Cell and Bioscience最新文献

{"title":"Trehalose enhances macrophage autophagy to promote myelin debris clearance after spinal cord injury.","authors":"Zhida Ma, Congpeng Meng, Xiang Wang, Yuanzhe Zhao, Jingwen Wang, Yihao Chen, Yiteng Li, Yan Jiang, Fangru Ouyang, Jianjian Li, Meige Zheng, Li Cheng, Juehua Jing","doi":"10.1186/s13578-025-01357-2","DOIUrl":"10.1186/s13578-025-01357-2","url":null,"abstract":"<p><strong>Background: </strong>Myelin-laden foamy macrophages accumulate extensively in the lesion epicenter, exhibiting characteristics of autophagolysosomal dysfunction, which leads to prolonged inflammatory responses after spinal cord injury (SCI). Trehalose, known for its neuroprotective properties as an autophagy inducer, has yet to be fully explored for its potential to mitigate foamy macrophage formation and exert therapeutic effects in the context of SCI.</p><p><strong>Results: </strong>We observed that trehalose significantly enhances macrophage phagocytosis and clearance of myelin in a dose-dependent manner in vitro. In vivo, trehalose administration markedly reduced myelin debris accumulation, inhibited foamy macrophage formation, suppressed inflammatory responses, decreased fibrotic scarring, and promoted axonal growth and motor function recovery after SCI. These beneficial effects of trehalose may be related to the overexpression of transcription factor EB (TFEB), a key regulator of the autophagy-lysosomal system, which can rescue autophagic dysfunction in foamy macrophages and inhibit inflammatory responses. Additionally, the effects of trehalose on macrophages were abolished by chloroquine, an autophagy inhibitor, suggesting trehalose's potential as a therapeutic candidate for enhancing myelin debris clearance post-SCI.</p><p><strong>Conclusions: </strong>Our findings underscore the pivotal role of trehalose in modulating myelin debris clearance within macrophages, providing new perspectives for the treatment of spinal cord injury.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"11"},"PeriodicalIF":6.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway.","authors":"Hei-Yin Tam, Jiaxing Liu, Tsz-Ching Yiu, Adrian On-Wah Leung, Chang Li, Shen Gu, Owen Rennert, Boxian Huang, Hoi-Hung Cheung","doi":"10.1186/s13578-025-01355-4","DOIUrl":"10.1186/s13578-025-01355-4","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic or null mutations in WRN helicase is a cause of premature aging disease Werner syndrome (WS). WRN is known to protect somatic cells including adult stem cells from premature senescence. Loss of WRN in mesenchymal stem cells (MSCs) not only drives the cells to premature senescence but also significantly impairs the function of the stem cells in tissue repair or regeneration.</p><p><strong>Results: </strong>In this study, we profiled the signaling pathways altered in WRN-deficient MSC and applied pharmacological method to activate the AKT signaling in these cells and examined their cellular phenotype related to aging. We found that the AKT signaling in WRN-deficient MSCs was significantly suppressed while the AKT upstream phosphatases (SHIP1/2) were upregulated. Knockdown or inhibition of SHIP1/2 could ameliorate premature senescence in WRN-deficient MSCs. Moreover, SHIP inhibition stimulated MSC proliferation and suppressed expression of pro-inflammatory cytokines IL-6 and IL-8. The stemness of WRN-deficient MSC was also improved upon pharmacological treatments with the inhibitors.</p><p><strong>Conclusions: </strong>These results suggested that targeting the SHIP/AKT signaling pathway is beneficial to WRN-deficient stem cells and fibroblasts, which might be applied for improving the trophic function of MSC in, for instance, promoting angiogenesis.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"10"},"PeriodicalIF":6.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial base editing: from principle, optimization to application.","authors":"Jinling Tang, Kunzhao Du","doi":"10.1186/s13578-025-01351-8","DOIUrl":"10.1186/s13578-025-01351-8","url":null,"abstract":"<p><p>In recent years, mitochondrial DNA (mtDNA) base editing systems have emerged as bioengineering tools. DddA-derived cytosine base editors (DdCBEs) have been developed to specifically induce C-to-T conversion in mtDNA by the fusion of sequence-programmable transcription activator-like effector nucleases (TALENs) or zinc-finger nucleases (ZFNs), and split deaminase derived from interbacterial toxins. Similar to DdCBEs, mtDNA adenine base editors have been developed with the ability to introduce targeted A-to-G conversions into human mtDNA. In this review, we summarize the principles of mtDNA base-editing systems and elaborate on the evolution of different platforms of mtDNA base editors, including their deaminase replacement, engineering of DddA_tox variants, structure optimization and editing outcomes. Finally, we highlight their applications in animal models and human embroys and discuss the future developmental direction and challenges of mtDNA base editors.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"9"},"PeriodicalIF":6.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial deconvolution from bulk DNA methylation profiles determines intratumoral epigenetic heterogeneity.","authors":"Binbin Liu, Yumo Xie, Yu Zhang, Guannan Tang, Jinxin Lin, Ze Yuan, Xiaoxia Liu, Xiaolin Wang, Meijin Huang, Yanxin Luo, Huichuan Yu","doi":"10.1186/s13578-024-01337-y","DOIUrl":"10.1186/s13578-024-01337-y","url":null,"abstract":"<p><strong>Background: </strong>Intratumoral heterogeneity emerges from accumulating genetic and epigenetic changes during tumorigenesis, which may contribute to therapeutic failure and drug resistance. However, the lack of a quick and convenient approach to determine the intratumoral epigenetic heterogeneity (eITH) limit the application of eITH in clinical settings. Here, we aimed to develop a tool that can evaluate the eITH using the DNA methylation profiles from bulk tumors.</p><p><strong>Methods: </strong>Genomic DNA of three laser micro-dissected tumor regions, including digestive tract surface, central bulk, and invasive front, was extracted from formalin-fixed paraffin-embedded sections of colorectal cancer patients. The genome-wide methylation profiles were generated with methylation array. The most variable methylated probes were selected to construct a DNA methylation-based heterogeneity (MeHEG) estimation tool that can deconvolve the proportion of each reference tumor region with the support vector machine model-based method. A PCR-based assay for quantitative analysis of DNA methylation (QASM) was developed to specifically determine the methylation status of each CpG in MeHEG assay at single-base resolution to realize fast evaluation of epigenetic heterogeneity.</p><p><strong>Results: </strong>In the discovery set with 79 patients, the differentially methylated CpGs among the three tumor regions were found. The 7 most representative CpGs were identified and subsequently selected to develop the MeHEG algorithm. We validated its performance of deconvolution of tumor regions in an independent cohort. In addition, we showed the significant association of MeHEG-based epigenetic heterogeneity with the genomic heterogeneity in mutation and copy number variation in our in-house and TCGA cohorts. Besides, we found that the patients with higher MeHEG score had worse disease-free and overall survival outcomes. Finally, we found dynamic change of epigenetic heterogeneity based on MeHEG score in cancer cells under the treatment of therapeutic drugs.</p><p><strong>Conclusion: </strong>By developing a 7-loci panel using a machine learning approach combined with the QASM assay for PCR-based application, we present a valuable method for evaluating intratumoral heterogeneity. The MeHEG algorithm offers novel insights into tumor heterogeneity from an epigenetic perspective, potentially enriching current knowledge of tumor complexity and providing a new tool for clinical and research applications in cancer biology.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"7"},"PeriodicalIF":6.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3.","authors":"Jing Gu, Yang-Fan Lv, Ji-Ying Xia, Fu-Hai Bai, Ji Gong, Guang-Qiang Pan, Bo Liu, Lu Huang, Qiao-Nan Guo, Xiang-Lin Hao","doi":"10.1186/s13578-025-01348-3","DOIUrl":"10.1186/s13578-025-01348-3","url":null,"abstract":"<p><strong>Background: </strong>Tandem C2 domains, nuclear (TC2N) is a protein that has been characterized to contain C2A domain, C2B domain, and a short C-terminus with a WHXL motif. In previous studies, we have uncovered the oncogenic role and mechanisms of TC2N in lung cancer: TC2N achieves this by inhibiting the p53 signaling pathway and activating the NF-kappaB signaling pathway. Beyond that, its precise function in tumorigenesis is not fully understood.</p><p><strong>Methods: </strong>TC2N-engineered mice model was used to assess the effect of TC2N knockout on normal lung and urethane-induced carcinogenesis. Tumor tissues of 395 lung cancer patients were subjected to tissue microarray and further assessed the associations of TC2N expression with tumor differentiation degree. The protein levels of TC2N and stem cell markers in cell lines and tissue specimens were monitored by WB and immunohistochemistry. In vitro cell assays were performed to assess the effect of TC2N ectopic expression on the stem cell-like characteristics of lung cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics and proteomics, and the underlying mechanism was explored by WB and co-IP assays.</p><p><strong>Results: </strong>Herein, TC2N appeared to have a strong effect in promoting lung tumorigenesis caused by urethane, whereas it seemed to lose its function in the normal lung. Meanwhile, we found that the functional differences of TC2N between lung tumor and normal lung were linked to its potential role in cancer cell stemness. Function-wise, TC2N overexpression maintained stem-like properties of lung cancer cell. Mechanism-wise, TC2N upregulated the phosphorylation of EGFR, ERK, STAT3 and FAK1 to activate these signaling pathways by the inhibition of DUSP3 phosphatase via a dual mechanism. Firstly, TC2N competes with EGFR, ERK, STAT3 and FAK1 for binding to DUSP3. This competition prevents these signaling molecules from being dephosphorylated by DUSP3, resulting in their sustained activation. Secondly, TC2N bind to DUSP3 and restrict the enzyme's ability to dephosphorylate the signaling molecules.</p><p><strong>Conclusions: </strong>Overall, this study revealed a previously unknown role and mechanism of TC2N in the regulation of tumorigenesis and stemness in lung cancer cells.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"8"},"PeriodicalIF":6.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamine-glutamate centered metabolism as the potential therapeutic target against Japanese encephalitis virus-induced encephalitis.","authors":"Mengyuan Li, Hang Yuan, Xiaofei Yang, Yingfeng Lei, Jianqi Lian","doi":"10.1186/s13578-024-01340-3","DOIUrl":"10.1186/s13578-024-01340-3","url":null,"abstract":"<p><strong>Background: </strong>Japanese encephalitis (JE) induced by Japanese encephalitis virus (JEV) infection is the most prevalent diagnosed epidemic viral encephalitis globally. The underlying pathological mechanisms remain largely unknown. Given that viruses are obligate intracellular parasites, cellular metabolic reprogramming triggered by viral infection is intricately related to the establishment of infection and progression of disease. Therefore, uncovering and manipulating the metabolic reprogramming that underlies viral infection will help elucidate the pathogenic mechanisms and develop novel therapeutic strategies.</p><p><strong>Methods: </strong>Metabolomics analysis was performed to comprehensively delineate the metabolic profiles in JEV-infected mice brains and neurons. Metabolic flux analysis, quantitative real-time PCR, western blotting and fluorescence immunohistochemistry were utilized to describe detailed glutamine-glutamate metabolic profiles during JEV infection. Exogenous addition of metabolites and associated compounds and RNA interference were employed to manipulate glutamine-glutamate metabolism to clarify its effects on viral replication. The survival rate, severity of neuroinflammation, and levels of viral replication were assessed to determine the efficacy of glutamine supplementation in JEV-challenged mice.</p><p><strong>Results: </strong>Here, we have delineated a novel perspective on the pathogenesis of JE by identifying an aberrant low flux in glutamine-glutamate metabolism both in vivo and in vitro, which was critical in the establishment of JEV infection and progression of JE. The perturbed glutamine-glutamate metabolism induced neurotransmitter imbalance and created an immune-inhibitory state with increased gamma-aminobutyric acid/glutamate ratio, thus facilitating efficient viral replication both in JEV-infected neurons and the brain of JEV-infected mice. In addition, viral infection restrained the utilization of glutamine via the glutamate-α-ketoglutaric acid axis in neurons, thus avoiding the adverse effects of glutamine oxidation on viral propagation. As the conversion of glutamine to glutamate was inhibited after JEV infection, the metabolism of glutathione (GSH) was simultaneously impaired, exacerbating oxidative stress in JEV-infected neurons and mice brains and promoting the progression of JE. Importantly, the supplementation of glutamine in vivo alleviated the intracranial inflammation and enhanced the survival of JEV-challenged mice.</p><p><strong>Conclusion: </strong>Altogether, our study highlights an aberrant glutamine-glutamate metabolism during JEV infection and unveils how this facilitates viral replication and promotes JE progression. Manipulation of these metabolic alterations may potentially be exploited to develop therapeutic approaches for JEV infection.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"6"},"PeriodicalIF":6.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sperm-borne small non-coding RNAs: potential functions and mechanisms as epigenetic carriers.","authors":"Muhammad Naveed, Zhaokang Shen, Jianqiang Bao","doi":"10.1186/s13578-025-01347-4","DOIUrl":"10.1186/s13578-025-01347-4","url":null,"abstract":"<p><p>Over the past two decades, the study of sperm-borne small non-coding RNAs (sncRNAs) has garnered substantial growth. Once considered mere byproducts during germ cell maturation, these sncRNAs have now been recognized as crucial carriers of epigenetic information, playing a significant role in transmitting acquired traits from paternal to offspring, particularly under environmental influences. A growing body of evidence highlights the pivotal role of these sncRNAs in facilitating epigenetic inheritance across generations. However, the exact mechanisms through which these paternally supplied epigenetic carriers operate remain unclear and are under hot debate. This concise review presents the most extensive evidence to date on environmentally-responsive sperm-borne sncRNAs, encompassing brief summary of their origin, dynamics, compartmentalization, characteristics, as well as in-depth elaboration of their functional roles in epigenetic and transgenerational inheritance. Additionally, the review delves into the potential mechanisms by which sperm-delivered sncRNAs may acquire and transmit paternally acquired traits to offspring, modulating zygotic gene expression and influencing early embryonic development.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"5"},"PeriodicalIF":6.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human epicardial organoids from pluripotent stem cells resemble fetal stage with potential cardiomyocyte- transdifferentiation.","authors":"Fanwen Wang, Xinle Zou, Huilin Zheng, Tianci Kong, Duanqing Pei","doi":"10.1186/s13578-024-01339-w","DOIUrl":"10.1186/s13578-024-01339-w","url":null,"abstract":"<p><p>Epicardium, the most outer mesothelium, exerts crucial functions in fetal heart development and adult heart regeneration. Here we use a three-step manipulation of WNT signalling entwined with BMP and RA signalling for generating a self-organized epicardial organoid that highly express with epicardium makers WT1 and TCF21 from human embryonic stem cells. After 8-days treatment of TGF-beta following by bFGF, cells enter into epithelium-mesenchymal transition and give rise to smooth muscle cells. Epicardium could also integrate and invade into mouse heart with SNAI1 expression, and give birth to numerous cardiomyocyte-like cells. Single-cell RNA seq unveils the heterogeneity and multipotency exhibited by epicardium-derived-cells and fetal-like epicardium. Meanwhile, extracellular matrix and growth factors secreted by epicardial organoid mimics the ecology of subepicardial space between the epicardium and cardiomyocytes. As such, this epicardial organoid offers a unique ground for investigating and exploring the potential of epicardium in heart development and regeneration.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"4"},"PeriodicalIF":6.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma.","authors":"Ze Qian, Yifan Jiang, Yacong Wang, Yu Li, Lin Zhang, Xiaofeng Xu, Diyu Chen","doi":"10.1186/s13578-024-01334-1","DOIUrl":"10.1186/s13578-024-01334-1","url":null,"abstract":"<p><strong>Background: </strong>Altered metabolism has become an important characteristic of cancer, and acyl-CoA dehydrogenase short-chain (ACADS), a regulator of lipid synthesis, is involved in carcinogenesis-associated metabolic pathways. DNA methylation is an important mechanism for silencing ACADS in various malignancies. However, the specific role of ACADS in hepatocellular carcinoma (HCC) pathogenesis remains poorly understood.</p><p><strong>Methods and results: </strong>Using RNA sequencing data from different tumours in The Cancer Genome Atlas database, we observed that ACADS was downregulated and hypermethylated in HCC. Three potential CpG island sites (cg01535453, cg08618068, and cg10174836) were identified in the ACADS promoter. Through in vivo and in vitro experiments, we confirmed that cg08618068 was methylated in HCC. We defined this site as ACADS methylation site-2 (ACADS MS-2). Methylation of ACADS MS-2 was associated with worse survival, and mutation of MS-2 increased ACADS mRNA levels in five HCC cell lines. Sustained overexpression of ACADS not only suppressed the proliferation, migration, and invasion of HCC cells but also promoted immunogenic cell death (ICD) via the upregulation of calreticulin. Subsequently, we established a specific nomogram based on ACADS methylation levels to evaluate the 3- and 5-year overall survival rates of patients with HCC who underwent surgical resection.</p><p><strong>Conclusions: </strong>Our work clarified that ACADS acts as a putative tumour suppressor in HCC and confirmed that a nomogram including ACADS methylation had good predictive performance in HCC. We also discovered a correlation between ACADS and ICD, suggesting that ACADS is an essential target for immunotherapy in HCC.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"3"},"PeriodicalIF":6.1,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maladaptive changes in the homeostasis of AEA-TRPV1/CB1R induces pain-related hyperactivity of nociceptors after spinal cord injury.","authors":"JiaQi Hu, WenYong Fan, Yue Xu, XiaoFei Li, HaoYang Zhang, Shun Li, Lei Xue","doi":"10.1186/s13578-025-01345-6","DOIUrl":"10.1186/s13578-025-01345-6","url":null,"abstract":"<p><strong>Background: </strong>Neuropathic pain resulting from spinal cord injury (SCI) is associated with persistent hyperactivity of primary nociceptors. Anandamide (AEA) has been reported to modulate neuronal excitability and synaptic transmission through activation of cannabinoid type-1 receptors (CB1Rs) and transient receptor potential vanilloid 1 (TRPV1). However, the role of AEA and these receptors in the hyperactivity of nociceptors after SCI remains unclear.</p><p><strong>Results: </strong>In this study, we investigated the effects of AEA and its receptors on the hyperexcitability of mouse dorsal root ganglion (DRG) neurons after SCI. Using a whole-cell patch-clamp technique, we found that the timing of SCI-induced hyperexcitability in nociceptors paralleled an increase in the endocannabinoid AEA content. The expression of TRPV1 and CB1R was also upregulated at different time points after SCI. High-dose extracellular administration of AEA increased the excitability of naive DRG neurons, leading to the transition from a rapidly accommodating (RA) hypoexcitable state to a highly excitable non-accommodating (NA) state. These AEA-induced transitions were facilitated by increased TRPV1 transcription. Pharmacological and Ca²⁺ imaging experiments revealed that AEA induced hyperexcitability in nociceptors after SCI via the AEA-TRPV1-Ca²⁺ pathway, whereas activation of CB1Rs reduced SCI-induced hyperexcitability and maintained cytosolic Ca²⁺ concentration ([Ca²⁺]_cyto) at low levels in the early stages of SCI. As the AEA and TRPV1 levels increased after SCI, adaptive neuroprotection transitioned to a maladaptive hyperactive state, leading to sustained pain.</p><p><strong>Conclusions: </strong>Taken together, this study provides new insights into how endocannabinoids regulate nociceptor activity after SCI, offering potential targets for the treatment of neuropathic pain.</p>","PeriodicalId":49095,"journal":{"name":"Cell and Bioscience","volume":"15 1","pages":"2"},"PeriodicalIF":6.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}