Discovery of a triphenylamine-based ligand that targets mitochondrial DNA G-quadruplexes and activates the cGAS-STING immunomodulatory pathway
In this study, we engineered a series of triphenylamine-based analogues targeting mtDNA G4s, and A6 was determined as the most promising compound. Cellular studies indicated that A6 caused severe mtDNA damage. Then, damaged mtDNA stimulated cGAS-STING pathway, resulting in the following cytokine production of tumor cells and the maturation of DCs. In vivo experiments certified that A6 exerted suppressive influences on tumor growth and metastasis in 4T1 cell-bearing mice by the regulation of TME, including the remodeling of macrophages and the activation of T cells. To our knowledge, it is the first time to report a ligand ...
Source: European Journal of Medicinal Chemistry - March 28, 2024 Category: Chemistry Authors: Xiao-Dong Wang Yong-Si Liu Meng-Die Chen Ming-Hao Hu Source Type: research
Enhanced GATA4 expression in senescent systemic lupus erythematosus monocytes promotes high levels of IFN α production
Enhanced interferon α (IFNα) production has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We previously reported IFNα production by monocytes upon activation of the stimulator of IFN genes (STING) pathway was enhanced in patients with SLE. We investigated the mechanism of enhanced IFNα production in SLE monocytes. Monocytes enriched from the peripheral blood of SLE patients and healthy controls (HC) were stimulated with 2′3′-cyclic GAMP (2′3′-cGAMP), a ligand of STING. IFNα positive/negative cells were FACS-sorted for RNA-sequencing analysis. Gene expression in untreated and 2′3â...
Source: Frontiers in Immunology - March 28, 2024 Category: Allergy & Immunology Source Type: research
Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma
Oncogene, Published online: 28 March 2024; doi:10.1038/s41388-024-03013-4Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma (Source: Oncogene)
Source: Oncogene - March 28, 2024 Category: Cancer & Oncology Authors: Shengpan Wu Baojun Wang Hongzhao Li Hanfeng Wang Songliang Du Xing Huang Yang Fan Yu Gao Liangyou Gu Qingbo Huang Jianjun Chen Xu Zhang Yan Huang Xin Ma Source Type: research
A Novel Inhibitor of Poly(ADP-Ribose) Polymerase-1 Inhibits Proliferation of a BRCA-Deficient Breast Cancer Cell Line via the DNA Damage-Activated cGAS-STING Pathway
Chem Res Toxicol. 2024 Mar 27. doi: 10.1021/acs.chemrestox.3c00343. Online ahead of print.ABSTRACTLoss-of-function mutations in the Breast Cancer Susceptibility Gene (BRCA1 and BRCA2) are often detected in patients with breast cancer. Poly(ADP-ribose) polymerase-1 (PARP1) plays a key role in the repair of DNA strand breaks, and PARP inhibitors have been shown to induce highly selective killing of BRCA1/2-deficient tumor cells, a mechanism termed synthetic lethality. In our previous study, a novel PARP1 inhibitor─(E)-2-(2,3-dibromo-4,5-dimethoxybenzylidene)-N-(4-fluorophenyl) hydrazine-1-carbothioamide (4F-DDC)─was synt...
Source: Cell Research - March 27, 2024 Category: Cytology Authors: Yonglong Jin Lijie Wang Chengxue Jin Na Zhang Shosei Shimizu Wenjing Xiao Chuanlong Guo Xiguang Liu Hongzong Si Source Type: research
VRK1 promotes DNA-induced type I interferon production
CONCLUSIONS: Our study reveals a novel function of VRK1 in regulating the production of type I IFNs. VRK-IN-1 might be a potential lead compound for suppressing aberrant type I IFNs in autoimmune disorders.PMID:38536553 | DOI:10.1007/s11033-024-09414-8 (Source: Molecular Biology Reports)
Source: Molecular Biology Reports - March 27, 2024 Category: Molecular Biology Authors: Zhechen Fan Xiong Wang Hao Cheng Mingyu Pan Source Type: research
VRK1 promotes DNA-induced type I interferon production
CONCLUSIONS: Our study reveals a novel function of VRK1 in regulating the production of type I IFNs. VRK-IN-1 might be a potential lead compound for suppressing aberrant type I IFNs in autoimmune disorders.PMID:38536553 | DOI:10.1007/s11033-024-09414-8 (Source: Mol Biol Cell)
Source: Mol Biol Cell - March 27, 2024 Category: Molecular Biology Authors: Zhechen Fan Xiong Wang Hao Cheng Mingyu Pan Source Type: research
Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice
Sci Signal. 2024 Mar 26;17(829):eadk8249. doi: 10.1126/scisignal.adk8249. Epub 2024 Mar 26.ABSTRACTMutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulati...
Source: Science Signaling - March 26, 2024 Category: Biomedical Science Authors: Rui Wang Hongyang Sun Yifan Cao Zhixiong Zhang Yajing Chen Xiying Wang Lele Liu Jin Wu Hao Xu Dan Wu Chenchen Mu Zongbing Hao Song Qin Haigang Ren Junhai Han Ming Fang Guanghui Wang Source Type: research
Enzymatic activity of cGAS in the presence of three types of DNAs: Limited cGAS stimulation by single-stranded HIV-1 SL2 DNA
Biosci Rep. 2024 Mar 26:BSR20240269. doi: 10.1042/BSR20240269. Online ahead of print.ABSTRACTCyclic GMP-AMP (cGAMP) synthase (cGAS) is activated by binding to DNA. Activated cGAS produces 2'3'-cGAMP, which subsequently binds to the adaptor protein STING (stimulator of interferon genes). This interaction triggers the cGAS/STING signaling pathway, leading to the production of type I interferons. Three types of DNA, namely double-stranded DNA longer than 40 base pairs, a 70-nucleotide single-stranded HIV-1 DNA known as SL2, and Y-form DNA with unpaired guanosine trimers (G3 Y-form DNA), induce interferon production by activat...
Source: Bioscience Reports - March 26, 2024 Category: Biomedical Science Authors: Mineyuki Mizuguchi Niko Kyan Suzuka Nishimata Yuko Nabeshima Takayuki Obita Source Type: research
Feedback activation of CD73-Adenosine axis attenuates the antitumor immunity of STING pathway
In this study, we demonstrated that STING activation enhanced the expression of CD73 and the subsequent production of adenosine in immune cells and cancer cells. Mechanistically, the feedback activation of CD73 depended on the type I IFN/IFNAR axis induced by STING activation. Furthermore, the combination of STING agonist and anti-CD73 mAb markedly blocked tumor growth in vivo by promoting the infiltration of CD8+ T cells and reducing the accumulation of Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment. Our work provides a rationale for the combination of STING agonists and CD73 inhibitors in cancer immunoth...
Source: Biochemical and Biophysical Research communications - March 26, 2024 Category: Biochemistry Authors: Nannan Fu Ziang Zhang Junmin Quan Source Type: research
Formononetin Restrains Tumorigenesis of Breast Tumor by Restraining STING-NF- κB and Interfering with the Activation of PD-L1
CONCLUSION: Formononetin can restrain the proliferation of BC cells, which may be mediated through the interference of PD-L1 and suppression of the activation of the STING-NF-κB pathway.PMID:38531802 | DOI:10.24976/Discov.Med.202436182.58 (Source: Discovery Medicine)
Source: Discovery Medicine - March 26, 2024 Category: Research Authors: Hongmei Liu Zhipeng Wang Zhigang Liu Source Type: research
Enzymatic activity of cGAS in the presence of three types of DNAs: Limited cGAS stimulation by single-stranded HIV-1 SL2 DNA
Biosci Rep. 2024 Mar 26:BSR20240269. doi: 10.1042/BSR20240269. Online ahead of print.ABSTRACTCyclic GMP-AMP (cGAMP) synthase (cGAS) is activated by binding to DNA. Activated cGAS produces 2'3'-cGAMP, which subsequently binds to the adaptor protein STING (stimulator of interferon genes). This interaction triggers the cGAS/STING signaling pathway, leading to the production of type I interferons. Three types of DNA, namely double-stranded DNA longer than 40 base pairs, a 70-nucleotide single-stranded HIV-1 DNA known as SL2, and Y-form DNA with unpaired guanosine trimers (G3 Y-form DNA), induce interferon production by activat...
Source: Bioscience Reports - March 26, 2024 Category: Biomedical Science Authors: Mineyuki Mizuguchi Niko Kyan Suzuka Nishimata Yuko Nabeshima Takayuki Obita Source Type: research
Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice
Sci Signal. 2024 Mar 26;17(829):eadk8249. doi: 10.1126/scisignal.adk8249. Epub 2024 Mar 26.ABSTRACTMutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulati...
Source: Science Signaling - March 26, 2024 Category: Biomedical Science Authors: Rui Wang Hongyang Sun Yifan Cao Zhixiong Zhang Yajing Chen Xiying Wang Lele Liu Jin Wu Hao Xu Dan Wu Chenchen Mu Zongbing Hao Song Qin Haigang Ren Junhai Han Ming Fang Guanghui Wang Source Type: research
Feedback activation of CD73-Adenosine axis attenuates the antitumor immunity of STING pathway
In this study, we demonstrated that STING activation enhanced the expression of CD73 and the subsequent production of adenosine in immune cells and cancer cells. Mechanistically, the feedback activation of CD73 depended on the type I IFN/IFNAR axis induced by STING activation. Furthermore, the combination of STING agonist and anti-CD73 mAb markedly blocked tumor growth in vivo by promoting the infiltration of CD8+ T cells and reducing the accumulation of Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment. Our work provides a rationale for the combination of STING agonists and CD73 inhibitors in cancer immunoth...
Source: Biochemical and Biophysical Research communications - March 26, 2024 Category: Biochemistry Authors: Nannan Fu Ziang Zhang Junmin Quan Source Type: research
Formononetin Restrains Tumorigenesis of Breast Tumor by Restraining STING-NF- κB and Interfering with the Activation of PD-L1
CONCLUSION: Formononetin can restrain the proliferation of BC cells, which may be mediated through the interference of PD-L1 and suppression of the activation of the STING-NF-κB pathway.PMID:38531802 | DOI:10.24976/Discov.Med.202436182.58 (Source: Discovery Medicine)
Source: Discovery Medicine - March 26, 2024 Category: Research Authors: Hongmei Liu Zhipeng Wang Zhigang Liu Source Type: research
Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice
Sci Signal. 2024 Mar 26;17(829):eadk8249. doi: 10.1126/scisignal.adk8249. Epub 2024 Mar 26.ABSTRACTMutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulati...
Source: Science Signaling - March 26, 2024 Category: Biomedical Science Authors: Rui Wang Hongyang Sun Yifan Cao Zhixiong Zhang Yajing Chen Xiying Wang Lele Liu Jin Wu Hao Xu Dan Wu Chenchen Mu Zongbing Hao Song Qin Haigang Ren Junhai Han Ming Fang Guanghui Wang Source Type: research
