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Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS Homeostasis

Signal Transduction and Targeted Therapy 2024年第4期9卷 1637-1650页

作者： Yuanliang Yan Shangjun Zhou Xi Chen Qiaoli Yi Songshan Feng Zjjin Zhao Yuanhong Liu Qiuju Liang Zhijie Xu Zhi Li Lunquan Sun Department of Pharmacy Xiangya HospitalCentral South UniversityChangsha 410008China Department of Neurosurgery Xiangya HospitalCentral South UniversityChangsha 410008China Department of Pathology Xiangya HospitalCentral South UniversityChangsha 410008China Xiangya Cancer Center Xiangya HospitalCentral South UniversityChangsha 410008China Key Laboratory of Molecular Radiation Oncology Hunan Province Changsha 410008China institute of Cancer Research National Clinical Research Center for Geriatric Disorders(Xiangya)Xiangya HospitalCentral South UniversityChangsha 410008China

Temozolomide(TMZ)represents a standard-of-care chemotherapeutic agent in glioblastoma(GBM).However,the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma.Although specific innovative approaches,such as immunotherapy,have shown favorable clinical outcomes,the inherent invasiveness of most gliomas continues to make them challenging to treat.Consequently,there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development.This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors.A total of 648 proteins exhibiting significant differential expression were identified.Gene Set Enrichment Analysis(GSEA)unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups.Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate(IP3)kinase B(ITPKB)in the recurrence group,correlating with poor survival in glioma patients.In TMZ-resistant cells,the depletion of ITPKB led to an increase in reactive oxygen species(ROS)related to NADPH oxidase(NOX)activity and restored cell sensitivity to TMz.Mechanistically,the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination.This,in turn,elevated ITPKB stability and impaired ROS production.Furthermore,ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model.These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target forTMZ-resistant GBM.

关键词： TMZ Homeostasis impaired

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RIPK1 plays a crucial role in maintaining regulatory T-Cell Homeostasis by inhibiting both RIPK3-and FADD-mediated cell death

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Cellular & Molecular Immunology 2024年第1期21卷 80-90页

作者： Xiaoxue Deng Lingxia Wang Yunze Zhai Qiuyue Liu Fengxue Du Yu Zhang Wenxing Zhao Tingtao Wu Yiwen Tao Jie Deng Yongbing Cao Pei Hao Jiazi Ren Yunli Shen Zuoren Yu Yuejuan Zheng Haibing Zhang Haikun Wang State Key Laboratory of Cardiology Shanghai East HospitalTongji University School of MedicineShanghai200120China CAS Key Laboratory of Molecular Virology and Immunology Shanghai Institute of Immunity and InfectionChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai200031China CAS Key Laboratory of Nutrition Metabolism and Food SafetyShanghai Institute of Nutrition and HealthShanghai Institutes for Biological SciencesUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China The Research Center for Traditional Chinese Medicine Shanghai Institute of Infectious Diseases and BiosecurityShanghai University of Traditional Chinese MedicineShanghai201203China Institute of Vascular Disease Shanghai TCM-Integrated HospitalShanghai University of Traditional Chinese MedicineShanghai200433China

Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)Homeostasis remain incompletely understood.Here,we report that RIPK1 is crucial for T_(reg) cell survival and Homeostasis.We generated mice with T_(reg) cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death.Unlike conventional T cells,Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis.However,simultaneous removal of both Fadd and Ripk3 completely restored the Homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways.Thus,our study highlights the critical role of RIPK1 in regulating Treg cell Homeostasis by controlling both apoptosis and necroptosis,thereby providing novel insights into the mechanisms of Treg cell Homeostasis.

关键词： Treg cell Homeostasis Apoptosis Necroptosis

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MFSD12 affects glycosphingolipid metabolism by modulating lysosome Homeostasis

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Protein & Cell 2023年第6期14卷 459-463页

作者： Yun Hong Zheng Tian Liangjie Jia Yiguo Wang MOE Key Laboratory of Bioinformatics Tsinghua-Peking Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

Dear Editor,Glycosphingolipid(GSL)catabolism is strictly regulated in a sequential manner by lysosomal hydrolases with the help of lipid-binding proteins.Impairments of the catabolic pathway cause the onset of lysosomal storage diseases(LsDs),which are characterized by the aberrant accumulation of GSLs(Hannun and Obeid 2018;Breiden and Sandhoff 2019).The primary LSDs occur through the well-known mechanism of inherited defects in genes encoding the catabolic enzymes(or their related cofactors)which reside in the lumen of lysosomes(Hannun and Obeid 2018;Breiden and Sandhoff 2019).However,in some LSDs,the inherited mutations affect other proteins,such as those residing in the lysosomal membrane;these mutations are associated with defects in traffcking and fusion in the endocytic system(Platt et al.2012).However,the non-lumenal lysosomal membrane proteins involved in GSL metabolism remain to be identified.

关键词： metabolism Homeostasis defects

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Antioxidant-enriched autologous biogel promoted diabetic wound healing by remodeling inherent posttraumatic inflammatory patterning and restoring compromised microenvironment Homeostasis

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Regenerative Biomaterials 2022年第1期9卷 202-218页

作者： Yixi Yang Le Wang Yonglin Zhou Yijun He Shaozhang Lin Yuwei Zeng Yunhe Zhou Wei Li Zaopeng He Qi Zhao Lihao Chen Zijie Li Wenhao Wang Zhi-Yong Zhang Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University Guangdong Province Engineering Research Center for Biomedical EngineeringState Key Laboratory of Respiratory DiseaseThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510150P.R.China Department of Orthopaedic Surgery The Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510150P.R.China Medical Technology and Related Equipment Laboratory The Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510150P.R.China Hand and Foot Surgery&Plastic Surgery Affiliated Shunde Hospital of Guangzhou Medical UniversityShunde DistrictFoshanP.R.China

Successful wound healing depends on the reconstruction of proper tissue Homeostasis,particularly in the posttraumatic inflammatory tissue microenvironment.Diabetes jeopardizes tissues’immune Homeostasis in cutaneous wounds,causing persistent chronic inflammation and cytokine dysfunction.Previously,we developed an autologous regeneration factor(ARF)technology to extract the cytokine composite from autologous tissue to restore immune Homeostasis and promote wound healing.However,treatment efficacy was significantly compromised in diabetic conditions.Therefore,we proposed that a combination of melatonin and ARF,which is beneficial for proper immune Homeostasis reconstruction,could be an effective treatment for diabetic wounds.Our research showed that the utilization of melatonin-mediated ARF biogel(AM gel)promoted diabetic wound regeneration at a more rapid healing rate.RNA-Seq analysis showed that AM gel treatment could restore more favorable immune tissue Homeostasis with unique inflammatory patterning as a result of the diminished intensity of acute and chronic inflammation.Currently,AM gel could be a novel and promising therapeutic strategy for diabetic wounds in clinical practice through favorable immune homeostatic reconstructions in the tissue microenvironment and proper posttraumatic inflammation patterning.

关键词： autologous regeneration factors wound healing Homeostasis tissue microenvironment inflammation patterning

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A long non-coding RNA LncSync regulates mouse cardiomyocyte Homeostasis and cardiac hypertrophy through coordination of miRNA actions

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Protein & Cell 2023年第2期14卷 153-157页

作者： Rujin Huang Jinyang Liu Xi Chen Ying Zhi Shuangyuan Ding Jia Ming Yulin Li Yangming Wang Jie Na Center for Stem Cell Biology and Regenerative Medicine School of MedicineTsinghua UniversityBeijing 100084China School of Life Sciences Tsinghua UniversityBeijing 100084China Capital Medical University Beijing 100084China Beijing Key Laboratory of Cardiometabolic Molecular Medicine Peking-Tsinghua Center for Life SciencesInstitute of Molecular MedicinePeking UniversityBeijing 100871China

Dear Editor,Maintenance of cardiomyocyte(CM)Homeostasis is essential for normal heart function.Long-term imbalance in heart Homeostasis could elicit irreversible adaptive change in cell structure and function and tissue architecture,exemplified as cardiac hyper-trophy and fibrosis,and eventually develop into heart failure(Shiojima et al.,2005).Therefore,identifying new genes and path-ways regulating CM Homeostasis may help better understand the cause of cardiac hypertrophy.

关键词： Homeostasis cardiac hypertrophy

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The HB40-JUB1 transcriptional regulatory network controls gibberellin Homeostasis in Arabidopsis

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Molecular Plant 2022年第2期15卷 322-339页

作者： Shuchao Dong Danuse Tarkowska Mastoureh Sedaghatmehr Maryna Welsch Saurabh Gupta Bernd Mueller-Roeber Salma Balazadeh Max-Planck Institute of Molecular Plant Physiology Am Mühlenberg 114476 Potsdam-GolmGermany Institute of Biology Leiden UniversitySylviusweg 722333 BE LeidenThe Netherlands Laboratory of Growth Regulators Czech Academy of SciencesInstitute of Experimental Botany&Palacky UniversityŠlechtitelû2778371 OlomoucCzech Republic University of Potsdam Institute of Biochemistry and BiologyKarl-Liebknecht-Stra?e 24-25Haus 2014476 Potsdam-GolmGermany

The gibberellins(GAs)are phytohormones that play fundamental roles in almost every aspect of plant growth and development.Although GA biosynthetic and signaling pathways are well understood,the mechanisms that control GA Homeostasis remain largely unclear in plants.Here,we demonstrate that the homeobox transcription factor(TF)HB40 of the HD-Zip family regulates GA content at two additive con-trol levels in Arabidopsis thaliana.We show that HB40 expression is induced by GA and in turn reduces the levels of endogenous bioactive GAs by simultaneously reducing GA biosynthesis and increasing GA deac-tivation.Consistently,HB40 overexpression leads to typical GA-deficiency traits,such as small rosettes,reduced plant height,delayed flowering,and male sterility.By contrast,a loss-of-function hb40 mutation enhances GA-controlled growth.Genome-wide RNA sequencing combined with molecular-genetic ana-lyses revealed that HB40 directly activates the transcription of JUNGBRUNNEN1(JJUB1),a key TF that re-presses growth by suppressing GA biosynthesis and signaling.HB40 also activates genes encoding GA 2-oxidases(GA2oxs),which are major GA-catabolic enzymes.The effect of HB40 on plant growth is ultimately mediated through the induction of nuclear growth-repressing DELLA proteins.Collectively,our results reveal the important role of the HB40-JUB1 regulatory network in controlling GA Homeostasis during plant growth.

关键词： Arabidopsis growth gibberellin Homeostasis transcription factor HB40 JUB1 GA 2-oxidase DELLA proteins

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Gut microbiota and differential genes-maintained Homeostasis is key to maintaining health of individuals with Yang-deficiency constitution

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Journal of Traditional Chinese Medicine 2022年第1期42卷 96-101页

作者： ZHANG Huixiang WANG Limei GUO Jipeng WANG Jiai ZHANG Qianqian WANG Yutao LIU Xun ZHANG Lihuan SHI Lanlan WU Hongxiang CAO Xue Institute of Neuroscience Basic Medical CollegeKunming Medical UniversityKunming 650500China Department of Laboratory Animal Science Kunming Medical UniversityKunming 650500China Department of Laboratory Animal Science Kunming Medical UniversityState Key Laboratory for Conservation and Utilization of Bio-Resources in YunnanYunnan UniversityKunming 650500Chin Faculty of Rehabilitation Medicine Kunming Medical UniversityKunming 650500China School of Electrical and Information Technology Yunnan Minzu UniversityKunming 650500China School of Medicine Kunming UniversityKunming 650214China Basic Medical College Kunming Medical UniversityKunming 650500China Department of Anatomy Histology and EmbryologyBasic Medical CollegeKunming Medical UniversityKunming 650500China

OBJECTIVE:Yang-deficiency constitution(YADC)is a common unbalanced constitution that predisposes individuals to certain diseases.However,not all people with YADC manifest develop diseases.This calls for delineation of the underlying molecular mechanisms.Previous studies suggested that the gut microbiota and gene differential expression should be considered.METHODS:In the present study,we compared profiles of gut microbiota between four healthy YADC individuals and those of five healthy balanced constitution(BC)counterparts,based on 16 S r RNA gene sequence analysis.Furthermore,YADC relevant genes identified by comparing 62 healthy YADC and 58 healthy BC individuals in total to perform intersection analysis,functional clustering and pathway enrichment analyses.RESULTS:The levels of harmful gut microbiota(Prevotellaceae,LDA score>4.0,P=0.0141)and beneficial gut microbiota(Ruminococcaceae,LDA score>4.0,P=0.0025,Faecalibacterium,LDA score>4.0,P=0.0484)were both elevated in healthy YADC individuals.Also,we found that the specific metabolic pathway with 2,6-Dichloro-p-hydroquinone 1,2-Dioxygenase(Pcp A)as the core in gut microbiota and the glutathione transferase activity has been enriched by YADC relevant genes in healthy YADC individuals were both responsible for the detoxification of halogenated aromatic hydrocarbon substances.CONCLUSIONS:Both beneficial and harmful factors had been detected in healthy YADC individuals,functionally,they may have triggered Homeostasis to maintain the health of individuals with YADC.The Homeostasis may be maintained by beneficial and harmful factors from gut flora and genes.Future studies are expected to focus on halogenated aromatic hydrocarbons and their detoxification processes.

关键词： Yang deficiency physical constitution theory health promotion gastrointestinal microbiome genes hydrocarbons aromatic Homeostasis

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A feedback regulation between ARF7-mediated auxin signaling and auxin Homeostasis involving MES17 affects plant gravitropism

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Journal of Integrative Plant Biology 2022年第7期64卷 1339-1351页

作者： Feng Zhang Cuiling Li Xingzhen Qu Jiajia Liu Zipeng Yu Junxia Wang Jiayong Zhu Yongqiang Yu Zhaojun Ding The Key Laboratory of Plant Development and Environmental Adaptation Biology Ministry of EducationCollege of Life SciencesShandong UniversityQingdao 266237China Horticulture Biology and Metabolomics Center Haixia Institute of Science and TechnologyFujian Agriculture and Forestry UniversityFuzhou 350002China

Gravitropism is an essential adaptive response of land plants.Asymmetric auxin gradients across plant organs,interpreted by multiple auxin signaling components including AUXIN RESPONSE FACTOR7(ARF7),trigger differential growth and bending response.However,how this fundamental process is strictly maintained in nature remains unclear.Here,we report that gravity stimulates the transcription of METHYL ESTERASE17(MES17)along the lower side of the hypocotyl via ARF7-dependent auxin signaling.The asymmetric distribution of MES17,a methyltransferase that converts auxin from its inactive form methyl indole-3-acetic acid ester(MeI AA)to its biologically active form free-IAA,enhanced the gradient of active auxin across the hypocotyl,which in turn reversely amplified the asymmetric auxin responses and differential growth that shape gravitropic bending.Taken together,our findings reveal the novel role of MES17-mediated auxin Homeostasis in gravitropic responses and identify an ARF7-triggered feedback mechanism that reinforces the asymmetric distribution of active auxin and strictly controls gravitropism in plants.

关键词： ARF7 auxin gravitropism Homeostasis MES17

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Phosphate-dependent regulation of vacuolar trafficking of OsSPX-MFSs is critical for maintaining intracellular phosphate Homeostasis in rice

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Molecular Plant 2023年第8期16卷 1304-1320页

作者： Runze Guo Qi Zhang Kun Qian Yinghui Ying Wenying Liao Lening Gan Chuanzao Mao Yong Wang James Whelan Huixia Shou State Key Laboratory of Piant Physiology and Biochemistry Cllege of Life SciencesZhejiang UniversityHangzhouZhejang 310058P.R.China Hainan Institute Zhejiang UniversitySanya 572025China The Provincial International Science and Technology Cooperation Base on Engineering Biology International Campus of Zhejiang UniversityHainingZhejang 314400China Zhijiang lab Hangzhou 310012China

Vacuolar storage of inorganic phosphate(Pi)is essential for Pi Homeostasis in plants.The SPX-MFS family proteins have been demonstrated to be vacuolar Pi transporters in many plant species.Transcriptional regulation of the predominant transporter among rice SPX-MFSs,OsSPX-MFS3,was only moderately suppressed by Pi starvation.Thus,post-transcriptional mechanisms were hypothesized to regulate the activity of OsSPX-MFS3.In this study,we found that the tonoplast localization of OsSPX-MFSs is inhibited under Pi-depleted conditions,resulting in their retention in the pre-vacuolar compartments(PVCs).A yeast two-hybrid screen identified that two SNARE proteins,OsSYP21 and OsSYP22,interact with the MFS domain of OsSPX-MFS3.Further genetic and cytological analyses indicate that OsSYP21 and OsSYP22 facilitate trafficking of OsSPX-MFS3 from PVCs to the tonoplast.Although a homozygous frameshift mutation in OsSYP22 appeared to be lethal,tonoplast localization of OsSPX-MFS3 was significantly inhibited in transgenic plants expressing a negative-dominant form of OsSYP22(OsSYP22-ND),resulting in reduced vacuolar Pi concentrations in OsSYP22-ND plants.Under Pi-depleted conditions,the interaction between OsSYP22 and OsSPX-MFS3 was disrupted,and this process depended on the presence of the SPX domain.Deleting the SPX domains of OsSPX-MFSs resulted in their tonoplast localization under both Pi-depleted and Pi-replete conditions.Complementation of the osspx-mfs1/2/3 triple mutants with the MFS domain or the SPX domain of OsSPX-MFS3 confirmed that the MFS and SPX domains are responsive to Pi transport activity and Pi-dependent regulation,respectively.These data indicated that the SPX domains of OsSPX-MFSs sense cellular Pi(InsP)levels and,under Pi-depleted conditions,inhibit the interaction between OsSPX-MFSs and OsSYP21/22 and subsequent trafficking of OsSPX-MFSs from PVCs to the tonoplast.

关键词： fir Homeostasis inhibited

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Runx1 is a key regulator of articular cartilage Homeostasis by orchestrating YAP,TGFβ,and Wnt signaling in articular cartilage formation and osteoarthritis

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Bone Research 2022年第4期10卷 882-892页

作者： Yan Zhang Tao Zuo Abigail McVicar Hui-Lin Yang Yi-Ping Li Wei Chen Department of Pathology University of Alabama at BirminghamBirminghamAL 35294USA Key Laboratory of Biomedical Information Engineering of Ministry of Education Biomedical Informatics and Genomics CenterSchool of Life Science and TechnologyXi’an Jiaotong UniversityXi’an 710049 ShaanxiP.R.China Department of Orthopaedics the First Affiliated Hospital of Soochow UniversityOrthopaedic Institute of Soochow University899 Pinghai RoadSuzhou 215031 JiangsuP.R.China Division in Cellular and Molecular Medicine Department of Pathology and Laboratory MedicineTulane University School of MedicineTulane UniversityNew OrleansLA 70112USA

Runt-related transcription factor 1(Runx1)plays a key role in cartilage formation,but its function in articular cartilage formation is unclear.We generated non-inducible and inducible Runx1-deficient mice(Runx1^(f/f)Col2α1-Cre and Runx1^(f/f)Col2α1-CreER mice)and found that chondrocyte-specific Runx1-deficient mice developed a spontaneous osteoarthritis(OA)-like phenotype and showed exacerbated articular cartilage destruction under OA,characterized by articular cartilage degradation and cartilage ossification,with decreased Col2α1 expression and increased Mmp13 and Adamts5 expression.RNA-sequencing analysis of hip articular cartilage from the Runx1^(f/f)Col2α1-Cre mice compared to that from wild-type mice and subsequent validation analyses demonstrated that Runx1 is a central regulator in multiple signaling pathways,converging signals of the Hippo/Yap,TGFβ/Smad,and Wnt/β-catenin pathways into a complex network to regulate the expression of downstream genes,thereby controlling a series of osteoarthritic pathological processes.RNA-sequencing analysis of mutant knee joints showed that Runx1’s role in signaling pathways in articular cartilage is different from that in whole knee joints,indicating that Runx1 regulation is tissue-specific.Histopathologic analysis confirmed that Runx1 deficiency decreased the levels of YAP and p-Smad2/3 and increased the levels of activeβ-catenin.Overexpression of Runx1 dramatically increased YAP expression in chondrocytes.Adeno-associated virus-mediated Runx1 overexpression in the knee joints of osteoarthritic mice showed the protective effect of Runx1 on articular cartilage damaged in OA.Our results notably showed that Runx1 is a central regulator of articular cartilage Homeostasis by orchestrating the YAP,TGFβ,and Wnt signaling pathways in the formation of articular cartilage and OA,and targeting Runx1 and its downstream genes may facilitate the design of novel therapeutic approaches for OA.

关键词： cartilage Homeostasis protective

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