Advances in biological regulation最新文献

{"title":"Group photo","authors":"","doi":"10.1016/j.jbior.2026.101150","DOIUrl":"10.1016/j.jbior.2026.101150","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101150"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146161762","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}

{"title":"OGT's inner circle: Protein interactions and functional impact","authors":"Fiddia Zahra ,&nbsp;Natasha E. Zachara","doi":"10.1016/j.jbior.2025.101120","DOIUrl":"10.1016/j.jbior.2025.101120","url":null,"abstract":"<div><div>The modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as an essential post-translational modification in mammals. More than 5000 human proteins are subject to O-GlcNAcylation, influencing key cellular processes such as signal transduction, epigenetic regulation, transcription, translation, and bioenergetics. Dysregulation of this modification has been implicated in a wide range of diseases, including metabolic disorders, cancer, neurodegeneration, ischemic injury, and heart failure. O-GlcNAc-cycling is orchestrated by two enzymes: the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze the addition and removal of O-GlcNAc, respectively. A central challenge in the field is understanding how this minimal enzymatic machinery achieves such broad substrate specificity. It is hypothesized that OGT's functional versatility is mediated through interactions with a diverse network of protein partners that act as adaptors, scaffolds, or substrates, thereby directing its localization, modulating its activity, and shaping its substrate selectivity. In this review, we discuss key interactors and their functional impact on OGT. We also explore how post-translational modifications and substrate availability contribute to OGT regulation and specificity.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101120"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327966","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}

{"title":"Group photo","authors":"","doi":"10.1016/j.jbior.2026.101149","DOIUrl":"10.1016/j.jbior.2026.101149","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101149"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146161766","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}

{"title":"DGKζ depletion attenuates BRCA1-mediated DNA repair mechanism","authors":"Toshiaki Tanaka ,&nbsp;Mitsuyoshi Iino ,&nbsp;Kaoru Goto","doi":"10.1016/j.jbior.2025.101118","DOIUrl":"10.1016/j.jbior.2025.101118","url":null,"abstract":"<div><div>DNA double-strand breakage is the most lethal damage to chromosomal DNA. It activates a series of cellular DNA damage response pathways, including DNA damage sensing, control of cell cycle arrest and apoptosis, and DNA repair. DNA damage response pathways are regulated by complex signaling machineries. Of the intracellular signaling cascades, diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Because both DG and PA serve as second messengers, DGK activity induces a shift of signaling pathways from DG-mediated to PA-mediated cascades, thereby implicating DGK in the regulation of widely various functions. Reportedly, one member of the DGK family, DGKζ, is intimately involved in the regulation of stress responses through p53 and NF-κB. Stresses such as ischemia and infarction cause DGKζ downregulation. Experimental DGKζ depletion renders cells and mice vulnerable to various stressors such as chemotherapeutic agents and ionizing irradiation. Nevertheless, how DGKζ is involved in DNA repair, a critical event of DNA damage response for survival remains unknown. For this study, we examined how DGKζ depletion affects DNA repair mechanisms. We demonstrated that DGKζ depletion causes attenuation of Akt activation and DNA-PK protein expression upon DNA damage, which might engender downregulated BRCA1 protein synthesis and stability. Results suggest that DGKζ depletion attenuates BRCA1-mediated DNA repair machinery, thereby conferring vulnerability to DNA damage.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101118"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145375878","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}

{"title":"Harnessing lipid metabolism through diacylglycerol kinases: implications for immune modulation and cancer therapy","authors":"Juan José Sánchez-Cabezón,&nbsp;Antonia Ávila-Flores,&nbsp;Isabel Mérida","doi":"10.1016/j.jbior.2025.101129","DOIUrl":"10.1016/j.jbior.2025.101129","url":null,"abstract":"<div><div>Diacylglycerol kinases (DGKs) are key enzymes that integrate lipid metabolism with multiple signaling pathways. DGKs regulate the conversion of diacylglycerol (DAG) into phosphatidic acid (PA), two essential bioactive lipids that promote the activation of distinctive proteins controlling cell growth, proliferation and differentiation. The variety of DGK isoforms enables them to perform specialized functions in different tissues, and dysregulation of DGK activity and expression contributes to diverse pathological conditions. DGKs exert potent inhibitory functions in T cells and are aberrantly expressed in a wide range of cancer types, which make DGKs attractive therapeutic targets for cancer immunotherapy. In recent years, the development of novel and highly isoform-specific inhibitors has opened exciting opportunities to further explore the fundamental functions of lipid metabolism in the maintenance of immune cell homeostasis and in the progression of several diseases. Besides T cells, DGKs play important roles in regulating inflammatory processes across distinct immune populations. The therapeutic potential of these drugs has been translated in several ongoing clinical trials. Therefore, it is crucial to delineate DGK-controlled signaling hubs to better understand their impact on immune signatures. In this work, we aimed to recapitulate the effects of modulating DAG/PA balance on immune cells that are relevant in the tumor microenvironment. By dissecting how DGK-mediated lipid signaling shapes immune cell behavior in the tumor microenvironment, we seek to provide mechanistic insights that may guide the rational use of drugs targeting DGKs to improve antitumor immunity.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101129"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686797","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}

{"title":"Alpha-to-beta cell crosstalk: Adaptive mechanisms shaping islet function","authors":"Philip Tröster ,&nbsp;Montse Visa ,&nbsp;Per-Olof Berggren","doi":"10.1016/j.jbior.2025.101121","DOIUrl":"10.1016/j.jbior.2025.101121","url":null,"abstract":"<div><div>The pancreatic islet, historically described as a binary system of insulin-secreting beta cells and glucagon-secreting alpha cells, is increasingly recognized as a complex paracrine network contributing to glucose homeostasis. Alpha-to-beta cell communication is not merely modulatory but a decisive mechanism sustaining islet function under metabolic stress. Alpha cell distribution, structural specializations at the alpha–beta interface, and adaptations in signaling pathways collectively shape glycemic set points and beta cell resilience. Recent studies highlight the context-dependent nature of this intra-islet crosstalk. Visa et al. demonstrated that prediabetic stress in Western diet-fed mice remodels islet cytoarchitecture in a sex-dependent manner, enhancing alpha-to-beta signaling and Ca²⁺ dynamics, and thereby preserving insulin secretion more effectively in females than in males. Experiments using a glucagon receptor antagonist in human islets confirmed that glucagon paracrine signaling is essential for this adaptive enhancement, particularly the increased Ca²⁺ dynamics in female islets under high metabolic demand. Mechanistic studies further revealed that the GLP-1 receptor forms specialized nanodomains at the alpha–beta junction that undergo pre-internalization, priming beta cells for rapid Ca²⁺ influx and heightened metabolic responsiveness. Collectively, these findings highlight intra-islet communication as a critical determinant of adaptation or failure in diabetes progression. However, conflicting evidence from beta cell-only islets, which display enhanced glucose-stimulated insulin secretion, together with reports that long-term exposure to the GLP-1 analog liraglutide can compromise beta cell function, presents a paradox that challenges current models of intra-islet regulation. Understanding these nuances is crucial for translating intra-islet signaling into targeted therapeutic strategies and regenerative tissue engineering.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101121"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257213","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}

{"title":"PKCα as a signaling gatekeeper upstream of mTORC1 in mEGFR NSCLC","authors":"Mojtaba Sadeghi ,&nbsp;Sam B. Chiappone ,&nbsp;Mohamed F. Salama ,&nbsp;Yusuf A. Hannun","doi":"10.1016/j.jbior.2025.101122","DOIUrl":"10.1016/j.jbior.2025.101122","url":null,"abstract":"<div><div>Despite decades of research since phorbol esters first linked protein kinase C (PKC) to tumor promotion, the biological role of this family of kinases in cancer has remained ambiguous because of isozyme-specific functions and tissue-type-dependent effects. Here, we delineate critical roles for PKC in lung cancer. We previously showed that sustained activation of PKCβ_II activates mTOR, an effect evident in lung cancer cell lines with high expression of classical PKCs (cPKCs). These findings prompted us to examine lung cancers driven by mutant EGFR (mEGFR), in which PKCα is highly expressed. We find that mEGFR-dependent activation of PKCα drives serum-deprived proliferation, anchorage-independent growth (AIG), and anchorage-independent survival (AIS). Subsequent studies revealed that the mutant receptor is impaired in ligand-independent activation and, due to altered autophosphorylation, exhibits biased activation of the PLC arm, preferentially propagating signals through a PLC-PKCα-AKT-mTORC1 axis required for AIG and AIS. In parallel, we investigated the basis of PKCα upregulation and found that elevated PKCα levels are independent of mEGFR. Bioinformatic analysis of mEGFR lung cancers highlighted basal cells, a subtype of lung cell which intrinsically express high <em>PRKCA</em>, as the likely cell-of-origin, suggesting that cell lineage sets a high ceiling for PKCα abundance, while mEGFR licenses the activation of the kinase. Collectively, these data define a pathway-specific role for cPKCs, particularly PKCα, as upstream effectors of mTORC1 in mEGFR systems, establishing a neomorphic dependency on the PKCα-AKT-mTORC1 signaling arm that sustains tumorigenesis via biased signaling by the mutant receptor.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101122"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443767","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}

{"title":"Computational docking of sphingolipids into the regulatory binding site of serine palmitoyltransferase","authors":"Matthew Peart ,&nbsp;Balaji Nagarajan ,&nbsp;Glen E. Kellogg ,&nbsp;Binks W. Wattenberg","doi":"10.1016/j.jbior.2025.101125","DOIUrl":"10.1016/j.jbior.2025.101125","url":null,"abstract":"<div><div>Canonically known both for structural contributions to lipid bilayers and roles in cell signaling, the sphingolipids comprise a dynamic, multifaceted class of molecules which are studied to understand cell biology and pathophysiology. All sphingolipids are downstream products of the rate-limiting and initiating enzyme in the <em>de novo</em> sphingolipid synthesis pathway, serine palmitoyltransferase (SPT). SPT activity is strictly regulated. This regulation is accomplished through the ORMDLs, transmembrane polypeptides embedded in the lipid bilayer of the endoplasmic reticulum, which are the regulatory subunits of the SPT complex. Recently the specific mechanism of ORMDL's regulation of SPT was established: ceramide, a downstream product of the <em>de novo</em> biosynthetic pathway, binds directly to a binding site of ORMDL to induce an inhibitory conformational change. Here, we validate a computational docking approach to interrogate the binding efficiency of a range of sphingolipids in the ceramide binding site. We demonstrate that docking poses predicted by this <em>in silico</em> approach reflect experimental data on the efficiency of sphingolipid species to accomplish ORMDL-dependent inhibition of SPT. We propose that this docking analysis will be a valuable complement to experimental tests of compounds that bind to this site to regulate sphingolipid biosynthesis.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101125"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145407744","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}

{"title":"Plant-derived immunomodulators in cancer: Balancing immune activation and suppression within the tumor microenvironment","authors":"Verena Beier ,&nbsp;Michael Wink ,&nbsp;Yvonne Samstag","doi":"10.1016/j.jbior.2025.101132","DOIUrl":"10.1016/j.jbior.2025.101132","url":null,"abstract":"<div><div>The immune system is central to the prevention and control of cancer, yet tumors evolve multiple strategies to subvert immune surveillance. Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have revolutionized oncology by demonstrating that therapeutic restoration of T cell activity can yield durable remissions. However, their efficacy remains limited by the profoundly immunosuppressive tumor microenvironment (TME), where regulatory immune cells, suppressive cytokines, and metabolic stressors converge to dampen effector function. As interest in integrative and complementary approaches grows, plant-derived compounds - long used in traditional medicine - have been identified as bioactive agents capable of modulating immune function.</div><div>This review focuses on three key phytochemicals: piperlongumine, berberine, and epigallocatechin gallate (EGCG). Piperlongumine, a pro-oxidative alkaloid from <em>Piper longum</em>, suppresses T cell activation and promotes regulatory T cell differentiation, suggesting potential for chronic inflammation but raising caution in oncology. Berberine, an isoquinoline alkaloid from <em>Berberis vulgaris</em>, reduces PD-L1 expression via CSN5 inhibition, thereby mimicking checkpoint blockade and enhancing cytotoxic T cell activity in preclinical models. EGCG, the major polyphenol in green tea, downregulates PD-L1 expression and augments anti-tumor immunity in murine melanoma.</div><div>We critically assess the promise and pitfalls of these compounds in cancer immunotherapy, emphasizing mechanistic insights, pharmacokinetics, translational hurdles, and potential risks of interfering with established therapies. A precision immunology framework - integrating immune monitoring, patient stratification, and controlled clinical trials - will be essential to determine whether phytochemicals can be safely and effectively incorporated into oncology. Far from being benign, plant-derived agents exert potent immune effects that could either complement or compromise modern immunotherapy, underscoring the need for rigorous evaluation.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101132"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601750","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}

{"title":"Induced pluripotent stem cell-based modelling of disease evolution in myeloid leukemia: MDS to AML","authors":"Jacqueline Boultwood","doi":"10.1016/j.jbior.2025.101119","DOIUrl":"10.1016/j.jbior.2025.101119","url":null,"abstract":"<div><div>The myelodysplastic syndromes (MDS) are common myeloid malignancies that develop from the successive acquisition of driver mutations in hematopoietic stem cells residing in the bone marrow. Around a third of MDS patients will develop secondary acute myeloid leukemia (sAML) and patients with high-risk MDS or sAML have a dismal prognosis. The study of disease progression in myeloid malignancy has been enhanced in recent years by the use of induced pluripotent stem cells (iPSCs) technology. iPSCs offer the advantage of indefinite expansion and the potential for genetic modification, with reprogramming enabling the capture of the full complement of genetic lesions found in primary patient bone marrow samples. The power of iPSC and CRISPR-Cas9 gene editing technologies have been harnessed to generate a range of iPSC-based cellular models of MDS, reflecting the genetic and biologic heterogeneity of the disease. Stage-specific patient iPSC lines have been produced and sequential gene editing in normal human iPSCs has been performed to map the evolution of MDS to AML. These studies have increased our understanding of the impact of driver mutations, and co-mutations, on disease phenotype and revealed mechanisms underlying disease stage transitions in myeloid malignancy. iPSC-based models of MDS have also proven important tools in high throughput drug screening and have empowered drug testing and drug discovery, offering a new platform to develop personalized therapy.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101119"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231209","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}