Cellular and Molecular Life Sciences最新文献

{"title":"Esc peptides and derivatives potentiate the activity of CFTR with gating defects and display antipseudomonal activity in cystic fibrosis-like lung disease.","authors":"Loretta Ferrera, Floriana Cappiello, Arianna Venturini, Hexin Lu, Bruno Casciaro, Giacomo Cappella, Giulio Bontempi, Alessandra Corrente, Raffaele Strippoli, Federico Zara, Y Peter Di, Luis J V Galietta, Mattia Mori, Maria Luisa Mangoni","doi":"10.1007/s00018-025-05633-9","DOIUrl":"10.1007/s00018-025-05633-9","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is a rare disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a chloride channel with an important role in the airways. Despite the clinical efficacy of present modulators in restoring the activity of defective CFTR, there are patients who show persistent pulmonary infections, mainly due to Pseudomonas aeruginosa. Recently, we reported an unprecedented property of antimicrobial peptides i.e. Esc peptides, which consists in their ability to act as potentiators of CFTR carrying the most common mutation (the loss of phenylalanine 508) affecting protein folding, trafficking and gating. In this work, by electrophysiology experiments and computational studies, the capability of these peptides and de-novo designed analogs was demonstrated to recover the function of other mutated forms of CFTR which severely affect the channel gating (G551D and G1349D). This is presumably due to direct interaction of the peptides with the nucleotide binding domains (NBDs) of CFTR, followed by a novel local phenomenon consisting in distancing residues located at the cytosolic side of the NBDs interface, thus stabilizing the open conformation of the pore at its cytosolic end. The most promising peptides for the dual antimicrobial and CFTR potentiator activities were also shown to display antipseudomonal activity in conditions mimicking the CF pulmonary ion transport and mucus obstruction, with a higher efficacy than the clinically used colistin. These studies should assist in development of novel drugs for lung pathology in CF, with dual CFTR potentiator and large spectrum antibiotic activities.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"121"},"PeriodicalIF":6.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11920571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656424","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":"What are the ethical limits of claimed scientific authorship? a case report of relevance.","authors":"Juan-Carlos Argüelles","doi":"10.1007/s00018-025-05650-8","DOIUrl":"10.1007/s00018-025-05650-8","url":null,"abstract":"<p><p>Since its discovery in the middle of the XX century, research into autophagy has undergone a spectacular expansion, particularly in the early 1990s. A number of physiological processes involving autophagy have been revealed and important human pathologies have been associated with perturbations in autophagy. In 2008 the \"Guidelines for the use and interpretation of assays for monitoring autophagy\" was launched with the purpose of collecting in a single document all the available information to monitor autophagy, which, it was thought, might be useful for established groups and any new scientists attracted by this field. The usefulness and success of this Guidelines has led to the subsequent publication of editions every 4 years, a task in which a growing number of authors have become involved and consequently included in the list of contributors. However, this worthy initiative and closely associated metric parameters has led to important scholarly repercussions in terms of perceived merits, grants and financial support obtained, professional careers and other areas concerning scientific activity. All these aspects are carefully examined in this contribution.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"120"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647522","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":"Interneuron migration impairment and brain region-specific DNA damage response following irradiation during early neurogenesis in mice.","authors":"Lisa Berden, Nicholas Rajan, André Claude Mbouombouo Mfossa, Isabeau De Bie, Emre Etlioglu, Mohammed Abderrafi Benotmane, Mieke Verslegers, Najat Aourz, Ilse Smolders, Jean-Michel Rigo, Bert Brône, Roel Quintens","doi":"10.1007/s00018-025-05643-7","DOIUrl":"10.1007/s00018-025-05643-7","url":null,"abstract":"<p><p>Embryonic DNA damage resulting from DNA repair deficiencies or exposure to ionizing radiation during early neurogenesis can lead to neurodevelopmental disorders, including microcephaly. This has been linked to an excessive DNA damage response in dorsal neural progenitor cells (NPCs), resulting in p53-dependent apoptosis and premature neuronal differentiation which culminates in depletion of the NPC pool. However, the effect of DNA damage on ventral forebrain NPCs, the origin of interneurons, remains unclear. In this study, we investigated the sequelae of irradiation of mouse fetuses at an early timepoint of forebrain neurogenesis. We focused on the neocortex (NCX) and medial ganglionic eminence (MGE), key regions for developing dorsal and ventral NPCs, respectively. Although both regions showed a typical p53-mediated DNA damage response consisting of cell cycle arrest, DNA repair and apoptosis, NCX cells displayed prolonged cell cycle arrest, while MGE cells exhibited more sustained apoptosis. Moreover, irradiation reduced the migration speed of interneurons in acute living brain slices and MGE explants, the latter indicating a cell-intrinsic component in the defect. RNA sequencing and protein analyses revealed disruptions in actin and microtubule cytoskeletal-related cellular machinery, particularly in MGE cells. Despite massive acute apoptosis and an obvious interneuron migration defect, prenatally irradiated animals did not show increased sensitivity to pentylenetetrazole-induced seizures, nor was there a reduction in cortical interneurons in young adult mice. This suggests a high plasticity of the developing brain to acute insults during early neurogenesis. Overall, our findings indicate that embryonic DNA damage induces region-specific responses, potentially linked to neurodevelopmental disorders.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"118"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647513","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":"Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade.","authors":"Felipe I Espinoza, Stoyan Tankov, Sylvie Chliate, Joana Pereira Couto, Eliana Marinari, Thibaud Vermeil, Marc Lecoultre, Nadia El Harane, Valérie Dutoit, Denis Migliorini, Paul R Walker","doi":"10.1007/s00018-025-05642-8","DOIUrl":"10.1007/s00018-025-05642-8","url":null,"abstract":"<p><p>Glioblastoma (GBM) is an aggressive primary brain tumor with dismal clinical prognosis and resistance to current therapies. GBM progression is facilitated by the tumor microenvironment (TME), with an immune infiltrate dominated by tumor-associated microglia/macrophages (TAMs) and regulatory T cells (Tregs). The TME is also characterized by hypoxia and the expression of hypoxia-inducible factors (HIFs), with HIF-2α emerging as a potential regulator of tumor progression. However, its role in GBM immunosuppression remains unknown. Here, we investigate HIF-2α and the use of the HIF-2α inhibitor PT2385 to modulate the TME in the immunocompetent GL261 mouse GBM model. PT2385 administration in vivo decreased tumor volume and prolonged survival of tumor-bearing mice, without affecting GL261 viability in vitro. Notably, HIF-2α inhibition alleviated the immunosuppressive TME and synergized with immune checkpoint blockade (ICB) using αPD-1 and αTIM-3 antibodies to promote long-term survival. Comprehensive analysis of the immune infiltrate through single-cell RNA sequencing and flow cytometry revealed that combining PT2385 with ICB reduced numbers of pro-tumoral macrophages and Tregs while increasing numbers of microglia, with a corresponding transcriptional modulation towards an anti-tumoral profile of these TAMs. In vitro, deletion of HIF-2α in microglia impeded their polarization towards a pro-tumoral M2-like profile, and its inhibition impaired Treg migration. Our results show that targeting HIF-2α can switch an immunosuppressive TME towards one that favors a robust and sustained response to ICB based immunotherapy. These findings establish that clinically relevant HIF-2α inhibitors should be explored not only in malignancies with defects in the HIF-2α axis, but also in those exhibiting an immunosuppressive TME that limits immunotherapy responsiveness.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"119"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647521","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":"Loss of Cep135 causes oligoasthenoteratozoospermia and male infertility in mice.","authors":"Hui Liu, Haozheng Zhang, Guanghao Qin, Tingting Song, Xin Liu, Zongzhuang Wen, Min Liu, Xianmei Wang, Xiaolong Fu, Jiangang Gao","doi":"10.1007/s00018-025-05616-w","DOIUrl":"10.1007/s00018-025-05616-w","url":null,"abstract":"<p><p>Centrosomal proteins (Cep), as crucial scaffolding molecules, play a pivotal role in the biogenesis of centrioles and the regulation of the cell cycle. To date, mutation in Cep135 has been reported to be closely associated with multiple morphological abnormalities of the flagella (MMAF) in humans. However, the specific mechanism of Cep135 in spermatogenesis and its detailed role in male infertility remains largely unexplored. In this study, we present compelling evidence that Cep135 functions as a pathogenic gene responsible for oligoasthenoteratozoospermia (OAT) and male infertility in mice. By selectively deleting Cep135 in premeiotic germ cells using Stra8-Cre mice crossed with Cep135^flox/flox mice, we observed that Cep135 knockdown produced abnormal sperm morphology, germ cell apoptosis and consequentlybecame complete infertility, but did not impact premeiosis. Scanning and transmission electron microscopy revealed defects in acrosome, flagellum, and head-to-tail connections during spermatogenesis. Proteomic analysis further indicated that CEP135 deletion led to a significant reduction in proteins mainly associated with acrosome formation, sperm heads, sperm flagellum and microtubule assembly. Additionally, CEP135 interacts with spermatogenic proteins SPATA6 and AKAP3, regulating their expression and stability. Deficiency in CEP135 or its interacting proteins resulted in ciliary shortening. In conclusion, our study profoundly unveils the central role of Cep135 in spermatogenesis and male fertility. This discovery not only deepens our comprehension of spermatogenesis but also furnishes a solid theoretical foundation and experimental evidence that can guide the formulation of therapeutic and preventive strategies for male infertility.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"117"},"PeriodicalIF":6.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647515","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":"Neutrophil-modulated Dicer expression in macrophages influences inflammation resolution.","authors":"Zhishang Wang, Wenhua Li, Jia Li, Tianrong Jin, Hong Chen, Feihong Liang, Shengran Liu, Jialin Jia, Tingting Liu, Yu Liu, Liming Yu, Xiaodong Xue, Jikai Zhao, Tao Huang, Xinyi Huang, Huishan Wang, Yongsheng Li, Bangwei Luo, Zhiren Zhang","doi":"10.1007/s00018-025-05644-6","DOIUrl":"10.1007/s00018-025-05644-6","url":null,"abstract":"<p><p>The precise molecular mechanisms through which neutrophils regulate macrophages in the progression and resolution of acute inflammation remain poorly understood. Here, we present new findings on the role of Dicer in regulating macrophage phenotypic transitions essential for proper inflammatory progression and resolution, influenced by neutrophils. Using a zymosan A (Zym A)-induced self-limited mouse peritonitis model, we observed that Dicer expression in macrophages was significantly reduced by neutrophil-derived IFN-γ during the progression phase, but gradually returned to normal levels during the resolution phase following the engulfment of apoptotic neutrophils. Our study on macrophage-specific Dicer1-depletion (Dicer1-CKO) mice demonstrated that inflammation in these mice was more severe during the progression phase, characterized by increased pro-inflammatory cytokines and enhanced neutrophil trafficking. Additionally, resolution was impaired in Dicer1-CKO mice, leading to the accumulation of uncleared apoptotic neutrophils. Specifically, the absence of Dicer in macrophages resulted in M1 polarization and heightened bactericidal activity, facilitating the progression of acute inflammation. Conversely, inducing Dicer expression promoted macrophage transition to M2 polarization, enhancing apoptotic cell clearance and expediting the resolution of inflammation. Our findings suggest that Dicer plays a central role in regulating the progression and resolution of acute inflammation, with implications for the treatment of inflammatory diseases.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"114"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613744","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":"New perspectives on gastric disorders: the relationship between innate lymphoid cells and microbes in the stomach.","authors":"Yunzi Yan, Naoko Satoh-Takayama","doi":"10.1007/s00018-025-05632-w","DOIUrl":"10.1007/s00018-025-05632-w","url":null,"abstract":"<p><p>A growing number of studies in recent years have revealed the changes in the gastric microbiota during the development of gastric diseases, breaking the stereotype that the stomach is hostile to microorganisms beyond H. pylori. After a decade of intensive research, the discovery of innate lymphoid cells (ILCs) has provided a new perspective on the immune response in many diseases. In the context of defense against infectious pathogens, the pre-existing innate defense mechanism of tissue-resident ILCs can rapidly recognize and respond to microbes to eliminate infection at the earliest stages. Here, we outline the basic function of ILCs in the gastric mucosa and in shaping the gastric microbiome. We discuss the interactions between the gastric microbiota and ILCs, explaining how the ILCs actively drive the immune response against bacterial pathogens that can lead to the development of the gastric disease.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"113"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613746","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":"Anti-interferon armamentarium of human coronaviruses.","authors":"Oyahida Khatun, Sumandeep Kaur, Shashank Tripathi","doi":"10.1007/s00018-025-05605-z","DOIUrl":"10.1007/s00018-025-05605-z","url":null,"abstract":"<p><p>Cellular innate immune pathways are formidable barriers against viral invasion, creating an environment unfavorable for virus replication. Interferons (IFNs) play a crucial role in driving and regulating these cell-intrinsic innate antiviral mechanisms through the action of interferon-stimulated genes (ISGs). The host IFN response obstructs viral replication at every stage, prompting viruses to evolve various strategies to counteract or evade this response. Understanding the interplay between viral proteins and cell-intrinsic IFN-mediated immune mechanisms is essential for developing antiviral and anti-inflammatory strategies. Human coronaviruses (HCoVs), including SARS-CoV-2, MERS-CoV, SARS-CoV, and seasonal coronaviruses, encode a range of proteins that, through shared and distinct mechanisms, inhibit IFN-mediated innate immune responses. Compounding the issue, a dysregulated early IFN response can lead to a hyper-inflammatory immune reaction later in the infection, resulting in severe disease. This review provides a brief overview of HCoV replication and a detailed account of its interaction with host cellular innate immune pathways regulated by IFN.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"116"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613733","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":"AMPK activation by hepatitis E virus infection inhibits viral replication through attenuation of autophagosomes and promotion of innate immunity.","authors":"Chunling Wang, Xiaoman Liu, Yao Zhao, Shumin Liao, Jiayue Zhang, Yanhong Huang, Yue Shi, Liang Li, Qiuwei Pan, Jian Wu, Yijin Wang","doi":"10.1007/s00018-025-05634-8","DOIUrl":"10.1007/s00018-025-05634-8","url":null,"abstract":"<p><p>Hepatitis E virus (HEV) infection is generally asymptomatic or leads to acute and self-limiting hepatitis. The mechanisms orchestrating such an infection course remain to be elucidated. AMP-activated protein kinase (AMPK) is a pivotal cellular sensor for maintaining metabolic homeostasis. Here, we show that AMPK is activated in response to HEV infection and is associated with mitochondrial damage and ATP deficiency. AMPK activation, in turn, inhibits HEV replication. Mechanistic studies reveal that AMPK activation triggers the expression of interferon (IFN)-stimulated genes that possess antiviral properties. In parallel, AMPK inhibits autophagosome accumulation to exert antiviral effects. Interestingly, AMPK activation also suppresses the inflammatory response triggered by HEV infection. Consistently, AMPK activation simultaneously exerts anti-inflammatory and antiviral effects in a coculture system of HEV-infected liver cells with macrophages. These findings pave the way for the development of AMPK-targeted therapeutics to treat hepatitis E.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"111"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613731","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":"Identification of early genes in the pathophysiology of fibrotic interstitial lung disease in a new model of pulmonary fibrosis.","authors":"Nathan Hennion, Corentin Bedart, Léonie Vandomber, Frédéric Gottrand, Sarah Humez, Cécile Chenivesse, Jean-Luc Desseyn, Valérie Gouyer","doi":"10.1007/s00018-025-05620-0","DOIUrl":"10.1007/s00018-025-05620-0","url":null,"abstract":"<p><p>Some interstitial lung diseases involve pulmonary fibrosis, which is a process that is characterized by the excessive and abnormal accumulation of extracellular matrix in the pulmonary interalveolar space. Although the current anti-fibrotic therapy aims at slowing down the progression of pulmonary fibrosis, it does not reverse it, and many of the drugs that were identified in basic-research studies failed in clinical phases, mainly because of the lack of a model that can recapitulate the pathophysiological mechanisms of human pulmonary fibrosis. We developed a novel experimental model of pulmonary fibrosis induced by a cocktail of molecules on an air/liquid interface culture of mouse embryonic lung explants. Histological analyses revealed a pattern of usual interstitial pneumonia, the worst-prognosis form of pulmonary fibrosis. We performed a transcriptomics analysis at the single-cell level after the induction of fibrosis and before any histological signs of fibrosis could be observed. The results revealed increased expression of several gene families that are involved in early inflammation, fibrosis and iron homeostasis, as well as potential new genetic targets.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"115"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613742","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}