查看更多>>摘要：Background:The essential roles of platelets in thrombosis have been well recognized.Unexpectedly,thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological,physical and chemical origins,which could be suffered by military personnel and civilians during chemical,biological,radioactive,and nuclear events.Especially,thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia,while the underlying pathogenic mechanism remains elusive.Methods:A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation(IR).The phenotypic and functional changes of platelets and megakaryocytes(MKs)were determined by a comprehensive set of in vitro and in vivo assays,including flow cytometry,flow chamber,histopathology,Western blotting,and chromatin immunoprecipitation,in combination with transcriptomic analysis.The molecular mechanism was investigated both in vitro and in vivo,and was consolidated using MK-specific knockout mice.The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors.Results:In contrast to primitive MKs,mature MKs(mMKs)are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis.Interestingly,mMKs undergo minority mitochondrial outer membrane permeabilization(MOMP)post IR,resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes(cGAS-STING)pathway via the release of mitochondrial DNA.The subsequent interferon-β(IFN-β)response in mMKs upregulates a GTPase guanylate-binding protein 2(GBP2)to produce large and hyperreactive platelets that favor thrombosis.Further,we unmask that autophagy restrains minority MOMP in mMKs post IR.Conclusions:Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.
查看更多>>摘要：Background:Kirsten rat sarcoma(KRAS)and mutant KRAS G12D have been implicated in human cancers,but it remains unclear whether their activation requires ubiquitination.This study aimed to investigate whether and how F-box and leucine-rich repeat 6(FBXL6)regulates KRAS and KRAS G12D activity in hepatocellular carcinoma(HCC).Methods:We constructed transgenic mouse strains LC(LSL-Fbxl6KI/+;Alb-Cre,n=13),KC(LSL-KrasG12D/+;Alb-Cre,n=10)and KLC(LSL-KrasG12D/+;LSL-Fbxl6KI/+;Alb-Cre,n=12)mice,and then monitored HCC for 320d.Multiomics approaches and pharmacological inhibitors were used to determine oncogenic signaling in the context of elevated FBXL6 and KRAS activation.Co-immunoprecipitation(Co-IP),Western blotting,ubiquitination assay,and RAS activity detection assay were employed to investigate the underlying molecular mechanism by which FBXL6 activates KRAS.The pathological relevance of the FBXL6/KRAS/extracellular signal-regulated kinase(ERK)/mammalian target of rapamycin(mTOR)/proteins of relevant evolutionary and lymphoid interest domain 2(PRELID2)axis was evaluated in 129 paired samples from HCC patients.Results:FBXL6 is highly expressed in HCC as well as other human cancers(P＜0.001).Interestingly,FBXL6 drives HCC in transgenic mice.Mechanistically,elevated FBXL6 promotes the polyubiquitination of both wild-type KRAS and KRAS G12D at lysine 128,leading to the activation of both KRAS and KRAS G12D and promoting their binding to the serine/threonine-protein kinase RAF,which is followed by the activation of mitogen-activated protein kinase kinase(MEK)/ERK/mTOR signaling.The oncogenic activity of the MEK/ERK/mTOR axis relies on PRELID2,which induces reactive oxygen species(ROS)generation.Furthermore,hepatic FBXL6 upregulation facilitates KRAS G12D to induce more severe hepatocarcinogenesis and lung metastasis via the MEK/ERK/mTOR/PRELID2/ROS axis.Dual inhibition of MEK and mTOR effectively suppresses tumor growth and metastasis in this subtype of cancer in vivo.In clinical samples,FBXL6 expression positively correlates with p-ERK(x2=85.067,P＜0.001),p-mTOR(x2=66.919,P＜0.001)and PRELID2(x2=20.891,P＜0.001).The Kaplan-Meier survival analyses suggested that HCC patients with high FBXL6/p-ERK levels predicted worse overall survival(log-rank P＜0.001).Conclusions:FBXL6 activates KRAS or KRAS G12D via ubiquitination at the site K128,leading to activation of the ERK/mTOR/PRELID2/ROS axis and tumorigenesis.Dual inhibition of MEK and mTOR effectively protects against FBXL6-and KRAS G12D-induced tumorigenesis,providing a potential therapeutic strategy to treat this aggressive subtype of liver cancer.
查看更多>>摘要：Degenerative musculoskeletal diseases are structural and functional failures of the musculoskeletal system,including osteoarthritis,osteoporosis,intervertebral disc degeneration(IVDD),and sarcopenia.As the global population ages,degenerative musculoskeletal diseases are becoming more prevalent.However,the pathogenesis of degenerative musculoskeletal diseases is not fully understood.Previous studies have revealed that endoplasmic reticulum(ER)stress is a stress response that occurs when impairment of the protein folding capacity of the ER leads to the accumulation of misfolded or unfolded proteins in the ER,contributing to degenerative musculoskeletal diseases.By affecting cartilage degeneration,synovitis,meniscal lesion,subchondral bone remodeling of osteoarthritis,bone remodeling and angiogenesis of osteoporosis,nucleus pulposus degeneration,annulus fibrosus rupture,cartilaginous endplate degeneration of IVDD,and sarcopenia,ER stress is involved in the pathogenesis of degenerative musculoskeletal diseases.Preclinical studies have found that regulation of ER stress can delay the progression of multiple degenerative musculoskeletal diseases.These pilot studies provide foundations for further evaluation of the feasibility,efficacy,and safety of ER stress modulators in the treatment of musculoskeletal degenerative diseases in clinical trials.In this review,we have integrated up-to-date research findings of ER stress into the pathogenesis of degenerative musculoskeletal diseases.In a future perspective,we have also discussed possible directions of ER stress in the investigation of degenerative musculoskeletal disease,potential therapeutic strategies for degenerative musculoskeletal diseases using ER stress modulators,as well as underlying challenges and obstacles in bench-to-beside research.
查看更多>>摘要：Cancer immunotherapy using immune-checkpoint inhibitors(ICIs)has revolutionized the field of cancer treatment;however,ICI efficacy is constrained by progressive dysfunction of CD8+tumor-infiltrating lymphocytes(TILs),which is termed T cell exhaustion.This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment(TIME).Simultaneously,tumorigenesis entails robust reshaping of the epigenetic landscape,potentially instigating T cell exhaustion.In this review,we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion,and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies.Finally,we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.
查看更多>>摘要：Nuclear receptor subfamily 1,group D,member 1(NR1D1,also known as REV-ERBα)belongs to the nuclear receptor(NR)family,and is a heme-binding component of the circadian clock that consolidates circadian oscillators.In addition to repressing the transcription of multiple clock genes associated with circadian rhythms,NR1D1 has a wide range of downstream target genes that are intimately involved in many physiopathological processes,including autophagy,immunity,inflammation,metabolism,and aging in multiple organs.This review focuses on the pivotal role of NR1D1 as a key transcription factor in the gene regulatory network,with particular emphasis on the milestones of the latest discoveries of NR1D1 ligands.NR1D1 is considered as a promising drug target for treating diverse diseases and may contribute to research on innovative biomarkers and therapeutic targets for organ injury-related diseases.Further research on NR1D1 ligands in prospective human trials may pave the way for their clinical application in many organ injury-related disorders.
查看更多>>摘要：Electroencephalography(EEG)is a non-invasive measurement method for brain activity.Due to its safety,high resolution,and hypersensitivity to dynamic changes in brain neural signals,EEG has aroused much interest in scientific research and medical felds.This article reviews the types of EEG signals,multiple EEG signal analysis methods,and the application of relevant methods in the neuroscience feld and for diagnosing neurological diseases.First,3 types of EEG signals,including time-invariant EEG,accurate event-related EEG,and random event-related EEG,are introduced.Second,5 main directions for the methods of EEG analysis,including power spectrum analysis,time-frequency analysis,connectivity analysis,source localization methods,and machine learning methods,are described in the main section,along with diferent sub-methods and effect evaluations for solving the same problem.Finally,the application scenarios of different EEG analysis methods are emphasized,and the advantages and disadvantages of similar methods are distinguished.This article is expected to assist researchers in selecting suitable EEG analysis methods based on their research objectives,provide references for subsequent research,and summarize current issues and prospects for the future.
查看更多>>摘要：The global prevalence rate for congenital hydrocephalus(CH)is approximately one out of every five hundred births with multifaceted predisposing factors at play.Genetic influences stand as a major contributor to CH pathogenesis,and epidemiological evidence suggests their involvement in up to 40％of all cases observed globally.Knowledge about an individual's genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes.However,the precise genetic etiology has only been pinpointed in fewer than 5％of human instances.More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci.A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder.This review provides a summary of pertinent genes identified through gene sequencing technologies in humans,in addition to the 4 genes currently associated with CH(2 X-linked genes L1CAM and AP1S2,2 autosomal recessive MPDZ and CCDC88C).Others predominantly participate in aqueduct abnormalities,ciliary movement,and nervous system development.The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined,focusing mainly on 4 pathways,namely cilia synthesis and movement,ion channels and transportation,Reissner's fiber(RF)synthesis,cell apoptosis,and neurogenesis.Notably,the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid(CSF)circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition.So far,only a limited number of CH-associated genes have been identified in humans.The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field.Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications,such as renal cysts,scoliosis,and cardiomyopathy,as these genes may also play a role in the development of these diseases.Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.
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