Cell Communication and Signaling最新文献

{"title":"Atovaquone-induced activation of the PERK/eIF2α signaling axis mitigates metabolic radiosensitisation.","authors":"Jie Feng, Varun Pathak, Niall M Byrne, Sarah Chambers, Tongchuan Wang, Rayhanul Islam, Reinhold J Medina, Jonathan A Coulter","doi":"10.1186/s12964-025-02160-9","DOIUrl":"10.1186/s12964-025-02160-9","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia, a key feature of most solid tumours, including head and neck cancer, reduces radiotherapy efficacy by promoting radiation resistance through micro-environmental and genomic alterations. Addressing these resistance mechanisms is crucial, as radiotherapy remains central to managing locally advanced disease. Atovaquone, a mitochondrial electron transport chain complex III inhibitor, is reported to reduce tumour hypoxia in preclinical models, however, this response does not consistently enhance radiation sensitivity. This work examines the potential of atovaquone to modify the hypoxic response in models of head and neck squamous cell carcinoma (HNSCC), uncovering an adaptive resistance mechanism driven by integrated stress response (ISR) signaling that limits the radiosensitising potential of this approach.</p><p><strong>Methods: </strong>The bioenergetic response of HNSCC cells to atovaquone was assessed using the Seahorse XFe96 Analyzer with the XF Cell Mito Stress Test. Radiation dose modifying effects of atovaquone were tested by clonogenic survival assays, while ROS yields were analysed by flow cytometry. Western blotting and quantitative reverse transcription-PCR were employed to study activation of ISR signaling and the overall influence of atovaquone on the hypoxic response. Finally, the role of the ISR activation in modulating radiosensitivity was investigated using both siRNA and pharmacological inhibition of eIF2α, a central regulator of the ISR.</p><p><strong>Results: </strong>Herein we report that atovaquone significantly disrupts mitochondrial respiration, triggering phosphorylation of eIF2α, a pivotal regulator of the ISR, and a master regulator of protein synthesis. Notably, atovaquone also increased the autophagic load under hypoxia, while autophagy inhibition significantly enhanced apoptosis, improving radiation sensitivity. Combined eIF2α inhibition and atovaquone promotes cell cycle redistribution and significantly enhances mitochondrial ROS production and compared to atovaquone alone, restoring atovaquone mediated radiosensitisation.</p><p><strong>Conclusions: </strong>Our data highlight dual counter opposing impacts of atovaquone, serving as a hypoxic radiosensitiser though oxidative phosphorylation (OXPHOS) inhibition, but also in promoting stress induced ISR signaling, conferring resistance to radiation treatment. Importantly, if ISR activation is impeded, the metabolic radiosensitising properties of atovaquone is restored. These data provide a new insight to a molecular response that could help counteract hypoxia-induced radioresistance.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"164"},"PeriodicalIF":8.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774893","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":"Decursin induces FLT3-ITD acute myeloid leukemia cell apoptosis by increasing the expression of the ubiquitin-conjugase UBE2L6.","authors":"Tianxin Zhang, Yuchen Li, Wenhao Liao, Yu Mou, Xue Zhan, Qiongying Hu, Ziyi Zhao, Daqian Xiong","doi":"10.1186/s12964-025-02157-4","DOIUrl":"10.1186/s12964-025-02157-4","url":null,"abstract":"<p><p>Mutation in the internal tandem duplication sequence of the FLT3 gene (FLT3-ITD) is linked to a poor clinical prognosis in acute myeloid leukemia (AML) patients. FLT3 inhibitors have demonstrated efficacy in improving the prognosis of AML patients with FLT3-ITD. However, the efficacy of FLT3 inhibitors is short-lived, and is often limited by secondary drug resistance when used alone. Recent investigations have provided an innovative approach for treating FLT3-ITD AML by targeting FLT3 protein degradation. Our study revealed that decursin selectively impaired the viability of FLT3-ITD-positive AML cells. Subsequent analysis revealed that decursin preferentially induced cell cycle arrest and apoptosis in FLT3-ITD-positive AML cells through proteasome-mediated FLT3-ITD degradation. Further research revealed that decursin significantly increased the expression of UBE2L6, an e2-conjugating enzyme that degrades FLT3-ITD. Downregulation of UBE2L6 by small hairpin RNA (shRNA) reduced decursin-induced FLT3-ITD-linked apoptosis and degradation. The anti-FLT3-ITD AML effect of decursin was also validated in cell lines and patient-derived mouse models. Moreover, decursin synergistically enhanced venetoclax-induced apoptosis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"162"},"PeriodicalIF":8.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774895","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":"Reversal of epithelial to mesenchymal transition in triple negative breast cancer through epigenetic modulations by dietary flavonoid Galangin and its combination with SAHA.","authors":"Snehal Nimal, Navanath Kumbhar, Manasi S Pote, Rahul Bankar, Mahemud Shaikh, Rajesh Gacche","doi":"10.1186/s12964-025-02174-3","DOIUrl":"10.1186/s12964-025-02174-3","url":null,"abstract":"<p><strong>Background: </strong>TNBC is an aggressive metastatic cancer that poses considerable treatment challenges because of its acquired drug resistance towards the existing targeted and hormonal therapies. The epigenetic modulation including HDACs triggers the EMT in TNBC which produces a more aggressive tumor phenotype. Chemotherapy and radiotherapy cause severe side effects which make treatment complex and challenging. To avoid these serious side effects and boost the effectiveness of current anti-cancer medications, plant flavonoids have been investigated.</p><p><strong>Aim of the study: </strong>The present investigation is aimed to understand the role of dietary flavonoid Gal in the modulation of epigenetic regulators such as HDACs and HATs and their impact on the reversal of the EMT process in TNBCs.</p><p><strong>Methodology: </strong>Here, we have examined the anti-TNBC potential of Gal alone and in combination with SAHA by performing series of in vitro cell culture assays such MTT, migration and invasion, cell cycle regulation, ROS generation & mitochondrial dysfunction, nuclear fragmentation & apoptosis induction etc. The expression profiles of epigenetic regulators, apoptosis regulating proteins, and EMT markers were analysed by performing transcriptomic and proteomic studies. The in vivo efficacy of Gal was studied using BALB/c mice xenograft model studies.</p><p><strong>Results: </strong>At IC₅₀ = 50 µM/mL, Gal significantly inhibited the cell proliferation, migration, and invasion, arrested cell cycle at sub G0/G1 phases, generated ROS, reduced MMP and induced apoptosis in MDA-MB-231. Transcriptomic, proteomic, and calorimetric analysis revealed that Gal has potential to downregulate the expression of HDAC1/HDAC3 and elevate the expression levels of HAT. Gal also modulated the process of EMT by downregulating the mesenchymal markers and upregulating the epithelial marker. The synergistic mechanism of Gal and SAHA against the TNBCs was elucidated by understanding the expression levels of epigenetic regulators & EMT markers. Interestingly, Gal increased the expression of tumour suppressor protein pTEN and suppressed the expression of AKT, PI3K, and mTOR proteins involved in the cancer proliferation pathway. Gal also demonstrated impressive antitumor effect under in vivo settings.</p><p><strong>Conclusion: </strong>In-vitro and In vivo studies confirmed Gal's potent anticancer efficacy and highlighted its potential as a promising therapeutic agent that possibly can be used with conventional chemotherapy against TNBC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"163"},"PeriodicalIF":8.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774900","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":"SIRT1 prevents noise-induced hearing loss by enhancing cochlear mitochondrial function.","authors":"Yuelian Luo, Haoyang Wu, Xin Min, Yi Chen, Wenting Deng, Minjun Chen, Chuxuan Yang, Hao Xiong","doi":"10.1186/s12964-025-02152-9","DOIUrl":"10.1186/s12964-025-02152-9","url":null,"abstract":"<p><p>Exposure to traumatic noise triggers cochlear damage and consequently causes permanent sensorineural hearing loss. However, effective treatment strategies for noise-induced hearing loss (NIHL) are lacking. Sirtuin 1 (SIRT1) is a NAD⁺-dependent deacetylase that plays a critical role in multiple physiological and pathological events. However, its role in NIHL pathogenesis remains elusive. This study revealed that SIRT1 expression in the cochlea progressively decreases in a mouse model of NIHL. Hair cell-specific knockout of SIRT1 exacerbates the noise-induced loss of outer and inner hair cell synaptic ribbons, retraction of cochlear nerve terminals, and oxidative stress, leading to more severe NIHL. Conversely, adeno-associated virus (AAV)-mediated SIRT1 overexpression effectively attenuated most noise-induced cochlear damage and alleviated NIHL. Transcriptomic analysis revealed that SIRT1 deficiency impairs glucose metabolism and inhibits antioxidant pathways in the cochlea following exposure to noise. Further investigation revealed that SIRT1 exerts an antioxidant effect, at least in part, through AMPK activation in cultured auditory HEI-OC1 cells exposed to oxidative stress. Collectively, these findings indicate that SIRT1 is essential for the maintenance of redox balance and mitochondrial function in the cochlea after traumatic noise exposure, thus providing a promising therapeutic target for NIHL treatment.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"160"},"PeriodicalIF":8.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774902","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":"Restoration of Miro1's N-terminal GTPase function alleviates prenatal stress-induced mitochondrial fission via Drp1 modulation.","authors":"Gee Euhn Choi, Ji Yong Park, Mo Ran Park, Chang Woo Chae, Young Hyun Jung, Jae Ryong Lim, Jee Hyeon Yoon, Ji Hyeon Cho, Ho Jae Han","doi":"10.1186/s12964-025-02172-5","DOIUrl":"10.1186/s12964-025-02172-5","url":null,"abstract":"<p><strong>Background: </strong>Prenatal stress exposure irreversibly impairs mitochondrial dynamics, including mitochondrial trafficking and morphology in offspring, leading to neurodevelopmental and neuropsychiatric disorders in adulthood. Thus, understanding the molecular mechanism controlling mitochondrial dynamics in differentiating neurons is crucial to prevent the prenatal stress-induced impairments in behavior. We investigated the interplay between mitochondrial transport and fusion/fission in differentiating neurons exposed to prenatal stress, leading to ensuing behavior impairments, and then tried to identify the primary regulator that modulates both phenomena.</p><p><strong>Methods: </strong>We used primary hippocampal neurons of mice exposed to prenatal stress and human induced-pluripotent stem cell (hiPSC)-derived neurons, for investigating the impact of glucocorticoid on mitochondrial dynamics during differentiation. For constructing mouse models, we used AAV vectors into mouse pups exposed to prenatal stress to regulate protein expressions in hippocampal regions.</p><p><strong>Results: </strong>We first observed that prenatal exposure to glucocorticoids induced motility arrest and fragmentation of mitochondria in differentiating neurons derived from mouse fetuses (E18) and human induced pluripotent stem cells (hiPSCs). Further, glucocorticoid exposure during neurogenesis selectively downregulated Miro1 and increased Drp1 phosphorylation (Ser616). MIRO1 overexpression restored mitochondrial motility and increased intramitochondrial calcium influx through ER-mitochondria contact (ERMC) formation. Furthermore, we determined that the N-terminal GTPase domain of Miro1 plays a critical role in ERMC formation, which then decreased Drp1 phosphorylation (Ser616). Similarly, prenatal corticosterone exposure led to impaired neuropsychiatric and cognitive function in the offspring by affecting mitochondrial distribution and synaptogenesis, rescued by Miro1^WT, but not N-terminal GTPase active form Miro1^P26V, expression.</p><p><strong>Conclusion: </strong>Prenatal glucocorticoid-mediated Miro1 downregulation contributes to dysfunction in mitochondrial dynamics through Drp1 phosphorylation (Ser616) in differentiating neurons.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"166"},"PeriodicalIF":8.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774898","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":"c-Ski is a novel repressor of NF-κB through interaction with p65 and HDAC1 in U937 cells.","authors":"Yan Peng, Ren-Ping Xiong, Bo Wang, Xing Chen, Ya-Lie Ning, Yan Zhao, Nan Yang, Jing Zhang, Chang-Hong Li, Yuan-Guo Zhou, Ping Li","doi":"10.1186/s12964-025-02178-z","DOIUrl":"10.1186/s12964-025-02178-z","url":null,"abstract":"<p><p>The nuclear factor kappa B (NF-κB) signalling pathway plays a crucial role in the regulation of inflammation, and previous research from our lab and others suggests that c-Ski has potential anti-inflammatory effects. However, the role and mechanism of c-Ski, which are related to the regulation of the NF-κB pathway, are still unclear. Here, U937 cells were used, and increasing c-Ski protein levels inhibited inflammatory factor production, invasion, and phagocytosis. The anti-inflammatory effect of c-Ski was similar to that of hormones. Subsequently, immunoprecipitation (IP), Western blot (WB), electrophoretic mobility shift assays (EMSAs), and dual-luciferase reporter assays were used to determine whether increasing c-Ski protein levels could increase c-Ski binding to NF-κB p65 (p65), leading to a decrease in the acetylation level and transcriptional activity of p65. Conversely, decreased p65 expression through targeted small interfering RNA (siRNA) caused the loss of the anti-inflammatory effects of c-Ski. Furthermore, immunoprecipitation confirmed the mutual interaction of c-Ski with HDAC1 and p65, and WB revealed that the anti-inflammatory effect of c-Ski was achieved through the deacetylation of p65 by HDAC1 combined with HDAC1 siRNA and inhibitors. Additionally, through quantitative proteomic analysis, we determined that increasing c-Ski levels had inhibitory effects on the NF-κB pathway. Finally, similar results were also obtained using primary bone marrow-derived macrophages (BMDMs). These findings not only confirm the anti-inflammatory effect of c-Ski but also reveal novel molecular pathways and regulatory molecules of c-Ski, which may be promising targets for direct intervention in the inflammatory response through regulation of c-Ski.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"165"},"PeriodicalIF":8.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774894","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":"ECM-binding properties of extracellular vesicles: advanced delivery strategies for therapeutic applications in bone and joint diseases.","authors":"Peng Wang, Johanna F A Husch, Onno J Arntz, Peter M van der Kraan, Fons A J van de Loo, Jeroen J J P van den Beucken","doi":"10.1186/s12964-025-02156-5","DOIUrl":"10.1186/s12964-025-02156-5","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) and the extracellular matrix (ECM) are essential in maintaining bone and joint health by facilitating intercellular communication, regulating tissue processes and providing structural support. EVs with a large surface area carry diverse biomolecules to steer the function of cells in their surroundings. To understand how EVs localize to specific sites, we here review the available knowledge on EV surface biomolecules and their interactions with ECM components that are crucial for regulating bone remodeling, cartilage maintenance, and immune responses, playing roles in both tissue homeostasis and pathological conditions, such as arthritis and osteoporosis. More importantly, using analyses of animal experimental data, we illustrate the effect of ECM-based biomaterials (e.g. hydrogels, decellularized matrices, and ECM-mimetic scaffolds) as carriers for EVs toward effective EV delivery in regenerative and immunomodulatory therapies in bone and joint tissue. These biomaterials enable sustained release and targeted delivery of EVs, promoting bone and cartilage regeneration. The insights of this review can be utilized to advance the development of cutting-edge therapies for skeletal tissue regeneration and disease management.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"161"},"PeriodicalIF":8.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774896","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":"DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.","authors":"Fasih A Rahman, Jasmine M Friedrich Yap, Tyler M Joseph, Amanda M Adam, Sarah M Chapman, Joe Quadrilatero","doi":"10.1186/s12964-025-02142-x","DOIUrl":"10.1186/s12964-025-02142-x","url":null,"abstract":"<p><strong>Background: </strong>Remodeling of the mitochondrial network is implicated in myogenesis. Remodeling processes including mitochondrial fission, mitophagy, and biogenesis are important as they finetune the mitochondrial network to meet the increased energetic demand of myotubes. Evidence suggests that mitochondrial fission governs other mitochondrial remodeling processes; however, this relationship is unclear in the context of myogenesis.</p><p><strong>Methods: </strong>We used C2C12 myoblasts to study changes in mitochondrial remodeling processes and their role in regulating myogenesis. To investigate this, we employed genetic manipulation with adenoviruses to modify the levels of key molecules involved in mitochondrial remodeling, including DNM1L, BNIP3, and PPARGC1A.</p><p><strong>Results: </strong>We demonstrate that overexpression of fission protein DNM1L accelerated mitophagic flux, but reduced myotube size without affecting mitochondrial biogenesis. Conversely, DNM1L knockdown reduced mitophagic flux, impaired myoblast differentiation, and suppressed mitochondrial biogenesis signaling. Additionally, DNM1L knockdown increased mitochondrial apoptotic signaling through CASP9 and CASP3 activation. Attempts to rescue myogenesis through overexpression of the mitophagy receptor BNIP3 or the biogenesis regulator PPARGC1A were unsuccessful in the absence of proper mitochondrial fission. Furthermore, DNM1L overexpression in BNIP3-deficient cells enhanced mitophagic flux, but did not promote myogenesis.</p><p><strong>Conclusion: </strong>These results underscore the complex interdependencies among mitochondrial remodeling processes and highlight the necessity for sequential activation of mitochondrial fission, mitophagy, and biogenesis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"158"},"PeriodicalIF":8.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765816","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":"A temperature-responsive PLA-based nanosponge as a novel nanoadjuvant and efficient delivery carrier of Ag85B for effective vaccine against Mycobacterium tuberculosis.","authors":"Jin-Seung Yun, Soo-Min Kim, Jin Sil Lee, Su Hyun Jeong, Hyeryeon Oh, Panmo Son, Sunghyun Kim, Young-Ran Lee, Eunkyung Shin, Sang-Jun Ha, Yong-Woo Jung, Dokeun Kim, Hye-Sook Jeong, Won Il Choi","doi":"10.1186/s12964-025-02105-2","DOIUrl":"10.1186/s12964-025-02105-2","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) is a contagious disease and the second leading cause of death worldwide. The Bacille Calmette-Guérin (BCG) vaccine, the only licensed TB vaccine, has insufficient protective efficacy in adults, necessitating the development of new TB vaccines. Ag85B, a protein-subunit TB vaccine, is a promising candidate due to its high immunogenicity. However, its hydrophobicity presents challenges in manufacturing, expression, and purification, and Ag85B alone does not elicit sufficient immune stimulation. To overcome these limitations, this study aimed to design a temperature-responsive amine-terminated polylactic acid (PLA)-based nanosponge (aPNS) as both a nanoadjuvant and an efficient delivery carrier for Ag85B.</p><p><strong>Methods: </strong>Ag85B was produced using an EZtag fusion tag vector, achieving high product yield and purity. It was then loaded into aPNS, a nanoparticle system with a PLA core and Pluronic shell, through a temperature-responsive process at 4 °C that preserved protein bioactivity. The stability and sustained-release profile of Ag85B@aPNS were evaluated. In vitro cytotoxicity and cellular uptake studies were conducted using macrophages. Protective efficacy and immunogenicity were assessed in M. tuberculosis-challenged mice and BCG-primed mice.</p><p><strong>Results: </strong>The Ag85B protein was successfully produced and loaded into aPNS, which exhibited good colloidal stability and a sustained-release profile. Neither the synthesized Ag85B nor the aPNS showed significant cytotoxicity. aPNS enhanced the cellular uptake of antigens by macrophages. Compared to BCG, Ag85B@aPNS demonstrated superior protective efficacy against M. tuberculosis in mice and improved immunogenicity in BCG-primed mice.</p><p><strong>Conclusion: </strong>Ag85B@aPNS is a viable candidate for TB vaccination, showing potential as both a standalone vaccine and a BCG-booster. Its ability to enhance immunogenicity and provide protection highlights its promise in addressing the limitations of current TB vaccines.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"159"},"PeriodicalIF":8.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765686","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":"NEDD4 E3 ligase-catalyzed NAMPT ubiquitination and autophagy activation are essential for pyroptosis-independent NAMPT secretion in human monocytes.","authors":"Marisela Rodriguez, Haifei Xu, Annie Hernandez, Julia Ingraham, Jason Canizales, Fernando Teran Arce, Sara M Camp, Skyler Briggs, Aikseng Ooi, James M Burke, Jin H Song, Joe G N Garcia","doi":"10.1186/s12964-025-02164-5","DOIUrl":"10.1186/s12964-025-02164-5","url":null,"abstract":"<p><p>NAMPT is an important intracellular metabolic enzyme (iNAMPT) regulating the NAD⁺ salvage pathway. However, increased cellular stress (infection, inflammation, hypoxia) promotes the secretion of extracellular NAMPT (eNAMPT), a TLR4 ligand and damage-associated molecular pattern protein (DAMP) that directly drives amplification of innate immune-mediated inflammatory, fibrotic, and neoplastic responses to influence disease severity. We sought to examine the mechanisms underlying pyroptotic eNAMPT release from human monocytic THP-1 cells, evoked by Nigericin, and non-pyroptotic eNAMPT secretion elicited by lipopolysaccharide (LPS). Our data indicate eNAMPT secretion/release requires NLRP3 inflammasome activation with substantial attenuation by either NLRP3 inhibition (MCC-950) or targeted genetic deletion of key inflammasome components, including NLRP3, caspase-1, or gasdermin D (GSDMD). Pyroptosis-associated eNAMPT release involved cleavage of the pore-forming GSDMD protein resulting in plasma membrane rupture (PMR) whereas non-pyroptotic LPS-induced eNAMPT secretion involved neither GSDMD cleavage nor PMR, verified utilizing non-cleavable GSDMD mutant constructs. LPS-induced eNAMPT secretion, however, was highly dependent upon NAMPT ubiquitination catalyzed by a complex containing the NEDD4 E3 ligase, Hsp90 (a selective chaperone), and intact GSDMD verified by enzymatic inhibition or silencing of NEDD4, GSDMD, or Hsp90. NAMPT ubiquitination and secretion involves autophagy activation as super-resolution microscopy analyses demonstrate NAMPT co-localization with autophagosome marker LC3B and eNAMPT secretion was significantly reduced by targeted ATG5 and ATG7 inhibition, critical components of the autophagy E3-like complex. These studies provide key insights into eNAMPT secretion that may accelerate the development of therapeutic strategies that address unmet therapeutic needs in inflammatory, fibrotic and neoplastic disorders.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"157"},"PeriodicalIF":8.2,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756083","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}