. Similar results are obtained using isolated primary islet cells. Collectively, these data demonstrate that AMPK activation potentiates beta-cell apoptosis induced by chronic high glucose through augmented GCK downregulation mediated by enhanced ROS production.

AMP-Activated Protein Kinases↗
PubMed2006

Functional expression of a Drosophila antifungal peptide in Escherichia coli.

Drosomycin is a key effector molecule involved in Drosophila innate immunity against fungal infection. This peptide is composed of 44 residues stabilized by four disulfide bridges. As the first step towards the understanding of the molecular basis for its specific antifungal activity, rapid and efficient production of the wild-type peptide and its mutants is needed. Here, we report a pGEX system for high-level expression of recombinant Drosomycin. The fusion Drosomycin protein with a carrier of Glutathione S-transferase (GST) was initially purified by affinity chromatography followed by Enterokinase cleavage. The digested product was separated by gel filtration and reverse phase HPLC. Mass spectrometry and circular dichroism spectroscopy analysis revealed that the recombinant peptide has identical molecular weight and correct structural conformation to native Drosomycin. Classical inhibition assay showed clear antifungal activity against Neurospora crassa with the IC(50) of 1.0muM. Successful expression of the CSalphabeta-type antifungal peptide in E. coli offers a basis for further studying its functional surface by alanine scanning mutagenesis strategy. Also, our work should be helpful in developing this peptide to an antifungal drug.

Amino Acid Sequence↗
PubMed2006

Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.

Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.

Animals↗
PubMed2006

Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism.

Administration of concanavalin A (Con A) induces a rapid and severe liver injury in mice. Natural killer T (NKT) cells are recognized to be the key effector cells, and a variety of cytokines [e.g., interleukin 4 (IL-4), IL-5, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha)] have been shown to play vital roles in Con A-induced liver injury, whereas the role of IL-15, a critical cytokine in the development and homeostasis of NKT cells, remains obscure. In this study, pretreatment with IL-15 prevented mice from Con A-induced mortality, elevation of serum transaminase, liver necrosis, and hepatocyte apoptosis. Depletion of NKT cells abolished Con A-induced liver injury, which could be restored by adoptive transfer of purified NKT cells but not by that of in vivo or in vitro IL-15-treated hepatic NKT cells. Furthermore, transfer of wild-type NKT cells to CD1d-/- mice restored liver injury, whereas transfer of IL-15-treated NKT cells did not. IL-15 pretreatment decreased the NKT-derived IL-4, IL-5, and TNF-alpha production, thereby resulting in less infiltration of eosinophils, which play a critical role in Con A-induced liver injury. In conclusion, IL-15 protects against Con A-induced liver injury via an NKT cell-dependent mechanism by reducing their production of IL-4, IL-5, and infiltration of eosinophils. These findings suggest that IL-15 may be of therapeutic relevance in human autoimmune-related hepatitis.

Animals↗
PubMed2006

STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice.

Increasing evidence suggests that liver regeneration is suppressed in patients with chronic HCV infection; however, the underlying mechanisms remain unclear. Previously, we demonstrated that injection of the synthetic double-stranded RNA (dsRNA) poly I:C to mimic viral infection suppresses liver regeneration in the partial hepatectomy (PHx) model, whereby IFN-gamma contributes to the inhibition. In this study, we examined the role of the IFN-gamma-activated downstream signal (STAT1) and genes (IRF-1, p21(cip1), and SOCS1) in liver regeneration and hepatocyte proliferation. Results show that disruption of the STAT1 gene abolished poly I:C suppression of liver regeneration and the inhibitory effect of poly I:C on liver regeneration was diminished in IRF-1(-/-) and p21(cip1-/-)mice. Treatment with IFN-gamma in vitro inhibited cell proliferation of wild-type mouse hepatocytes, but not STAT1(-/-) hepatocytes. The inhibitory effect of IFN-gamma on cell proliferation was also diminished in IRF-1(-/-) and p21(cip1-/-) hepatocytes, but enhanced in SOCS1(-/-) hepatocytes. Hepatocyte proliferation was unaffected by treatment with poly I:C alone, but when hepatocytes were co-cultured with liver lymphocytes, proliferation was inhibited by IFN-gamma/STAT1-dependent mechanisms. Moreover, in HCV-infected livers with cirrhosis, activation of STAT1 was detected and correlated positively with liver injury (elevated serum levels of AST) but negatively with hepatocyte proliferation (hepatocyte PCNA and Ki-67 positive immunostaining). In conclusion, STAT1 is involved in dsRNA suppression of liver regeneration; not only does STAT1 activation contribute to liver injury, it may also block liver repair through inhibition of hepatocyte proliferation in HCV-infected patients, playing an important role in the pathogenesis of disease.

Animals↗
PubMed2006

STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity.

Liver fibrosis, a common scarring response to chronic liver injury, is a precursor to cirrhosis and liver cancer. Here, we identified signal transducer and activator of transcription 1 (STAT1) as an important negative regulator in liver fibrosis. Our findings show that disruption of the STAT1 gene accelerated liver fibrosis and hepatic stellate cell (HSC) proliferation in an in vivo model of carbon tetrachloride (CCl4)-induced liver fibrosis. In vitro treatment with IFN-gamma inhibited proliferation and activation of wild-type HSCs, but not STAT1-/- HSCs. Moreover, compared to wild-type cells, cellular proliferation stimulated by serum or platelet-derived growth factor (PDGF) was enhanced and accelerated in STAT1-/- HSCs, which was partially mediated via elevated PDGF receptor beta expression on such cells. Polyinosinic-polycytidylic acid (poly I:C) or IFN-gamma treatment inhibited liver fibrosis in wild-type mice but not in STAT1-/- mice. Induction of NK cell killing of activated HSCs by poly I:C was attenuated in STAT1-/- mice compared to wild-type mice, which was likely due to reduced NKG2D and TRAIL expression on STAT1-/- NK cells. Finally, activation of TGF-beta/Smad3 signaling pathway was accelerated, whereas induction of Smad7 was diminished in the liver of STAT1-/- mice after CCl4 administration compared to wild-type mice. In conclusion, activation of STAT1 attenuates liver fibrosis through inhibition of HSC proliferation, attenuation of TGF-beta signaling, and stimulation of NK cell killing of activated HSCs. STAT1 could be a new therapeutic target for treating liver fibrosis.

Animals↗
PubMed2006

[High-level expression of phenylalanine ammonia-lyase in Lactococcus Lactis via synthesized sequence based on bias codons].

To construct a safer and more efficient gene engineering Lactococcus Lactis for expressing phenylalaine ammonia lyase (PAL) which will be benefit for PKU therapy, pal cDNA of Parsly and synthesized sequence based on Lactococcus Lactis bias codons were recombined into two Lactococcus Lactis NICE systems. The activities of the expressed PAL were detected, and the effect of Lactococcus Lactis bias codons on the expression of exterior protein was analyzed. The results showed that the expression level of PAL was increased by using Lactococcus Lactis bias codons in both Lactococcus Lactis NICE systems. Through which several safer andmore efficient strains of the gene engineering Lactococcus Lactis were obtained.

Cloning, Molecular↗
PubMed2006

Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners.

BACKGROUND & AIMS: Viral hepatitis infection, which is a major cause of liver fibrosis, is associated with activation of innate immunity. However, the role of innate immunity in liver fibrosis remains obscure. METHODS: Liver fibrosis was induced either by feeding mice with the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet or by injecting them with carbon tetrachloride. The Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid, was used to activate innate immunity cells and mediators, including natural killer cells and interferon gamma. RESULTS: In the mouse model of DDC-induced liver fibrosis, natural killer cell activation by polyinosinic-polycytidylic acid induced cell death to activated hepatic stellate cells and attenuated the severity of liver fibrosis. Polyinosinic-polycytidylic acid treatment also ameliorated liver fibrosis induced by carbon tetrachloride. The observed protective effect of polyinosinic-polycytidylic acid on liver fibrosis was diminished through either depletion of natural killer cells or by disruption of the interferon gamma gene. Expression of retinoic acid early inducible 1, the NKG2D ligand, was undetectable on quiescent hepatic stellate cells, whereas high levels were found on activated hepatic stellate cells, which correlated with the resistance and susceptibility of quiescent hepatic stellate cells and activated hepatic stellate cells to natural killer cell lysis, respectively. Moreover, treatment with polyinosinic-polycytidylic acid or interferon gamma enhanced the cytotoxicity of natural killer cells against activated hepatic stellate cells and increased the expression of NKG2D and tumor necrosis factor-related apoptosis-inducing ligand on liver natural killer cells. Blocking NKG2D or tumor necrosis factor-related apoptosis-inducing ligand with neutralizing antibodies markedly diminished the cytotoxicity of polyinosinic-polycytidylic acid-activated natural killer cells against activated hepatic stellate cells. CONCLUSIONS: Our findings suggest that natural killer cells kill activated hepatic stellate cells via retinoic acid early inducible 1/NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent mechanisms, thereby ameliorating liver fibrosis.

Animals↗
PubMed2006

Chronic ethanol consumption inhibits hepatic natural killer cell activity and accelerates murine cytomegalovirus-induced hepatitis.

BACKGROUND: Chronic alcohol drinking accelerates the progression of liver disease in patients with hepatitis viral infection; however, the underlying mechanisms are not fully understood. METHODS: Here, we examined the effects of chronic ethanol feeding on hepatic natural killer (NK) cells and liver injury in 2 murine models of liver injury: injection of synthetic double-stranded RNA polyinosinic-polycytidylic acid (poly I:C), which mimics viral infection, and infection with murine cytomegalovirus (MCMV). Mice were fed the Lieber-DeCarli liquid diet containing 5% (vol/vol) ethanol for 8 weeks, resulting in a significant decrease in the percentage and total number of NK cells in the liver. RESULTS: In control, pair-fed mice, poly I:C injection induced NK cell accumulation in the liver and activated hepatic NK cell cytotoxicity, whereas such induction and activation were diminished in ethanol-fed mice. Treatment with poly I:C also induced expression of NKG2D, granzyme B, perforin, Fas L, TRAIL, and IFN-gamma on liver lymphocytes, which were delayed or reduced in ethanol-treated mice compared with pair-fed mice. In contrast, chronic ethanol feeding did not affect poly I:C-induced mild liver injury. Furthermore, MCMV infection activated hepatic NK cells and induced hepatic inflammation and injury. Chronic ethanol consumption inhibited hepatic NK cell activation during MCMV infection, but enhanced MCMV-induced liver injury, viral titer, and inflammation in the liver. CONCLUSIONS: Taken together, these findings suggest that chronic ethanol consumption decreases hepatic NK activity, thereby accelerating MCMV-induced hepatitis and liver injury.

Alanine Transaminase↗
PubMed2006

The complement system in liver diseases.

The complement system plays an important role in mediating both acquired and innate responses to defend against microbial infection, and in disposing immunoglobins and apoptotic cells. The liver (mainly hepatocytes) is responsible for biosynthesis of about 80-90% of plasma complement components and expresses a variety of complement receptors. Recent evidence from several studies suggests that the complement system is also involved in the pathogenesis of a variety of liver disorders including liver injury and repair, fibrosis, viral hepatitis, alcoholic liver disease, and liver ischemia/reperfusion injury. In this review, we will discuss the potential role of the complement system in the pathogenesis of liver diseases.

Animals↗
PubMed2005

IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: regulation by SOCS3.

The precise role of IL-6 in liver regeneration and hepatocyte proliferation is controversial and the role of SOCS3 in liver regeneration remains unknown. Here we show that in vitro treatment with IL-6 inhibited primary mouse hepatocyte proliferation. IL-6 induced p21cip1 protein expression in primary mouse hepatocytes. Disruption of the p21cip1 gene abolished the inhibitory effect of IL-6 on cell proliferation. Co-culture with nonparenchymal liver cells diminished IL-6 inhibition of hepatocyte proliferation, which was likely due to IL-6 stimulation of nonparenchymal cells to produce HGF. Finally, IL-6 induced higher levels of p21cip1 protein expression and a slightly stronger inhibition of cell proliferation in SOCS3+/- mouse hepatocytes compared to wild-type hepatocytes, while liver regeneration was enhanced and prolonged in SOCS3+/- mice. Our findings suggest that IL-6 directly inhibits hepatocyte proliferation via a p21cip1-dependent mechanism and indirectly enhances hepatocyte proliferation via stimulating nonparenchymal cells to produce HGF. SOCS3 negatively regulates liver regeneration.

Animals↗
PubMed2005

A p53 polymorphism modifies the risk of hepatocellular carcinoma among non-carriers but not carriers of chronic hepatitis B virus infection.

To clarify the modifying effect of the codon 72 p53 polymorphism on hepatocellular carcinoma (HCC) stratified by chronic hepatitis B virus (HBV) infection status, 111 incident cases of HCC and 424 controls in HBV-negative subjects and 135 cases and 125 controls in HBV-positive subjects were identified. No correlation between the polymorphism and HCC risk was found when comparing the HBV-positive cases to controls. However, in HBV-negative subjects, Arg/Pro and Pro/Pro genotypes had a 1.97-fold and a 3.36-fold increased risk for HCC, respectively. In subjects with the Pro allele and family history of HCC yielded an 11.81-fold increased risk of HCC.

Adult↗
PubMed2005

Poly I:C prevents T cell-mediated hepatitis via an NK-dependent mechanism.

BACKGROUND/AIMS: T cell immune responses play key roles in the pathogenesis of viral hepatitis, and innate immunity is known to be also activated during this process, however, the effects of innate immunity activation on T cell-mediated hepatitis remain obscure. Here we examined the effect of the activation of NK cells induced by toll-like receptor 3 (TLR3) ligand, polyinosinic-polycytidylic acid (poly I:C), on concanavalin A (Con A)-induced T cell-mediated liver injury. METHODS: Mice received nontoxic intraperitoneal poly I:C injection before Con A intravenous administration. The liver injury was examined by measuring serum transaminase and pathology, and the function of hepatic lymphocytes was detected by FACS analysis. RESULTS: Poly I:C pretreatment protected against T cell-mediated hepatitis, as evidenced by decreased mortality, hepatic necrosis, serum transaminase levels and inflammatory cytokines (IL-4, IFN-gamma). The protective effect of poly I:C was diminished in NK-depleted mice, which could be partially restored by adoptive transfer of NK cells. Administration of poly I:C caused NKT and T cell apoptosis via enhancing expression of Fas protein on these cells and expression of Fas ligand on NK cells. CONCLUSIONS: These findings suggest that activation of NK cells by poly I:C prevents Con A-induced T cell-hepatitis via downregulation of T/NKT cells and subsequent reduction of inflammatory cytokines.

Animals↗
PubMed2005

Generation of functional ion-channel tools by E3 targeting.

Here we describe a strategy for generating ion-channel inhibitors. It takes advantage of antibody specificity combined with a pattern recognition approach that targets the third extracellular region (E3) of a channel. To test the concept, we first focused on TRPC5, a member of the transient receptor potential (TRP) calcium channel family, the study of which has been hindered by poor pharmacological tools. Extracellular application of E3-targeted anti-TRPC5 antibody led to a specific TRPC5 inhibitor, enabling TRPC5 to be distinguished from its closest family members, and TRPC5 function to be explored in a relatively intractable physiological system. E3 targeting was further applied to voltage-gated sodium channels, leading to discovery of a subtype-specific inhibitor of Na(V)1.5. These examples illustrate the potential power of E3 targeting as a systematic method for producing gene-type specific ion-channel inhibitors for use in routine assays on cells or tissues from a range of species and having therapeutic potential.

Antibodies, Monoclonal↗