Cells

35 pages, 2416 KB

Open AccessReview

Adenosine Receptors in Neuroinflammation and Neurodegeneration

by Veronica Salmaso, Silvia Menin, Stefano Moro, Giampiero Spalluto and Stephanie Federico

Cells 2025, 14(20), 1585; https://doi.org/10.3390/cells14201585 (registering DOI) - 11 Oct 2025

Adenosine plays a crucial role in various pathophysiological conditions, including neuroinflammation and neurodegeneration. Neuroinflammation can be either beneficial or detrimental to the central nervous system, depending on the intensity and duration of the inflammatory response. Across a wide range of brain disorders, neuroinflammation [...] Read more.

Adenosine plays a crucial role in various pathophysiological conditions, including neuroinflammation and neurodegeneration. Neuroinflammation can be either beneficial or detrimental to the central nervous system, depending on the intensity and duration of the inflammatory response. Across a wide range of brain disorders, neuroinflammation contributes to both the onset and progression of disease. Notably, neuroinflammation is not limited to conditions primarily classified as neuroinflammatory but is also a key factor in other neurological disorders, including life-threatening neurodegenerative diseases. All four adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃) are implicated, to varying degrees, in these conditions. This review aims to summarize the roles of individual adenosine receptor subtypes in neuroinflammation and neurodegenerative diseases, emphasizing their therapeutic potential. While some therapeutic applications are well-established with clinically approved drugs, others warrant further investigation due to their promising potential. Full article

(This article belongs to the Special Issue Adenosine and Purinergic Receptors: Regulation and Essential Role in Human Disease)

► Show Figures

Figure 1

16 pages, 2417 KB

Open AccessArticle

Angiotensin II Promotes Progressive Activation of Fibrogenic Periostin-Lineage Cells in Lung and Kidney

by Mustafa Ozdemir, José P. Guirao-Abad, Daniel A. Kasprovic, Robert M. Jaggers and Onur Kanisicak

Cells 2025, 14(20), 1584; https://doi.org/10.3390/cells14201584 (registering DOI) - 11 Oct 2025

Abstract

Angiotensin II (AngII), the primary effector of the renin-angiotensin system, is essential for maintaining blood pressure and fluid-electrolyte homeostasis. However, elevated AngII levels are a feature of disease conditions such as heart failure and chronic kidney disease, where it is associated with pathological [...] Read more.

Angiotensin II (AngII), the primary effector of the renin-angiotensin system, is essential for maintaining blood pressure and fluid-electrolyte homeostasis. However, elevated AngII levels are a feature of disease conditions such as heart failure and chronic kidney disease, where it is associated with pathological tissue remodeling and fibrosis. AngII-mediated fibrosis has been documented in multiple organs and is characterized by fibroblast expansion, myofibroblast differentiation, and excessive extracellular matrix deposition. Periostin has recently emerged as a marker of fibroblast activation. Notably, periostin expression is highly upregulated during fibrotic remodeling in the kidney and lung, which is strongly linked with impaired organ function. While AngII-induced activation of periostin-lineage (Postn^Lin) cells is well established in the heart, the temporal dynamics of Postn^Lin activation in response to AngII infusion in the lung and kidney remain unexplored. Here, we used a Postn-MerCreMer lineage-tracing approach, combined with continuous AngII infusion over an experimental period of one week and two weeks to assess Postn^Lin responses in lung and kidney. Our findings reveal a progressive activation of Postn^Lin cells in both organs, characterized by myofibroblast phenotype, together with increased collagen deposition and macrophage infiltration. These results highlight the potential of Postn^Lin fibroblasts as a key effector of AngII-mediated tissue remodeling and fibrosis in the lung and kidney. Full article

(This article belongs to the Topic Application of Animal Models: From Physiology to Pathology)

► Show Figures

Figure 1

23 pages, 3127 KB

Open AccessArticle

Suppression of Cornea Stromal Fibrosis by Vitamin D

by Xiaowen Lu, Zhong Chen, Jerry Lu and Mitchell A. Watsky

Cells 2025, 14(20), 1583; https://doi.org/10.3390/cells14201583 (registering DOI) - 11 Oct 2025

Abstract

Corneal fibrosis, a significant source of visual impairment, can result from keratocyte-to-myofibroblast transdifferentiation during wound healing. This study investigated the antifibrotic role of 1,25-dihydroxyvitamin D₃ (1,25 Vit D) and the lesser-known vitamin D, 24,25-dihydroxyvitamin D₃ (24,25 Vit D), in human and [...] Read more.

Corneal fibrosis, a significant source of visual impairment, can result from keratocyte-to-myofibroblast transdifferentiation during wound healing. This study investigated the antifibrotic role of 1,25-dihydroxyvitamin D₃ (1,25 Vit D) and the lesser-known vitamin D, 24,25-dihydroxyvitamin D₃ (24,25 Vit D), in human and mouse corneal stromal cells (HSCs and MSCs) and in a Vit D receptor knockout (VDR KO) mouse model. Cells were treated with TGF-β1 ± Vit D metabolites and the expression of fibrotic and antifibrotic genes and proteins was evaluated. Both metabolites significantly reduced α-smooth muscle actin levels in HSCs, MSCs and organ-cultured mouse corneas (p < 0.05). They also upregulated the mRNA expression of BMP2, BMP6, BMPR2, and TGF-β3, as well as the protein expression of BMP6 and TGF-β3. VDR KO corneas subjected to alkali injury exhibited increased fibrotic responses and reduced CD45+ immune cell infiltration compared to wild-type controls. Notably, 24,25 Vit D exerted antifibrotic effects even in VDR KO cells, and the alternative 24,25 Vit D receptor FAM57B was expressed in all corneal cell layers. These results reveal consistent antifibrotic effects of both 1,25 and 24,25 Vit D across species, support the existence of VDR-independent mechanisms in the cornea, and offer new insights into potential therapeutic strategies for preventing corneal fibrosis. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling During Eye Development and Diseases—Second Edition)

► Show Figures

Figure 1

44 pages, 2405 KB

Open AccessReview

Plasma Membrane Epichaperome–Lipid Interface: Regulating Dynamics and Trafficking

by Haneef Ahmed Amissah, Ruslana Likhomanova, Gabriel Opoku, Tawfeek Ahmed Amissah, Zsolt Balogi, Zsolt Török, László Vigh, Stephanie E. Combs and Maxim Shevtsov

Cells 2025, 14(20), 1582; https://doi.org/10.3390/cells14201582 (registering DOI) - 11 Oct 2025

Abstract

The plasma membrane (PM) of eukaryotic cells plays a key role in the response to stress, acting as the first line of defense against environmental changes and protecting cells against intracellular perturbations. In this work, we explore how membrane-bound chaperones and membrane lipid [...] Read more.

The plasma membrane (PM) of eukaryotic cells plays a key role in the response to stress, acting as the first line of defense against environmental changes and protecting cells against intracellular perturbations. In this work, we explore how membrane-bound chaperones and membrane lipid domains work together to shape plasma membrane properties—a partnership we refer to as the “epichaperome–plasma membrane lipid axis.” This axis influences membrane fluidity, curvature, and domain organization, which in turn shapes the spatial and temporal modulation of signaling platforms and pathways essential for maintaining cellular integrity and homeostasis. Changes in PM fluidity can modulate the activity of ion channels, such as transient receptor potential (TRP) channels. These changes also affect processes such as endocytosis and mechanical signal transduction. The PM proteome undergoes rapid changes in response to membrane perturbations. Among these changes, the expression of heat shock proteins (HSPs) and their accumulation at the PM are essential mediators in regulating the physical state and functional properties of the membrane. Because of the pivotal role in stress adaptation, HSPs influence a wide range of cellular processes, which we grouped into three main categories: (i) mechanistic insights, differentiating in vitro (liposome, reconstituted membrane systems) and in vivo evidence for HSP-PM recruitment; (ii) functional outputs, spanning how ion channels are affected, changes in membrane fluidity, transcytosis, and the process of endocytosis and exosome release; and (iii) pathological effects, focusing on how rewired lipid–chaperone crosstalk in cancer drives resistance to drugs through altered membrane composition and signaling. Finally, we highlight Membrane Lipid Therapy (MLT) strategies, such as nanocarriers targeting specific PM compartments or small molecules that inhibit HSP recruitment, as promising approaches to modulate the functional stability of epichaperome assembly and membrane functionality, with profound implications for tumorigenesis. Full article

(This article belongs to the Special Issue Lipid Homeostasis: Mechanisms, Regulation, and Implications for Health and Disease)

► Show Figures

Figure 1

21 pages, 2913 KB

Open AccessArticle

Structural Variants of Dermatan Sulfate Can Affect the Expression of Proteins Involved in Breast Cancer Cell Survival

by Grzegorz Wisowski, Monika Paul-Samojedny, Katarzyna Komosińska-Vassev, Adam Pudełko and Ewa M. Koźma

Cells 2025, 14(20), 1581; https://doi.org/10.3390/cells14201581 (registering DOI) - 11 Oct 2025

Abstract

Dermatan sulfate (DS) is an animal glycosaminoglycan with significant structural heterogeneity and a high, but variable density of negative electric charge. Owing to these characteristics DS displays a high degree of biological reactivity that is subject to regulation. We previously demonstrated that structural [...] Read more.

Dermatan sulfate (DS) is an animal glycosaminoglycan with significant structural heterogeneity and a high, but variable density of negative electric charge. Owing to these characteristics DS displays a high degree of biological reactivity that is subject to regulation. We previously demonstrated that structural variants of DS rapidly induce moderate necroptosis in luminal breast cancer cells. In the present study, we investigated the intracellular molecular mechanism(s) that may underlie this effect, focusing on the expression of key regulators of intrinsic (BCL-2A1) and extrinsic (cFLIP) apoptosis, autophagy (Beclin-1), and oxidative stress protection (heme oxygenase-1 (HO-1)). Using RT-qPCR, Western blotting, immunofluorescence, and pharmacological inhibition, we have shown for the first time that DS, depending on its structure and the cancer cell line, can rapidly, albeit transiently, upregulate either the long or short cFLIP splicing variant and also reduce the level of HO-1. These effects are mediated via DS-triggered PI3K and/or NFκB signaling. Moreover, DS can also influence the intracellular distribution of these proteins. In contrast, this glycan did not affect the expression of BCL-2A1 and BECN1. These findings indicate that DS induces coordinated molecular remodeling in luminal breast cancer cells that creates an intracellular environment favorable for necroptosis induction. Full article

(This article belongs to the Special Issue The Interplay Between Tumor Metabolism, Microenvironment and Cell Survival)

► Show Figures

Figure 1

16 pages, 5456 KB

Open AccessArticle

A Novel Peptoid Hybrid of Alpha-Calcitonin Gene-Related Peptide (α-CGRP) Ameliorates Cardiac Remodeling in Pressure Overload-Induced Heart Failure

by Sarah Deloach, Ambrish Kumar, Emily Ruggiero, Ryan Ball, Kamryn Gleason, Jason Kubinak, Donald J. DiPette and Jay D. Potts

Cells 2025, 14(20), 1580; https://doi.org/10.3390/cells14201580 (registering DOI) - 11 Oct 2025

Abstract

α-CGRP (alpha-calcitonin gene-related peptide) is a vasoactive and anti-inflammatory neuropeptide that is cardioprotective in transverse aortic constriction (TAC)-induced pressure overload heart failure (HF) models. Our previous investigations established that a peptoid modification of α-CGRP, termed NMEG-CGRP, prevented left ventricular (LV) dysfunction and remodeling [...] Read more.

α-CGRP (alpha-calcitonin gene-related peptide) is a vasoactive and anti-inflammatory neuropeptide that is cardioprotective in transverse aortic constriction (TAC)-induced pressure overload heart failure (HF) models. Our previous investigations established that a peptoid modification of α-CGRP, termed NMEG-CGRP, prevented left ventricular (LV) dysfunction and remodeling when administered subcutaneously every other day for 28 days, starting two days post-TAC surgery (termed prevention study). Here, we determined whether NMEG-CGRP would be cardioprotective when administered after the development of LV dysfunction secondary to TAC surgery (termed treatment study). Starting 15 days post-sham or TAC surgery, we administered NMEG-CGRP (3.6 mg/kg/mouse) subcutaneously every other day for 28 days in mice assigned to treatment groups. In vivo assessments included weekly electrocardiography to evaluate cardiac function and blood sampling for immunophenotyping. On Day 45, mice were euthanized, and hearts were collected for gross, histological, and biochemical analyses. Compared to sham-operated mice, TAC mice exhibited decreased LV ejection fraction and increased hypertrophy, dilation, fibrosis, apoptosis, and oxidative stress. In contrast, TAC mice treated with NMEG-CGRP demonstrated significant improvements in cardiac function and cellular and biochemical parameters when compared to TAC mice. These findings demonstrate the therapeutic potential of NMEG-CGRP in the treatment of established cardiovascular dysfunction and its progression in pressure overload-induced HF. Full article

(This article belongs to the Special Issue The Roles of the Extracellular Matrix in Cardiac Structure and Function: A Commemorative Issue in Honor of Dr. Thomas K. Borg)

► Show Figures

Figure 1

20 pages, 41724 KB

Open AccessArticle

TRIC-A Facilitates Sarcoplasmic Reticulum–Mitochondrial Ca²⁺ Signaling Crosstalk in Cardiomyocytes

by Ang Li, Xinyu Zhou, Ki Ho Park, Jianxun Yi, Xuejun Li, Jae-Kyun Ko, Yuchen Chen, Miyuki Nishi, Daiju Yamazaki, Hiroshi Takeshima, Jingsong Zhou and Jianjie Ma

Cells 2025, 14(20), 1579; https://doi.org/10.3390/cells14201579 (registering DOI) - 11 Oct 2025

Abstract

TRIC-A is an intracellular cation channel enriched in excitable tissues that is recently identified as a key modulator of sarcoplasmic reticulum (SR) Ca²⁺ homeostasis through direct interaction with type 2 ryanodine receptors (RyR₂). Given the intimate anatomical and functional coupling [...] Read more.

TRIC-A is an intracellular cation channel enriched in excitable tissues that is recently identified as a key modulator of sarcoplasmic reticulum (SR) Ca²⁺ homeostasis through direct interaction with type 2 ryanodine receptors (RyR₂). Given the intimate anatomical and functional coupling between the SR and mitochondria, we investigated whether TRIC-A contributes to SR–mitochondrial crosstalk under cardiac stress conditions. Using a transverse aortic constriction (TAC) model, we found that TRIC-A^−/− mice developed more severe cardiac hypertrophy, underwent maladaptive remodeling, and activated apoptotic pathways compared with wild-type littermates. At the cellular level, TRIC-A-deficient cardiomyocytes were more susceptible to H₂O₂-induced mitochondrial injury and displayed abnormal mitochondrial morphology. Live-cell imaging revealed exaggerated mitochondrial Ca²⁺ uptake during caffeine stimulation and increased propensity for store-overload-induced Ca²⁺ release (SOICR). Complementary studies in HEK293 cells expressing RyR₂ demonstrated that exogenous TRIC-A expression attenuates RyR₂-mediated mitochondrial Ca²⁺ overload, preserves respiratory function, and suppresses superoxide generation. Together, these findings identify TRIC-A as a critical regulator of SR–mitochondrial Ca²⁺ signaling. By constraining mitochondrial Ca²⁺ influx and limiting oxidative stress, TRIC-A safeguards cardiomyocytes against SOICR-driven injury and confers protection against pressure overload-induced cardiac dysfunction. Full article

(This article belongs to the Special Issue Thirty plus Years’ Journey—Painting the Molecular Picture of E-C Coupling)

► Show Figures

Figure 1

20 pages, 368 KB

Open AccessReview

Influence of the Gut Microbiota on the Pathogenesis of Alzheimer’s Disease: A Literature Review

by Joanna Koga-Batko, Katarzyna Antosz-Popiołek, Wojciech Suchecki, Hubert Szyller, Martyna Wrześniewska, Maciej Dyda and Jerzy Leszek

Cells 2025, 14(20), 1578; https://doi.org/10.3390/cells14201578 (registering DOI) - 11 Oct 2025

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex etiology whose exact mechanisms are not fully understood. In recent years, there has been growing interest in the role of the gastrointestinal microbiota in the pathogenesis of AD, particularly in the context [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex etiology whose exact mechanisms are not fully understood. In recent years, there has been growing interest in the role of the gastrointestinal microbiota in the pathogenesis of AD, particularly in the context of the gut–brain axis. The purpose of this review is to discuss the current state of knowledge regarding potential relationships between the composition of the gut microbiota and the development and progression of AD. Preclinical and clinical studies indicating that microbiota imbalances (dysbiosis) may contribute to increased inflammation, increased permeability of the intestinal and blood–brain barriers, and accumulation of pathological proteins such as beta-amyloid and tau are analyzed. The effects of diet, probiotics and microbiota interventions on cognitive function were also discussed. An attempt was also made to evaluate microbiota disruption as a potential early marker of AD development. Although the mechanisms require further study, the role of the gut microbiota appears to be an important and promising direction in understanding the pathophysiology of AD and developing potential therapeutic and diagnostic strategies. Full article

27 pages, 3121 KB

Open AccessArticle

MicroRNA Deregulation and Immune Checkpoint Interactions in Common Variable Immunodeficiency and CLL-Associated Secondary Immunodeficiency

by Paulina Mertowska, Sebastian Mertowski, Milena Czosnek, Barbara Sosnowska-Pasiarska, Aleksandra Krasińska-Płachta, Zbigniew Krasiński, Tomasz Urbanowicz, Krzysztof Bojarski, Mansur Rahnama-Hezavah and Ewelina Grywalska

Cells 2025, 14(20), 1577; https://doi.org/10.3390/cells14201577 - 10 Oct 2025

Abstract

Background: Immunodeficiencies are a heterogeneous group of disorders classified etiologically as primary (congenital) or secondary (acquired). Primary immunodeficiencies (PIDs), such as common variable immunodeficiency (CVID), result from genetic mutations that impair the development and function of lymphocytes. Secondary immunodeficiencies (SIDs) arise as a [...] Read more.

Background: Immunodeficiencies are a heterogeneous group of disorders classified etiologically as primary (congenital) or secondary (acquired). Primary immunodeficiencies (PIDs), such as common variable immunodeficiency (CVID), result from genetic mutations that impair the development and function of lymphocytes. Secondary immunodeficiencies (SIDs) arise as a consequence of chronic diseases, lymphoid malignancies, or immunosuppressive therapies. Aim of the study: The purpose of this study was to assess the serum expression profile of selected microRNAs (miRNAs) in patients with CVID and in those with chronic lymphocytic leukemia (CLL) and coexisting SID, compared to healthy individuals. Methods: Digital PCR (dPCR) was applied to quantify the serum expression levels of selected miRNAs in patients with CVID, patients with CLL and SID, and in healthy controls. Results: dPCR revealed significantly reduced levels of miR-16, miR-30c, miR-181a, miR-29a, miR-150, and miR-326 in the CVID group, potentially reflecting impaired regulatory mechanisms of the immune system. In contrast, elevated levels of miR-21, miR-125b, and miR-155 were observed in the CLL group with SID, suggesting their role in tumorigenesis and secondary immunosuppression. Correlations between miRNA levels and the expression of immune checkpoints (PD-1, CTLA-4, CD200) indicated the involvement of a complex regulatory network encompassing both humoral and cellular immune mechanisms. Conclusions: The results provide preliminary evidence that selected miRNAs could reflect disease-specific immune dysregulation patterns and may hold potential as diagnostic and prognostic biomarkers in both PIDs and SIDs. Full article

(This article belongs to the Special Issue MicroRNAs: Regulators of Cellular Fate)

16 pages, 701 KB

Open AccessReview

The Autoimmune Gastritis Puzzle: Emerging Cellular Crosstalk and Molecular Pathways Driving Parietal Cell Loss and ECL Cell Hyperplasia

by Sara Massironi, Elena Oriani, Giuseppe Dell’Anna, Silvio Danese and Federica Facciotti

Cells 2025, 14(20), 1576; https://doi.org/10.3390/cells14201576 - 10 Oct 2025

Abstract

Autoimmune gastritis (AIG) is a chronic, organ-specific autoimmune disease characterized by progressive destruction of gastric parietal cells driven by autoreactive CD4⁺ T-cells, epithelial stress pathways, and microbial factors. Parietal cell loss results in achlorhydria, intrinsic factor deficiency, and vitamin B12 malabsorption, ultimately [...] Read more.

Autoimmune gastritis (AIG) is a chronic, organ-specific autoimmune disease characterized by progressive destruction of gastric parietal cells driven by autoreactive CD4⁺ T-cells, epithelial stress pathways, and microbial factors. Parietal cell loss results in achlorhydria, intrinsic factor deficiency, and vitamin B12 malabsorption, ultimately leading to pernicious anemia. Compensatory hypergastrinemia promotes enterochromaffin-like (ECL) cell hyperplasia and contributes to the development of type 1 gastric neuroendocrine neoplasms (gNENs). These clinical consequences are well recognized, yet the cellular and molecular mechanisms driving mucosal atrophy and neoplastic transformation remain incompletely defined. Recent advances highlight the role of endoplasmic reticulum stress, impaired autophagy, innate immune effectors, and dysbiosis in perpetuating inflammation and epithelial injury. The frequent coexistence of AIG with other autoimmune disorders further adds to its clinical complexity. Therapeutic options remain limited, spanning vitamin B12 replacement and endoscopic management to emerging targeted approaches. Netazepide, a gastrin/CCK2 receptor antagonist, is the only agent tested in clinical trials, whereas interventions targeting ER stress, autophagy, immune tolerance, or microbiome composition are still in the preclinical stage. Clarifying these mechanisms is crucial to improve biomarker development, optimize surveillance, and identify targeted therapies to prevent neoplastic transformation. Full article

(This article belongs to the Special Issue Advances in Cellular and Molecular Treatment of Autoimmune Diseases—Second Edition)

► Show Figures

Figure 1

30 pages, 4506 KB

Open AccessArticle

Biomarker-Based Pharmacological Characterization of ENX-102, a Novel α2/3/5 Subtype-Selective GABAA Receptor Positive Allo-Steric Modulator: Translational Insights from Rodent and Human Studies

by Pauline Nettesheim, Krishna C. Vadodaria, Kimberly E. Vanover, Laura G. J. M. Borghans, Estibaliz Arce, William Brubaker, Stephen Cunningham, Stephanie Parks, Jordi Serrats, Vikram Sudarsan, Eve Taylor, Erica Klaassen, Frederik E. Stuurman and Gabriel E. Jacobs

Cells 2025, 14(20), 1575; https://doi.org/10.3390/cells14201575 - 10 Oct 2025

Abstract

Gamma-aminobutyric acid type A receptors (GABA_ARs) are pentameric ligand-gated ion channels essential for inhibitory neurotransmission in the central nervous system. Subtype-specific expression patterns of GABA_AR subunits underlie their diverse roles in regulating anxiety, motor function, and sedation. While non-selective [...] Read more.

Gamma-aminobutyric acid type A receptors (GABA_ARs) are pentameric ligand-gated ion channels essential for inhibitory neurotransmission in the central nervous system. Subtype-specific expression patterns of GABA_AR subunits underlie their diverse roles in regulating anxiety, motor function, and sedation. While non-selective GABA_AR positive allosteric modulators (PAMs), such as benzodiazepines, are clinically effective anxiolytic drugs, their non-selective activity across α1/2/3/5 subunit-containing GABA_ARs leads to sedation, cognitive impairment, and risk of dependence. To address this, we evaluated ENX-102, a novel GABA_AR PAM, which exhibits selectivity for α2/3/5 subunits. In rodents, ENX-102 demonstrated dose-dependent anxiolytic-like activity following acute and sub-chronic administration, without sedation. ENX-102 exhibited a dose-dependent quantitative electroencephalography (qEEG) spectral signature in rodents that was distinct from that of benzodiazepines. In a double-blind, placebo-controlled, multiple-ascending dose study in healthy human volunteers, ENX-102 was evaluated using the NeuroCart, a CNS test battery including saccadic peak velocity (SPV), adaptive tracking, pupillometry, body sway, the Bond and Lader Visual Analog Scale (VAS), the Visual Verbal Learning Task (VVLT), and qEEG. ENX-102 produced reductions in SPV that were indicative of central target engagement, with minimal effects on alertness and motor coordination, which is consistent with subtype-selective GABA_AR targeting. Notably, qEEG revealed increased β-band power and decreased δ- and θ-band activity, which were distinct from the spectral profile of non-selective PAMs, supporting translational alignment with preclinical findings. Across dose levels, ENX-102 was well tolerated and exhibited favorable pharmacokinetics. These results support further clinical development of ENX-102 as a next-generation GABA_AR subtype-selective anxiolytic drug. Full article

(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)

► Show Figures

Figure 1

2 pages, 566 KB

Open AccessCorrection

Correction: Dallons et al. GPR91 Receptor Mediates Protection against Doxorubicin-Induced Cardiotoxicity without Altering Its Anticancer Efficacy. An In Vitro Study on H9C2 Cardiomyoblasts and Breast Cancer-Derived MCF-7 Cells. Cells 2020, 9, 2177

by Matthieu Dallons, Esma Alpan, Corentin Schepkens, Vanessa Tagliatti and Jean-Marie Colet

Cells 2025, 14(20), 1574; https://doi.org/10.3390/cells14201574 - 10 Oct 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

► Show Figures

Figure 1

18 pages, 1722 KB

Open AccessReview

Diverse Roles of Tubulin Polymerization Promoting Protein 3 (TPPP3) in Human Health and Disease

by James W. Lord and Sachi Horibata

Cells 2025, 14(20), 1573; https://doi.org/10.3390/cells14201573 - 10 Oct 2025

Abstract

The tubulin polymerization promoting proteins (TPPPs) are a small family of conserved proteins originally characterized as microtubule binding proteins. TPPP1, the first identified member, both binds to and bundles microtubules. Its homologs, TPPP2 and TPPP3, are encoded by separate genes on distinct chromosomes [...] Read more.

The tubulin polymerization promoting proteins (TPPPs) are a small family of conserved proteins originally characterized as microtubule binding proteins. TPPP1, the first identified member, both binds to and bundles microtubules. Its homologs, TPPP2 and TPPP3, are encoded by separate genes on distinct chromosomes but both lack the N-terminal tail present in TPPP1. Functional studies revealed that TPPP3 retains comparable microtubule binding and bundling capacity to TPPP1, whereas TPPP2 displays markedly reduced binding and no bundling activity. Intriguingly, TPPP3 has been implicated in many different diseases. In this review, we summarize the current findings on TPPP3 and its dysregulation in various diseases including cancer, reproductive dysfunction, musculoskeletal conditions, endothelial dysfunction, and neurodegenerative diseases. Full article

► Show Figures

Figure 1

19 pages, 7178 KB

Open AccessArticle

Pvalb8, a Type of Oncomodulin, Regulates Neuromast Development and Auditory Function in Zebrafish

by Guiyi Zhang, Qianqian Li, Ying Xu, Hanmeng Zhao, Chao Yang, Dong Liu and Jie Gong

Cells 2025, 14(19), 1572; https://doi.org/10.3390/cells14191572 - 9 Oct 2025

Abstract

Congenital hearing loss, frequently resulting from defective hair cells, remains poorly understood due to the incomplete identification of key pathogenic genes. Oncomodulin (OCM) is a kind of calcium-binding protein (CaBP) that regulates diverse cellular processes and is thought to play crucial roles in [...] Read more.

Congenital hearing loss, frequently resulting from defective hair cells, remains poorly understood due to the incomplete identification of key pathogenic genes. Oncomodulin (OCM) is a kind of calcium-binding protein (CaBP) that regulates diverse cellular processes and is thought to play crucial roles in auditory function. In teleost fish, parvalbumin 8 (pvalb8) and parvalbumin 9 (pvalb9) belong to the oncomodulin lineage and are highly expressed in hair cells. In this study, we first reported the oncomodulin lineage function in fish and identified pvalb8 as an essential regulator of hair cell development. Single-cell RNA sequencing (scRNA-seq) and whole-mount in situ hybridization (WISH) revealed that pvalb8 is highly and specifically expressed in supporting cells and hair cells. Functional loss of pvalb8, achieved via CRISPR/Cas9 knockout or morpholino knockdown, resulted in reduced neuromast size and a significant decrease in neuromast hair cell number, leading to auditory behavioral deficits. In addition, pvalb9 mutants exhibited hair cell defects similar to those observed in pvalb8 mutants, including a significant reduction in hair cell number. Moreover, pvalb8 loss strongly inhibited the proliferation of supporting cells, which likely accounts for the reduced number of differentiated hair cells. The expression levels of Wnt target genes, axin2, ccnd1, and myca, were all significantly reduced in pvalb8 mutants compared to control zebrafish, while activation of the Wnt signaling pathway rescued the hair cell loss observed in pvalb8 mutants, indicating that pvalb8 promotes hair cell development via Wnt-dependent proliferative signaling. These findings highlight pvalb8 as a critical factor in the regulation of auditory hair cell formation and function in zebrafish, offering new insights into the role of oncomodulin lineage in sensory cell development. Full article

► Show Figures

Figure 1

17 pages, 2580 KB

Open AccessFeature PaperArticle

Galectin-3 Mediated Endocytosis of the Orphan G-Protein-Coupled Receptor GPRC5A

by Abdeldjalil Boucheham, Jorge Mallor Franco, Séverine Bär, Ewan MacDonald, Solène Zuttion, Lana Blagec, Bruno Rinaldi, Johana Chicher, Laurianne Kuhn, Philippe Hammann, Christian Wunder, Ludger Johannes, Hocine Rechreche and Sylvie Friant

Cells 2025, 14(19), 1571; https://doi.org/10.3390/cells14191571 - 9 Oct 2025

Abstract

Galectins, a family of glycan-binding proteins, play crucial roles in various cellular functions, acting at both intracellular and extracellular levels. Among them, Galectin-3 (Gal-3) stands out as a unique member, possessing an intrinsically unstructured N-terminal oligomerization domain and a canonical carbohydrate-recognition domain (CRD). [...] Read more.

Galectins, a family of glycan-binding proteins, play crucial roles in various cellular functions, acting at both intracellular and extracellular levels. Among them, Galectin-3 (Gal-3) stands out as a unique member, possessing an intrinsically unstructured N-terminal oligomerization domain and a canonical carbohydrate-recognition domain (CRD). Gal-3 binding to glycosylated plasma membrane cargo leads to its oligomerization and membrane bending, ultimately resulting in the formation of endocytic invaginations. An interactomic assay using proteomic analysis of endogenous Gal-3 immunoprecipitates identified the orphan G protein-coupled receptor GPRC5A as a novel binding partner of Gal-3. GPRC5A, also known as Retinoic Acid-Induced protein 3 (RAI3), is transcriptionally induced by retinoic acid. Our results further demonstrate that extracellular recombinant Gal-3 stimulates GPRC5A internalization. In SW480 colorectal cancer cells, glycosylated GPRC5A interacts with Gal-3. Interestingly, while GPRC5A expression was upregulated by the addition of all-trans retinoic acid (ATRA), its endogenous internalization in SW480 cells was specifically triggered by extracellular Gal-3, but not by ATRA. This study provides new insights into the endocytic mechanisms of GPRC5A, for which no specific ligand has been identified to date. Further research may uncover additional Gal-3-mediated functions in GPRC5A cellular signaling and contribute to the development of innovative therapeutic strategies. Full article

► Show Figures

Figure 1

18 pages, 3480 KB

Open AccessArticle

Expression of Genes Encoding Receptors for Classical Neurotransmitters, Neuropeptides and Hormones in the Substantia Nigra, Especially in Dopaminergic Neurons, in Intact Mice and Mouse Models of Parkinson’s Disease

by Dmitry Troshev, Ekaterina Pavlova, Vsevolod Bogdanov and Michael Ugrumov

Cells 2025, 14(19), 1570; https://doi.org/10.3390/cells14191570 - 9 Oct 2025

Abstract

Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neurons (DNs) and movement disorders. Low efficiency of pharmacotherapy requires improvement, e.g., using receptor agonists or antagonists as drugs. Our work aims to initiate these developments by studying the expression levels of genes [...] Read more.

Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neurons (DNs) and movement disorders. Low efficiency of pharmacotherapy requires improvement, e.g., using receptor agonists or antagonists as drugs. Our work aims to initiate these developments by studying the expression levels of genes encoding neurotransmitters, neuropeptides and hormone receptors in substantia nigra pars compacta (SNpc) cells and in isolated DNs in intact mice, and changes in expression of these genes in MPTP mouse models of PD at preclinical and clinical stages. Expression of all 12 studied genes was detected in the SNpc and only 10 in DNs—Cckar and Glp1r were undetectable. In intact mice, the expression of Drd2, Grin2b, Grm1 and Ntsr2 predominates in SNpc tissue, whereas that of Gria2, Chrnb2, Gper1, Igf1r is higher in DNs. In PD models, change in receptor gene expression was detected in DNs but not in SNpc tissue. In the preclinical PD, Drd2 expression increased and Gria2 decreased, whereas in a clinical model, Drd2, Grm1, Ntsr2 expression decreased. Thus, the above genes are expressed in DNs and other cells of SNpc; expression of some genes changes in PD models, which opens up prospects for development of therapy using receptor agonists and antagonists. Full article

► Show Figures

Figure 1

19 pages, 6916 KB

Open AccessArticle

Short-Term Cryopreservation Preserved the Function of MSCs from Bone Marrow Aspirate Concentrate

by Jacob Singer, Haruki Nishimura, Zuokui Xiao, Xueqin Gao, Noah Knezic, Laura Chubb, Jonathan E. Layne, Ping Guo, Aiping Lu and Johnny Huard

Cells 2025, 14(19), 1569; https://doi.org/10.3390/cells14191569 - 9 Oct 2025

Abstract

Bone marrow aspirate concentrate (BMAC) is increasingly recognized as a valuable orthobiologic, offering promising outcomes in reducing inflammation, alleviating pain for patients with osteoarthritis (OA) and various musculoskeletal conditions. However, BMAC contains a very low percentage of mesenchymal stem cells (MSCs), and multiple [...] Read more.

Bone marrow aspirate concentrate (BMAC) is increasingly recognized as a valuable orthobiologic, offering promising outcomes in reducing inflammation, alleviating pain for patients with osteoarthritis (OA) and various musculoskeletal conditions. However, BMAC contains a very low percentage of mesenchymal stem cells (MSCs), and multiple injections are often required with multiple harvests, which can lead to scarring at the extraction site and patient discomfort. This study aimed to determine whether freezing BMAC affects the function of MSCs in vitro and their capacity to repair articular cartilage in vivo using an OA rat model. BMAC was obtained from patients undergoing BMAC treatment. The in vitro results showed that the proliferation and multilineage differentiation of MSCs remained similar after being frozen for 4 weeks at −80 °C. In vivo, both fresh and frozen BMAC demonstrated significantly improved ICRS histology score of tibial plateau cartilage compared to the PBS control. No significant difference was found between fresh and frozen BMAC treatment groups. Our results suggest that the freezing process does not negatively affect the function of MSCs from BMAC for cartilage repair. These findings support the potential future applications of a single harvest with BMAC storage for multiple injections, thereby enhancing the tissue repair capabilities of BMAC. Full article

(This article belongs to the Special Issue Stem Cells and Beyond: Innovations in Tissue Repair and Regeneration)

► Show Figures

Figure 1

20 pages, 936 KB

Open AccessArticle

Serum Interleukin-6 in Systemic Lupus Erythematosus: Insights into Immune Dysregulation, Disease Activity, and Clinical Manifestations

by Patricia Richter, Ciprian Rezus, Alexandra Maria Burlui, Thomas Gabriel Schreiner and Elena Rezus

Cells 2025, 14(19), 1568; https://doi.org/10.3390/cells14191568 - 9 Oct 2025

Abstract

Background: Interleukin-6 (IL-6) is a multifunctional cytokine implicated in various inflammatory and immune-mediated processes. Its involvement in systemic lupus erythematosus (SLE) has been increasingly investigated, particularly related to disease activity and tissue damage. This study aimed to quantify serum IL-6 levels in patients [...] Read more.

Background: Interleukin-6 (IL-6) is a multifunctional cytokine implicated in various inflammatory and immune-mediated processes. Its involvement in systemic lupus erythematosus (SLE) has been increasingly investigated, particularly related to disease activity and tissue damage. This study aimed to quantify serum IL-6 levels in patients with SLE and assess their associations with clinical manifestations and laboratory parameters. Methods: A total of 88 patients diagnosed with SLE and 87 matched healthy controls were included. Serum IL-6 concentrations were measured by ELISA. Clinical data, SLEDAI scores, organ involvement, inflammatory markers, and autoantibody profiles were recorded. The statistical analysis involved non-parametric testing, correlation analysis, and linear regression. Results: IL-6 concentrations were higher in SLE patients than in controls (7.46 ± 6.73 vs. 5.30 ± 10.89 pg/mL). Significantly increased IL-6 levels were observed in patients with active disease (SLEDAI ≥ 6; p = 0.025) and renal (p = 0.001) involvement. Positive correlations were identified between IL-6 and ESR, creatinine, ANA, and specific autoantibodies (anti-dsDNA, SSA, and SSB). IL-6 also correlated with IL-10 (p = 0.010) but showed no significant association with IL-17A, TNF-α, CRP, or complement levels. Conclusions: Elevated IL-6 levels are associated with greater disease activity and specific organ involvement in SLE. These findings highlight IL-6 as a measurable indicator of immunological and clinical disease expression, supporting its relevance in disease monitoring. Full article

(This article belongs to the Special Issue Soluble Interleukin-6 Receptor (sIL-6R): Role in Health and Disease)

► Show Figures

Figure 1

18 pages, 1458 KB

Open AccessArticle

Type 2 Diabetes Mellitus Impairs the Reverse Transendothelial Migration Capacity (rTEM) of Inflammatory CD14⁺CD16⁻ Monocytes: Novel Mechanism for Enhanced Subendothelial Monocyte Accumulation in Diabetes

by Dilvin Semo, Adama Sidibé, Kallipatti Sanjith Shanmuganathan, Nicolle Müller, Ulrich A. Müller, Beat A. Imhof, Rinesh Godfrey and Johannes Waltenberger

Cells 2025, 14(19), 1567; https://doi.org/10.3390/cells14191567 - 9 Oct 2025

Abstract

Background: Type 2 diabetes mellitus (DM) is a major cardiovascular risk factor that induces monocyte dysfunction and contributes to their accumulation in atherosclerotic lesions. Monocyte recruitment and accumulation in the tissues contribute to chronic inflammation and are essential to the pathobiology of diabetes-induced [...] Read more.

Background: Type 2 diabetes mellitus (DM) is a major cardiovascular risk factor that induces monocyte dysfunction and contributes to their accumulation in atherosclerotic lesions. Monocyte recruitment and accumulation in the tissues contribute to chronic inflammation and are essential to the pathobiology of diabetes-induced atherosclerosis. However, the mechanisms that drive the accumulation of monocytes in the diabetic environment are not clearly understood. Methods: Primary monocytes from type 2 (T2) DM and non-T2DM individuals were isolated using magnet-assisted cell sorting. To examine the influence of a diabetic milieu on monocyte function, monocytes from T2DM patients, db/db mice, or human monocytes subjected to hyperglycaemia were analysed for their responses to pro-atherogenic cytokines using Boyden chamber assays. Furthermore, the interactions of non-diabetic and diabetic monocytes with TNFα-inflamed endothelium were studied using live-cell imaging under physiological flow conditions. RT-qPCR and FACS were used to study the expression of relevant molecules involved in monocyte-endothelium interaction. Results: CD14⁺CD16⁻ monocytes isolated from T2DM patients or monocytes exposed to hyperglycaemic conditions showed reduced chemotactic responses towards atherosclerosis-promoting cytokines, CCL2 and CX3CL1, indicating monocyte dysfunction. Under flow conditions, the transendothelial migration (TEM) capacity of T2DM monocytes was significantly reduced. Even though these monocytes adhered to the endothelial monolayer, only a few transmigrated. Interestingly, the T2DM monocytes and monocytes exposed to hyperglycaemic conditions accumulated in the ablumen following transendothelial migration. The time period in the ablumen of T2DM cells was prolonged, as there was a significant impairment of the reverse transendothelial migration (rTEM). Mechanistically, the T2DM milieu specifically induced the activation of monocyte integrins, Macrophage-1 antigen (Mac-1; integrin αMβ2 consisting of CD11b and CD18), and Lymphocyte function-associated antigen 1 (LFA-1; αLβ2 consisting of CD11a and CD18). Furthermore, elevated levels of CD18 transcripts were detected in T2DM monocytes. Junctional Adhesion Molecule 3 (JAM-3)–MAC-1 interactions are known to impede rTEM and T2DM milieu-potentiated JAM-3 expression in human coronary artery endothelial cells (HCAEC). Finally, the overexpression of JAM-3 on HCAEC was sufficient to completely recapitulate the impaired rTEM phenotype. Conclusions: Our results revealed for the first time that the enhanced T2DM monocyte accumulation in the ablumen is not secondary to the elevated transmigration through the endothelium. Instead, the accumulation of monocytes is due to the direct consequence of a dysfunctional rTEM, potentially due to enhanced JAM3-MAC1 engagement. Our results highlight the importance of restoring the rTEM capacity of monocytes to reduce monocyte accumulation-dependent inflammation induction and atherogenesis in the T2DM environment. Full article

(This article belongs to the Special Issue Novel Insight into Endothelial Function and Atherosclerosis)

► Show Figures

Figure 1

Journal Description

Cells

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI