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Ion Channel Dysregulation Following Intracerebral Hemorrhage

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Neuroscience Bulletin 2024年第3期40卷 401-414页

作者： Xiangyu Zhang Yan Zhang Qiuyang Su Yang Liu Zhe Li V.Wee Yong Mengzhou Xue Department of Cerebrovascular Diseases The Second Afliated Hospital of Zhengzhou UniversityZhengzhou 450000China Academy of Medical Science Zhengzhou UniversityZhengzhou 450000China Hotchkiss Brain Institute and Department of Clinical Neurosciences University of CalgaryCalgaryAB T2N 1N4Canada

Injury to the brain after intracerebral hemorrhage(ICH)results from numerous complex cellular *** present,effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve *** is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following *** channels such as TWIK-related K+channel 1,sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in *** in turn participate in the formation of brain edema,disruption of the blood-brain barrier,and the generation of *** this review,we summarize the interaction between ions and ion channels,the effects of ion channel dysregulation,and we discuss some therapeutics based on ion-channel modulation following ICH.

关键词： Intracerebral hemorrhage Ion dyshomeostasis Sulfonylurea 1 transient receptor potential melastatin 4 TWIK-related K+channel 1 N-methyl-Daspartate receptor Transient receptor potential vanilloid 4

RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit Kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal Disorders and Mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on Membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA Metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment *** this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical *** analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL *** sequencing of human and mouse tissue supported these *** interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on *** results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within *** findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

Chemotherapy-induced small extracellular vesicles prime the pre-metastatic niche to accelerate neuroblastoma metastasis

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Genes & Diseases 2024年第4期11卷 65-68页

作者： Carson A.Wills Xiaoming Liu Longgui Chen Yuanjun Zhao Zhenqiu Liu Vladimir S.Spiegelman Jeffrey Sundstrom Hong-Gang Wang Department of Pediatrics Division of Pediatric Hematology and OncologyThe Pennsylvania State University Collegeof MedicinePA 17033USA Department of Ophthalmology The Pennsylvania State University College of MedicinePA 17033USA Department of Public health Sciences The Pennsylvania StateUniversityCollegeofMedicinePA 17033USA

Neuroblastoma is the most common extracranial solid tumor in children,accounting for more than 10%of cancerrelated deaths in this *** standard of care for patients diagnosed with medium-to high-risk neuroblastoma,incl... 详细信息

关键词： neuroblastoma metastatic metastasis

The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities

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Genes & Diseases 2024年第3期11卷 155-187页

作者： Michael Yu Kevin Qin Jiaming Fan Guozhi Zhao Piao Zhao Wei Zeng Connie Chen Annie Wang Yonghui Wang jiamin Zhong Yi Zhu William Wagstaff Rex C.Haydon Hue H.Luu Sherwin Ho Michael J.Lee Jason Strelzow Russell R.Reid Tong-Chuan He School of Medicine Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Department of Orthopedic Surgery The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China Department of Orthopaedic Surgery Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China

The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across *** proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling *** behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling *** signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various *** includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem *** signaling has also been implicated in tumor cells that exhibit stem cell-like *** signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone *** surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including *** of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and ***,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt *** with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

关键词： β-Catenin Cancer Canonical Wnt Disease Non-canonical Wnt Stem cells Targeted therapy Wnt signaling

Lipid phosphorylation by a diacylglycerol kinase suppresses ABA biosynthesis to regulate plant stress responses

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Molecular Plant 2024年第2期17卷 342-358页

作者： Jianwu Li Shuaibing Yao Sang-Chul Kim Xuemin Wang Department of Biology University of Missouri-St.LouisSt.LouisMO 63121USA Donald Danforth Plant Science Center St.LouisMO 63132USA

Lipid phosphorylation by diacylglycerol kinase(DGK)that produces phosphatidic acid(PA)plays important roles in various biological processes,including stress responses,but the underlying mechanisms remain ***,we show that DGK5 and its lipid product PA suppress ABA biosynthesis by interacting withABA-DEFICIENT2(ABA2),a key ABA biosynthesis enzyme,to negatively modulate plant responseto abiotic stress tested in Arabidopsis *** of DGK5 function rendered plants less damaged,whereas overexpression(OE)of DGK5 enhanced plant damage to water and salt *** dgk5 mutant plants exhibited decreased total cellular and nuclear levels of PA with increased levels of diacylglycerol,whereas DGK5-OE plants displayed the opposite ***,we found that both DGK5 and PA bind to the ABA-synthesizing enzyme ABA2 and suppress its enzymatic ***,the dgk5 mutant plants exhibited increased levels of ABA,while DGK5-OE plants showed reduced ABA *** addition,we showed that both DGK5 and ABA2 are detected in and outside the nuclei,and loss of DGK5 function decreased the nuclear association of *** found that both DGK5 activity and PA promote nuclear association of *** together,these results indicate that both DGK5 and PA interact with ABA2 to inhibit its enzymatic activity and promote its nuclear sequestration,thereby sup-pressing ABA production in response to abiotic *** study reveals a sophisticated mechanism by which DGK5 and PA regulate plant stress responses.

关键词： diacylglycerol kinase phosphatidic acid diacylglycerol lipid signaling stress responses lipid-protein binding protein-protein interaction Arabidopsis

Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

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Genes & Diseases 2024年第1期11卷 103-134页

作者： Kevin Qin Michael Yu Jiaming Fan Hongwei Wang Piao Zhao Guozhi Zhaoo Wei Zeng Connie Chen Yonghui Wang Annie Wang Zander Schwartz Jeffrey Hong Lily Song William Wagstaff Rex C.Haydon Hue H.Luu Sherwin H.Ho Jason Strelzow Russell R.Reid Tong-Chuan He Lewis L.Shi Chicago Medical School Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic Medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Departments of Orthopaedic Surgery and Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Department of Interventional Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China Department of Clinical Laboratory Medicine Shanghai Jiaotong University School of MedicineShanghai 200000China School of Biomedical Engineering Vanderbilt UniversityNashvilleTN 37235USA Laboratory of Craniofacial Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA

Wnt signaling plays a major role in regulating cell proliferation and *** Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical *** of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling *** crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ ***-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic *** complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic ***,both stimulatory and inhibitory treatments come with potential risks that need to be *** review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt *** thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+*** description involved each of its components and their involvement in other cellular ***,this review explained the various other pathways and processes that crosstalk with Wnt signaling.

关键词： β-catenin Canonical Wnt Noncanonical Wnt Signal transduction Signaling crosstalk

Automated and miniaturized screening of antibiotic combinations via robotic-printed combinatorial droplet platform

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1801-1813页

作者： Fangchi Shao Hui Li Kuangwen Hsieh Pengfei Zhang Sixuan Li Tza-Huei Wang Department of Biomedical Engineering Johns Hopkins UniversityBaltimoreMD 21218USA Department of Mechanical Engineering Johns Hopkins UniversityBaltimoreMD 21218USA

Antimicrobial resistance(AMR)has become a global health crisis in need of novel *** this end,antibiotic combination therapies,which combine multiple antibiotics for treatment,have at-tracted significant attention as a potential approach for combating *** facilitate advances in anti-biotic combination therapies,most notably in investigating antibiotic interactions and identifying synergistic antibiotic combinations however,there remains a need for automated high-throughput plat-forms that can create and examine antibiotic combinations on-demand,at scale,and with minimal reagent *** address these challenges,we have developed a Robotic-Printed Combinatorial Droplet(RoboDrop)platform by integrating a programmable droplet microfuidic device that generates antibiotic combinations in nanoliter droplets in automation,a robotic arm that arranges the droplets in an array,and a camera that images the array of thousands of droplets in *** further implement a resazurin-based bacterial viability assay to accelerate our antibiotic combination *** a demonstration,we use RoboDrop to corroborate two pairs of antibiotics with known interactions and subsequently identify a new synergistic combination of cefsulodin,penicillin,and oxacillin against a model *** *** therefore envision RoboDrop becoming a useful tool to efficiently identify new synergistic antibiotic combinations toward combating AMR.

关键词： Droplet microfluidics Antimicrobial resistance Antibiotic combinatorial screening Contact printing Robotics Pharmaceutical analysis High-throughput Antibiotic interactions

The physiological role of the unfolded protein response in the nervous system

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Neural Regeneration research 2024年第11期19卷 2411-2420页

作者： Shuangchan Wu Wensheng Lin Department of Neuroscience University of MinnesotaMinneapolisMNUSA Institute for Translational Neuroscience University of MinnesotaMinneapolisMNUSA

The unfolded protein response(UPR)is a cellular stress response pathway activated when the endoplasmic reticulum,a crucial organelle for protein folding and modification,encounters an accumulation of unfolded or misfolded *** UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity,reducing protein biosynthesis,and promoting protein *** also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum *** research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous ***,we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions,and highlight the critical role of the UPR in brain development,memory storage,retinal cone development,myelination,and maintenance of myelin thickness.

关键词： myelin neuron oligodendrocyte Schwann cell unfolded protein response

Syrosingopine,an anti-hypertensive drug and lactate transporter(MCT1/4)inhibitor,activates hepatic stellate cells and exacerbates liver fibrosis in a mouse model

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Genes & Diseases 2024年第4期11卷 28-30页

作者： Meichun Guo Yannian Gou Xiangyu Dong Jiamin Zhong Aohua Li Ailing Hao Tongchuan He Jiaming Fan Ministry of Education Key Laboratory of Diagnostic Medicine and the School of Laboratory Diagnostic MedicineChongqing Medical UniversityChongqing 400016China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA

Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and *** studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade,ATP depletion,and cell death in cancer due to high intracellular levels of lactate.

关键词： hypertensive MCT1 drug