Journal of Molecular Cell Biology
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2022
·Vol. 14
·期 12
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IF 8.185
Han Yuheng,Ouyang Xinxing,Chen Yao,Lai Shujing,Sun Hongxiang,Wu Ningbo,Ruan Chun,Lu Limin,Su Bing
It is well documented that the neonatal thymus-derived (neonatal-TD) regulatory T cells (Treg) are essential to prevent lethal autoimmune diseases and allergies, and neonatal and adult thymus possesses distinct output potentials for naïve T cells, including Treg. However, the molecular features and detailed functional differences between neonatal-TD and adult thymus-derived (adult-TD) T cells in terms of their ability to maintain immune homeostasis during long-term environmental influences are still largely unknown, partially due to the lack of appropriate animal models to precisely trace these cells at specific time points. In this study, neonatal-TD and adult-TD CD4+ T cells from the spleen and Peyer's patches were traced for 9 weeks by a T cell origin-time tracing mouse model and analysed by single-cell RNA sequencing. More Treg but fewer naïve T cells were found in neonatal-TD CD4+ T cells from both tissues than those from adult-TD counterparts. Interestingly, the neonatal-TD Treg in both the spleen and Peyer's patches exhibited augmented expression of Foxp3, Gata3, Ctla4, Icos, Il2ra, Tgfb1, and Nrp1, as well as enriched Gene Ontology terms like T cell activation and tolerance induction, indicating an enhanced immunosuppressive function. These results were further confirmed by flow cytometry analysis and in vitro immune suppression assays. Flow cytometry also revealed a significantly higher proportion of neonatal-TD Treg in total Treg than that of adult-TD counterparts, suggesting the longer lifespan of neonatal-TD Treg. To investigate the intrinsic features of neonatal-TD and adult-TD CD4+ T cells, a shortened tracing time was performed. Surprisingly, the neonatal-TD and adult-TD CD4+ T cells had similar proportions of Treg and did not exhibit significant differences in Foxp3, Gata3, Ctla4, Icos, Il2ra, and Tgfb1 expression levels after tracing for 12 days. On the other hand, neonatal-TD Treg present an increased Nrp1 expression level compared with adult-TD counterparts, indicating the enhanced stability. Together, our work reveals that the neonatal-TD Treg are more immunosuppressive, which is likely shaped primarily by environmental factors.
研究领域:
免疫学
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分子生物学
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基因组学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
Simiao Qiao,Xingpan Lian,Mengfan Yue,Qin Zhang,Zhifeng Wei,Li Chen,Yufeng Xia,Yue Dai
Previously, we reported that oral administration of madecassoside, the main active triterpene in Centella asiatica L., exerted anti-arthritis effect by inducing the generation of regulatory T (Treg) cells in small intestine. This study investigates the action site and mechanism of madecassoside to induce Treg cells. In collagen-induced arthritis (CIA) of rats, oral administration of madecassoside significantly alleviated arthritis symptoms, but its main metabolite madecassic acid did not, suggesting that madecassoside functions in the parent form. Madecassoside was shown to increase the number of Treg cells and promote the expression of Foxp3 and IL-10 in rat ileum rather than duodenum and jejunum, as detected using the immunohistochemistry assay and quantitative PCR assay, respectively. Unexpectedly, madecassoside was absent of significant effect on in vitro Treg cell differentiation and the expression of Foxp3 and IL-10. A combined use of broad-spectrum antibiotics resulted in significant reduction of the anti-arthritis effect of madecassoside in CIA rats. The 16S rRNA gene sequence showed that madecassoside could reverse the changes of gut microbiota under arthritis condition, and enrich several bacteria such as Lachnospiraceae, Butyricicoccus, Faecalibacterium, Butyricicoccus pullicaecorum and so on. GC-MS assay showed that madecassoside elevated the levels of acetic acid and butyric acid, but not other short chain fatty acids (SCFAs) in the cecum contents of CIA rats. Butyric acid rather than acetic acid could induce the in vitro differentiation of Treg cells and the expression of Foxp3 and IL-10. Accordingly, when madecassoside was co-administered with heptanoyl CoA, the competitive inhibitor of butyrate synthase, its effect on butyric acid production, Treg cell proportion and arthritis nearly disappeared. These findings indicate that oral madecassoside induces the generation of Treg cells and therefore displays anti-arthritis effect in the parent form but not metabolites, and the ileum is the main action site. The mechanism of madecassoside can be summarized as: expansion of the richness of butyrate-producing bacteria-up-regulation of intestinal butyrate level-induction of Treg cell differentiation and IL-10 expression.
研究领域:
免疫学
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药理学
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微生物学
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风湿病学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2024
·
IF 4
Lv ZhaoHui,Chen Xiao C.
Postmenopausal osteoporosis (PMOP) is a common chronic disease, and the loss of bone density and bone strength after menopause is its main symptom. Effective treatments for PMOP are still uncertain, but Chinese medicine has some advantages in slowing down bone loss. Shengu granules are often used clinically to treat PMOP. It has been shown to be an effective prescription for the treatment of PMOP, and there is evidence that gut flora may play an important role.However, whether Shengu granules attenuate PMOP by modulating gut flora and related mechanisms remains unclear. In this study. We examined the bone strength of the femur, the structure of the intestinal microbiota and SCFAs in the feces, the level of FOXP3 cells in the colon, the condition of the mucosa, and the level of cytokines in the serum, the protein expression of OPG and RANKL in femur, the protein expression of ZO-1 and Occludin in colon. Our research has found that Shengu granules restored a significant amount of intestinal flora. Improvement of intestinal flora disorders, elevation of its metabolite SCFAs and elevation of the proportion of FOXP3 cells decreased the expression of serum IL-17 and TNF-α and increased the expression of serum IL-10 and TGF-β. On the one hand, it reduced intestinal inflammation and repaired the intestinal barrier; on the other hand, it regulated the OPG/RANKL signaling axis, thus thereby ameliorating bone loss.
研究领域:
药理学
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免疫学
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内分泌学
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胃肠病学
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2023
·
IF 7.3
Ben Yi,Shuai Zhang,Suying Yan,Yanfei Liu,Zhiqiang Feng,Tianhao Chu,Jun Liu,Wei Wang,Jun Xue,Chunze Zhang,Yijia Wang
Introduction Tumor-infiltrating T lymphocytes in the tumor microenvironment are critical factors influencing the prognosis and chemotherapy outcomes. As a Chinese herbal medicine, Marsdenia tenacissima extract (MTE) has been widely used to treat cancer in China. Its immunoregulatory effects on tumor-associated macrophages is well known, but whether it regulates tumor-infiltrating T-cell functions remains unclear. Method We collected 17 tumor samples from MTE-administered colorectal cancer patients, 13 of which showed upregulation of CD3+/CD8+ tumor-infiltrating T cells. Further in vitro and in vivo experiments were performed to investigate the regulatory effects of MTE on tumor-infiltrating T cells and immune escape of tumors. Results Under single and co-culture conditions, MTE inhibited TGF-β1 and PD-L1 expression in the colorectal cancer (CRC) cell lines HCT116 and LoVo. In Jurkat cells, MTE inhibited FOXP3 and IL-10 expression, increased IL-2 expression, but had no effect on PD-1 expression. These findings were confirmed in vitro using subcutaneous and colitis-associated CRC mouse models. MTE also increased the density of CD3+/CD8+ tumor-infiltrating T cells and exhibited considerable tumor-suppressive effects in these two tumor mouse models. Conclusions Our findings suggested that MTE inhibits the immune escape of cancer cells, a precipitating factor increasing the immune response of T lymphocytes.
研究领域:
肿瘤学
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免疫学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Yumei Sun,Jihong Wang,Peiyao Hu,Yi Tang,Yanwen Wang,Jianzhou Ye,Xuesong Yang,Junlin Yin
Tripterygium hypoglaucum (Lévl.) Hutch rhizome (THH) is mainly used in the clinical setting for the treatment of autoimmune diseases such as rheumatoid arthritis. In total, four active compounds were isolated from THH methanol extract （THH-MeOH）and identified. The HPLC results showed that the proportions of the active ingredients in THH-MeOH (i.e., celastrol, triptolide, and 3- O -acetyloleanolic acid) were 0.79 ‰, 0.46 ‰, and 0.76 ‰, respectively. THH-MeOH attenuated the M5-induced hyperproliferation of HaCaT cells, decreased the mRNA expression levels of inflammatory cytokines, and inhibited the phosphorylation of I κ B α , NF- κ B p65, MAPK, and STAT3/JAK2. Furthermore, THH-MeOH significantly reduced PASI scores in mice; reduced the level of Ki67 expression in skin tissues; decreased the expression of inflammatory cytokines in the skin lesions and serum; and ameliorated the IMQ-induced imbalance in the ROR γ t / Foxp3 ratio. The extract can attenuate psoriasis-like lesions by inhibiting cellular hyperproliferation, ameliorating inflammatory reactions, and modulating immune responses. Our work provides a theoretical basis to support the use of THH for treating psoriasis.
研究领域:
药理学
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免疫学
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皮肤科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
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2023
·
IF 4
Ran Tu,Cheng Zhou,Wenfeng Huang,Zhengping Feng,Qiufang Zhao,Xiaofei Shi,Langjun Cui,Keke Chen
Rationale and objectives Fuzi, the dried root of Aconitum carmichaelii Debx, is one of the widely used traditional Chinese medicines. Fuzi polysaccharides are considered the most bioactive compounds with immunomodulatory functions, however, the mechanisms have not been evaluated. This study aims to systematically investigate the effects of Fuzi polysaccharides on the gut microbiota and immune function using a mouse model immunosuppressed with cyclophosphamide. Methods The short-chain fatty acid levels in cecal contents were measured by gas chromatography-mass spectrometry. The gut microbiota 16S rRNA gene were sequenced by next generation sequencing. The mRNA expression levels of NF-κB, IL-6, TNF-α, iNOS and COX-2 were measured using quantitative real-time polymerase chain reaction. The protein expression of occludin and zonula occludens-1 were analyzed by Western blot. The white blood cells were counted using automated hematology analyzer, and CD4 + FOXP3 + /CD4 + ratio was measured by flow cytometry. Results and Conclusions Fuzi polysaccharides had the function of elevating the concentration of acetic acid, propionic acid, isobutyric acid, and n-butyric acid in the cecum. Meanwhile, Fuzi polysaccharides could decrease the relative abundance of Helicobacter , Anaerotruncus , Faecalibacterium , Lachnospira , Erysipelotrichaceae _UCG-003, Mucispirillum , and Mycoplasma , and increase the relative abundance of Rhodospirillales , Ruminococcaceae _UCG-013, Mollicutes _RF39, Ruminococcus _1, Christensenellaceae _R-7_group, and Muribaculaceae in the gut. Furthermore, Fuzi polysaccharides exhibited the function of increasing spleen and thymus indices and number of white blood cells and lymphocytes. Fuzi polysaccharides could reverse the decreased mRNA expression of NF-кB, IL-6, and iNOS, differentiation of CD4 + FOXP3 + regulatory T cells as well as protein expression of occludin and zonula occludens-1 induced by cyclophosphamide. In addition, the mRNA and protein expression of cytokines were significantly correlated with the abundance of gut microbiota under Fuzi polysaccharides treatment. Collectively, the above results demonstrated that Fuzi polysaccharides could regulate inflammatory cytokines and gut microbiota composition of immunosuppressive mice to improve immunity, thereby shedding light on revealing the molecular mechanism of polysaccharides of traditional Chinese medicines in the future.
研究领域:
免疫学
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微生物学
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药理学
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中药学
✓ 已验证
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Huiting Fang,Huizhen Li,Yang Chen,Xiaoming Liu,Jianxin Zhao,Paul Ross,Catherine Stanton,Wei Chen,Bo Yang
There has been a rising interest in studying how Bifidobacterium breve can affect the immune system over the years. The aim of this study was to evaluate the effect of B. breve on the immune system and to explore the mechanism in a mouse model of cyclophosphamide (CTX)-induced immunosuppression. The results of the study showed that B. breve CCFM1310 significantly increased the thymus index (p < 0.05), promoting the secretion of immunoglobulins and the number of immune cells in the blood. Moreover, B. breve CCFM1310 could repair the spleen injury. It increased the mRNA expression level of T-bet (p < 0.05) and decreased the mRNA expression level of TGF-β and FOXP3 (p < 0.05). B. breve CCFM1310 alleviated oxidative stress by increasing enzymatic activities of SOD, CAT and T-AOC and reducing the concentration of MDA. Moreover, it repaired intestinal damage by increasing the number of goblet cells, upregulating mRNA expression of tight junction proteins, and promoting the production of short-chain fatty acids (SCFA). B. breve CCFM1310 could regulate the gut microbiota by increasing the relative abundance of Lactobacillus (p < 0.05) and decreasing the relative abudance of Lachnospiraceae NK4A136 group . Overall, our study suggests that B. breve CCFM1310 could enhance immunity in CTX-induced immunosuppressed mice by affecting immune responses, oxidative stress and gut microbiota.
研究领域:
免疫学
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微生物学
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药理学
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Qi Sun,Zhenzhen Yang,Meng Lin,Yiwei Peng,Rudong Wang,Yitian Du,Yu Zhou,Jiajia Li,Xianrong Qi
Phototherapy and immunogenic cell death (ICD) are powerful strategies to fight cancer. However, their therapeutic outcomes are diminished by immunosuppressive and hypoxia microenvironment . Herein, a photo-based, immunomodulating and hypoxia-alleviated nanosystem , [email protected] , is proposed to achieve the synergism between phototherapy and immunotherapy. Catalase (CAT) and anti-GITR antibody (DTA-1) are loaded to photothermal agent and photosensitizer composed PDA-ICG nanoparticles . The [email protected] exhibits intrinsic local hyperthermia and enhanced ROS generation in tumor, and abrogates tumor immune suppression. It results in reduction of intratumoral FOXP3 + regulatory T cells (4.3-fold) and increase of CD4 + effector T cells (1.5-fold) compare with the control, and promotes damage associated molecular patterns generation to reinvigorate ICD effect. The potent antitumor of [email protected] is proved in 4T1 bilateral tumor-bearing mice, with inhibition ratio of 95.1% for primary cancers and 68.7% for abscopal cancers. Our findings highlight great promise of the constructed versatility nanosystem to fix bottlenecks for cancer therapy.
研究领域:
肿瘤学
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免疫治疗
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纳米技术
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癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
·
2023
·
IF 3.3
Xiulian Zhang,Xueliang Li,Wei Ma,Fangying Liu,Pinxian Huang,Lei Wei,Li Li,Yechang Qian
Background Chronic obstructive pulmonary disease (COPD) has a high fatality rate and poses a great threat to human health. Astragaloside IV (AS-IV) is proven to attenuate cigarette smoke (CS)-induced pulmonary inflammation, based on which this research focuses on the mechanism of AS-IV in COPD.Methods To evaluate the effects of AS-IV, CD4+ T cells received different concentrations of AS-IV. CD4+ T cell viability, T helper 17 (Th17)/regulatory T (Treg) markers and CXCR4 expressions in CD4+ T cells or spleen/lung tissues were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, quantitative real-time polymerase chain reaction and Western blot. The proportions of Treg and Th17 cells were assessed by flow cytometry. Enzyme-linked immune sorbent assay was employed to determine cytokine contents in serum and lung tissues.Results AS-IV with concentration exceeding 40 µM inhibited CD4+ T cell viability. In vitro, AS-IV suppressed the expressions of CXCR4, retinoid-related orphan receptor γt (RORγt), and interleukin (IL)-17A as well as Th17 cells but promoted the expressions of forkhead box p3 (Foxp3) and IL-10 as well as Treg cells, while CXCR4 overexpression reversed the effects of AS-IV. In vivo, AS-IV alleviated COPD, and CS-induced Th17/Treg imbalance in mice and reduced CS-induced down-regulation of IL-10 in serum and lung tissues and Foxp3 and up-regulation of IL-1β, tumor necrosis factor alpha (TNF-α), IL-6, and IL-17A in serum and lung tissues and RORγt. AS-IV mitigated CS-induced CXCR4 up-regulation. Above effects of AS-IV on mice were offset by CXCR4 overexpression.Conclusions AS-IV restores Th17/Treg balance via impeding CXCR4 to ameliorate COPD.
研究领域:
免疫学
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肺科学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Research
·
2020
·Vol. 13
·期 12
·3403-3415
·
IF 8.183
Zeng Fanchu,Qin Huan,Liu Liming,Chang Haocai,Chen Qun,Wu Linghua,Zhang Le,Wu Zhujun,Xing Da
Effective therapeutic strategies to precisely eradicate primary tumors with minimal side effects on normal tissue, inhibit metastases, and prevent tumor relapses, are the ultimate goals in the battle against cancer. We report a novel therapeutic strategy that combines adjuvant black phosphorus nanoparticle-based photoacoustic (PA) therapy with checkpoint-blockade immunotherapy. With the mitochondria targeting nanoparticle, PA therapy can achieve localized mechanical damage of mitochondria via PA cavitation and thus achieve precise eradication of the primary tumor. More importantly, PA therapy can generate tumor-associated antigens via the presence of the R848-containing nanoparticles as an adjuvant to promote strong antitumor immune responses. When combined with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4, the generated immunological responses will further promote the infiltrating CD8 and CD4 T-cells to increase the CD8/Foxp3 T-cell ratio to inhibit the growth of distant tumors beyond the direct impact range of the PA therapy. Furthermore, the number of memory T cells detected in the spleen is increased, and these cells inhibit tumor recurrence. This proposed strategy offers precise eradication of the primary tumor and can induce long-term tumor-specific immunity.
研究领域:
肿瘤学
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纳米技术
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免疫治疗
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生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Journal of Oncology
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2022
·
IF 4.501
Liping Qian,Lihua Mao,Weixing Mo,Rong Wang,Yunlong Zhang
Glioblastoma (GBM) is the most common intracranial tumor with characteristic of malignancy. Resveratrol, a natural originated polyphenolic compound, has been reported to act as a potential radiosensitizer in cancer therapy. Magnetic resonance imaging (MRI) is the first choice for the diagnosis, pathological grading, and efficacy evaluation of GBM. In this study, MRI was applied to observe whether resveratrol could intensify the anti-GBM tumor effect by enhancing antitumor immunity during radiotherapy. We established an intracranial C6 GBM model in SD rats, treated with radiation and resveratrol. The increased body weight, the inhibition on mortality, and tumor volume in radiated- GBM rats were further enhanced by resveratrol addition, while the pathological damage of brain was alleviated. The modulation of radiation on inflammation, cell cycle, and apoptosis was strengthened by resveratrol; and Ki-67, PD-L1, and cell cycle- and apoptosis-related protein expressions were also improved by cotreatment. Besides, cotreatment attenuated DNA damage and induced G0/G1-phase cell arrest of GBM rats, accompanied with the changed expression of ATM-AKT-STAT3 pathway-related proteins. Moreover, the percentages of CD3+CD8+T cells and IFN-γ+CD8+T cells were enhanced, while (CD4+CD25+Foxp3)/CD4+T cells were decreased by radiation or resveratrol, which was strengthened by cotreatment. The modulation effect of cotreatment on CD3, Foxp3, and IFN-γ levels was also stronger than radiation or resveratrol alone. To conclude, resveratrol enhanced the effect of radiotherapy by inducing DNA damage and antitumor immunity in the intracranial C6 GBM.
研究领域:
肿瘤学
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放射学
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免疫学
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神经科学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Zhaoting Li,Yueyang Deng,Honghao Sun,Caixia Tan,Heming Li,Fanyi Mo,Yixin Wang,Jing Li,Zhanwei Zhou,Minjie Sun
Tumor hypoxia and high glutathione (GSH) expression promote regulatory T cell (Treg) infiltration and maintain its immunosuppressive function, which significantly reduces the response rate of cancer immunotherapy . Here, we developed an immunomodulatory nano-formulation ( [email protected] ) to reverse Treg-mediated immunosuppression by redox regulation in the tumor microenvironment (TME). Oxygen carried in perfluorocarbon (PFC) was delivered to the TME, thus relieving the hypoxic condition and inhibiting Treg infiltration. More importantly, GSH depletion by the prodrug efficiently restricted the Foxp3 expression and immunosuppressive function of Tregs, thus breaking the shackles of tumor immunosuppression. Additionally, the supplement of oxygen cooperated with the consumption of GSH to enhance the irradiation-induced immunogenic cell death and subsequent dendritic cell (DC) maturation, thereby efficiently promoting the activation of effector T cells and restricting the immunosuppression of Tregs. Collectively, the [email protected] nano-formulation reverses Treg-mediated immunosuppression and regulates the redox balance in the TME to boost anti-tumor immunity and prolong the survival of tumor-bearing mice, which provides a new immunoregulatory strategy from the perspective of redox modulation.
研究领域:
癌症免疫学
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纳米技术
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免疫治疗
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肿瘤微环境
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氧化还原生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）