J. Cell. Physiol. [JOURNAL]
Sun
200 papers
Correction to "Rce1 Suppresses Invasion and Metastasis of Hepatocellular Carcinoma via Epithelial-Mesenchymal Transition Induced by the TGF-Beta1/H-Ras Signaling Pathway".
J Cell Physiol · 2026 Jan · PMID 41566797 · Publisher ↗
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Cellular Senescence in Heart Failure: A Review.
Krauz K, Czarzasta K, Bugajewski M … +3 more , Momot K, Wojciechowska M, Cudnoch-Jędrzejewska A
J Cell Physiol · 2026 Jan · PMID 41562381 · Publisher ↗
Heart failure (HF) significantly limits survival and decreases quality of life. The global incidence of HF is rising. The pathogenesis of HF is not yet fully understood, which results in the present treatment options sti...
Heart failure (HF) significantly limits survival and decreases quality of life. The global incidence of HF is rising. The pathogenesis of HF is not yet fully understood, which results in the present treatment options still being imperfect. Therefore, there is a need to deepen the knowledge about HF pathogenesis and identify potential therapeutic targets. Aging increases the risk of developing HF. Recently, cellular senescence, a stable state of cell cycle arrest induced by various stressors or genomic damage, has been recognized to be involved in HF pathogenesis. Senescent cells may be involved in the development of age-related diseases. However, cellular senescence may occur in correlation with aging or be age-independent. Its impact is complex, especially since the heart is composed of different cell types, each of which may undergo senescence in diverse ways. Elimination of senescent cells also emerges as a potential treatment option. This article extensively reviews relations between cellular senescence and HF. Moreover, it describes the role of plasma proteins related to cellular senescence as potential biomarkers and prognostic factors in HF. This review also summarizes data concerning therapeutics targeting senescence in the HF context and implicates future research perspectives.
Blocking Sphingosine 1-phosphate Metabolism With Fingolimod Prevents the Progression of Vascular Smooth Muscle Cells Calcification in Chronic Kidney Disease.
Skafi N, Pelletier S, Soulage CO … +14 more , Nahle S, Da Cruz BO, Othmani R, Briolay A, Reibel S, Vitale N, Hamade E, Badran B, Magne D, Buchet R, Stockler-Pinto MB, Fouque D, Mebarek S, Brizuela L
J Cell Physiol · 2026 Jan · PMID 41560531 · Full text
Patients with chronic kidney disease, and particularly those under hemodialysis, are prone to develop cardiovascular complications, mostly due to the exacerbation of vascular calcification. Vascular calcification relies...
Patients with chronic kidney disease, and particularly those under hemodialysis, are prone to develop cardiovascular complications, mostly due to the exacerbation of vascular calcification. Vascular calcification relies on the transdifferentiation of vascular smooth muscle cells into calcifying cells. Sphingosine 1-phosphate is a pleiotropic sphingolipid and an important regulator of osteogenesis and the cardiovascular system. Therefore, we explored the role of sphingosine 1-phosphate metabolism in chronic kidney disease-derived vascular calcification. Vascular calcification progression in chronic kidney disease and sphingosine 1-phosphate signaling were examined in calcified vascular smooth muscle cells, in aortic explants, in rats with adenine-induced chronic kidney disease, as well as in serum from hemodialysis patients. Sphingosine kinase 2 activity and sphingosine 1-phosphate secretion, under the control of phospholipase D1, were exacerbated in calcified vascular smooth muscle cells. Furthermore, phospholipase D1 knockout mice display significantly less circulating sphingosine 1-phosphate, supporting intertwined signalization cascades. Overall, sphingosine kinase expression and activity were upregulated in calcified aortic explants and in calcified aortas from rats. Sphingosine 1-phosphate was increased in the serum of rats with mild vascular calcification. The Food and Drug Administration-approved immunosuppressant drug fingolimod, a general modulator of S1P metabolism, strongly inhibited calcification in vascular smooth muscle cells and aortic explants. Additionally, fingolimod significantly reduced inflammation, attenuated metabolic syndrome and moderately inhibited aortic calcification in rats. Finally, we demonstrated for the first time that serum sphingosine 1-phosphate was significantly increased in hemodialysis patients with mild abdominal aortic calcification. Our findings open an unexplored therapeutic option, which is targeting sphingosine 1-phosphate metabolism, eventually with fingolimod, for the prevention and treatment of vascular calcification in chronic kidney disease patients.
LncRNA ZFAS1 Promotes Alveolar Bone Resorption by Enhancing Osteoclastogenesis in Periodontitis.
Aol L, Zhou X, Cao Z … +7 more , Yao D, Zhang W, Yang Y, Bao Z, Su L, Hao H, Xue W
J Cell Physiol · 2026 Jan · PMID 41549697 · Publisher ↗
Periodontitis is a predominant persistent inflammatory disease marked by consistent destruction of tooth-supporting tissues including periodontal ligament and alveolar bone. Although some cytokines have been identified a...
Periodontitis is a predominant persistent inflammatory disease marked by consistent destruction of tooth-supporting tissues including periodontal ligament and alveolar bone. Although some cytokines have been identified as key mediators, the upstream regulatory molecules that drives this pathological bone loss remains elusive. This study explores the mechanistic role of lncRNA ZFAS1 in the dysregulated bone remodeling of periodontitis microenvironment. We utilized single-cell and bulk RNA sequencing to profile cellular and molecular landscape in healthy and diseased periodontal tissues. GSEA analysis of bulk transcriptomes confirmed a significant activation of osteoclast-related pathways in disease (NES = 1.7, FDR q = 0.025). Findings were validated through qPCR, histology, and immunohistochemistry. The gain- and loss-of-function models in RAW264.7 and MC3T3-E1 cells to characterize the role of lncRNA ZFAS1 in vitro. The scRNA-seq analysis unveiled a marked 11-fold increase in osteoclast-osteoblast ratio in periodontitis, which was further confirmed histologically. This shift was accompanied by a specific inflammatory profile, and a marked upregulation of lncRNA ZFAS1 in diseased tissues. Notably, ZFAS1 expression showed a robust positive correlation with early osteoclast marker genes NFATC1 (R = 0.2056, p = 0.015) and TRAP1 (R = 0.784, p < 0.0001) but not the late-stage effector CTSK (R = 0.0011, p = 0.792). We confirmed that lncRNA ZFAS1 expression was precisely induced by the synergetic effect of differentiation (RANKL) and inflammatory (LPS) signals. Functionally, lncRNA ZFAS1 overexpression in RAW264.7 potentiated osteoclastogenesis, enhanced TRAP-positive osteoclasts and increased resorptive gene expression (NFATC1, Dcstamp, ACP5, CTSK, V-ATPase d2), while its knockdown exhibited the opposite effect. In contrast, lncRNA ZFAS1 knockdown in MC3T3-E1 boosted differentiation and matrix mineralization, augmented osteoblast-related gene expression (Runx2, ALP, OCN). In summary, lncRNA ZFAS1 is a critical driver of inflammatory bone loss, functioning as a dual-path regulator that promotes osteoclastogenesis and inhibits osteoblastogenesis. Its physiological role as a negative osteogenic regulator is evidenced by its downregulation during normal differentiation, highlighting its therapeutic potential for periodontitis and related conditions.
Modulating O-GlcNAcylation Alters Salivary Acinar Cell Differentiation.
Pokharel E, Kim TY, Aryal YP … +13 more , Rana B, Kim JY, Jang JH, Lee JH, An SY, Ha JH, An CH, Cho SW, Kim DY, Sohn WJ, Cho SJ, Jung JK, Kim JY
J Cell Physiol · 2026 Jan · PMID 41549625 · Publisher ↗
O-GlcNAcylation is a post-translational modification involved in various cellular processes, including cell cycle progression, signaling, transcription, and stress response. Mouse salivary gland morphogenesis shows speci...
O-GlcNAcylation is a post-translational modification involved in various cellular processes, including cell cycle progression, signaling, transcription, and stress response. Mouse salivary gland morphogenesis shows specific localization patterns of O-GlcNAc transferase (OGT) and O-GlcNAc in developing acinar cells, suggesting a potential involvement of O-GlcNAcylation in acinar cell differentiation-related signaling molecules. To define its underlying mechanisms, this study used an OGT inhibitor, OSMI-1, and small interfering RNA (siRNA) targeting OGT, during in vitro cultivation of submandibular glands and assessed morphological and molecular alterations using histology, immunohistochemistry, Western blot, and RT-qPCR. As expected, OGT inhibition impaired terminal bud morphogenesis and altered cellular physiology. OSMI-1 treatment disrupted acinar cell differentiation, reflected by changes in expression patterns of signaling molecules crucial to acinar cell differentiation, including Sox9, Sox10, E-cadherin, and Mist1. Altered expression patterns of cytokeratins, including CK14 and CK18, confirmed altered ductal morphology. Therefore, our findings highlight the essential role of OGT-mediated O-GlcNAcylation in salivary gland morphogenesis with post-translational regulation of key signaling molecules governing functional differentiation of acinar cells.
G Protein-Coupled Receptor Signaling in Atherosclerosis: Mechanistic Insights and Therapeutic Targeting.
Feng Y, He L
J Cell Physiol · 2026 Jan · PMID 41540839 · Publisher ↗
Atherosclerosis (AS), the primary pathological basis of cardiovascular diseases, is driven by lipid deposition, chronic inflammation, and vascular wall fibrosis. Nevertheless, persistent inflammatory environments and pla...
Atherosclerosis (AS), the primary pathological basis of cardiovascular diseases, is driven by lipid deposition, chronic inflammation, and vascular wall fibrosis. Nevertheless, persistent inflammatory environments and plaque instability remain significant clinical challenges. G protein-coupled receptors (GPCRs), constituting the largest family of membrane receptors in humans, play a central role in AS progression by modulating macrophage polarization, vascular smooth muscle cells (VSMCs) proliferation and migration, and oxidized low-density lipoprotein (ox-LDL) metabolism. Macrophage polarization dictates the inflammatory microenvironment within plaques; GPCRs modulate macrophage phenotypes through downstream signaling pathways, thereby exacerbating or mitigating inflammation. Furthermore, GPCRs regulate VSMCs phenotypic switching, critically influencing the stability of the plaque fibrous cap. Additionally, the interplay between GPCRs and ox-LDL exacerbates endothelial dysfunction and amplifies inflammatory signaling. This review comprehensively summarizes the roles of GPCR family members in AS pathogenesis and explores targeting these molecules as a promising therapeutic strategy for AS, thus highlighting their potential for multi-targeted intervention.
Glycation-Driven Impairment of Cytoskeletal Homeostasis and Viability Disables Glyoxalase-Low Mesothelia From Resisting Cancer Colonization.
Mishra S, Vidhipriya K, Gopikrishnan A … +7 more , Sarkar P, Mishra S, Prasanna CVS, Hari PS, Korlimarla A, Sen P, Bhat R
J Cell Physiol · 2026 Jan · PMID 41536167 · Publisher ↗
Chronic metabolic disorders and aging cause accumulation of dicarbonyls that glycate and render biomolecules dysfunctional. Although systemic metabolic dysregulation is associated with faster cancer progression, their me...
Chronic metabolic disorders and aging cause accumulation of dicarbonyls that glycate and render biomolecules dysfunctional. Although systemic metabolic dysregulation is associated with faster cancer progression, their mechanistic determinants remain elusive. We move between time-lapse and end-point experiments and tissue-scale simulations to build a systems model of ovarian cancer colonization and show that confluent healthy serosal mesothelia can stall spheroidal adhesion and spread. However, mesothelial clearance by spheroids continues under increasing concentrations of the dicarbonyl methylglyoxal (MG). High MG levels glycate mesothelia and destabilize their adhesion and motility through mislocalization of F-actin, ezrin, and ZO-1. This explains preferential spheroidal spreading amidst sub-confluent mesothelia. Confluence is dependent on mesothelial viability, which is also decreased by MG. Intriguingly, cancer cells escape glycation and its cytopathological effects by expressing relatively higher levels of glyoxalase 1 (GLO1); pharmacological GLO1 inhibition renders cancer cells vulnerable to MG. Thus, inhibition of stromal glycation holds promise for incorporation into personalized oncotherapy.
Mapping of PTP1B, TCPTP, SHP2, and Putative Substrates Reveals Novel Networks in Glomerular Podocytes.
LeBleu G, Hsu MF, Ito Y … +4 more , Liang SY, Ma KL, Meng TC, Haj FG
J Cell Physiol · 2026 Jan · PMID 41520218 · Full text
Preservation of the insulin-sensitive glomerular podocyte is imperative for normal kidney function. The protein tyrosine phosphatases (PTPs), protein tyrosine phosphatase 1B (PTP1B), T-cell protein tyrosine phosphatase (...
Preservation of the insulin-sensitive glomerular podocyte is imperative for normal kidney function. The protein tyrosine phosphatases (PTPs), protein tyrosine phosphatase 1B (PTP1B), T-cell protein tyrosine phosphatase (TCPTP), and Src homology phosphatase 2 (SHP2) are established regulators of insulin signaling in vivo and implicated in renal function. However, knowledge gaps exist regarding the roles of these enzymes and their integrated modulation of signaling in podocytes. Accordingly, uncovering the mediators of PTP function is critical to elucidate their modes of action and help develop mechanism-based interventions for podocytopathies. We generated E11 podocyte cell lines expressing the substrate-trapping mutants of these PTPs and then used immunoprecipitation and mass spectrometry to identify their putative substrates. Bioinformatic analyses were used to decipher the pathways affected by these enzymes in the insulin-stimulated podocytes. We identified known and novel targets, some common across the three PTPs, others shared between two PTPs, and others unique to a single phosphatase. Additionally, cytoskeleton and cellular junction-associated pathways were significantly enriched among the phosphatases and their putative substrates. Moreover, we uncovered a signaling node that is likely key to the action of these PTPs, comprising the protein tyrosine kinase Src, cortactin, and lamin A/C, interconnected via vimentin. To further validate this, we demonstrated that vimentin is a substrate of SHP2 in podocytes. The current findings suggest that PTP1B, TCPTP, and SHP2 act coordinately and engage numerous targets to orchestrate an integrated response to insulin in podocytes. Notably, these enzymes are components of a crucial signaling node that modulates cytoskeletal and junctional proteins, thereby influencing podocyte function.
MKRN1 Regulates RANKL-Induced Differentiation Via Akt and AMPK Pathways.
Kim I, Kim JH, Kim K … +3 more , Seong S, Koh JT, Kim N
J Cell Physiol · 2025 Dec · PMID 41457534 · Publisher ↗
Osteoclasts are bone-resorbing cells, and understanding the pathways involved in osteoclast differentiation and activation is essential for developing treatments for bone diseases such as osteoporosis. Since osteoclast d...
Osteoclasts are bone-resorbing cells, and understanding the pathways involved in osteoclast differentiation and activation is essential for developing treatments for bone diseases such as osteoporosis. Since osteoclast differentiation is regulated by signaling pathways such as Akt, MAPK, and NF-κB, it is important to identify their regulators. Makorin ring finger protein 1 (MKRN1), a conserved member of the ring finger protein family, is closely linked to the regulation of Akt and AMP-activated protein kinase (AMPK), important signaling pathways in osteoclastogenesis. However, its specific role in osteoclasts has not been revealed. Mkrn1 was overexpressed using a retrovirus or silenced using small interfering RNA (siRNA) in bone marrow-derived macrophages (BMMs). Subsequently, osteoclast differentiation was induced using receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) and assessed via tartrate-resistant acid phosphatase (TRAP) staining. Additionally, the role of Mkrn1 in osteoclastogenesis was confirmed using Mkrn1-deficient cells. Western blot analysis was employed to evaluate Mkrn1-associated Akt and AMPK activation. The bone phenotype of Mkrn1-deficient mice was investigated through bone analysis. This study revealed that Mkrn1 significantly influences RANKL-induced osteoclastogenesis. Overexpression of Mkrn1 in BMMs enhanced osteoclast differentiation by promoting Akt phosphorylation and inhibiting AMPK phosphorylation upon RANKL stimulation. Conversely, siRNA-mediated downregulation of MKRN1 reduced Akt phosphorylation and increased AMPK phosphorylation, impairing osteoclastogenesis. Furthermore, in vivo studies using Mkrn1 knockout mice revealed a phenotype with increased bone volume. Our findings establish Mkrn1 as a positive regulator of osteoclast differentiation, highlighting its potential as a therapeutic target for bone diseases characterized by excessive bone resorption.
TRPV4 Orchestrates Distinct Calcium and Cell Growth Responses in Non-Tumorigenic and Clear Cell Renal Carcinoma-Derived Cells.
Sterba JJ, Beltramone N, Celi AB … +6 more , Casal JJ, Fanelli MA, Capurro C, Rivarola V, Di Giusto G, Ford P
J Cell Physiol · 2025 Dec · PMID 41457365 · Publisher ↗
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and often exhibits resistance to conventional therapies. Calcium signaling plays a critical role in cancer progression, and the non-sele...
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and often exhibits resistance to conventional therapies. Calcium signaling plays a critical role in cancer progression, and the non-selective cation channel TRPV4 (Transient Receptor Potential Vanilloid 4) has been implicated in tumorigenesis across multiple cancer types. However, its specific role in ccRCC remains poorly understood. In this study, we investigated TRPV4 subcellular localization and functional activity in ccRCC-derived cell lines (786-O and Caki-1) compared to non-tumorigenic renal epithelial cells (HK-2). Immunofluorescence analyses revealed stronger TRPV4 colocalization with Hoechst-stained nuclei in carcinoma-derived renal cells compared with non-tumorigenic controls. TRPV4 activation elicited a faster and more robust intracellular calcium increase in ccRCC cells. Quantification of cell number after 96 h revealed that TRPV4 inhibition reduced cell growth, whereas activation increased it, particularly in metastatic Caki-1 cells. In 3D cultures, Caki-1 cells formed spheroids whose size, morphology, and viability were significantly modulated by TRPV4 activity. TRPV4 inhibition produced smaller, more compact spheroids with reduced viability, while activation promoted the formation of larger structures. Notably, TRPV4 inhibition induced its exclusion from the nucleus and redistribution to the cytoplasm, where it colocalized with aquaporin-1 (AQP1), a water channel associated with favorable prognosis in ccRCC. These findings suggest that TRPV4 contributes to ccRCC progression by modulating calcium dynamics, subcellular organization, and tumor cell behavior. Taken together, our findings position TRPV4 as a functionally relevant ion channel in ccRCC, supporting its further exploration as a therapeutic target in renal cancer.
Ghrelin Increases Glutamate Release at the Perforant Path-Dentate Gyrus Granule Cell Synapses by Cross-Activating Dopamine D Receptors.
Oraegbuna CS, Hasler WA, Chen X … +1 more , Lei S
J Cell Physiol · 2025 Dec · PMID 41457342 · Full text
Ghrelin is a multifunctional peptide hormone with receptors present in various brain tissues including the hippocampus and has been associated with neuroprotection, neuromodulation, and memory processing. Ghrelin is an e...
Ghrelin is a multifunctional peptide hormone with receptors present in various brain tissues including the hippocampus and has been associated with neuroprotection, neuromodulation, and memory processing. Ghrelin is an endogenous ligand for growth hormone secretagogue receptors (GHSRs). Here we studied the roles and mechanisms of ghrelin in glutamatergic transmission at the perforant path (PP)-granule cell (GC) synapses in the dentate gyrus by recording AMPA EPSCs in hippocampal slices cut from both male and female C57BL/6 J mice. Our results showed that ghrelin concentration-dependently elicited a persistent enhancement of AMPA EPSCs. The ghrelin-induced augmentation of glutamatergic transmission was mediated by increasing presynaptic glutamate release because ghrelin decreased the coefficient of variation (C.V.) and paired-pulse ratio of AMPA EPSCs, increased NMDA EPSCs as well and enhanced the frequency with no effect on the amplitude of mEPSCs. Ghrelin enlarged the size of readily releasable pool and increased release probability. Ghrelin-elicited increases in glutamate release did not require the functions of Gαq-phospholipase C pathway and Gαi, but was dependent on Gαs and cAMP/EPAC/PI3K pathway. As GHSRs have been shown to activate cAMP signals via heterodimerization with dopamine D receptors, we probed the roles of D receptors in ghrelin-mediated facilitation of glutamate release. Our results indicated that ghrelin enhanced glutamate release via interaction with D receptors. Our results may provide a novel cellular and molecular mechanism whereby ghrelin enhances glutamatergic transmission.
Altered Metabolism in Idiopathic Pulmonary Fibrosis.
Callaghan NI, Davenport Huyer L
J Cell Physiol · 2025 Dec · PMID 41424408 · Full text
Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease that ultimately terminates in death or lung transplantation. It is characterized by a restrictive pattern with impaired diffusion capacity, and typically p...
Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease that ultimately terminates in death or lung transplantation. It is characterized by a restrictive pattern with impaired diffusion capacity, and typically presents with repeated acute exacerbations that result in permanent and progressive loss of respiratory function. IPF bears complicated and likely multifactorial etiology manifesting in the dysfunction of multiple cell types, a 2-year mortality over 40%, and available treatments can only slow disease progression. Distinct metabolic disturbances in IPF underscore the mechanisms of deranged cell function, including regional oxidative stress, fibrotic extracellular matrix production, and epithelial dysfunction including impaired pulmonary surfactant production. Although the precise profile of metabolic derangements in IPF remain contentious across multiple studies and models of disease, metabolism represents a critically untapped pathway for therapeutic intervention. In this review, the mechanisms underlying IPF development and progression are isolated and linked to cell-specific alterations in metabolic function. We furthermore compare various in vivo and in vitro models of IPF with focus on metabolic analyses, and critically compare them to patient-derived data. Finally, new metabolically-associated biomarkers of IPF progression are discussed, and recommendations for further IPF modeling and metabolic targeting of IPF-related processes are provided. This review serves to provide a consensus survey of the current metabolomic IPF landscape, as well as a critical discussion of next steps for in vitro modeling to develop disease-modifying therapeutics targeting dysregulated metabolism in IPF.
Exploring the Cell Biological and Functional Effects of the First Disease Associated KCC1 Genetic Variant.
Bloothooft M, Huang J, Hamze M … +7 more , Houtman MJC, de Boer TP, van Hasselt PM, Ecker GF, Porcher C, Medina I, van der Heyden MAG
J Cell Physiol · 2025 Dec · PMID 41414942 · Full text
The potassium chloride cotransporter 1 (KCC1) is ubiquitously expressed and essential for regulating cellular fluid balance. We identified a patient carrying a genetic variant (E1065K) in the KCC1 coding gene SLC12A4. Th...
The potassium chloride cotransporter 1 (KCC1) is ubiquitously expressed and essential for regulating cellular fluid balance. We identified a patient carrying a genetic variant (E1065K) in the KCC1 coding gene SLC12A4. This study explored the impact of the variant in ectopic cell systems and enhanced the understanding of cell biological properties of the KCC1 protein. KCC1 WT and E1065K DNA expression constructs were transfected in HEK293T, EPI7 or COS7 cells. KCC1 protein expression levels, glycosylation, intracellular trafficking, half-life and protein localization were determined with western blot and immunofluorescence microscopy. Molecular docking investigated interactions within the cotransporter. Cotransporter activity was tested with NH flux measurements. The variant reduces interactions within the cotransporter and functional activation decreases in hypotonic conditions. Other cell biology characteristics with respect to protein expression level, half-life or subcellular localization did not show any statistical difference between KCC1 WT and E1065K. However, this data provided new characteristics of KCC1 protein. Altogether, these findings are the first description of a potential pathogenic human variant in the KCC1 protein.
Corrigendum to: "Moderate Mechanical Stress Suppresses the IL-1β-Induced Chondrocyte Apoptosis by Regulating Mitochondrial Dynamics".
J Cell Physiol · 2025 Dec · PMID 41414812 · Publisher ↗
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MiR-101-3p Promotes Cardiac Senescence and Inflammation via Targeting Tbx20 and Bmp2 to Perturb Cardiac Homeostasis.
Das S, Das M, Chakraborty S … +1 more , Sengupta A
J Cell Physiol · 2025 Dec · PMID 41413924 · Publisher ↗
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with limited cardiac regeneration hindering recovery in damaged hearts. We previously demonstrated that T-box transcription factor 20 (Tbx20) and b...
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with limited cardiac regeneration hindering recovery in damaged hearts. We previously demonstrated that T-box transcription factor 20 (Tbx20) and bone morphogenetic protein 2 (Bmp2) are crucial for cardiac homeostasis by promoting cardiomyocyte proliferation following endoplasmic reticulum (ER) stress. Here we showed that various stressors (ER stress, diabetes, type2 myocardial infarction, high-fat diet) over shorter and longer durations in vivo lead to distinct expression patterns of Tbx20 and Bmp2 in cardiomyocytes and fibroblasts. In vitro, stress induction resulted in similar expression patterns of Tbx20 and Bmp2, initially increasing in H9c2 cardiomyocytes before showing a sharp decline. In contrast, Bmp2 significantly increased in primary rat adult cardiac fibroblasts during increasing stress. MicroRNAs (miRNAs) are pleiotropic regulators of cardiac development and disease, and are promising therapeutic interventions for regulating cardiac regeneration. Upon delineating the cause of the differential regulation, in silico analysis revealed the presence of putative miR-101-3p binding site in the 3'UTR of tbx20 and Bmp2 inhibitor noggin (nog) gene, which was corroborated by dual-luciferase reporter assay. The expression of miR-101-3p was elevated upon prolonged stress across all the cardiac injury models. In vitro, increasing stress resulted in increased expression of miR-101-3p. MiR-101-3p agonist suppressed and antagonist elevated the expression of Tbx20 in H9c2 cardiomyocytes. Ectopic overexpression of miR-101-3p or siRNA-mediated knockdown of Tbx20 in H9c2 cardiomyocytes heightened the expression of senescence markers (p21, p16, γHAX). Furthermore, miR-101-3p targeted Nog under stress, indirectly raising Bmp2 and inflammatory response (TNF-α and IL6) in primary cardiac fibroblasts, thereby exacerbating cardiomyopathy. Inhibition of miR-101-3p reversed its inhibitory effect on Tbx20 and Nog. This study uncovers a novel regulatory mechanism where miR-101-3p acts as a repressor of cardiac genes to induce cardiac senescence and inflammation, positioning miR-101-3p as a therapeutic target for cardiomyopathy.
TTC7B Activates the AKT-JKAMP Signaling Axis to Promote Tumor Progression in Head and Neck Cancer.
Lin YH, Chou CY, Yu PL … +1 more , Yang YF
J Cell Physiol · 2025 Dec · PMID 41392613 · Publisher ↗
The tetratricopeptide repeat domain 7 (TTC7) family, comprising the paralogs TTC7A and TTC7B, encodes scaffold proteins that are critical for membrane signaling and cellular homeostasis. Although mutations in TTC7 family...
The tetratricopeptide repeat domain 7 (TTC7) family, comprising the paralogs TTC7A and TTC7B, encodes scaffold proteins that are critical for membrane signaling and cellular homeostasis. Although mutations in TTC7 family have been implicated in immune and developmental disorders, their roles in cancer, particularly head and neck cancer (HNC), remain largely unexplored. In this study, we systematically analyzed the expression, prognostic relevance, and biological functions of TTC7B in HNC using transcriptomic data, immunohistochemistry on tissue microarrays, in vitro functional assays, and integrative bioinformatic approaches. Compared with TTC7A, TTC7B was markedly upregulated in HNC and associated with poor survival. In vitro assays confirmed that TTC7B promotes HNC cell migration and invasion. Among the potential co-dependent molecules, JNK1-associated membrane protein (JKAMP) emerged as a significantly co-expressed transcript, with TTC7B/JKAMP patients consistently exhibiting the poorest survival rates. Mechanistically, TTC7B activated AKT to upregulate JKAMP, thereby enhancing malignant phenotypes. Pharmacological inhibition of AKT abolished TTC7B-induced phosphorylation of AKT and JKAMP expression, suppressing migration and invasion, whereas IGF-1-mediated AKT activation restored JKAMP expression and rescued TTC7B-knockdown phenotypes. Moreover, JKAMP silencing in TTC7B-overexpressing cells markedly reduced migration and invasion, indicating the oncogenic TTC7B-AKT-JKAMP signaling axis. In parallel, miR-183-5p suppressed TTC7B-AKT-JKAMP signaling, suggesting a potential regulatory mechanism. High TTC7B expression also attenuated the survival advantage conferred by tumor-infiltrating CD8⁺ T cells, suggesting that TTC7B may promote immunosuppressive tumor microenvironment. Collectively, our findings establish TTC7B as a novel oncogenic factor in HNC that promotes tumor progression through the TTC7B-AKT-JKAMP axis and immune modulation, highlighting its potential as a prognostic biomarker and therapeutic target for HNC.
Neuronatin in Metabolic Regulation: Molecular Interplay in Obesity and Type 2 Diabetes Pathogenesis.
Zhang T, Ju W, Han X … +1 more , Liu Y
J Cell Physiol · 2025 Dec · PMID 41358811 · Publisher ↗
Growing evidence has established the imprinted gene neuronatin (NNAT) as a key regulator in human metabolic disorders, particularly obesity and type 2 diabetes. Its expression is prominently detected in major neuroendocr...
Growing evidence has established the imprinted gene neuronatin (NNAT) as a key regulator in human metabolic disorders, particularly obesity and type 2 diabetes. Its expression is prominently detected in major neuroendocrine and metabolic tissues, including the hypothalamus, pancreas, adipose tissue, and skeletal muscle. NNAT orchestrates diverse cellular processes through its regulation of intracellular calcium dynamics and pathological insulin secretion. Notably, NNAT exhibits nutrient-responsive regulation and is a crucial modulator of glucose homeostasis, adaptive thermogenesis, and overall energy balance. These pleiotropic functions position NNAT as an attractive therapeutic target for obesity-related metabolic disorders. This comprehensive review systematically evaluates the multifaceted roles of NNAT in metabolic regulation, with a particular focus on its tissue-specific mechanisms in both physiological and pathological states while integrating the current understanding of its contributions to systemic metabolic homeostasis.
Metabolic Reprograming in Cancer.
Liebermann DA, Soboloff J
J Cell Physiol · 2025 Dec · PMID 41358780 · Publisher ↗
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Lactobacillus acidophilus Ameliorates Inflammatory Bone Loss Under Postmenopausal Osteoporotic Conditions via Modulating the Gut-Resident RORγT pTreg Cell Population.
Bhardwaj A, Sapra L, Saini C … +4 more , Tiwari A, Nilakhe A, Mishra PK, Srivastava RK
J Cell Physiol · 2025 Dec · PMID 41340496 · Publisher ↗
Research in the past decade has elucidated the explicit role of the immune system in the pathophysiology of osteoporosis. Recent studies have further unraveled the complex interactions between bone and immune cells and e...
Research in the past decade has elucidated the explicit role of the immune system in the pathophysiology of osteoporosis. Recent studies have further unraveled the complex interactions between bone and immune cells and explored safe, effective immunomodulatory approaches-such as probiotics-for preventing and managing osteoporosis. As a result, various immune factors have continuously been discovered to play specific roles in maintaining bone homeostasis. The role of Tregs in the context of postmenopausal osteoporosis (PMO) is already well established. While Foxp3 Tregs are mostly matured in the thymus (tTregs), some are also produced from Foxp3CD4 T-cell precursors in the peripheral tissues (i.e., pTregs). Notably, the specific role of pTregs and tTregs in PMO remains to be elucidated. Here, we reveal that estrogen-deficient inflammatory conditions in PMO disrupt the balance of tTregs and pTregs. Interestingly, within pTregs, the population of RORγT pTregs and RORγT pTregs is further altered, along with simultaneous expansion of Th17 cells-likely through the conversion of RORγT pTregs into Th17 cells. Notably, supplementation with Lactobacillus acidophilus (LA) restores the homeostasis of RORγT pTregs and Th17 cells in a butyrate-mediated manner. Moreover, it was observed that butyrate-primed RORγT pTregs have reduced osteoclastogenic potential. Collectively, our findings for the first time reveal the pivotal role of gut resident RORγT pTregs-Th17 cell axis in the pathophysiology of PMO.
A Novel Role of Neutrophil Elastase in Podocyte Dysfunction Induced by High Glucose, PMA, and MDP.
Kulesza T, Wróblewska A, Sawicka J … +7 more , Audzeyenka I, Rachubik P, Rogacka D, Mallek W, Wysocka M, Lesner A, Piwkowska A
J Cell Physiol · 2025 Dec · PMID 41340462 · Full text
Podocytes are not only the key regulators of glomerular filtration barrier dynamics but also exhibit immunological properties. They are capable of antigen presentation and possess a receptor system recognizing pathogen-a...
Podocytes are not only the key regulators of glomerular filtration barrier dynamics but also exhibit immunological properties. They are capable of antigen presentation and possess a receptor system recognizing pathogen-associated molecular patterns. Our earlier study further demonstrated that podocytes share additional similarities with immune cells, as they can synthesize and secrete the active form of cathepsin C - an enzyme that controls the activation of neutrophil serine proteases (NSPs). In this study, we established that podocytes synthesize neutrophil elastase (NE), proteinase 3 (PR 3), and cathepsin G (CatG) but also release their active forms into the extracellular environment. We found that NSPs contribute to podocyte dysfunction upon inflammation induction by PMA and under conditions of insulin insensitivity. Moreover, actin cytoskeleton rearrangement and increased albumin permeability of the podocyte monolayer were triggered by nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) activation via muramyl dipeptide (MDP), which consequently enhanced NE and PR 3 activity. Notably, silencing the ELANE gene, which encodes NE, exerted a protective effect on podocytes even after NOD2 activation. These findings indicate that NSPs, especially NE, contribute to podocyte dysfunction in diabetes and diabetic kidney disease, a condition characterized by chronic inflammation and insulin resistance.
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