Abstract Understanding the mechanisms that lead to autoimmunity is critical for defining potential therapeutic pathways. In this regard there have been considerable efforts in investigating the interacting roles of TGF- β and IL-2 on the function regulatory T cells. We have taken advantage of dnTGF- β RII Il2ra −/− (abbreviated as Il2ra −/− Tg) mouse model, which allows a direct mechanistic approach to define the relative roles of TGF- β and IL-2 on Treg development. Il2ra −/− Tg mice spontaneously developed multi-organ autoimmune diseases with expansion of pathogenic T cells and enhanced germinal center response at 3–4 weeks of age. Importantly, peripheral Treg cells from Il2ra −/− Tg mice demonstrated an activated Th1-like stable phenotype and normal in vitro suppressive function, while thymus Treg increased but manifested decreased suppressive function. Interestingly, neither thymus nor peripheral Treg cells of Il2ra −/− Tg mice contained Neuropilin-1 + or PD-1 hi phenotype, resulting in defective follicular regulatory T (Tfr) cell development. Such defective Tfr development led to elevated follicular T helper cells, enhanced germinal center responses and increased plasma cell infiltration. These data demonstrate an important synergetic role of TGF- β and IL-2 in the generation, activation and stability of Treg cells, as well as their subsequent development into Tfr cells.
Interleukin-2 (IL-2) is a potent T-cell mitogen that can adjuvant anti-cancer adoptive T-cell transfer (ACT) immunotherapy by promoting T-cell engraftment.
Unlike nucleobase modifications in canonical restriction-modification systems, DNA phosphorothioate (PT) epigenetic modification occurs in the DNA sugar-phosphate backbone when the nonbridging oxygen is replaced by sulfur in a double-stranded (ds) or single-stranded (ss) manner governed by DndABCDE or SspABCD, respectively. SspABCD coupled with SspE constitutes a defense barrier in which SspE depends on sequence-specific PT modifications to exert its antiphage activity. Here, we identified a new type of ssDNA PT-based SspABCD-SspFGH defense system capable of providing protection against phages through a mode of action different from that of SspABCD-SspE. We provide further evidence that SspFGH damages non-PT-modified DNA and exerts antiphage activity by suppressing phage DNA replication. Despite their different defense mechanisms, SspFGH and SspE are compatible and pair simultaneously with one SspABCD module, greatly enhancing the protection against phages. Together with the observation that the sspBCD-sspFGH cassette is widely distributed in bacterial genomes, this study highlights the diversity of PT-based defense barriers and expands our knowledge of the arsenal of phage defense mechanisms.IMPORTANCE We recently found that SspABCD, catalyzing single-stranded (ss) DNA phosphorothioate (PT) modification, coupled with SspE provides protection against phage infection. SspE performs both PT-simulated NTPase and DNA-nicking nuclease activities to damage phage DNA, rendering SspA-E a PT-sensing defense system. To our surprise, ssDNA PT modification can also pair with a newly identified 3-gene sspFGH cassette to fend off phage infection with a different mode of action from that of SspE. Interestingly, both SspFGH and SspE can pair with the same SspABCD module for antiphage defense, and their combination provides Escherichia coli JM109 with additive phage resistance up to 105-fold compared to that for either barrier alone. This agrees with our observation that SspFGH and SspE coexist in 36 bacterial genomes, highlighting the diversity of the gene contents and molecular mechanisms of PT-based defense systems.
Yiqi Liangxue Jiedu prescription (YLJP), a Chinese medicine that is commonly used to prevent liver cancer and is authorized by a national patent (patent No. ZL202110889980.5) has a therapeutic effect on precancerous lesions; however, the underlying mechanism remains unclear. This study is aimed at determining the clinical therapeutic efficacy of YLJP in patients with precancerous liver lesions and to explore and validate its possible effector mechanism.
Sleep habits are associated with stroke in western populations, but this relation has been rarely investigated in China. Moreover, the differences among stroke subtypes remain unclear. This study aimed to explore the associations of total stroke, including ischemic and hemorrhagic type, with sleep habits of a population in southern China. We performed a case-control study in patients admitted to the hospital with first stroke and community control subjects. A total of 333 patients (n = 223, 67.0%, with ischemic stroke; n = 110, 23.0%, with hemorrhagic stroke) and 547 controls were enrolled in the study. Participants completed a structured questionnaire to identify sleep habits and other stroke risk factors. Least absolute shrinkage and selection operator (Lasso) and multiple logistic regression were performed to identify risk factors of disease. Incidence of stroke, and its subtypes, was significantly associated with snorting/gasping, snoring, sleep duration, and daytime napping. Snorting/gasping was identified as an important risk factor in the Lasso logistic regression model (Lasso' β = 0.84), and the result was proven to be robust. This study showed the association between stroke and sleep habits in the southern Chinese population and might help in better detecting important sleep-related factors for stroke risk.
Abstract Objective To identify the key drugs of Yangyin Fuzheng Jiedu prescription (YFJP) and investigate their therapeutic effects against hepatocellular carcinoma (HCC) and the potential mechanism using network pharmacology. Methods The H22 tumor‐bearing mouse model was established. Thirty male BALB/c mice were divided randomly into five groups. The mice were orally treated with either disassembled prescriptions of YFJP or saline solution continuously for 14 days. The mice were weighed every 2 days during treatment and the appearance of tumors was observed by photographing. The tumor inhibition rate and the spleen and thymus indexes were calculated. Hematoxylin and eosin and immunohistochemical staining were performed to observe the histological changes and tumor‐infiltrating lymphocytes. Cell apoptosis was determined by terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling staining. The proportion of CD8 + T cells and the expression of programmed cell death protein 1 (PD‐1), T cell immunoglobulin domain and mucin domain‐3 (Tim‐3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were analyzed using flow cytometry. The production of serum cytokines was detected using the Milliplex® MAP mouse high sensitivity T cell panel kit. The active components of the key drugs and HCC‐related target proteins were obtained from the corresponding databases. The putative targets for HCC treatment were screened by target mapping, and potential active components were screened by constructing a component‐target network. The interactive targets of putative targets were obtained from the STRING database to construct the protein–protein interaction network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed based on potential targets. The gene–gene inner and component‐target‐pathway networks were constructed and analyzed to screen the key targets. Western blotting was used to evaluate the protein expression of the key targets in the tumor‐bearing mouse model. The binding activity of the key targets and compounds was verified by molecular docking. Results Among the three disassembled prescriptions of YFJP, the Fuzheng prescription (FZP) showed significant antitumor effects and inhibited weight loss during the treatment of H22 tumor‐bearing mice. FZP increased the immune organ index and the levels of CD8 + and CD3 + T cells in the spleen and peripheral blood of H22 tumor‐bearing mice. FZP also reduced the expression of PD‐1, TIGIT, and TIM3 in CD8 + T cells and the production of IL‐10, IL‐4, IL‐6, and IL‐1β. Network pharmacology and experimental validation showed that the key targets of FZP in the treatment of HCC were PIK3CA, TP53, MAPK1, MAPK3, and EGFR. The therapeutic effect on HCC was evaluated based on HCC‐related signaling pathways, including the PIK3‐Akt signaling pathway, PD‐L1 expression, and PD‐1 checkpoint pathway in cancer. GO enrichment analysis indicated that FZP positively regulated the molecular functions of transferases and kinases on the cell surface through membrane raft, membrane microarea, and other cell components to inhibit cell death and programmed cell death. Conclusion FZP was found to be the key disassembled prescription of YFJP that exerted antitumor and immunoregulatory effects against HCC. FZP alleviated T cell exhaustion and improved the immunosuppressive microenvironment via HCC‐related targets, pathways, and biological processes.
Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) indicated for the treatment of hepatocellular carcinoma (HCC). Its potential targets and molecular mechanisms are not clear. Therefore, this study intends to explore the molecular mechanism of YFJP based on network pharmacology analysis and in vitro validation.Through univariate and multivariate analyses and survival analysis in HCC patients with or without YFJP treatment we found that drinking alcohol, alfafeto protein ≥ 400 ng/l, baseline portal vein tumor thrombus and total bilirubin level ≥ 18.8 μM) were independent risk factors for poor prognosis, while red blood cell count ≥ 4 × 109/l and TCM treatment were independent protective factors. Besides, YFJP prolonged the cumulative survival of HCC patients. Using online pharmacological methods, we obtained 58 relevant compounds and molecular 53 targets. By using scratch test, Transwell assay, EdU assay, and TUNEL staining, we found that YFJP-containing serum repressed the migration, invasion and proliferation of HCC cells in vitro, and induced cell apoptosis. Moreover, YFJP diminished the gene expression of TP53, CCND1, p-EGFR, EGF, VEGFA, JUN, IL6, COX-2, AKT1, and MAPK1 in HCC cells, but elevated the expression of ESR1 and CASP3.Taken together, results showed that YFJP attenuated HCC progression through mediating effects on HCC-related genes.
Many human cancers manifest the capability to circumvent attack by the adaptive immune system. In this work, we identified a component of immune evasion that involves frequent up-regulation of fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses immune attack, as revealed by cancer cells engineered to lack its expression. FMRP-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, FMRP's immunosuppression was multifactorial, involving repression of the chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with up-regulation of three immunomodulators-interleukin-33 (IL-33), tumor-secreted protein S (PROS1), and extracellular vesicles. Gene signatures associate FMRP's cancer network with poor prognosis and response to therapy in cancer patients. Collectively, FMRP is implicated as a regulator that orchestrates a multifaceted barrier to antitumor immune responses.
Immune stimulatory antibodies and cytokines elicit potent antitumor immunity. However, the dose-limiting systemic toxicity greatly hinders their clinical applications. Here, we demonstrate a chemical approach, termed “switchable” immune modulator (Sw-IM), to limit the systemic exposure and therefore ameliorate their toxicities. Sw-IM is a biomacromolecular therapeutic reversibly masked by biocompatible polymers through chemical linkers that are responsive to tumor-specific stimuli, such as high reducing potential and acidic pH. Sw-IMs stay inert (switch off) in the circulation and healthy tissues but get reactivated (switch on) selectively in tumor via responsive removal of the polymer masks, thus focusing the immune boosting activities in the tumor microenvironment. Sw-IMs applied to anti–4-1BB agonistic antibody and IL-15 cytokine led to equivalent antitumor efficacy to the parental IMs with markedly reduced toxicities. Sw-IM provides a highly modular and generic approach to improve the therapeutic window and clinical applicability of potent IMs in mono- and combinational immunotherapies.
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