MOLECULAR CELL
·
2024
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IF 14.5
Wei Luo,Yunyuan Xu,Jie Cao,Xiaoyu Guo,Jingdan Han,Yuanyuan Zhang,Yuda Niu,Meiling Zhang,Yi Wang,Guohua Liang,Qian Qian,Song Ge,Kang Chong
While it is known that temperature sensors trigger calcium (Ca 2+ ) signaling to confer cold tolerance in cells, less is known about sensors that couple with other secondary messengers. Here, we identify a cold sensor complex of CHILLING-TOLERANCE DIVERGENCE 6 (COLD6) and osmotin-like 1 (OSM1), which triggers 2′,3′-cyclic adenosine monophosphate (2′,3′-cAMP) production to enhance cold tolerance in rice. COLD6, which is encoded by a major quantitative trait locus (QTL) gene, interacts with the rice G protein α subunit (RGA1) at the plasma membrane under normal conditions. Upon exposure to chilling, cold-induced OSM1 binds to COLD6, kicking out RGA1 from interaction. This triggers an elevation of 2′,3′-cAMP levels for enhancing chilling tolerance. Genetic data show that COLD6 negatively regulates cold tolerance and functionally depends on OSM1 in chilling stress. COLD6 alleles were selected during rice domestication. Knockout and natural variation of COLD6 in hybrid rice enhanced chilling tolerance, hinting design potential for breeding. This highlighted a module triggering 2′,3′-cAMP to improve chilling tolerance in crops.
研究领域:
植物学
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遗传学
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分子生物学
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2023
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IF 4.8
Junhui He,Dongbo Han,Chunlian Jia,Jiaxiu Xie,Fucui Zhu,Jie Wei,Dongmei Li,Dongmei Wei,Yi Li,Li Tang,Guining Wei,Jing Yan,Yuanming Tong,Lifang Yang,Xuecai Tan
Purpose To investigate the mechanisms of antidepressant action of active fraction of Polyrhachis vicina Rogers (AFPR) through network pharmacology, molecular docking and experimental validation.Methods GC-MS was used to predict chemical compounds, corresponding databases were used to predict chemical compound targets and depression targets, Cytoscape software was used to construct and analyze the protein interaction network map, DAVID database was used to analyze gene ontology (GO) and KEGG signaling pathway, and AGFR software was used to perform molecular docking. Subsequently, the underlying action mechanisms of AFPR on depression predicted by network pharmacology analyses were experimentally validated in a CORT-induced depression model in vitro and in vivo.Results A total of 52 potential targets of AFPR on antidepressant were obtained. GO is mainly related to chemical synaptic transmission, signal transduction and others. KEGG signaling pathways are mainly related to cAMP signaling pathway and C-type lectin receptor signaling pathway. The experiment results showed that AFPR significantly increased the expression of PRKACA, CREB and BDNF in mouse brain tissue and PC12 cells. Furthermore, after interfered of cAMP in PC12 cells, the decreased expression of PRKACA, CREB and BDNF was reversed by AFPR.Conclusion AFPR may exert antidepressant effects through multiple components, targets and pathways. Furthermore, it could improve neuroplasticity via the cAMP signaling pathway to improve depression-like symptoms.
研究领域:
药理学
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神经科学
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DOI
PubMed
高影响因子
Cell Reports
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2025
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IF 6.9
Mingfang Wang,Jia Zeng,Binbin Cui,Guangliang Wu,Xiayu Chen,Yikai Fu,Bing Gu,Yinyue Deng
It was previously demonstrated that intestinal pathogens have evolved different mechanisms to enhance their infection and colonization in the intestines of hosts. However, it is unclear how Shigella effectively survives in the presence of bile salts. Here, we report that the biofilm formation and pathogenicity of S . sonnei are induced by primary bile salts through the two-component system EvgS/EvgA. The response regulator EvgA controls the transcription of the cyclic AMP synthase-encoding gene. Furthermore, the effector protein CRP of the cyclic AMP (cAMP) signal not only positively controls the transcription of ydeH , a gene encoding cyclic di-GMP (c-di-GMP) synthase, but also forms a complex with YdeH to improve its catalytic production of c-di-GMP. Additionally, interacting with YdeH enhances the ability of CRP to bind to the promoter of ydeH . Our work provides insights into how S . sonnei utilizes cascade amplification of c-di-GMP to promote fitness and pathogenicity in response to primary bile salts.
研究领域:
微生物学
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分子生物学
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感染与免疫
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信号转导
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病原生物学
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环境应答
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DOI
PubMed
高影响因子
PLoS Pathogens
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2019
·Vol. 15
·期 2
·e1007382
·
IF 6.463
Xiao Li,Kaili Zhong,Ziyi Yin,Jiexiong Hu,Wenhao Wang,Lianwei Li,Haifeng Zhang,Xiaobo Zheng,Ping Wang,Zhengguang Zhang
Regulator of G-protein signaling (RGS) proteins primarily function as GTPase-accelerating proteins (GAPs) to promote GTP hydrolysis of Gα subunits, thereby regulating G-protein mediated signal transduction. RGS proteins could also contain additional domains such as GoLoco to inhibit GDP dissociation. The rice blast fungus Magnaporthe oryzae encodes eight RGS and RGS-like proteins (MoRgs1 to MoRgs8) that have shared and distinct functions in growth, appressorium formation and pathogenicity. Interestingly, MoRgs7 and MoRgs8 contain a C-terminal seven-transmembrane domain (7-TM) motif typical of G-protein coupled receptor (GPCR) proteins, in addition to the conserved RGS domain. We found that MoRgs7, but not MoRgs8, couples with Gα MoMagA to undergo endocytic transport from the plasma membrane to the endosome upon sensing of surface hydrophobicity. We also found that MoRgs7 can interact with hydrophobic surfaces via a hydrophobic interaction, leading to the perception of environmental hydrophobiccues. Moreover, we found that MoRgs7-MoMagA endocytosis is regulated by actin patch-associated protein MoCrn1, linking it to cAMP signaling. Our studies provided evidence suggesting that MoRgs7 could also function in a GPCR-like manner to sense environmental signals and it, together with additional proteins of diverse functions, promotes cAMP signaling required for developmental processes underlying appressorium function and pathogenicity.
The 7-TM domain is considered the hallmark of GPCR proteins, which activate G proteins upon ligand binding and undergo endocytosis for regeneration or recycling. Among eight RGS and RGS-like proteins of M . oryzae , MoRgs7 and MoRgs8 contain a 7-TM domain in addition to the RGS domain. We found that MoRgs7 can form hydrophobic interactions with the hydrophobic surface. This interaction is important in sensing hydrophobic cues by the fungus. We also found that, in response to surface hydrophobicity, MoRgs7 couples with Gα subunit MoMagA to undergo endocytosis leading to the activation of cAMP signaling. Moreover, we found that such an endocytic event requires functions of the actin-binding protein MoCrn1. Our results revealed that MoRgs7 also functions as a GPCR-like receptor protein to sense surface cues and activate signaling required for pathogenesis, providing new insights into G-protein regulatory mechanisms in this and other pathogenic fungi.
研究领域:
真菌学
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分子生物学
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植物病理学
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DOI
PubMed
高影响因子
JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
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2025
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IF 1.3
Ying Liu,Miao Wang,Guang-Xiong Zhou
The threat posed by microorganisms to food safety in development necessitates the discovery of new antimicrobial agents. Here, we unravel the antifungal activity of 6-methoxydihydrosanguinarine (6-ME) derived from Hylomecon japonica. 6-ME disrupted the biofilm formation of Candida albicans (C. albicans). 6-ME could cause the blockage of filamentation and classical cyclic adenosine monophosphate (cAMP) signaling pathway is involved in this process. 6-ME downregulated the expression of EFG1, CDC35, RAS1, and TPK2, all of which are critical components of the cAMP pathway. Furthermore, 6-ME changed the membrane permeability of C. albicans and caused reactive oxygen species accumulation, leading to cell death.
研究领域:
微生物学
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药理学
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真菌学
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生物化学
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食品安全
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产品关联
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
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2024
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IF 5.7
Hui Zhang,Jiangyu Yao,Guyu Xiao,Jianhui Xie,Shuying Mao,Chenghong Sun,Jingchun Yao,Jizhong Yan,Pengfei Tu
Target discovery of natural products is a key step in the development of new drugs, and it is also a difficult speed-limiting step. In this study, a traditional Chinese medicine microspheres (TCM-MPs) target fishing strategy was developed to discover the key drug targets from complex system. The microspheres are composed of Fe 3 O 4 magnetic nanolayer, oleic acid modified layer, the photoaffinity group (4- [3-(Trifluoromethyl)-3H-diazirin-3-yl] benzoic acid, TAD) layer and active small molecule layer from inside to outside. TAD produces highly reactive carbene under ultraviolet light, which can realize the self-assembly and fixation of drug active small molecules with non-selective properties. Here, taking Shenqi Jiangtang Granules (SJG) as an example, the constructed TCM-MPs was used to fish the related proteins of human glomerular mesangial cells (HMCs) lysate. 28 differential proteins were screened. According to the target analysis based on bioinformatics, GNAS was selected as the key target, which participated in insulin secretion and cAMP signaling pathway. To further verify the interaction effect of GNAS and small molecules, a reverse fishing technique was established based on bio-layer interferometry (BLI) coupled with UHPLC-Q/TOF-MS/MS. The results displayed that 26 small molecules may potentially interact with GNAS, and 7 of them were found to have strong binding activity. In vitro experiments for HMCs have shown that 7 active compounds can significantly activate the cAMP pathway by binding to GNAS. The developed TCM-MPs target fishing strategy combined with BLI reverse fishing technology to screen out key proteins that directly interact with active ingredients from complex target protein systems is significant for the discovery of drug targets for complex systems of TCM.
研究领域:
药学
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生物技术
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分子生物学
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中医药
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2022
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IF 7.419
Li-hua Bian,Zi-wei Yao,Zhe-yi Wang,Xiao-mei Wang,Qiu-yu Li,Xue Yang,Jia-yuan Li,Xiao-jia Wei,Guo-hui Wan,Yu-qing Wang,Jin-li Shi,Jian-you Guo
In a rotenone-induced Parkinson’s disease (PD) rat model, behavioral investigation, pathological examination, inflammatory factor analysis, and mitochondrial structure and function investigation verified the anti-PD efficacy of nardosinone. A combined transcriptome and proteome analysis proposed that the anti-PD target of nardosinone is the slc38a2 gene and may involve the GABAergic synaptic pathway and cAMP-signaling pathway. Analysis of targeted slc38a2 knockout cells and expression of key enzyme-encoding genes in both pathways verified the target and pathways proposed by the ‘omics analysis. This further confirms that nardosinone can regulate the slc38a2 gene, a potential new target for the treatment of Parkinson's disease, and plays an anti-PD role through the GABAergic synaptic and cAMP pathways.
研究领域:
神经科学
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药理学
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分子生物学
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基因组学
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产品关联
DOI
PubMed
高影响因子
Comparative Biochemistry and Physiology D-Genomics & Proteomics
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2025
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IF 2.4
Sumbul Mureed Mastoi,Yang Hua,Waqar Ali Chandio,Paras Mureed Mastoi,Yang Wei
The female parasitoid wasp Scleroderma sichuanensis (Hymenoptera: Bethylidae) utilizes various intricate behavior strategies, including host detection, learning, and memory, to enhance its survival and reproductive success. RNA-Seq analysis conducted under sublethal insecticide stress identified three differentially expressed genes, SsOR5, SsGRIN2B, and SsPDE8A, selected for functional validation due to their likely roles in host searching behavior. The SsOR5, an odorant receptor, is believed to interact with other olfactory receptors and downstream signaling molecules to improve host detection. In contrast, SsGRIN2B, an NMDA-type glutamate receptor, may influence synaptic plasticity and neural transmission, thereby affecting leering behavior. Additionally, SsPDE8A modulates cAMP-dependent signaling pathways, which are crucial for memory consolidation and behavioral response. This research investigates these genes in S. sichuanensis using RNA interference (RNAi) to assess changes in host finding efficiency. Adult female wasp received dsRNA treatments at doses of (0.5 μL, 1 μL, and 3 μL) and time durations (12, 24, 48, and 72 h), with the most significant gene silencing observed at 3 μL for 48–72 h. Behavioral assays conducted with a Y-tube olfactometer revealed that knockdown of SsOR5 significantly reduced host attraction, while knockdown of SsGRIN2B and SsPDE8A led to moderate reeducations, highlighting the varying contributions of these genes to olfactory drive behavior. This study demonstrates that insecticides induced changes in gene expression can disrupt neural and olfactory pathways essential for host location, and emphasizes the potential of RNAi-based approaches to target behaviorally significant genes, offering new strategies for parasitoid-mediated pest management.
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Jinfeng Shang,Qiannan Li,Tingyue Jiang,Lei Bi,Yinghui Lu,Jiakang Jiao,Qi Song,Mingxue Yan,Lizha Shabuerjiang,Jingyi Wang,Xin Liu
Ethnopharmacological relevance Huanglian Jiedu Decoction (HLJDD) has the effect of clearing heat and detoxifying, and has been considered as an effective prescription for cerebral ischemia (CI) for thousands of years in traditional Chinese medicine (TCM). It can improve the quality of life of patients with ischemic stroke, but its pharmacological mechanism remains unclear. Aim of the study The study aimed to explore the pharmacological action and potential mechanism of HLJDD against CI by systems pharmacology, proteomics and in vivo experiments. Materials and methods In this study, databases such as TCMIP V2.0 and Genecards were used to predict compounds, targets and CI related targets, and network topology criteria of protein-protein interaction (PPI) network was used to screen core targets. The Database for Annotation, Visualization and Integrated Discovery database (DAVID) was used to discover biological processes and pathways. In addition, molecular docking was performed between the screened core biological active compounds and targets to verify the binding activity. Finally, proteomics and Western blot were performed on cerebral cortex tissues of middle cerebral artery occlusion (MCAO) model rats with HLJDD intervention to further verify the predicted results. Results 77 compounds and 308 targets of HLJDD were identified, 54 of which were predicted to be associated with cerebral ischemia. PPI network and enrichment results showed that 8 targets, including AKT1, PTGS2 and TLR4 , were core targets of HLJDD in CI. And 19 signaling pathways, including Rap1 signaling pathway, cAMP signaling pathway and arachidonic acid metabolism, were identified as key pathways to the therapeutic activity of HLJDD in CI. Combined with proteomics studies, we identified that Rap1 signaling pathway and upstream and downstream targets were the key mechanisms. Molecular biology experiments showed that RAP1A and AKT expression levels were significantly up-regulated in middle cerebral artery occlusion (MCAO) rats treated with HLJDD ( P < 0.0001), GRIN1 expression level was significantly down-regulated ( P < 0.0001). However, ACTB expression level was slightly down-regulated ( P > 0.05), which may be related to the biological function. Conclusion This study confirms the pharmacological effect of HLJDD on cerebral ischemia. These results indicate that HLJDD mediates various pathways such as inhibition of apoptosis , regulation of oxygen balance, inhibition of excitatory toxicity and maintenance of basic cell functions to improve CI by regulating Rap1 signaling pathway.
研究领域:
药理学
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神经科学
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中医
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分子生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2022
·
IF 31.373
Jie Cheng,Zhao Yang,Xiao-Yan Ge,Ming-Xin Gao,Ran Meng,Xin Xu,Yu-Qi Zhang,Rui-Zhe Li,Jing-Yu Lin,Zhao-Mei Tian,Jin Wang,Shang-Lei Ning,Yun-Fei Xu,Fan Yang,Jing-Kai Gu,Jin-Peng Sun,Xiao Yu
Summary Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by β cells. By screening the expression and functional characterization of olfactory receptors (ORs) in pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a β cell-macrophage circuit and a β-arrestin-1-mediated CCL2 pathway, as evidenced by β-arrestin-1 −/− mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdx1-Cre +/− Olfr109 fl/fl specifically alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita - and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic β cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.
研究领域:
内分泌学
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免疫学
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分子生物学
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糖尿病研究
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DOI
PubMed
高影响因子
BMC Medical Genomics
·
2024
·Vol. 17
·期 1
·1-10
·
IF 2.1
Xu Kuishuai,Zhang Liang,Wang Tianrui,Yu Tengbo,Zhao Xia,Zhang Yingze
Objective There is increasing evidence that type 2 diabetes mellitus (T2DM) is an independent risk factor for the occur of tendinopathy. Therefore, this study is the first to explore the dynamic changes of the “gene profile” of supraspinatus tendon in rats at different time points after T2DM induction through transcriptomics, providing potential molecular markers for exploring the pathogenesis of diabetic tendinopathy. Methods A total of 40 Sprague-Dawley rats were randomly divided into normal (NG, n = 10) and T2DM groups (T2DM, n = 30) and subdivided into three groups according to the duration of diabetes: T2DM-4w, T2DM-8w, and T2DM-12w groups; the duration was calculated from the time point of T2DM rat model establishment. The three comparison groups were set up in this study, T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG. Differentially expressed genes (DEGs) in 3 comparison groups were screened. The intersection of the three comparison groups’ DEGs was defined as key genes that changed consistently in the supraspinatus tendon after diabetes induction. Cluster analysis, gene ontology (GO) functional annotation analysis and Kyoto encyclopedia of genes and genomes (KEGG) functional annotation and enrichment analysis were performed for DEGs. Results T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG detected 519 (251 up-regulated and 268 down-regulated), 459 (342 up-regulated and 117 down-regulated) and 328 (255 up-regulated and 73 down-regulated) DEGs, respectively. 103 key genes of sustained changes in the supraspinatus tendon following induction of diabetes, which are the first identified biomarkers of the supraspinatus tendon as it progresses through the course of diabetes.The GO analysis results showed that the most significant enrichment in biological processes was calcium ion transmembrane import into cytosol (3 DEGs). The most significant enrichment in cellular component was extracellular matrix (9 DEGs). The most significant enrichment in molecular function was glutamate-gated calcium ion channel activity (3 DEGs). The results of KEGG pathway enrichment analysis showed that there were 17 major pathways ( p < 0.05) that diabetes affected supratinusculus tendinopathy, including cAMP signaling pathway and Calcium signaling pathway. Conclusions Transcriptomics reveals dynamic changes in the“gene profiles”of rat supraspinatus tendon at three different time points after diabetes induction. The 103 DEGs identified in this study may provide potential molecular markers for exploring the pathogenesis of diabetic tendinopathy, and the 17 major pathways enriched in KEGG may provide new ideas for exploring the pathogenesis of diabetic tendinopathy.
研究领域:
分子生物学
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基因组学
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糖尿病研究
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肌肉骨骼疾病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Jing Zhang,Chengcheng Lv,Zhenyang Yu,Yangyuan Zhou
Reproductive toxicities of imidazolium- ([EMIM]X) and pyridinium-based ([APYR]X) ionic liquids (ILs) are essential to fully assess their hazards. Presently, effects of five ILs on the intricate processes of reproduction, including sperm-oocyte interactions, were explored in Caenorhabditis elegans . Results showed that 1-ethylpyridinium bromide ([EPYR]Br) stimulated oocytes, zygotes and total reproduction. 1-Octylpyyridinium bromide ([OPYR]Br) inhibited oocytes and stimulated zygotes, it inhibited the initial and total reproduction. 1-Dodecylpyridinium bromide ([DPYR]Br) inhibited oocytes and zygotes, but stimulated the initial and total reproduction. 1-Ethyl-3-methylimidazolium bromide ([EMIM]Br) inhibited oocytes, but stimulated zygotes and reproduction. 1-Ethyl-3-methylimidazolium iodide ([EMIM]I) inhibited germcells and oocytes but stimulated zygotes and reproduction. Regarding hormones and lipid metabolism, the ILs commonly reduced main sperm protein, sperm transmembrane protein 9 and spermatocyte protein 8. The qRT-PCR results showed that the ILs commonly down-regulated the expressions of mpk-1 , while up-regulated those of inx-14 , with influences on the expressions of vab-1 , unc-43 and rme-2 . These biochemicals and genes were directly connected with the sperm-oocyte interactions. Transcriptomic analysis results supported the involvement of cAMP and cGMP-PKG signaling pathways underlying the effects on the sperm-oocyte interactions. The results also implied ILs’ impacts on neural and immune diseases and even cancers that should be considered in the future.
研究领域:
毒理学
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生殖生物学
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分子生物学
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遗传学
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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）