Advances in biological regulation最新文献

{"title":"Complex role of mTOR signaling pathway in glioblastoma and its stem cells","authors":"Austin B. Carpenter,&nbsp;Ariel Sacknovitz,&nbsp;Simon Hanft,&nbsp;Chirag D. Gandhi,&nbsp;Meena Jhanwar-Uniyal","doi":"10.1016/j.jbior.2025.101143","DOIUrl":"10.1016/j.jbior.2025.101143","url":null,"abstract":"<div><div>Mechanistic target of rapamycin (mTOR: aka mammalian target of rapamycin), a serine threonine kinase, functions by forming two multiprotein complexes designated mTORC1 and mTORC2. This signaling cascade of PI3K/AKT/mTOR is often upregulated due to frequent loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. Aberrant signaling of mTOR is shown to be associated with tumorigenesis of numerous malignancies including glioblastoma (GBM). mTORC1 and mTORC2 activate downstream substrates that execute cellular and metabolic functions. Experimental models have provided evidence of the existence of cancer stem cells (CSCs), also known as tumor-initiating cells within the tumor mass, that may play an active role in development, progression and reformation of GBM. In addition, presence of highly infiltrative CSCs in the peritumoral region of GBM may appear to play an important role in recurrence of disease. Since rapamycin and its analogues are less effective in treatment of GBM, the use of ATP-competitive dual inhibitors of mTORC1 and mTORC2 have been increasingly investigated. These attempt to suppress GBM growth by pharmacodynamically inhibiting phosphorylation of the mTORC1 substrates S6K Ser235/236 and 4E-BP1 Thr37/46. These inhibitors also cause down-regulation of mTORC2 substrate AKT Ser473. These reactions result in reduction of cell growth and migration. Notably, these inhibitors of mTOR also alter self-renewal and growth of CSC of GBM. The aim of this review is to reiterate the use of mTOR inhibitors in the treatment of GBM and its stem cells associated with progression and recurrence of the disease. In addition, understanding the peritumor area of GBM is a crucial means to control the recurrence of the disease.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"100 ","pages":"Article 101143"},"PeriodicalIF":2.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736285","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":"Ecnomotopic expression of olfactory receptors is affected by human apolipoproteins A-IMilano and A-II: evidence from liver microarray analyses","authors":"Amedeo Amedei ,&nbsp;Cinzia Parolini","doi":"10.1016/j.jbior.2026.101158","DOIUrl":"10.1016/j.jbior.2026.101158","url":null,"abstract":"<div><div>Olfactory receptors (ORs) are seven transmembrane domains G protein-coupled receptors (GPCRs) located in the olfactory sensory neurons (OSNs) of the nasal olfactory epithelium. Although OR expression was initially hypothesized to be restricted to the OSNs, an ecnomotopic expression has been identified and associated with the modulation of different physiological functions, such as glucose and lipid metabolism, hypoxia sensing, wound healing and sperm chemiotaxis. However, the role of most ORs in non-olfactory tissues is still a matter of debate, as well as their specific ligands and mechanisms of action. High-density lipoproteins (HDL) are heterogenous, and multifunctional nanoparticles constituted primarily of proteins and lipids. Their main structural protein, namely, apolipoprotein A-I (A-I) has been recognized as the major determinant of the biological activities of HDL. Recently, our group, by using unique mouse models and microarray methodology, has demonstrated that human A-II (hA-II) and A-I_Milano (A-I_M), a molecular variant of A-I, strongly modulate the hepatic expression of different genes involved in lipid metabolism and immune/inflammatory pathways. Therefore, aiming at investigating the impact of these apolipoproteins on the hepatic expression of mouse ORs (Olfrs), we have performed a new bioinformatic analysis of the differentially expressed genes (DEGs) found in the liver of hA-II/A-I k-in versus hA-II/A-I_M k-in; A-I_M k-in versus hA-II/A-I_M k-in; A-I k-in versus A-I_M k-in; A-I k-in versus hA-II/A-I k-in mice. Our results suggest that the presence of A-I_M, either alone or in combination with hA-II, is critical for the efficient trafficking and functional expression of Olfrs at the cell surface. Moreover, co-expression of hA-II with A-I resulted in down-regulation of previously uncharacterized Olfrs genes an up-regulation of several known Olfrs, which are likely responsive to short-chain fatty acids and signal through the cAMP/CREB pathway.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"100 ","pages":"Article 101158"},"PeriodicalIF":2.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130834","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":"Adrenergic receptor activation shapes circadian clock gene oscillations in HL-1 cardiomyocyte cell line","authors":"Elena Crecca ,&nbsp;Martina Pinna ,&nbsp;Maria Rita Assenza ,&nbsp;Andrea M. Isidori ,&nbsp;Federica Barbagallo","doi":"10.1016/j.jbior.2026.101159","DOIUrl":"10.1016/j.jbior.2026.101159","url":null,"abstract":"<div><div>Circadian rhythms are physiological, biochemical and behavioural processes with a 24-h period molecularly regulated by clock genes. Cardiovascular physiology is subject to circadian variations in heart rate, blood pressure and contractility to optimize its function according to the rest-activity phases. Adrenergic receptors (ARs), activated by endogenous catecholamine hormones, are crucial in the regulation of cardiac functions; however, controllable <em>in vitro</em> models to study the intrinsic cardiomyocyte circadian clock with minimal systemic timing cues remain limited. Here, we use HL-1 cardiomyocyte cell line (HL-1 cells), in which serum shock induces synchronized oscillations of core clock gene transcripts compared with unsynchronized cultures. Different ARs activators onto HL-1 cells were applied under non-synchronized or synchronized conditions and circadian oscillation of representative clock genes was determined. We show that alpha- and beta-AR activation differentially modulates clock gene mesor, amplitude and phase. These findings support HL-1 cells as a convenient <em>in vitro</em> platform to investigate interactions between adrenergic signaling and cardiomyocyte clock gene oscillations.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"100 ","pages":"Article 101159"},"PeriodicalIF":2.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130820","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":"An integrative multi-cohort transcriptomic study reveals cell cycle– and adhesion-related hub genes as diagnostic biomarkers for pulmonary arterial hypertension","authors":"Jiajia Zou ,&nbsp;Guojiao Rao ,&nbsp;Xiaomin Hou ,&nbsp;Zhifa Zheng ,&nbsp;Mengjie Xu ,&nbsp;Xian Li ,&nbsp;Yan Gao ,&nbsp;Yiwei Shi ,&nbsp;Xiaojiang Qin","doi":"10.1016/j.jbior.2026.101145","DOIUrl":"10.1016/j.jbior.2026.101145","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a progressive and fatal vascular disorder for which reliable and non-invasive diagnostic biomarkers remain limited. This study aims to screen and verify the hub genes related to PAH by integrating bioinformatics and experimental verification. We analyzed four GEO datasets (GSE117261, GSE24988, GSE53408, GSE113439) to identify differentially expressed genes and co-expressed modules. Functional enrichment analysis revealed the pathways related to vascular smooth muscle contraction and organ development. Protein-protein interaction network analysis screened out 4 hub genes. These genes showed different expression dysfunctions in the training set, an independent validation set and a Single-cell sequencing dataset (GSE33463, GSE228644), and demonstrated good diagnostic value through ROC curve analysis. Crucially, in the nicotine-induced PAH mouse model, RT-qPCR experiments confirmed the significant upregulation of these 4 genes. Our research results have established CDK1, TPX2, IGF1 and VCAM1 as robust polygenic markers related to PAH, providing potential evidence for clarifying their molecular mechanisms and developing non-invasive diagnostic tools.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"100 ","pages":"Article 101145"},"PeriodicalIF":2.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023238","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":"Afatinib alters DNA methylation and Paneth-like differentiation markers in Caco-2 cells","authors":"Ippei Uemura,&nbsp;Natsuko Takahashi-Suzuki,&nbsp;Takashi Satoh","doi":"10.1016/j.jbior.2026.101146","DOIUrl":"10.1016/j.jbior.2026.101146","url":null,"abstract":"<div><div>Afatinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used to treat EGFR-mutant non–small cell lung cancer. It frequently causes gastrointestinal toxicity that perturbs intestinal homeostasis, and its impact on Paneth-like lineage differentiation along the crypt–villus axis remains unclear. Using a controlled differentiation-stage framework in Caco-2 cells, we examined how afatinib affects Paneth-like differentiation markers. We incubated undifferentiated Caco-2 cells with afatinib (10–5000 nM) for 24 h during early culture and evaluated downstream DNA methylation and differentiation-associated readouts up to day 14. We quantified proteins (western blotting), mRNAs (RT–qPCR), and promoter methylation (methylation-sensitive restriction enzyme–qPCR). Afatinib increased DNA methylation at the SRY-box transcription factor 9 (SOX9) and defensin alpha 5 (DEFA5) promoters and reduced their protein expression. Immunostaining indicated reduced expression of Paneth-like differentiation markers in Caco-2 cells. In contrast, mRNA levels of the SOX9 regulators odd-skipped related transcription factor 1 (OSR1) and receptor-interacting protein 140 (RIP140) were upregulated without changes in promoter methylation at the analyzed sites, indicating DNA methylation–independent regulation at these promoters. These findings suggest that DNMT1/3B-skewed methylation at the SOX9/DEFA5 promoters may be counteracted by ten-eleven translocation–mediated counter-demethylation. Collectively, our data indicate that afatinib modulates Paneth-like differentiation markers via DNA methylation–dependent repression of SOX9/DEFA5 and DNA methylation–independent induction of OSR1/RIP140 in Caco-2 cells, which may be relevant to crypt-associated epithelial function and gastrointestinal safety.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"100 ","pages":"Article 101146"},"PeriodicalIF":2.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074230","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":"From stress to homeostasis: Mass spectrometry–based insights into the unfolded protein response (UPR) and proteostasis","authors":"Lea A. Barny ,&nbsp;Lars Plate","doi":"10.1016/j.jbior.2025.101127","DOIUrl":"10.1016/j.jbior.2025.101127","url":null,"abstract":"<div><div>The unfolded protein response (UPR) is a central regulator of proteostasis, coordinating cellular adaptation to endoplasmic reticulum (ER) stress. It is comprised of three signaling branches: ATF6 (activating transcription factor 6), IRE1 (inositol-requiring enzyme 1), and PERK (protein kinase RNA-like ER kinase), which mediate transcriptional and translational reprogramming of the proteostasis network. These pathways display both functional redundancy and branch-specific activities. Dysregulated UPR signaling contributes to diverse pathologies: in cancer, UPR activation supports uncontrolled proliferation and treatment resistance, whereas in aging, proteostasis decline and diminished UPR responsiveness are hallmarks. Traditional approaches, including transcriptomics and western blotting, have been widely used to monitor UPR activity, but they offer limited insight into its regulation at the protein level. In contrast, liquid chromatography–tandem mass spectrometry (LC-MS/MS) based proteomics allows comprehensive, branch-specific profiling of UPR signaling. Recent advances, including data-independent acquisition (DIA) MS and automated sample preparation, have further improved sensitivity, reproducibility, and detection of low-abundance UPR target proteins. Proteomics thus provides a systematic and scalable framework to interrogate UPR regulation across cell types and disease models. When integrated with complementary datasets, protein-level measurements can uncover context-dependent molecular signatures of UPR activity, offering insights into disease mechanisms and guiding the rational design of targeted pharmacological interventions. Future work integrating high-resolution LC-MS/MS proteomics with tissue and single-cell analyses will further clarify the role of the UPR in health and disease.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101127"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562361","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":"Pharmacological SHIP2 blockade enhances sensitivity to standard and targeted cancer therapies","authors":"Nadia Gillet,&nbsp;Cyril Bodart,&nbsp;Benjamin Beck","doi":"10.1016/j.jbior.2025.101130","DOIUrl":"10.1016/j.jbior.2025.101130","url":null,"abstract":"<div><div>Esophageal squamous cell carcinoma (eSCC) is an aggressive malignancy with poor prognosis and limited therapeutic options. The phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently activated in eSCC, but clinical use of PI3K or AKT inhibitors is restricted by toxicity and compensatory signaling. SHIP2, an inositol 5-phosphatase encoded by <em>INPPL1</em>, modulates this pathway by converting PI(3,4,5)P₃ to PI(3,4)P₂, thereby regulating AKT activation. We previously identified <em>INPPL1</em> amplification as recurrent in eSCC and demonstrated that SHIP2 inhibition suppresses tumor growth and synergizes with PLK1 inhibition.</div><div>Here, we extend these findings and show that SHIP2–PLK1 synergy is not confined to eSCC but is also observed in multiple colorectal cancer cell lines, revealing a conserved vulnerability across tumor types. Mechanistic analyses demonstrate that this synergy depends on PI3K/AKT signaling, with SHIP2 inhibition producing stronger effects than direct PI3K blockade, suggesting additional regulatory functions beyond canonical PI3K control. Furthermore, SHIP2 inhibition enhances the cytotoxic activity of standard chemotherapies, including 5-fluorouracil and paclitaxel, in eSCC cells. Importantly, these effects occur at sub-cytotoxic drug concentrations, indicating potential therapeutic benefit with reduced toxicity.</div><div>Collectively, our results identify SHIP2 as a central regulator of the PI3K/AKT axis in eSCC and colorectal cancer and highlight its value as a combinatorial target. SHIP2 inhibition represents a promising strategy to potentiate existing chemotherapies and targeted agents, opening new avenues for the treatment of refractory gastrointestinal cancers.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101130"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457149","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":"The interplay between phosphoinositides and ESCRT proteins","authors":"Chiara Giannini,&nbsp;Luca Ponzone,&nbsp;Nicola Barroero,&nbsp;Emilio Hirsch","doi":"10.1016/j.jbior.2025.101126","DOIUrl":"10.1016/j.jbior.2025.101126","url":null,"abstract":"<div><div>The Endosomal Sorting Complex Required for Transport (ESCRT) machinery orchestrates a wide range of membrane remodeling and repair events, spanning multivesicular body biogenesis, viral budding, nuclear envelope surveillance, cytokinesis, lysosomal repair and plasma membrane resealing. These processes depend on the hierarchical assembly of ESCRT complexes to detect and remodel membranes, ultimately driving membrane scission with topological precision. A growing body of evidence indicates that phosphoinositides (PtdIns), a versatile class of phosphorylated lipids, are central determinants of ESCRT function by defining membrane identity, recruiting specific ESCRT modules and integrating lipid signaling into biological processes. This review synthesizes current understanding of how distinct phosphoinositide pools govern ESCRT recruitment and activity, with a focus on the molecular components and their interaction.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101126"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385658","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":"CD19 structure, expression, and signaling: From basic mechanisms to therapeutic targeting","authors":"Stéphane Schurmans ,&nbsp;Bastien Moës","doi":"10.1016/j.jbior.2025.101116","DOIUrl":"10.1016/j.jbior.2025.101116","url":null,"abstract":"<div><div>CD19 is a central regulator of B-cell biology, acting both as a lineage marker and a critical modulator of signaling thresholds that govern development, activation, and tolerance. Structurally, CD19 is a heavily glycosylated transmembrane protein whose cytoplasmic domain harbors multiple tyrosine motifs serving as docking sites for key signaling molecules, including PI3K. Its expression is tightly regulated by transcriptional, post-transcriptional, and post-translational mechanisms, as well as by interactions with CD21 and CD81 in surface complexes. Genetic studies in mice and humans demonstrate that CD19 acts as a molecular rheostat, with both deficiency and overexpression leading to profound immunological dysfunctions ranging from hypogammaglobulinemia to autoimmunity. Importantly, recent work has revealed an additional level of CD19 signaling regulation mediated by conformational control of the CD19 cytoplasmic domain. A basic CD19 cytoplasmic juxtamembrane region engages in ionic interactions with PtdIns(4,5)P2, thereby influencing CD19 activation state. Loss of the 5-phosphatase INPP5K increases PtdIns(4,5)P2 levels, leading to constitutive CD19 signaling, impaired B-cell development and hypogammaglobulinemia. This discovery underscores the role of lipid–protein interactions in restraining inappropriate CD19 activation. Clinically, CD19 has emerged as a validated therapeutic target, with CAR T cells, bispecific antibodies, and monoclonal antibodies achieving remarkable efficacy in B-cell malignancies and autoimmune disorders. Understanding the fine regulation of CD19 expression, structure, and signaling remains essential to optimize therapeutic strategies.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101116"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205350","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":"Sixty-fifth international symposium on biological regulation and enzyme activity in normal and neoplastic tissues","authors":"","doi":"10.1016/j.jbior.2026.101148","DOIUrl":"10.1016/j.jbior.2026.101148","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101148"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146161765","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}