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The dual-action mechanism of Arabidopsis cryptochromes

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Journal of Integrative Plant Biology 2024年第5期66卷 883-896页

作者： Gao-Ping Qu Bochen Jiang Chentao Lin Basic Forestry and Plant proteomics Research Center Fujian Agriculture and Forestry UniversityFuzhou 350002China department of Chemistry Department of Biochemistry and Molecular BiologyInstitute for Biophysical DynamicsThe University of ChicagoChicagoIL 60637USA

Photoreceptor cryptochromes (CRYs) mediate blue-light regulation of plant growth and development. It has been reported that Arabidopsis CRY1and CRY2 function by physically interacting with at least 84 proteins, including transcription factors or co-factors, chromatin regulators, splicing factors, messenger RNA methyltransferases, DNA repair proteins, E3 ubiquitin ligases, protein kinases and so on. Of these 84 proteins, 47 have been reported to exhibit altered binding affinity to CRYs in response to blue light, and 41 have been shown to exhibit condensation to CRY photobodies. The blue light-regulated composition or condensation of CRY complexes results in changes of gene expression and developmental programs. In this mini-review, we analyzed recent studies of the photoregulatory mechanisms of Arabidopsis CRY complexes and proposed the dual mechanisms of action, including the “Lock-and-Key” and the “Liquid-Liquid Phase Separation (LLPS)” mechanisms. The dual CRY action mechanisms explain, at least partially, the structural diversity of CRY-interacting proteins and the functional diversity of the CRY photoreceptors.

关键词： Arabidopsis blue light cryptochrome CRY1 CRY2 phaseseparation

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KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer’s disease

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World Journal of Psychiatry 2024年第3期14卷 445-455页

作者： Qun-Shan Lu Lin Ma Wen-Jing Jiang Xing-Bang Wang Mei Lu department of Geriatric Medicine Qilu Hospital of Shandong UniversityJinan 250012Shandong ProvinceChina Key Laboratory of Cardiovascular proteomics of Shandong Province Qilu Hospital of Shandong UniversityJinan 250012Shandong ProvinceChina

BACKGROUND Epidemiological studies have revealed a correlation between Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2D).Insulin resistance in the brain is a common feature in patients with T2D and ***7 is a histone acetyltransferase that participates in the modulation of various *** To determine the effects of KAT7 on insulin patients with *** APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes,*** in vitro model of AD was established by Aβ*** resistance was induced by chronic stimulation with high insulin *** expression of microtubule-associated protein 2(MAP2)was assessed using *** protein levels of MAP2,Aβ,dual-specificity tyrosine phosphorylation-regulated kinase-1A(DYRK1A),IRS-1,p-AKT,total AKT,p-GSK3β,total GSK3β,DYRK1A,and KAT7 were measured via western *** of reactive oxygen species(ROS),malondialdehyde(MDA),and SOD activity was measured to determine cellular oxidative *** cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation,*** RNA levels of KAT7 and DYRK1A were examined using quantitative PCR.A chromatin immunoprecipitation assay was conducted to detect H3K14ac in *** KAT7 expression was suppressed in the AD *** of KAT7 decreased Aβaccumulation and MAP2 expression in AD ***7 overexpression decreased ROS and MDA levels,elevated SOD activity in brain tissues and neurons,and simultaneously suppressed neuronal ***7 upregulated levels of p-AKT and p-GSK3βto alleviate insulin resistance,along with elevated expression of ***7 depletion suppressed DYRK1A expression and impaired H3K14ac of ***1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 *** We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylati

关键词： Alzheimer's disease Diabetes Insulin resistance KAT7 Dual-specificity tyrosine phosphorylation-regulated kinase-1A HMGN1

CYP3A5 unexpectedly regulates glucose metabolism through the AKT-TXNIP-GLUT1 axis in pancreatic cancer

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Genes & Diseases 2024年第4期11卷 381-399页

作者： Ming Shao Qingfei Pan Haiyan Tan Jing Wu Ha Won Lee Andrew D.Huber William C.Wright Ji-Hoon Cho Jiyang Yu Junmin Peng Taosheng Chen department of Chemical Biology and Therapeutics St.Jude Children's Research HospitalMemphisTN 38105USA department of Computational Biology St.Jude Children's Research HospitalMemphisTN 38105USA Center for proteomics and Metabolomics St.Jude Children's Research HospitalMemphisTN 38105USA department of Structural Biology St.Jude Children's Research HospitalMemphisTN 38105USA department of Developmental Neurobiology St.Jude Children's Research HospitalMemphisTN 38105USA

CYP3A5 is a cytochrome P450(CYP)enzyme that metabolizes drugs and contributes to drug resistance in ***,it remains unclear whether CYP3A5 directly influences cancer *** this report,we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal ***-omics analysis showed that CYP3A5 knockdown re-sults in a decrease in various glucose-related metabolites through its effect on glucose trans-port.A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP,a negative regulator of ***,CYP3A5-generated reactive oxygen species were proved to be responsible for atten-uating the AKT-4EBP1-TXNIP signaling ***3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic *** together,our results,for the first time,reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.

关键词： Cell migration CYP3A5 Glucose metabolism GLUT1 Pancreatic cancer TXNIP

Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

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Journal of Pharmaceutical Analysis 2024年第1期14卷 100-114页

作者： Sze Wan Hung Massimiliano Gaetani Yiran Li Zhouyurong Tan Xu Zheng Ruizhe Zhang Yang Ding Gene Chi Wai Man Tao Zhang Yi Song Yao Wang Jacqueline Pui Wah Chung Tak Hang Chan Roman A.Zubarev Chi Chiu Wang department of Obstetrics&Gynaecology The Chinese University of Hong KongHong KongChina Division of Physiological Chemistry I Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Chemical proteomics Core Facility Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Unit of Chemical proteomics Science for Life Laboratory(SciLifeLab)StockholmSE 17177Sweden Center for Reproductive Medicine Henan Key Laboratory of Reproduction and GeneticsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450003China department of Chemistry McGill UniversityMontrealH3A2K6Canada department of Pharmacological&Technological Chemistry I.M.Sechenov First Moscow State Medical UniversityMoscow119146Russia Reproduction and Development Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong KongChina School of Biomedical Sciences The Chinese University of Hong KongHong KongChina Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine The Chinese University of Hong KongHong KongChina

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the *** is a major pathophysiology in *** previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain *** this study,we demonstrated that oral ProEGCG can be effective in preventing and treating ***,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,*** simulation and BioLayer interferometry were used to confirm their binding *** results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)*** vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling ***,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

关键词： Molecular targets ProEGCG EGCG Angiogenesis Treatment Endometriosis

APIR:Aggregating Universal proteomics Database Search Algorithms for Peptide Identification with FDR Control

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Genomics, proteomics & Bioinformatics 2024年第2期22卷 171-187页

作者： Yiling Elaine Chen Xinzhou Ge Kyla Woyshner MeiLu McDermott Antigoni Manousopoulou Scott B.Ficarro Jarrod A.Marto Kexin Li Leo David Wang Jingyi Jessica Li department of Statistics and Data Science University of CaliforniaLos AngelesCA 90095USA department of Immuno-Oncology Beckman Research InstituteCity of Hope National Medical CenterDuarteCA 91010USA department of Quantitative and Computational Biology University of Southern CaliforniaLos AngelesCA 90089USA department of Cancer Biology and Blais proteomics Center Dana-Farber Cancer InstituteDepartment of PathologyBrigham and Women’s Hospital and Harvard Medical SchoolBostonMA 02215USA department of Pediatrics City of Hope National Medical CenterDuarteCA 91010USA Bioinformatics Interdepartmental Program University of CaliforniaLos AngelesCA 90095USA department of Human Genetics University of CaliforniaLos AngelesCA 90095USA department of Computational Medicine University of CaliforniaLos AngelesCA 90095USA department of Biostatistics University of CaliforniaLos AngelesCA 90095USA

Advances in mass spectrometry(MS)have enabled high-throughput analysis of proteomes in biological *** state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide–spectrum matches(PSMs),which convert mass spectra to peptide *** database search algorithms use distinct search strategies and thus may identify unique ***,no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and a control on the false discovery rate(FDR).To fill in this gap,we proposed a statistical framework,Aggregation of Peptide Identification Results(APIR),that is universally compatible with all database search ***,under an FDR threshold,APIR is guaranteed to identify at least as many,if not more,peptides as individual database search algorithms *** of APIR on a complex proteomics standard dataset showed that APIR outpowers individual database search algorithms and empirically controls the *** data studies showed that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search *** APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis,e.g.,differential gene expression analysis on RNA sequencing *** APIR R package is available at https://***/yiling0210/APIR.

关键词： Shotgun proteomics Peptide–spectrum match Peptide identification Aggregation of lists FDR control

High-fat diet impairs gut barrier through intestinal microbiota-derived reactive oxygen species

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Science China(Life Sciences) 2024年第5期67卷 879-891页

作者： Nianyi Zeng Fan Wu Junqi Lu Xiang Li Shaomei Lin Lang Zhou Zhongwei Wang Guangyan Wu Qingfa Huang Daowen Zheng Jie Gao Shan Wu Xiaojiao Chen Muxuan Chen Fanguo Meng Haitao Shang Yan He Peng Chen Hong Wei Zhuang Li Hongwei Zhou Microbiome Medicine Center Department of Laboratory MedicineZhujiang HospitalSouthern Medical UniversityGuangzhou 510282China department of Environmental Health Guangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public Health and Tropical MedicineSouthern Medical UniversityGuangzhou 510515China Redox Medical Center for Public Health Soochow UniversitySuzhou 215301China Precision Medicine Institute The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China department of Pathophysiology Guangdong Provincial Key Laboratory of ProteomicsSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China

Gut barrier disruption is a key event in bridging gut microbiota dysbiosis and high-fat diet(HFD)-associated metabolic ***,the underlying mechanism remains *** the present study,by comparing HFD-and normal diet(ND)-treated mice,we found that the HFD instantly altered the composition of the gut microbiota and subsequently damaged the integrity of the gut *** sequencing revealed that the HFD upregulates gut microbial functions related to redox reactions,as confirmed by the increased reactive oxygen species(ROS)levels in fecal microbiota incubation in vitro and in the lumen,which were detected using in vivo fluorescence *** microbial ROS-producing capability induced by HFD can be transferred through fecal microbiota transplantation(FMT)into germ-free(GF)mice,downregulating the gut barrier tight ***,mono-colonizing GF mice with an Enterococcus strain excelled in ROS production,damaged the gut barrier,induced mitochondrial malfunction and apoptosis of the intestinal epithelial cells,and exacerbated fatty liver,compared with other low-ROS-producing Enterococcus *** administration of recombinant high-stability-superoxide dismutase(SOD)significantly reduced intestinal ROS,protected the gut barrier,and improved fatty liver against the *** conclusion,our study suggests that extracellular ROS derived from gut microbiota play a pivotal role in HFD-induced gut barrier disruption and is a potential therapeutic target for HFD-associated metabolic diseases.

关键词： fatty liver disease gut microbiota gut barrier high-fat diet oxidative stress reactive oxygen species

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Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3068-3085页

作者： Dongping Li Rongjuan Wei Xianglong Zhang Shenhai Gong Meijuan Wan Fangzhao Wang Jiaxin Li Meiling Chen Ruofan Liu Yantong Wan Yinghao Hong Zhenhua Zeng Peng Gu Zhang Wang Kutty Selva Nandakumar Yong Jiang Hongwei Zhou Peng Chen department of Pathophysiology Guangdong Provincial Key Laboratory of ProteomicsSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510000China department of Critical Care Medicine Nanfang HospitalSouthern Medical UniversityGuangzhou 510000China department of Gastroenterology Shenzhen HospitalSouthern Medical UniversityShenzhen 518000China Institute of Ecological Sciences School of Life SciencesSouth China Normal UniversityGuangzhou 510000China department of Environmental and Biosciences School of BusinessInnovation and SustainabilityKristian IV’s vag 3Halmstad UniversityHalmstad 30004Sweden Microbiome Medicine Center Zhujiang HospitalSouthern Medical UniversityGuangzhou 510000China

Sepsis progression is significantly associated with the disruption of gut ***,the modulatory mechanisms of gut microbiota operating during sepsis are still ***,we investigated how gut commensals impact sepsis development in a pre-clinical *** ligation and puncture(CLP)surgery was used to establish polymicrobial sepsis in *** depleted of gut microbiota by an antibiotic cocktail(ABX)exhibited a significantly higher level of mortality than *** determined by metabolomics analysis,ABX treatment has depleted many metabolites,and subsequent supplementation with L-rhamnose(rhamnose,Rha),a bacterial carbohydrate metabolite,exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis,which in turn improved organ damage and ***,rhamnose binds directly to and activates the solute carrier family 12(potassium-chloride symporter),member 4(SLC12A4)in macrophages and promotes phagocytosis by activating the small G-proteins,Ras-related C3 botulinum toxin substrate1(Rac1)and cell division control protein 42 homolog(Cdc42).Interestingly,rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis *** conclusion,by identifying SLC12A4 as the host interacting protein,we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.

关键词： Gut microbiota Sepsis Rhamnose SLC12A4 GTP-Rac1 GTP-Cdc42 Macrophage Phagocytosis

Data-driven drug repositioning using olfactory omics profiles:challenges and perspectives in neurodegeneration

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Neural Regeneration Research 2025年第7期20卷 1997-1998页

作者： Paz Cartas-Cejudo Adriana Cortés Mercedes Lachén-Montes Elena Anaya-Cubero Joaquín Fernández-Irigoyen Enrique Santamaría Clinical Neuroproteomics Unit Proteomics PlatformNavarrabiomedHospitalario Universitario de Navarra(HUN)Universidad Pública de Navarra(UPNA)IdiSNANavarra Institute for Health ResearchPamplonaSpain

Data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous *** diseases are often characterized as proteinopathies,which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells,leading to their dysfunction and eventual *** the gain-of-function hypothesis related to the aggregation of these proteins,recently,an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining *** last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body(Ezzat et al.,2023).It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased.

关键词： diseases drug amyloid

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Optimizing ABA-based chemically induced proximity for enhanced intracellular transcriptional activation and modification response to ABA

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Science China Life Sciences 2024年

作者： Zeng Zhou Yue-Qi Wang Xu-Nan Zheng Xiao-Hong Zhang Lu-Yao Ji Jun-You Han Ze-Cheng Zuo Wei-Liang Mo Li Zhang College of Life Sciences Fujian Agriculture and Forestry University Basic Forestry and proteomics Research Center Fujian Agriculture and Forestry University Jilin Province Engineering Laboratory of Plant Genetic Improvement College of Plant Science Jilin University

Abscisic acid(ABA)-based chemically induced proximity(CIP) is primarily mediated by the interaction of the ABA receptor pyrabactin resistance 1-like 1(PYL1) and the 2C-type protein phosphatase ABI1, which confers ABA-induced proximity to their fusion proteins, and offers precise temporal control of a wide array of biological processes. However, broad application of ABA-based CIP has been limited by ABA response intensity. In this study, we demonstrated that ABA-induced interaction between another ABA receptor pyrabactin resistance 1(PYR1) and ABI1 exhibited higher ABA response intensity than that between PYL1 and ABI1 in HEK293T cells. We engineered PYR1-ABI1and PYL1-ABI1 into ABA-induced transcriptional activation tools in mammalian cells by integration with CRISPR/dCas9 and found that the tool based on PYR1-ABI1 demonstrated better ABA response intensity than that based on PYL1-ABI1 for both exogenous and endogenous genes in mammalian cells. We further achieved ABA-induced RNA m6A modification installation and erasure by combining ABA-induced PYR1-ABI1 interaction with CRISPR/dCas13, successfully inhibiting tumor cell proliferation. We subsequently improved the interaction of PYR1-ABI1 through phage-assisted continuous evolution(PACE), successfully generating a PYR1 mutant(PYR1m) whose interaction with ABI1 exhibited a higher ABA response intensity than that of the wild-type. In addition, we tested the transcriptional activation tool based on PYRm-ABI1 and found that it also showed a higher ABA response intensity than that of the wild type. These results demonstrate that we have developed a novel ABA-based CIP and further improved upon it using PACE, providing a new approach for the modification of other CIP systems.

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