Yi-Ling Ge, Jin Xu, Yue Cai, Bin Zhang, Si-Yuan He, Pei-Jie Li, Ying-Rui Bu, Lin Zhang, Zhi-Bin Yu, Heng Ma, Yong Liu, Xiong-Wen Chen, Man-Jiang Xie
{"title":"BMAL1 modulation alleviates inflammatory responses in monocytes by targeting the Fis1-mediated mitochondrial unfolded protein response in high-altitude hypoxia.","authors":"Yi-Ling Ge, Jin Xu, Yue Cai, Bin Zhang, Si-Yuan He, Pei-Jie Li, Ying-Rui Bu, Lin Zhang, Zhi-Bin Yu, Heng Ma, Yong Liu, Xiong-Wen Chen, Man-Jiang Xie","doi":"10.1186/s12964-025-02420-8","DOIUrl":"https://doi.org/10.1186/s12964-025-02420-8","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia-induced inflammation has been implicated in the progression of high-altitude illnesses. Mitochondria are key organelles for oxygen metabolism and inflammation that are controlled by circadian clocks. However, little is known regarding how circadian clocks sense hypoxic signals and trigger downstream mitochondrial responses.</p><p><strong>Methods: </strong>Human participants and mice were exposed to a real or simulated high-altitude setting of 5500 m. Multichannel fluorescence intravital microscopy was used for in vivo molecular imaging of inflammation. Bioinformatics analysis, myeloid-specific knockout mice, and RAW 264.7 cells were used to investigate the underlying inflammatory mechanisms.</p><p><strong>Results: </strong>We found that high-altitude hypoxia induced dynamic inflammatory activity in monocytes, characterized by significantly increased levels of cytokines (interleukin-6 [IL-6], IL-1β and monocyte chemoattractant protein-1) after acute (3-day) exposure, which returned to control levels after a prolonged (30-day) exposure. Bioinformatics analysis revealed that the core circadian transcription factor brain and muscle Arnt-like 1 (BMAL1) correlated positively with hypoxia-induced inflammation in monocytes. Mechanistically, BMAL1 induced NOD-like receptor protein 3 inflammasome activation in monocytes by targeting the Fis1-mediated mitochondrial unfolded protein response. Basic helix-loop-helix family member E40, a hypoxic stress-responsive transcription factor, directly promoted Bmal1 transcription and triggered inflammation in monocytes. In contrast, myeloid-specific deletion of BMAL1 alleviated the inflammatory activity of monocytes and circulating inflammation, both in vitro and in vivo, under high-altitude hypoxia.</p><p><strong>Conclusions: </strong>Our findings indicate that transcriptional activation of Bmal1 in monocytes can potentially serve as a novel biomarker of hypoxia-induced inflammation. Our findings also suggest a novel approach for modulating the intrinsic clock, which might render organisms less vulnerable to high-altitude hypoxia.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"420"},"PeriodicalIF":8.2,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yunzhong Zhang, Dan You, Chenhao Che, Xinyuan Wang, Huawei Li, Yi-Quan Tang, Shan Sun
{"title":"Ototoxicity-induced c-Fos activation underlies the regenerative capacity of the vestibular sensory epithelia.","authors":"Yunzhong Zhang, Dan You, Chenhao Che, Xinyuan Wang, Huawei Li, Yi-Quan Tang, Shan Sun","doi":"10.1186/s12964-025-02446-y","DOIUrl":"https://doi.org/10.1186/s12964-025-02446-y","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"421"},"PeriodicalIF":8.2,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caitlin L Vella, Pamali Fonseka, Emma J Grant, Stephanie F Rutter, Donia Y Abeid, Dilara C Ozkocak, Tien K Nguyen, Antony Vinh, Stephanie Paone, Grant R Drummond, Christopher G Sobey, Stephanie Gras, Mark D Hulett, Suresh Mathivanan, Ivan K H Poon, Amy A Baxter
{"title":"Endothelial cell-derived apoptotic bodies modulate innate and adaptive immune responses during inflammation.","authors":"Caitlin L Vella, Pamali Fonseka, Emma J Grant, Stephanie F Rutter, Donia Y Abeid, Dilara C Ozkocak, Tien K Nguyen, Antony Vinh, Stephanie Paone, Grant R Drummond, Christopher G Sobey, Stephanie Gras, Mark D Hulett, Suresh Mathivanan, Ivan K H Poon, Amy A Baxter","doi":"10.1186/s12964-025-02382-x","DOIUrl":"10.1186/s12964-025-02382-x","url":null,"abstract":"<p><p>Endothelial cells (ECs) act as gatekeepers and signalling hubs that coordinate communication between blood vessels and surrounding tissues by regulating vascular tone, immune responses and numerous other physiological processes. During vascular inflammation commonly associated with aging, atherosclerosis, diabetes and autoimmunity, a range of biological, environmental and physical stressors can induce activation and apoptosis of ECs. Apoptotic bodies (ApoBDs) are large (~ 1-5 μm), membrane‑bound extracellular vesicles generated solely through apoptotic cell disassembly, that are increasingly recognised as mediators of intercellular communication via the transfer of bioactive molecules to target cells. Although EC apoptosis is a central feature of vascular inflammatory disorders, the formation of EC‑derived ApoBDs and their immunomodulatory roles when formed in an inflammatory environment, remains poorly defined. This study aimed to characterise the functional properties of EC‑derived ApoBDs generated under inflammatory conditions in vitro. A proteomics analysis of EC‑derived ApoBDs revealed that EC‑ApoBDs generated during inflammation ('iApoBDs') were enriched in inflammatory cytokines/chemokines, adhesion molecules and antigen presentation machinery compared with non-inflammatory ('ApoBD') controls. Functionally, iApoBDs promoted monocyte chemotaxis via the release of MCP-1, while altered expression of the adhesion molecule ICAM-1 enhanced efferocytosis by macrophages in vitro and in vivo. Furthermore, iApoBDs generated from antigen-pulsed HUVECs promoted IFN‑𝛾 expression by peptide specific CD8 T cells in an in vitro model of antigen presentation. These findings demonstrate that within an inflammatory setting, apoptotic ECs can participate in continued communication with their environment via the generation of ApoBDs, thereby modulating innate and adaptive immune processes. The formation of ApoBDs by ECs may serve as a target for therapeutic interventions in inflammatory vascular diseases.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"418"},"PeriodicalIF":8.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245848","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}
Hui Luo, Jianhua Chen, Zhihan Guo, Yanyan Zhu, Yipin Wang, Tian Wu, Siyue Yin, Cao Li, Youqiang Su, Yao Chen, Yun Qian, Congxiu Miao, Ruizhi Feng
{"title":"Tubacin alleviate the reproductive toxicity of deoxynivalenol in mouse oocytes and zygotes via strengthening microtubule stability.","authors":"Hui Luo, Jianhua Chen, Zhihan Guo, Yanyan Zhu, Yipin Wang, Tian Wu, Siyue Yin, Cao Li, Youqiang Su, Yao Chen, Yun Qian, Congxiu Miao, Ruizhi Feng","doi":"10.1186/s12964-025-02432-4","DOIUrl":"10.1186/s12964-025-02432-4","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"417"},"PeriodicalIF":8.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226238","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}
Margherita Grattarola, Nicolas Pons, Floriane Cannet, Müge Kaya, Abdessamad El Kaoutari, Christian Morel, Aurélie Dobric, Jean-Paul Borg, Celia Sequera, Flavio Maina
{"title":"Establishment of a mouse hepatocellular carcinoma tumoroid panel recapitulating inter- and intra- heterogeneity for disease modelling and combinatorial drug discovery.","authors":"Margherita Grattarola, Nicolas Pons, Floriane Cannet, Müge Kaya, Abdessamad El Kaoutari, Christian Morel, Aurélie Dobric, Jean-Paul Borg, Celia Sequera, Flavio Maina","doi":"10.1186/s12964-025-02391-w","DOIUrl":"10.1186/s12964-025-02391-w","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"410"},"PeriodicalIF":8.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214492","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}
Yena Cho, Jee Won Hwang, Mark T Bedford, Dong Hee Na, Dae-Geun Song, Su-Nam Kim, Yong Kee Kim
{"title":"Reversible arginine methylation of PI3KC2α controls mitotic spindle dynamics.","authors":"Yena Cho, Jee Won Hwang, Mark T Bedford, Dong Hee Na, Dae-Geun Song, Su-Nam Kim, Yong Kee Kim","doi":"10.1186/s12964-025-02419-1","DOIUrl":"10.1186/s12964-025-02419-1","url":null,"abstract":"<p><p>Microtubules, composed of αβ-tubulin dimers, undergo dynamic polymerization and are fundamental to cell structure and function. In the current study, we discovered that phosphatidylinositol 3-kinase class 2α (PI3KC2α) acts as a novel regulatory factor in microtubule dynamics. Specifically, asymmetric dimethylation of PI3KC2α at the R175 residue (R175me2a) by coactivator-associated arginine methyltransferase 1 (CARM1) enhances its interaction with α-tubulin, stabilizing microtubule assembly. Furthermore, lysine Demethylase 4 A (KDM4A) serves as an arginine demethylase for PI3KC2α R175me2a. During mitosis, protein kinase C (PKC)-mediated phosphorylation of KDM4A results in its dissociation from PI3KC2α, preventing demethylation and increasing R175me2a levels. This facilitates spindle formation and highlights the critical role of reversible arginine methylation in regulating mitotic spindle dynamics. Cumulatively, these findings reveal the coordinated interplay between CARM1 and KDM4A in modulating microtubule behavior through PI3KC2α R175 methylation, offering new insights into the regulatory mechanisms of mitotic progression.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"409"},"PeriodicalIF":8.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214607","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":"miR-125b-5p and miR-145a-5p modulation drives functional enhancement of Wharton's Jelly-MSCs derived small extracellular vesicles in response to hypoxia preconditioning.","authors":"Yashvi Sharma, Seema Kashyap, Aastha Singh, Ritu Kulshreshtha, Sefali Bhakuni, Sujata Mohanty","doi":"10.1186/s12964-025-02300-1","DOIUrl":"10.1186/s12964-025-02300-1","url":null,"abstract":"<p><strong>Background: </strong>Regenerative medicine therapies offer hope for conditions previously limited to supportive care. The COVID-19 pandemic underscored the urgent need for treatments targeting systemic inflammation. Mesenchymal stem cells (MSCs) are widely recognized for their regenerative and immunomodulatory properties. Recent research shows that hypoxic priming enhances MSCs' therapeutic potential, particularly by increasing the release and modifying the cargo of their extracellular vesicles (EVs). These EVs imitate many of the regenerative and immunomodulatory effects of MSCs, making them a promising cell-free therapeutic option. This study aimed to compare the regenerative and immunomodulatory capacities of small EVs (sEV; less than 200 nm) derived from bone marrow (BM) and wharton's jelly (WJ) MSCs, cultured under normoxic and hypoxic conditions, and decipher their underlying functional mechanisms.</p><p><strong>Methods: </strong>BM and WJ-MSCs were isolated and expanded. Hypoxia exposure was provided at 1% oxygen concentration for 24 h. sEV were isolated using ultracentrifugation, and in vitro functional assessments were performed using skin specific human sourced cell lines for fibroblasts, keratinocytes and macrophages. miRNA modulations were performed via transfection technique and mechanism of action of sEV were determined. Additionally, in vivo analysis was performed in a traumatic wound rat model, and molecular pathway analysis was performed in animal wound tissues.</p><p><strong>Results: </strong>Through comprehensive in vitro and in vivo evaluations, this study aimed to identify the most potent candidate for regenerative medicine while elucidating the underlying molecular mechanisms. By analysing sEV cargo and the associated molecular pathways within a traumatic wound model, the study revealed that WJ-MSCs exhibit superior regenerative potential. Furthermore, it demonstrated that hypoxia priming enhances their therapeutic efficacy through the involvement of miR-125b-5p and miR-145a-5p, which drive immunomodulation and regeneration by targeting IL-6R/NFκB axis and TGF-β2/SMAD4 pathway, respectively. These findings underscore the significance of WJ-sEV as a promising avenue for personalized regenerative therapies, positioning miR-125b-5p and miR-145a-5p as key therapeutic targets for bioengineering of sEVs.</p><p><strong>Conclusion: </strong>By exploring these comparative functions, the study provides insights into the optimization of sEV-based therapies as a cutting-edge approach in regenerative medicine, and reflects the suitability of WJ-sEV as an ideal acellular therapeutics' candidate for translational regenerative and immunomodulatory applications.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"407"},"PeriodicalIF":8.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214649","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}
Denis Corbeil, Kristina Thamm, Jana Karbanová, Christine A Fargeas, József Jászai
{"title":"The primary cilium as a multifunctional organelle: emerging roles and unanswered questions.","authors":"Denis Corbeil, Kristina Thamm, Jana Karbanová, Christine A Fargeas, József Jászai","doi":"10.1186/s12964-025-02403-9","DOIUrl":"10.1186/s12964-025-02403-9","url":null,"abstract":"<p><p>The primary cilium, a solitary membrane-bound, microtubule-based cellular organelle, has been considered an evolutionary relict for almost a century. Over the past three decades, interest in this protruding, non-motile structure of the plasma membrane has been boosted by the identification of ciliary dysfunctions as the underlying cause of developmental abnormalities and inherited disorders, commonly called ciliopathies. The primary cilium responds to environmental stimuli, such as mechanical, chemical, or light (in the case of the modified cilium of photoreceptors) signals. The membrane of primary cilia host specific sensory complexes and/or receptors associated with various pathways, predisposing them to transmit (or convert) spatiotemporal environmental information into cellular response. These dual mechanochemical aspects led to the recognition that primary cilia are multifunctional sensory organelles that act as \"cellular antennae\". Beyond their established role in signal transduction, primary cilia are newly recognized as important hubs for short- and long-distance intercellular communication due to their ability to release and, perhaps, selectively take up extracellular vesicles, which are biological carriers exchanged between cells. In addition, the physical contact of the primary cilium with other cilia, cytonemes or with nerve cell axons adds another layer of complexity to the mechanisms of sensory and/or intercellular communication between neighboring cells that needs to be further explored. In this review, we focus on these new and less-explored ciliary properties and processes, which can affect cell communication and signaling and thus have a direct impact on development, tissue homeostasis, and pathological conditions.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"406"},"PeriodicalIF":8.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214596","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":"IGFBP2 alteration contributes to prostate cancer progression by modulating prostate stroma activation.","authors":"Mingguo Huang, Shintaro Narita, Hiromi Sato, Yuya Sekine, Mizuki Kobayashi, Soki Kashima, Ryohei Yamamoto, Atsushi Koizumi, Taketoshi Nara, Kazuyuki Numakura, Mitsuru Saito, Hiroshi Nanjo, Takayuki Ikezoe, Tomonori Habuchi","doi":"10.1186/s12964-025-02414-6","DOIUrl":"10.1186/s12964-025-02414-6","url":null,"abstract":"<p><strong>Background: </strong>Insulin-like growth factor (IGF) binding protein-2 (IGFBP2) is a secretory protein that modulate the activity of IGFs. It is highly expressed in various cancers such as prostate cancer (PCa), in which it may play a controversial role in tumor progression, however, the molecular mechanisms of IGFBP2 in PCa progression remain unclear.</p><p><strong>Methods: </strong>In this study, we examined the expression pattern and role of IGFBP2 in PCa cells and the stroma during prostate tumor cell progression.</p><p><strong>Results: </strong>IGFBP2 was highly expressed in LNCaP cells and prostate stromal fibroblasts (PrSC) and was mainly secreted by PrSCs. Tumor cell growth and invasiveness were not directly affected by treatment with IGFBP2 siRNAs (siIGFBP2) or recombinant IGFBP2 (rIGFBP2). However, decreased expression of IGFBP2 significantly increased PrSC activation and the secretion of pro-tumorigenic cytokines IL-6, IL-8, IP10, and CCL5 through upregulation of TGF-β, which subsequently enhanced prostate tumor cell progression. Clinically, low expression of stromal IGFBP2 was associated with a high reactive prostate stroma, advanced PCa progression, and increased IGFBP2 levels in the serum.</p><p><strong>Conclusion: </strong>Here, we provide mechanistic evidence that IGFBP2 act as a critical regulatory factor in the activation of prostate stromal microenvironment and contributes to aggressive PCa progression.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"408"},"PeriodicalIF":8.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214526","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}