BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Yuge Long,Xiaoyuan Jia,Liang Chu
Gasdermin E ( GSDME ), which is also known as DFNA5 , was first identified as a deafness-related gene that is expressed in cochlear hair cells, and mutation of this gene causes autosomal dominant neurogenic hearing loss. Later studies revealed that GSDME is mostly expressed in the kidney, placenta, muscle and brain cells, but it is expressed at low levels in tumor cells. The GSDME gene encodes the GSDME protein, which is a member of the gasdermin (GSDM) family and has been shown to participate in the induction of apoptosis and pyroptosis. The current literature suggests that Caspase-3 and Granzyme B (Gzm B) can cleave GSDME to generate the active N-terminal fragment (GSDME-NT), which integrates with the cell membrane and forms pores in this membrane to induce pyroptosis. Furthermore, GSDME also forms pores in mitochondrial membranes to release apoptosis factors, such as cytochrome c (Cyt c ) and high-temperature requirement protein A2 (HtrA2/Omi), and subsequently activates the intrinsic apoptosis pathway. In recent years, GSDME has been shown to exert tumor-suppressive effects, suggesting that it has potential therapeutic effects on tumors. In this review, we introduce the structure and function of GSDME and the mechanism by which it induces cell death, and we discuss its tumor suppressive effect.
研究领域:
分子生物学
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细胞生物学
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肿瘤学
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遗传学
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产品关联
DOI
PubMed
高影响因子
ORAL DISEASES
·
2024
·
IF 2.9
Qin Jiang,Fang Wang,Gang Zhou
Objective Oral lichen planus (OLP) is a chronic inflammatory disease characterized by a dense T-cell infiltration and the degeneration of basal keratinocytes. The potential functions of mucosal associated invariant T (MAIT) cells in OLP have been analyzed in our previous study. Keratinocytes under proinflammatory conditions have been demonstrated to activate T cells. This study was aimed to investigate how keratinocytes stimulate MAIT cells in OLP, and to explore the role of activated MAIT cells on keratinocytes. Methods and Results Increased MAIT cells and higher activation marker CD69 were detected in OLP lesions by flow cytometry. The enhanced expression of MHC class I-like molecule (MR1) required for MAIT cell activation in the epithelial layer of OLP lesions was determined by immunohistochemistry. Keratinocytes treated by 5-A-RU prodrug and lipopolysaccharide, respectively, exhibited higher expression of MR1 and secretion of IL-18. In direct coculture systems consisting of keratinocytes and peripheral blood mononuclear cells, both 5-A-RU prodrug-pretreated keratinocytes and lipopolysaccharide-pretreated keratinocytes activated MAIT cells to secrete granzyme B, contributing to elevated keratinocyte apoptosis. Conclusions Keratinocytes were capable to activate MAIT cells via MR1 and cytokines in OLP, and granzyme B produced by activated MAIT cells intensified keratinocyte apoptosis, engaging in the pathogenesis of OLP.
研究领域:
免疫学
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皮肤病学
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口腔病理学
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DOI
PubMed
高影响因子
JOURNAL OF ORAL PATHOLOGY & MEDICINE
·
2021
·Vol. 51
·期 1
·74-85
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IF 4.253
Jing-Ya Yang,Fang Wang,Gang Zhou
Background Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory disease with uncertain aetiology. Mucosal-associated invariant T (MAIT) cells and γδT cells are unconventional, innate-like T cells with immunoregulatory capacity. This study aimed to investigate the potential effects of MAIT and γδT cells on the pathogenesis of OLP. Methods Circulating MAIT cells and γδT cells were identified using flow cytometry. Surface proteins including CD4, CD8, CD69, CD103, CD49d, programmed death-1 (PD-1) and its ligand PD-L1 were assessed. Cytokines containing interleukin (IL)-4, IL-17, interferon (IFN)-γ, granzyme B and tumour necrosis factor (TNF)-α released by MAIT and γδT cells were measured following PMA and ionomycin stimulation. Results Circulating MAIT and γδT cells were deficient in OLP. The percentage of CD4 + , CD69 + , CD103 + and PD-1 + MAIT cells was increased in OLP, while that of CD8 + and CD49d + MAIT cells was decreased. The percentage of CD103 + , PD-1 + and PD-L1 + γδT cells was upregulated in OLP. Both the MAIT and γδT cells in OLP produced less IL-4 than controls. The granzyme B-producing MAIT cells were increased, while γδT cells secreting granzyme B and TNF-α were reduced in OLP. IL-17 and IFN-γ in OLP MAIT and γδT cells were not significantly different from that in controls. The frequency of OLP MAIT cells and the MAIT/γδT rate were positively associated with the disease severity. Conclusion The deficient MAIT and γδT cells expressing functional proteins and releasing cytokines may play an immunoregulatory role in the pathogenesis of OLP.
研究领域:
免疫学
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炎症
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口腔疾病
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细胞生物学
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DOI
PubMed
高影响因子
Advanced Science
·
2022
·Vol. 9
·期 23
·2201271
·
IF 17.521
Yihang Gong,Wenjie Chen,Xiuxing Chen,Yizhan He,Hua Jiang,Xijian Zhang,Lijie Pan,Beibei Ni,Fan Yang,Yan Xu,Qi Zhang,Lei Zhou,Yusheng Cheng
Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.
研究领域:
肿瘤学
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免疫治疗
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药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Mucosal Immunology
·
2024
·
IF 7.9
Xixi Huang,Tingxuan Yin,Min Yu,Guohua Zhu,Xianyang Hu,Hailin Yu,Weijie Zhao,Jiajia Chen,Jiangyuan Du,Qingyu Wu,Wei Zhang,Lu Liu,Meirong Du
Decidual CD8 + T (dCD8 + T) cells are pivotal in the maintenance of the delicate balance between immune tolerance towards the fetus and immune resistance against pathogens. The endometrium and decidua represent uterine environments before and during pregnancy, respectively, and the composition and phenotypic alterations of uterine CD8 + T cells in these tissues remain unclear. Using flow cytometry and analysis of transcriptome profiles, we demonstrated that human dCD8 + T and endometrial CD8 + T (eCD8 + T) cells exhibited similar T cell differentiation statuses and phenotypes of tissue infiltrating or residency, compared to peripheral CD8 + T (pCD8 + T) cells. However, dCD8 + T cells showed decreased expression of coinhibitory (PD-1), chemotaxis (CXCR3), and tissue-resident (CD69 and CD103) markers and increased granzyme B and granulysin expression compared to eCD8 + T cells. In vitro, cytotoxicity assays demonstrated greater effector functions in dCD8 + T cells than in eCD8 + T cells. Further in vitro and in vivo chemotaxis assays confirmed the recruitment of non-resident effector memory T cell subsets to the pregnant decidua, contributing to the dCD8 + T cell-mediated anti-infection mechanism at the maternal-fetal interface. This work demonstrated dCD8 + T cells replenished from the circulation retained their cytotoxic capacity, which may serve as an enhanced defense mechanism against infection during pregnancy.
研究领域:
免疫学
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生殖生物学
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妊娠免疫学
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DOI
PubMed
高影响因子
Science Advances
·
2022
·Vol. 8
·期 46
·
IF 14.957
Zhanwei Zhou,Ruoxi Yang,Jingwen Dong,Yongxiang Di,Ying Yang,Ying Huang,Xue Yang,Wei Liu,Jinqiang Wang,Peifeng Liu,Zhen Gu,Minjie Sun
Directly delivering therapeutic proteins to their intracellular targets remains a great challenge. Here, we apply CD8+ T cells to form pores on the tumor cells’ plasma membranes, enabling perfusion of ribonuclease A (RNase A) and granzyme B into cells, therefore effectively inducing tumor apoptosis and pyroptosis by activating caspase 3 and gasdermin E pathways to potentiate the CD8+ T cell–mediated immunotherapy. Then, RNase A, programmed cell death ligand 1 antibody, and a photothermal agent were further loaded into an injectable hydrogel to treat the low immunogenic murine breast cancer. Notably, three courses of laser irradiation induced efficient cell apoptosis and immune activation, resulting in a notable therapeutic efficacy that 75% of the tumors were ablated without relapse.
研究领域:
癌症免疫治疗
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蛋白质递送
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细胞生物学
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免疫学
·
生物医学工程
✓ 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）