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

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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 Zijin 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 *** specific innovative approaches,such as immunotherapy,have shown favorable clinical outcomes,the inherent invasiveness of most gliomas continues to make them challenging to ***,there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug *** 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 *** Set Enrichment Analysis(GSEA)unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent *** 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 *** 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 ***,the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ***,in turn,elevated ITPKB stability and impaired ROS ***,ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse *** 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

Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

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Neural Regeneration Research 2024年第2期19卷 360-368页

作者： Leyi Huang Wenjie Xiao Yan Wang Juan Li Jiaoe Gong Ewen Tu Lili Long Bo Xiao Xiaoxin Yan Lily Wan department of Anatomy and Neurobiology Central South University Xiangya Medical SchoolChangshaHunan ProvinceChina department of neurology Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina department of neurology Hunan Children’s HospitalChangshaHunan ProvinceChina department of neurology Brain Hospital of Hunan ProvinceChangshaHunan ProvinceChina

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug *** signaling through the excitatory neurotransmitter glutamate is intricately associated with *** glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic *** mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of *** this review,we first introduce the three groups of mGluRs and their associated signaling ***,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in *** addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also *** hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

关键词： antiepileptic drugs epileptogenesis metabotropic glutamate receptors(mGluRs) signal pathways therapeutic potentials

A novel mutation of glycogen synthase kinase-3β leads to a reduced level of GSK3βprotein in a patient with dilated cardiomyopathy

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Genes & Diseases 2024年第1期11卷 84-86页

作者： Ke Gong Zhiping Tan Haidan Liu Xiaobo Liao Xinmin Zhou Bangliang Yin Shi Zeng Yao Yao Yifeng Yang Li Xie department of Cardiovascular Surgery The Second Xiangya Hospital of Central South UniversityCentral South UniversityChangshaHunan410011China department of Ultrasound The Second Xiangya Hospital of Central South UniversityCentral South UniversityChangshaHunan 410011China department of Blood Transfusion The Second Xiangya Hospital of Central South UniversityCentral South UniversityChangshaHunan 410011China

Dilated cardiomyopathy(DCM)is a frequently inherited heart condition.A familial transmission rate of 20%-35%has been documented,and most of these cases are autosomal *** condition has a high rate of morbidity and mort... 详细信息

关键词： GSK3β cardiomyopathy mortality

Hemorrhagic transformation in patients with large-artery atherosclerotic stroke is associated with the gut microbiota and lipopolysaccharide

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Neural Regeneration Research 2024年第7期19卷 1532-1540页

作者： Qin Huang Minping Wei Xianjing Feng Yunfang Luo Yunhai Liu Jian Xia department of neurology Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina department of neurology Peking University People’s HospitalBeijingChina Clinical Research Center for Cerebrovascular Disease of Hunan Province Central South UniversityChangshaHunan ProvinceChina National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina

Hemorrhagic transformation is a major complication of large-artery atheroscle rotic stroke(a major ischemic stro ke subtype)that wo rsens outcomes and increases *** of the gut microbiota is an important feature of stroke,and some specific bacteria and bacterial metabolites may contribute to hemorrhagic transformation *** aimed to investigate the relationship between the gut microbiota and hemorrhagic transformation in largearte ry atheroscle rotic stro *** observational retrospective study was *** May 2020 to September 2021,blood and fecal samples were obtained upon admission from 32 patients with first-ever acute ischemic stroke and not undergoing intravenous thrombolysis or endovascular thrombectomy,as well as 16 healthy *** with stro ke who developed hemorrhagic transfo rmation(n=15)were compared to those who did not develop hemorrhagic transformation(n=17)and with healthy *** gut microbiota was assessed through 16S ribosomal ribonucleic acid *** also examined key components of the lipopolysaccharide pathway:lipopolysaccharide,lipopolysaccharide-binding protein,and soluble *** observed that bacterial diversity was decreased in both the hemorrhagic transformation and non-hemorrhagic transfo rmation group compared with the healthy *** patients with ischemic stro ke who developed hemorrhagic transfo rmation exhibited altered gut micro biota composition,in particular an increase in the relative abundance and dive rsity of members belonging to the Enterobacteriaceae *** lipopolysaccharide and lipopolysaccharide-binding protein levels were higher in the hemorrhagic transformation group compared with the non-hemorrhagic transfo rmation ***,lipopolysaccharide-binding protein,and soluble CD14 concentrations were associated with increased abundance of Enterobacte ***,the role of the gut microbiota in hemorrhagic transformation was evaluated using

关键词： gut microbiota hemorrhagic transformation inflammation lipopolysaccharide stroke

Identification of a novel MYO1D variant associated with laterality defects,congenital heart diseases,and sperm defects in humans

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Frontiers of Medicine 2024年第3期18卷 558-564页

作者： Zhuangzhuang Yuan Xin Zhu Xiaohui Xie Chenyu Wang Heng Gu Junlin Yang Liangliang Fan Rong Xiang Yifeng Yang Zhiping Tan department of Cardiovascular Surgery The Second Xiangya Hospital of Central South UniversityChangsha410011China Clinical Center for Gene Diagnosis and Therapy The Second Xiangya Hospital of Central South UniversityChangsha410011China department of Cell Biology School of Life SciencesCentral South UniversityChangsha410013China department of Gynecology and Obstetrics Xiangya Hospital of Central South UniversityChangsha410008China

The establishment of left–right asymmetry is a fundamental process in animal *** with this process leads to a range of disorders collectively known as laterality defects,which manifest as abnormal arrangements of visceral *** patients with laterality defects,congenital heart diseases(CHD)are *** multiple model organisms,extant research has established that myosin-Id(MYO1D)deficiency causes laterality *** study investigated over a hundred cases and identified a novel biallelic variant of MYO1D(NM_015194:c.1531G>A;p.D511N)in a consanguineous family with complex CHD and laterality *** examination of the proband revealed asthenoteratozoospermia and shortened ***,the effects of the D511N variant and another known MYO1D variant(NM_015194:c.2293C>T;p.P765S)were *** assessment showed that both enhance the interaction withβ-actin and ***,this study revealed the genetic heterogeneity of this rare disease and found that MYO1D variants are correlated with laterality defects and CHD in ***,this research established a connection between sperm defects and MYO1D *** offers guidance for exploring infertility and reproductive health *** findings provide a critical basis for advancing personalized medicine and genetic counseling.

关键词： MYO1D laterality defect congenital heart disease sperm defect β-actin SPAG6

Glymphatic system:a gateway for neuroinflammation

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Neural Regeneration Research 2024年第12期19卷 2661-2672页

作者： Kailu Zou Qingwei Deng Hong Zhang Changsheng Huang department of Anesthesiology Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina xiangya School of Medicine Central South UniversityChangshaHunan ProvinceChina National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina

The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the *** evidence indicates thatglymphatic function is impaired not only in central nervous system disorders but also in systemic *** diseases can trigger the inflammatory responses in the central nervous system,occasionally leading to sustained inflammation and functional disturbance of the central nervous *** review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system *** addition,we discuss the hypothesis that disease conditions initially associated with peripheral inflammation ove rwhelm the performance of the glymphatic system,thereby triggering central nervous system dysfun ction,chronic neuroinflammation,and *** research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.

关键词： aquaporin-4 central nervous system disease cerebrospinal fluid chronic neuroinflammation glymphatic dysfunction neurodegeneration peripheral nerve injury perivascular space systemic disease vicious cycle

Apatinib and gamabufotalin co-loaded lipid/Prussian blue nanoparticles for synergistic therapy to gastric cancer with metastasis

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Journal of Pharmaceutical Analysis 2024年第5期14卷 707-721页

作者： Binlong Chen Yanzhong Zhao Zichang Lin Jiahao Liang Jialong Fan Yanyan Huang Leye He Bin Liu Health Management Center The Third Xiangya HospitalCentral South UniversityChangsha410013China department of Urology The Third Xiangya HospitalCentral South UniversityChangsha410013China department of Laboratory Medicine The Third Xiangya HospitalCentral South UniversityChangsha410013China College of Biology Hunan UniversityChangsha410082China

Due to the non-targeted release and low solubility of anti-gastric cancer agent,apatinib(Apa),a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side *** order to avoid these drawbacks,lipid-film-coated Prussian blue nanoparticles(PB NPs)with hyaluronan(HA)modification was used for Apa loading to improve its solubility and targeting ***,anti-tumor compound of gamabufotalin(CS-6)was selected as a partner of Apawith reducing dosage for combinational gastric ***,HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor *** vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating vascular endothelial growth factor receptor(VEGFR)and matrix metalloproteinase-9(MMP-9).In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic *** summary,we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer(GC)therapy.

关键词： Apatinib Gamabufotalin Lipid/Prussian blue nanoparticles Gastric cancer

Kdm6a-CNN1 axis orchestrates epigenetic control of traumainduced spinal cord microvascular endothelial cell senescence to balance neuroinflammation for improved neurological repair

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Bone Research 2024年第2期12卷 314-333页

作者： Chengjun Li Tian Qin Jinyun Zhao Yuxin Jin Yiming Qin Rundong He Tianding Wu Chunyue Duan Liyuan Jiang Feifei Yuan Hongbin Lu Yong Cao Jianzhong Hu department of Sports Medicine Xiangya HospitalCentral South UniversityXiangya Road 87Changsha 410008China Key Laboratory of Organ Injury Aging and Regenerative Medicine of Hunan ProvinceXiangya Road 87Changsha 410008China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityXiangya Road 87Changsha 410008China department of Spine Surgery and Orthopaedics Xiangya HospitalCentral South UniversityXiangya Road 87Changsha 410008China

Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory *** extensive investigations into vascular senescence associated with aging and degenerative diseases,the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress,particularly its involvement in senescence-induced inflammation,remain insufficiently *** this study,we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury(SCI).Lysine demethylase 6A(Kdm6a),commonly known as UTX,emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells(SCMECs).Upregulation of UTX induces senescence in SCMECs,leading to an amplified release of proinflammatory factors,specifically the senescenceassociated secretory phenotype(SASP)components,thereby modulating the inflammatory ***,the deletion of UTX in endothelial cells shields SCMECs against senescence,mitigates the release of proinflammatory SASP factors,and promotes neurological functional recovery after *** forms an epigenetic regulatory axis by binding to calponin 1(CNN1),orchestrating trauma-induced SCMECs senescence and SASP secretion,thereby influencing neuroinflammation and neurological functional ***,local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion,reinstating a local regenerative microenvironment and enhancing functional repair after *** conclusion,targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion,alleviate neuroinflammation,and provide a novel treatment strategy for SCI repair.

关键词： inflammation epigenetic neurological

Research Progress on the Association between Schizophrenia and Toxoplasma gondii Infection

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Biomedical and Environmental Sciences 2024年第6期37卷 647-660页

作者： Yiting Zhu Xiaohui Yang Miaoru Chen Yu Hu Yunfeng Chang Xiang Wu department of Forensic Medicine Science Xiangya School of Basic MedicineCentral South UniversityChangsha 410013HunanChina Nursing department The Third Xiangya Hospital of Central South UniversityChangsha 410013HunanChina department of Basic Medicine Science Xiangya School of Basic MedicineCentral South UniversityChangsha 410013HunanChina department of Parasitology Xiangya School of Basic MedicineCentral South UniversityChangsha 410013HunanChina

Toxoplasma gondii(*** or Tg),is an obligatory intracellular parasite with humans as its intermediate *** recent years,significant correlations between *** infection and schizophrenia have been reported,including the possible mediating ***,mechanisms and hypotheses focus on central neurotransmitters,immunity,neuroinflammation,and epigenetics;however,the exact underlying mechanisms remain *** this article,we review the studies related to *** infection and schizophrenia,particularly the latest research *** on dopamine(DA)and other neurotransmitters,the blood-brain barrier,inflammatory factors,disease heterogeneity,and other confounders is also *** addition,we also summarized the results of some new epidemiological investigations.

关键词： Toxoplasma gondii Schizophrenia Neurotransmitters Neuroinflammation Immunity Epigenetics