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cGAS-STING: mechanisms and therapeutic opportunities

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Science China Life Sciences 2025年

作者： Mengyuan Zhang Changxin Wu Defen Lu Xing Wang Guijun Shang shanxi Medical University School and Hospital of Stomatology shanxi Province key laboratory of Oral Diseases Prevention and New Materials The key laboratory of Medical Molecular Cell Biology of shanxi Province Institutes of Biomedical Sciences Shanxi University College of Life Sciences Shanxi Agricultural University

The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA) in the cytoplasm and triggering downstream signal transduction. Understanding the mechanisms by which cGAS and STING operate is vital for gaining insights into the biology of this pathway. This review provides a detailed examination of the structural features of cGAS and STING proteins, with a particular emphasis on their activation and inhibition mechanisms. We also discuss the novel discovery of STING functioning as an ion channel. Furthermore, we offer an overview of key agonists and antagonists of cGAS and STING, shedding light on their mechanisms of action. Deciphering the molecular intricacies of the cGAS-STING pathway holds significant promise for the development of targeted therapies aimed at maintaining immune homeostasis within both innate and adaptive immunity.

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Let-7 microRNA targets BmCentrin to modulate the development and functionality of the middle silk gland in the silkworm,Bombyx mori

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Insect Science 2025年第1期32卷 95-114页

作者： Yankun Xu Na Du Lili Xu Lu Zhao Ting Fan Tianqi Wei Qian Pu Shiping Liui State key laboratory of Resource Insects Southwest UniversityChongqingChina

The silk gland of the silkworm Bombyx mori serves as a valuable model for investigating the morphological structure and physiological functions of *** studies have demonstrated the notable regulatory role of let-7 microRNA in the silk gland,but its specific molecular mechanism remains to be elucidated across different segments of this *** this study,we further investigated the functional mechanism of let-7 in the middle silk gland(MSG).The MSG of a let-7 knockout strain was analyzed using a combined proteomic and metabolomic technique,revealing the enrichment of differential proteins and metabolites in the DNA synthesis and energy metabolism *** was identified as a novel target gene of let-7 in the MSG,and its downregulation inhibited the proliferation of BmN4-SID1 cells,which is exactly opposite to the role of let-7 in these ***/Cas9 genome editing and transgenic technologies were employed to manipulate BmCentrin in the *** of BmCentrin led to severe MSG atrophy,whereas the overexpression of BmCentrin resulted in beaded *** measurements of these knockout or overexpression strains revealed significant changes in the expression levels of sericin protein genes,the weight of the cocoon and the mechanical properties of the *** the biological role of BmCentrin in the silk gland offers valuable insights for elucidating the molecular mechanisms by which let-7 controls silk gland development and silk protein synthesis in the silkworm.

关键词： BmCentrin Bombyx mori CRISPR/Cas9 genome editing let-7 microRNA middle silk gland transgenic overexpression

Copper homeostasis and neurodegenerative diseases

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Neural Regeneration Research 2025年第11期20卷 3124-3143页

作者： Yuanyuan Wang Daidi Li Kaifei Xu Guoqing Wang Feng Zhang International Research laboratory of Ethnomedicine of Ministry of Education Key Laboratory of Basic Pharmacology of Ministry of EducationLaboratory Animal Center and Key Laboratory of Basic Pharmacology of Guizhou ProvinceZunyi Medical UniversityZunyiGuizhou ProvinceChina

Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of *** homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and *** in copper homeostasis can lead to either the deficiency or accumulation of copper in brain *** evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative ***,the exact mechanisms underlying these processes are not *** is a potent oxidant that increases reactive oxygen species production and promotes oxidative *** reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial *** oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory ***,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell *** study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease *** synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of heredit

关键词： Alzheimer's disease amyotrophic lateral sclerosis disease copper homeostasis copper toxicity Huntington's disease Menkes'disease multiple sclerosis neurodegenerative disease Parkinson's disease Wilson's disease

Musashi orchestrates melanism in Laodelphax striatellus

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Insect Science 2025年第1期32卷 140-150页

作者： Zeping Mao Biyun Wang Youyuan Chen Jinjun Ying Haiqiang Wang Junmin Li Chuanxi Zhang Jichong Zhuo State key laboratory for ManagingBiotic and Chemical Threats to the Quality and Safety of Agro-products Key Laboratory of Biotechnology in Plant Protection of MARA and Institute of Plant VirologyNingbo UniversityNingboZhejiang Province315211China

In insects,melanism,a fundamental pigmentation process,is of significant importance in evolutionary biology due to its complex genetic *** investigated the role of the RNA-binding gene Musashi(msi)in melanism in Laodelphax striatellus,a Hemiptera *** identified a single *** msi homolog,Lsmsi,encoding a 357 amino acid protein with 2 RNA recognition *** interference-mediated knockdown of LsMsi resulted in complete body melanism and increased cuticular ***,we found the involvement of G protein-coupled receptor A42 and tyrosine hydroxylase(Th)in *** *** of LsTh lightened the epidermis,showing dehydration signs,while LsA42 knockdown enhanced LsTh expression,leading to ***,Lsmsi knockdown decreased both LsA42 and LsTh expression,which was expected to cause whitening but resulted in ***,we found that Lsmsi influenced downstream genes like phenoloxidase homolog LsPo and dopa decarboxylase(Ddc)homolog LsDdc in the tyrosine-mediated melanism *** to Nilaparvata lugens and Sogatella furcifera,we demonstrated the conserved role of msi in melanism among *** MSI proteins’roles in cancer and tumors in vertebrates,our study is the first to link msi in insects to Delphacidae body color melanization via the tyrosine-mediated pathway,offering fresh perspectives on the genetic basis of insect melanism and msi functions.

关键词： dopa decarboxylase melanism Musashi phenoloxidase planthopper

Curcumin attenuates ochratoxin A and hypoxia co‑induced liver injury in grass carp(Ctenopharyngodon idella)by dual targeting endoplasmic reticulum stress and apoptosis via reducing ROS content

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Journal of Animal Science and Biotechnology 2025年第1期16卷 408-423页

作者： Liangqin Wu Piao Zhao Pei Wu Weidan Jiang Yang Liu Hongmei Ren Xiaowan Jin Xiaoqiu Zhou Lin Feng Animal Nutrition Institute Sichuan Agricultural UniversityChengdu 611130China Fish Nutrition and Safety Production University key laboratory of Sichuan Province Sichuan Agricultural UniversityChengdu 611130China key laboratory of Animal Disease-Resistance Nutrition Ministry of EducationMinistry of Agriculture and Rural AffairsKey Laboratory of Sichuan ProvinceChengduSichuan 611130China

Background Ochratoxin A(OTA)is a toxin widely found in aquafeed ingredients,and hypoxia is a common prob-lem in fish *** practice,aquatic animals tend to be more sensitive to hypoxia while feeds are contaminated with OTA,but no studies exist in this *** research investigated the multiple biotoxicities of OTA and hypoxia combined on the liver of grass carp and explored the mitigating effect of curcumin(CUR).Methods A total of 720 healthy juvenile grass carp(11.06±0.05 g)were selected and assigned randomly to 4 experi-mental groups:control group(without OTA and CUR),1.2 mg/kg OTA group,400 mg/kg CUR group,and 1.2 mg/kg OTA+400 mg/kg CUR group with three replicates each for 60 ***,32 fish were selected,divided into nor-moxia(18 fish)and hypoxia(18 fish)groups,and subjected to hypoxia stress for 96 *** CUR can attenuate histopathological damage caused by coming to OTA and hypoxia by reducing vacu-olation and nuclear *** alleviation of this damage was associated with the attenuation of apoptosis in the mitochondrial pathway by decreasing the expression of the pro-apoptotic proteins Caspase 3,8,9,Bax,and Apaf1 while increasing the expression of the anti-apoptotic protein Bcl-2,and attenuation of endoplasmic reticulum stress(ERS)by reducing Grp78 expression and chop *** may be attributed to the fact that the addi-tion of CUR increased the levels of catalase(CAT)and glutathione reductase(GSH),increased antioxidant capacity,and ensured the proper functioning of respiratory chain complexes I and II,which in turn reduced the high produc-tion of reactive oxygen species(ROS),thus alleviating apoptosis and *** In conclusion,our data demonstrate the effectiveness of CUR in attenuating liver injury caused by the combination of OTA and *** study confirms the feasibility and efficacy of adding natural products to mitigate toxic damage to aquatic animals.

关键词： Apoptosis Curcumin Endoplasmic reticulum stress Grass carp Hypoxia Ochratoxin A Oxidative damage

Supramolecular Ion Channel with Controlled K+/Na+Transport Behaviors

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Chemical Research in Chinese Universities 2025年第1期41卷 95-100页

作者： HE Lei LUO Yichen ZHANG Yang YAN Tengfei LIU Junqiu College of Material Chemistry and Chemical EngineeringKey Laboratory of Organosilicon Chemistry and Material Technology of Ministry of EducationKey Laboratory of Organosilicon Material Technology of Zhejiang ProvinceHangzhou Normal UniversityHangzhou310036P.R.China

Dysfunction of ion channels,often caused by mutations in natural proteins,can lead to various *** artificial analogs have shown great promise to substitute the abnormal ***,we report a supramolecular potassium channel that forms through the self-assembly of pyrene-crown ether conjugated by intermolecularπ-π*** self-assembled dimer of this channel was optimized and calculated to have a binding energy of−27.4 kcal/mol(1 kcal=4.18 kJ).Evidence for the formation of an active ion channel by PC5 was confirmed using a planar lipid bilayer(BLM)workstation,while no such activity was observed for *** K+/Na+selectivity was reversed in the reduced form,R-PC5,due to the elimination of the planar structure of PC5,resulting in R-PC5 functioning as a Na+***,incorporating the pyrene group facilitates imaging in living cells,providing a potentially viable method for investigating the behaviors of artificial ion channels in living systems.

关键词： Crown ether Pyrene Ion transport Self-assembly

Cobalamin-dependent radical S-adenosyl-L-methionine protein functions with a partner to successively methylate tricyclic indole alkaloid for chuangxinmycin maturation and derivatization

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Science China Chemistry 2025年第1期68卷 308-316页

作者： Sili Wang Jiancheng Huang Yanan Du Wei Huang Yufeng Xue Xiaokun Xu Guannan Zhong Yuanyuan Shi Bin Hong Xiaoying Bian Wen Liu State key laboratory of Chemical Biology Shanghai Institute of Organic ChemistryUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200032China State key laboratory of Microbial Technology Shandong UniversityQingdao 266237China National Health Commission(NHC)key laboratory of Biotechnology for Microbial Drugs Institute of Medicinal BiotechnologyChinese Academy of Medical Science&Peking Union Medical CollegeBeijing 100050China

Cobalamin(Cbl)-dependent radical S-adenosyl-L-methionine(SAM)proteins constitute the largest collection of the radical SAM superfamily that has hundreds of thousands of individual *** of these proteins are involved in the biosynthesis of pharmaceutically important natural products to catalyze chemically demanding *** the biosynthetic pathway of chuangxinmycin(CXM),a unique indole alkaloid antibiotic with potent anti-infective activity,functionalization of the characteristic thiopyrano[4,3,2-cd]indole scaffold by regio-and stereoselective C3-methylation is believed to rely on a Cbl-dependent radical process,which,however,remained to be reconstituted *** here report the dissection of this enzymatic process,which requires the incorporation of Cxm8,a Cbl-dependent radical SAM protein,with Cxm9,a DUF5825family protein that shares no homology to any proteins of known ***8 and Cxm9 function together by forming an unexpected heterodimeric complex that selectively catalyzes C3-methylation of the tricyclic indole-S-hetero ring system in a successive manner,achieving CXM and a recently identified,C3-dimethylated *** biochemical characterization,isotope labeling,structural simulation and bioinformatics analysis rationalized the catalysis of the Cxm8/Cxm9 complex and particularly the necessity of the DUF5825 protein for C3-methylase *** is the first example that a Cbl-dependent protein acts with a partner to exhibit radical SAM activity.

关键词： cbl-dependent radical SAM protein biosynthesis chuangxinmycin stereoselective methylation

AvERF73 positively regulates waterlogging tolerance in kiwifruit by participating in hypoxia response and mevalonate pathway

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Horticultural Plant Journal 2025年第1期11卷 162-174页

作者： Danfeng Bai Yunpeng Zhong Shichao Gu Xiujuan Qi Leiming Sun Miaomiao Lin Ran Wang Yukuo Li Chungen Hu Jinbao Fang National key laboratory for Germplasm Innovation&Utilization of Horticultural Crop Zhengzhou Fruit Research InstituteChinese Academy of Agricultural SciencesZhengzhouHenan 450009China key laboratory of Horticultural Plant Biology College of Horticulture&Forestry Sciences of Huazhong Agricultural UniversityWuhanHubei 430070China

Waterlogging stress is one of the greatest environmental threats to kiwifruit growth and ***-VII proteins have been demonstrated to play pivotal roles in regulating plant tolerance to ***,the genome-wide role of ERF-VII in kiwifruit waterlogging stress tolerance remains ***,we report the function and regulatory network of an ERF-VII transcription factor located to the nucleus,Av ERF73,in kiwifruit waterlogging *** of Av ERF73 in Arabidopsis thaliana and *** *** enhanced waterlogging tolerance in transgenic ***,we performed transcriptome analysis(RNA-seq)and DNA affinity purification sequencing(DAP-seq)to explore the regulatory mechanism of Av ***-seq coupled with DAP-seq showed that Av ERF73 might directly activate Ac NAC022 involved in the“cellular response to hypoxia”process and Ac HMGS1 involved in the mevalonate pathway to respond to waterlogging,which were also confirmed by a dual-luciferase reporter *** on our results,we propose a putative working model for controlling waterlogging tolerance by Av ERF73 in kiwifruit.

关键词： Actinidia ERF-VII Waterlogging stress RNA-seq DAP-seq

Effect and mechanism of Sanqi(Radix Notoginseng) in treating periodontitis

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Journal of Traditional Chinese Medicine 2025年第1期45卷 66-75页

作者： AN Yuanyuan LIU Wang LI Yanjie WANG Yanchun REN Xiaobin HE Hongbing Department of Periodontology Kunming Medical University School and Hospital of StomatologyYunnan Key Laboratory of Stomatology

OBJECTIVE: To investigate the effect and mechanism of Sanqi(Radix Notoginseng) in treating periodontitis. METHODS: The active components and periodontitis targets were analyzed through network pharmacology and molecular docking. A rat model of periodontitis was established and rats were treated by continuous intragastric administration of Sanqi(Radix Notoginseng) at different doses for 30 d. The alveolar bone structure was observed by micro-CT, the periodontal tissue structure was observed by hematoxylin-eosin staining, and the related proteins changes was detected by immunohistochemical staining. RESULTS: Sanqi(Radix Notoginseng) and periodontitis had a total of 96 coincident targets that were significantly enriched in the interleukin 17(IL-17), tumor necrosis factor(TNF), and advanced glycation endproducts and the receptor of advanced glycation endproducts signaling pathways. The active compound quercetin had good binding activity with interleukin 6(IL-6), vascular endothelial growth factor A(VEGFA), matrix metallopeptidase 9(MMP9), tumor necrosis factor α(TNF-α), Jun proto-oncogene(JUN), and C-X-C motif chemokine ligand 8(CXCL8) in periodontitis. Compared with normal group, the distance from the cementoenamel junction(CEJ) to the alveolar bone(AB) was increased, alveolar bone absorption was obvious, the periodontal tissue structure was disorganized, and IL-6 and TNF-α were upregulated in periodontitis group; meanwhile, the distance from CEJ to AB was significantly decreased, alveolar bone resorption was reduced, periodontal tissue structure was improved, the expression of IL-6, TNF-α, IL-17 and retinoid-ralated orphan receptor γt(RORγt) were decreased, Forkhead Box P3(FOXP3) and IL-10 were increased after Sanqi(Radix Notoginseng) treatment. CONCLUSIONS: Sanqi(Radix Notoginseng) improves the structure of alveolar bone and gum, and reduces inflammation; the mechanism involve in inhibiting IL-17 signaling pathway to suppress Th17 and promote Treg cells differentiati

关键词： Sanqi () inflammationSupporting information interleukin-17 periodontitis quercetin