BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
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IF 2.5
Han Liu,Zhuo Li,Xilin Zhu,Ying Liu,XiaoPan Wu
Background & aims Caspase-10 (CASP10) participates in death receptor–mediated apoptosis, but the relevance of the CASP10 coding variant rs13006529 (T > A; p.Leu522Ile) to PEG-IFN-α response in chronic hepatitis B (CHB) is unknown. We assessed this association and whether differential apoptotic activity explains variant-associated HBV burden. Methods rs13006529 was genotyped in 262 patients receiving PEG-IFN-α with or without nucleos(t)ide analogues. Allele and genotype frequencies were compared by χ 2 tests; sustained virological response (SVR) was analyzed by univariable and multivariable logistic regression. HBV-infected HepG2-NTCP cells expressing empty vector or either CASP10 variant were compared; variant-expressing cells received vehicle or zVAD-fmk. Apoptosis was assessed by flow cytometry, caspase-3/7 activity, and Western blotting. HBV total RNA and pgRNA, intracellular DNA, cccDNA, and HBsAg/HBeAg were measured by RT-qPCR, qPCR, Southern blotting, and ELISA, respectively. Results The A allele was more frequent in patients without than with SVR (30.6% vs 17.1%; P = 0.002) and independently associated with lower odds of SVR (adjusted OR per A allele, 0.50; 95% CI, 0.27–0.86; P = 0.017). SVR rates were 36.9% in TT and 19.8% in AT/AA carriers (P = 0.003). Leu522-expressing cells showed greater apoptosis and lower HBV total RNA, pgRNA, intracellular DNA, and cccDNA than Ile522-expressing cells. zVAD-fmk attenuated the between-variant difference in apoptosis and partially narrowed the corresponding differences in HBV RNA and intracellular DNA. Conclusions rs13006529 was independently associated with PEG-IFN-α response. Differential caspase-dependent apoptotic activity partly accounts for variant-associated HBV burden differences.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Heng Wang,Guojiang Zhang,Cai Zhao,Youan Xue,Di Zhu,Yan Chang
While interferon-alpha (IFN-α) demonstrates potent antineoplastic activity against hepatocellular carcinoma (HCC), but many patients have a low response rate and may even develop resistance to it. It is necessary to find new strategies to reduce IFN-α resistance and improve its efficacy. RAR-related orphan receptor gamma t (RORγt) agonists exhibit dual immunomodulatory functions, demonstrating both immunosuppression-reducing and immune-activating properties. In this study, we demonstrated that the combination of the RORγt agonist-LYC-55716 and IFN-α significantly promoted cytotoxic T cell 17 (Tc17 cell) differentiation and interleukin-17a (I1-17a) expression through activation of the Akt/Stat3 signal pathway. The combination therapy markedly enhanced the tumoricidal activity of differentiated Tc17 cells against hepatoma carcinoma cells. Moreover, this therapeutic strategy showed superior antitumor efficacy in multiple HCC models while maintaining a favorable safety profile compared to single-agent treatment. Importantly, our findings revealed that the combination treatment significantly enhanced CD8 + T cells infiltration into tumor tissues. Moreover, our mechanistic studies revealed that the observed synergistic antitumor effect was mediated by enhanced CD8 + T cell tumor infiltration, which was facilitated by the C-X-C motif chemokine ligand 10 (Cxcl10)- C-X-C motif chemokine receptor 3 (Cxcr3) interaction. Collectively, these findings support a novel immunoregulatory strategy that leverages RORγt agonists to enhance the efficacy of IFN-α in HCC therapy
研究领域:
肿瘤免疫学
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肝脏疾病
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分子生物学
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药物开发
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DOI
PubMed
高影响因子
Frontiers in Immunology
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2022
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IF 8.786
Qin Sheng,Huang Xianzhang,Qu Shaogang
Respiratory syncytial virus (RSV) infection is the most frequent cause of hospitalization in pediatric patients. Current systemic treatment and vaccines are not curative and re-infection is often associated with a more drastic incidence of the disease. Baicalin is a flavonoid isolated from Scutellaria baicalensis with potent anti-viral characteristics, namely against RSV. However, its precise mechanism of action remains unclear. Here, using in vitro methods and an in vivo murine model of RSV infection, we showed that baicalin inhibits RSV replication induces translational upregulation of type I interferons (IFNs), IFN-α and IFN-β, and reverses epithelial thickening in lung tissues. Moreover, baicalin inhibits transcription of the RSV non-structural proteins NS1 and NS2. Molecular docking and surface plasmon resonance-based affinity analysis showed that baicalin also binds to the α3 helix of the NS1 protein with an affinity constant of 1.119 × 10−5 M. Polysome profiling showed that baicalin inhibits translation of the RSV matrix protein (M) RNA. Baicalin mediates increased release of the ribosomal protein L13a from the large ribosomal subunit, where the extra ribosomal subunit L13a inhibits M RNA translation. These results comprehensively establish the multiple mechanisms by which baicalin induces a potent innate immune response against RSV infection.
研究领域:
病毒学
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免疫学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-20
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IF 11.4
Xu Wenjing,Li Yingqiu,Liu Lumei,Xie Jing,Hu Zongren,Kuang Shida,Fu Xinying,Li Bonan,Sun Tiansong,Zhu Congxu,He Qinghu,Sheng Wen
Background Prostate cancer (PCa) incidence and mortality rates are rising. Our previous research has shown that the combination of icariin (ICA) and curcumol (CUR) induced autophagy and ferroptosis in PCa cells, and altered lipid metabolism. We aimed to further explore the effects of the combination of ICA and CUR on gut microbiota, metabolism, and immunity in PCa. Methods A mouse subcutaneous RM-1 cell tumor model was established. 16 S rRNA sequencing was performed to detect changes in fecal gut microbiota. SCFAs in mouse feces, and the effect of ICA-CUR on T-cell immunity, IGFBP2, and DNMT1 were examined. Fecal microbiota transplantation (FMT) was conducted to explore the mechanism of ICA-CUR. Si-IGFBP2 and si/oe-DNMT1 were transfected into RM-1 and DU145 cells, and the cells were treated with ICA-CUR to investigate the mechanism of ICA-CUR on PCa development. Results After treatment with ICA-CUR, there was a decrease in tumor volume and weight, accompanied by changes in gut microbiota. ICA-CUR affected SCFAs and DNMT1/IGFBP2/EGFR/STAT3/PD-L1 pathway. ICA-CUR increased the positive rates of CD3 + CD8 + IFN-γ, CD3 + CD8 + Ki67 cells, and the levels of IFN-γ and IFN-α in the serum. After FMT (with donors from the ICA-CUR group), tumor volume and weight were decreased. SCFAs promote tumor development and the expression of IGFBP2. In vitro, DNMT1/IGFBP2 promotes cell migration and proliferation. ICA-CUR inhibits the expression of DNMT1/IGFBP2. Conclusions ICA-CUR mediates the interaction between gut microbiota and the DNMT1/IGFBP2 axis to inhibit the progression of PCa by regulating immune response and metabolism, suggesting a potential therapeutic strategy for PCa.
研究领域:
肿瘤学
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免疫学
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微生物学
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药理学
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DOI
PubMed
高影响因子
ARCHIVES OF VIROLOGY
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2024
·Vol. 169
·期 11
·1-10
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IF 2.5
Jiao Qian,Zhu Shu,Liao Baolin,Liu Huiyuan,Guo Xiaoyan,Wu Lina,Chen Chuming,Peng Liang,Xie Chan
NLR family member X1 (NLRX1) is an important member of the NOD-like receptor (NLR) family and plays unique roles in immune system regulation. Patients with hepatitis B virus (HBV) infection are more likely to have the NLRX1 mutation p.Arg707Cys than healthy individuals. It has been reported that NLRX1 increases the infection rate of HBV in HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). However, the role of NLRX1 mutation ( p.Arg707Cys ) in hepatitis remains unclear. We constructed Huh7 cells that stably overexpressed NTCP, using LV003 lentivirus. First, wild-type (WT) and mutant (MT) NLRX1 overexpression plasmids were constructed. The MT plasmid contained a point mutation at position 707 of the WT overexpression plasmid. Then, Huh7-NTCP cells were transfected with the WT or MT NLRX1 overexpression plasmid, and subsequent NLRX1 expression was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. HBV RNA levels were determined using RT-qPCR. HBsAg and HBcAg levels were confirmed immunohistochemically. Interferon alpha (IFN-α), interleukin 6 (IL-6), and type I interferon beta (IFN-β) levels were determined using enzyme-linked immunosorbent assay kits. p-p65, p-interferon regulatory factor (IRF) 3, and p-IRF7 expression levels were examined using western blot. The interaction of NLRX1 and retinoic acid-inducible gene (RIG)-1/mitochondrial antiviral signaling (MAVS) protein was confirmed by coimmunoprecipitation. The interaction of NLRX1 with IFN-α, IL-6, or IFN-β was analyzed by dual luciferase reporter gene assay. The levels of HBV RNA, HBsAg, and HBcAg in infected cells transfected with the WT NLRX1 or MT NLRX1 expression plasmid were higher than those in the untransfected control group; and these levels were lower in the cells transfected with MT NLRX1 than in those transfected with WT NLRX1. The levels of IFN-α, IFN-β, IL-6, p-p65, p-IRF3, and p-IRF7 were lower in cells transfected with WT NLRX1 or MT NLRX1 than in control cells. The levels of IFN-β, p-p65, p-IRF3, and p-IRF7 were higher in cells transfected with MT NLRX1 than in those transfected with WT NLRX1. Moreover, NLRX1 competitively inhibited RIG1 binding to MAVS, but the mutation in MT NLRX1 reduced this inhibitory effect. In addition, NLRX1 decreased the promoter activity of IFN-α, IFN-β, and IL-6. Our findings revealed that NLRX1 is a regulatory factor that inhibits the anti-HBV ability of hepatocytes and that the mutation p.Arg707Cys in NLRX1 suppresses HBV infection and activates the IFN/nuclear factor κB pathway.
研究领域:
免疫学
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病毒学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
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