The FEBS journal最新文献_第2页

Molecular mechanism for transcriptional regulation of the parathyroid hormone gene by Epiprofin.

The FEBS journal Pub Date : 2025-03-31 DOI: 10.1111/febs.70085

Takashi Nakamura, Hannah M Nakamura, Yasumasa Iwasaki, Motomi Enomoto-Iwamoto, Noriaki Nakashima, Satoshi Fukumoto, Maurizio Pacifici, Masahiro Iwamoto, Minoru Wakamori

{"title":"Molecular mechanism for transcriptional regulation of the parathyroid hormone gene by Epiprofin.","authors":"Takashi Nakamura, Hannah M Nakamura, Yasumasa Iwasaki, Motomi Enomoto-Iwamoto, Noriaki Nakashima, Satoshi Fukumoto, Maurizio Pacifici, Masahiro Iwamoto, Minoru Wakamori","doi":"10.1111/febs.70085","DOIUrl":"https://doi.org/10.1111/febs.70085","url":null,"abstract":"Epiprofin (Epfn), an Sp/KLF family transcription factor that regulates cell proliferation and determines cell fates, is essential for normal skin, hair follicle, and tooth development. We found that Epfn was expressed in parathyroid glands, and Epfn-knockout mice displayed elevated serum parathyroid hormone (PTH) concentrations, decreased bone volume, and intracranial ectopic calcification. To investigate the role of Epfn in the regulation of PTH expression, parathyroid gland explant and parathyroid cell line culture methods were used. Epfn expression was found to be upregulated in response to an increase in extracellular calcium concentration, whereas PTH expression was downregulated, thus demonstrating an inverse correlation. Forced expression of Epfn inhibited PTH gene expression and PTH promoter reporter activity in parathyroid cells. In addition, with a high extracellular calcium concentration, Epfn silencing in cultured parathyroid glands failed to block PTH gene expression. ChIP-qPCR analysis also revealed Epfn binding in the proximal region of the PTH promoter, which was accelerated in the presence of a high concentration of calcium ions. The results from our in vitro and ex vivo analyses suggest that Epfn is a newly identified negative regulator of PTH transcription by regulating the proximal PTH promoter. Furthermore, the expression of Epfn was significantly reduced in parathyroid adenomas of primary hyperparathyroidism patients. The identification of Epfn as a potential therapeutic target for the control of PTH production in hyperparathyroidism patients opens new avenues for targeted treatment approaches.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Realizing the promise of 'La Dolce Vita' via chemical biology: glycan-motif editing of sLe^X for precision cancer therapeutics.

The FEBS journal Pub Date : 2025-03-27 DOI: 10.1111/febs.70079

Barbara Richichi, Robert Sackstein

引用次数: 0

Decreased expression of the immune checkpoint regulator VISTA on neutrophils correlates with disease activity in autoimmune uveitis.

The FEBS journal Pub Date : 2025-03-27 DOI: 10.1111/febs.70071

Yujing Qian, Siya Zhang, Zhihui Zhang, Menghao Zhang, Zhanwu Lin, Yamei Li, Li Zhang, Yurong Tuo, Meifen Zhang, Hui Chen

{"title":"Decreased expression of the immune checkpoint regulator VISTA on neutrophils correlates with disease activity in autoimmune uveitis.","authors":"Yujing Qian, Siya Zhang, Zhihui Zhang, Menghao Zhang, Zhanwu Lin, Yamei Li, Li Zhang, Yurong Tuo, Meifen Zhang, Hui Chen","doi":"10.1111/febs.70071","DOIUrl":"https://doi.org/10.1111/febs.70071","url":null,"abstract":"Immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) exhibits distinct expression patterns and non-redundant immunoregulatory mechanisms in different autoimmune diseases. This study aims to investigate the expression of VISTA in patients with autoimmune uveitis and experimental autoimmune uveitis (EAU) mice, and explore its clinical significance and preliminary mechanisms in disease development. We found that VISTA expression on 12 subsets of peripheral blood immune cells was lower in autoimmune uveitis patients than in healthy volunteers, especially on neutrophils. The expression of neutrophil VISTA in active uveitis patients markedly increased when intraocular inflammation was ameliorated, indicating a significant correlation with disease activity. In vitro treatment of neutrophils from autoimmune uveitis patients with a VISTA antagonist markedly aggravated cell activation and neutrophil extracellular traps formation, whereas a VISTA agonist produced the opposite effect. Moreover, VISTA was constitutively expressed in the outer segments of retina in healthy mice, and decreased in EAU mice, reaching the lowest level of expression when the disease was at a peak stage. Taken together, this study investigates the relationship between neutrophil VISTA and the development of autoimmune uveitis, and provides new insights into the mechanisms and therapeutic roles of VISTA in autoimmune diseases.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

d-amino acids: new functional insights.

The FEBS journal Pub Date : 2025-03-27 DOI: 10.1111/febs.70083

Loredano Pollegioni, Natasa Kustrimovic, Luciano Piubelli, Elena Rosini, Valentina Rabattoni, Silvia Sacchi

{"title":"d-amino acids: new functional insights.","authors":"Loredano Pollegioni, Natasa Kustrimovic, Luciano Piubelli, Elena Rosini, Valentina Rabattoni, Silvia Sacchi","doi":"10.1111/febs.70083","DOIUrl":"https://doi.org/10.1111/febs.70083","url":null,"abstract":"The d-enantiomers of amino acids (d-AAs) were initially considered \"unnatural\" molecules. They are primarily of microbial origin, present in low amounts, and without biological functions in eukaryotes. However, over the past few decades, sensitive analytical methods have uncovered the presence of both free and peptide-bound d-AAs in higher organisms. During the same period, the discovery of serine racemase-the enzyme that catalyzes the reversible formation of d-serine from l-serine-in rat brains demonstrated that mammals synthesize d-AAs. Notably, the enzymes responsible for d-AAs catabolism were identified almost 90 years ago. Subsequently, free d-AAs such as d-serine, d-aspartate, d-alanine, and d-cysteine have emerged as a novel and important class of signaling molecules in various organs, including the brain and endocrine system. Their involvement in a wide range of neurological disorders has drawn significant scientific interest. We have focused on novel findings, based on the latest analytical techniques, that have reshaped our understanding of physiological processes across diverse organisms, from plants to humans. Beyond neurotransmission, recent studies have highlighted the versatile roles of d-AAs in cancer, inflammation, immune regulation, kidney disease, and diabetes. Moreover, these studies suggest that the levels of d-AAs in blood and urine could serve as early biomarkers for conditions such as Alzheimer's disease, schizophrenia, and chronic kidney disease. Understanding the role of d-AAs in certain pathological states is helping to identify new therapeutic targets, offering promising opportunities for clinical applications in treating various diseases.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The influence of fatty acid metabolism on T cell function in lung cancer.

The FEBS journal Pub Date : 2025-03-25 DOI: 10.1111/febs.70081

Jessica Petiti, Ludovica Arpinati, Alessio Menga, Giovanna Carrà

{"title":"The influence of fatty acid metabolism on T cell function in lung cancer.","authors":"Jessica Petiti, Ludovica Arpinati, Alessio Menga, Giovanna Carrà","doi":"10.1111/febs.70081","DOIUrl":"https://doi.org/10.1111/febs.70081","url":null,"abstract":"The tumor microenvironment (TME) is a complex ecosystem, encompassing a variety of cellular and non-cellular elements surrounding and interacting with cancer cells, overall promoting tumor growth, immune evasion, and therapy resistance. In the context of solid tumors, factors, such as hypoxia, nutritional competition, increased stress responses, glucose demand, and PD-1 signals strongly influence metabolic alterations in the TME, highly contributing to the maintenance of a tumor-supportive and immune-suppressive milieu. Cancer cell-induced metabolic alterations partly result in an increased fatty acid (FA) metabolism within the TME, which strongly favors the recruitment of immune-suppressive M2 macrophages and myeloid-derived suppressor cells, crucial contributors to T-cell exhaustion, tumor exclusion, and decreased effector functions. The drastic pro-tumoral changes induced by the tumor metabolic rewiring result in signaling loops that support tumor progression and metastatic spreading, and negatively impact therapy efficacy. As tumor- and immune metabolism are increasingly gaining attention due to their potential therapeutic implications, we discuss the effects of altered lipid metabolism on tumor progression, immune response, and therapeutic efficacy in the context of lung cancer. In particular, we focus our analysis on the tumor-induced metabolic alterations experienced by T lymphocytes and the possible strategies to overcome immunotherapy resistance by targeting specific metabolic pathways in T cells.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Natural aminosterols inhibit NMDA receptors with low nanomolar potency.

The FEBS journal Pub Date : 2025-03-24 DOI: 10.1111/febs.70072

Giulia Fani, Elisabetta Coppi, Silvia Errico, Federica Cherchi, Martina Gennari, Denise Barbut, Michele Vendruscolo, Michael Zasloff, Anna Maria Pugliese, Fabrizio Chiti

{"title":"Natural aminosterols inhibit NMDA receptors with low nanomolar potency.","authors":"Giulia Fani, Elisabetta Coppi, Silvia Errico, Federica Cherchi, Martina Gennari, Denise Barbut, Michele Vendruscolo, Michael Zasloff, Anna Maria Pugliese, Fabrizio Chiti","doi":"10.1111/febs.70072","DOIUrl":"https://doi.org/10.1111/febs.70072","url":null,"abstract":"Abnormal functions of N-methyl-D-aspartate receptors (NMDARs) are associated with many brain disorders, making them primary targets for drug discovery. We show that natural aminosterols inhibit the NMDAR-mediated increase of intracellular calcium ions in cultured primary neurons and neuroblastoma cells. Structural comparison with known NMDAR-negative allosteric modulators, such as pregnanolone-sulfate-2 (PAS), raises the hypothesis that aminosterols have the same mechanism of action. Fluorescence resonance energy transfer (FRET) measurements using labeled NMDAR and the labeled aminosterol trodusquemine (TRO) indicate close spatial proximity, likely arising from binding. Other indirect yet plausible mechanisms for NMDAR inhibition by TRO were excluded. Electrophysiological patch clamp measurements on primary neurons indicate that pre-incubated TRO inhibits NMDA-induced ion currents with a IC50 of 5 nm. Inhibition is observed only after cell membrane pre-adsorption, indicating accessibility to NMDAR from the cell membrane and binding to the transmembrane domains (TMDs) and TMD-ligand-binding domain (LBD) linkers, similarly to PAS. The TRO IC50 is 5000-fold higher than that of PAS and 20-16 000 times higher than those of other inhibitors binding to TMD/TMD-LBD regions, identifying aminosterols as promising and potent NMDAR modulators.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mammalian TatD DNase domain containing 1 (TATDN1) is a proteostasis-responsive gene with roles in ventricular structure and neuromuscular function. 哺乳动物 TatD DNase domain containing 1（TATDN1）是一种蛋白稳态响应基因，在心室结构和神经肌肉功能中发挥作用。

The FEBS journal Pub Date : 2025-03-23 DOI: 10.1111/febs.70077

Gisel Barés, Aida Beà, Anna Sancho-Balsells, Juan G Valero, David Aluja, Javier Inserte, Sandra García-Carpi, Elisabet Miró-Casas, Sara Borràs-Pernas, Sara Hernández, Ana Martínez-Val, Jesper V Olsen, Francesc Tebar, Xavier Cañas, Joan X Comella, Patricia Pérez-Galán, Marisol Ruiz-Meana, Albert Giralt, Marta Llovera, Daniel Sanchis

{"title":"Mammalian TatD DNase domain containing 1 (TATDN1) is a proteostasis-responsive gene with roles in ventricular structure and neuromuscular function.","authors":"Gisel Barés, Aida Beà, Anna Sancho-Balsells, Juan G Valero, David Aluja, Javier Inserte, Sandra García-Carpi, Elisabet Miró-Casas, Sara Borràs-Pernas, Sara Hernández, Ana Martínez-Val, Jesper V Olsen, Francesc Tebar, Xavier Cañas, Joan X Comella, Patricia Pérez-Galán, Marisol Ruiz-Meana, Albert Giralt, Marta Llovera, Daniel Sanchis","doi":"10.1111/febs.70077","DOIUrl":"https://doi.org/10.1111/febs.70077","url":null,"abstract":"The characterization of highly conserved but poorly understood genes often reveals unexpected biological roles, advancing our understanding of disease mechanisms. One such gene is Mammalian TatD DNase domain containing 1 (Tatdn1), the mammalian homolog of bacterial Twin-arginine translocation D (TatD), a protein proposed to have roles either in DNA degradation or protein quality control in unicellular organisms. Despite its association with different pathologies, including several cancer types and cardiovascular diseases, the role of TATDN1 in mammals remains unexplored. Here, we demonstrate that Tatdn1 encodes a cytoplasmic protein that does not participate in DNA degradation but is upregulated in cells under proteostasis stress. Tatdn1-deficient mice exhibit dysregulated expression of genes involved in membrane and extracellular protein biology, along with mild dilated cardiomyopathy and impaired motor coordination. These findings identify TATDN1 as a key player in cytosolic processes linked to protein homeostasis, with significant physiological implications for cardiac and neurological function.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An adamantane-based ligand as a novel chemical tool for thermosensory TRPM8 channel therapeutic modulation. 以金刚烷为基础的配体是一种新型化学工具，可用于热感 TRPM8 通道的治疗调节。

The FEBS journal Pub Date : 2025-03-23 DOI: 10.1111/febs.70065

Angela Lamberti, Silvio Aprile, David Cabañero, Fabio Travagin, Laura Butron, Gregorio Fernández-Ballester, Gian Cesare Tron, Asia Fernández-Carvajal, Antonio Ferrer-Montiel, Ubaldina Galli

{"title":"An adamantane-based ligand as a novel chemical tool for thermosensory TRPM8 channel therapeutic modulation.","authors":"Angela Lamberti, Silvio Aprile, David Cabañero, Fabio Travagin, Laura Butron, Gregorio Fernández-Ballester, Gian Cesare Tron, Asia Fernández-Carvajal, Antonio Ferrer-Montiel, Ubaldina Galli","doi":"10.1111/febs.70065","DOIUrl":"https://doi.org/10.1111/febs.70065","url":null,"abstract":"Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a nonselective thermosensory cation channel expressed in peripheral nociceptor terminals where it transduces cold temperatures and cooling agents such as menthol. TRPM8 dysfunction has been involved in disabling sensory symptoms, such as cold allodynia. In addition, its widespread expression has signaled this channel as a pivotal therapeutic target for a variety of diseases, from peripheral neuropathies to cancer. Thus, the design and therapeutic validation of TRPM8 antagonists is an important endeavor in biomedicine. To address this, we used the multicomponent Passerini and Ugi reactions to design a novel family of TRPM8 modulators using as a scaffold the adamantane ring that exhibits drug-like qualities. These green chemistry transformations are ideal for the fast synthesis of libraries of medium complexity with minimal or no generation of waste by-products. We report the identification of a family of TRPM8 agonists and antagonists. Among them, 2-((3S,5S,7S)-adamantan-1-ylamino)-2-oxoethyl [1,1'-biphenyl]-2-carboxylate (referred to as compound 23) is a potent and selective antagonist that reduces TRPM8-induced neuronal firing in primary nociceptor cultures. Compound 23 exhibits 10-fold higher potency for human TRPM8 (hTRPM8) than for hTRPV1 and hTRPA1 channels. Notably, local administration of compound 23 significantly attenuated oxaliplatin-induced peripheral cold allodynia by modulating epidermal TRPM8 sensory endings. Thus, α-acyloxy carboxamide 23 appears as a promising therapeutic candidate to topically intervene on TRPM8-mediated peripheral neuropathies.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The complete absence of cytoplasmic γ-actin results in no discernible phenotype in mice or primary fibroblasts. 细胞质 γ-肌动蛋白的完全缺失不会导致小鼠或原代成纤维细胞出现明显的表型。

The FEBS journal Pub Date : 2025-03-20 DOI: 10.1111/febs.70075

Lauren J Sundby, Katelin M Hawbaker, Jacob Powers, William M Southern, Erynn E Johnson, Xiaobai Patrinostro, Benjamin J Perrin, James M Ervasti

引用次数: 0

Estrogen in the brain - neuroestrogens can regulate appetite and influence body weight.

The FEBS journal Pub Date : 2025-03-20 DOI: 10.1111/febs.70078

Tram Thi-Ngoc Nguyen, Yoshiaki Kanemoto, Tomohiro Kurokawa, Shigeaki Kato

引用次数: 0