Cells

22 pages, 4181 KiB

Open AccessArticle

Mimicking the Liver Sinusoidal Endothelial Cell Niche In Vitro to Enhance Fenestration in a Genetic Model of Systemic Inflammation

by Dibakar Borah, Oliwia Blacharczyk, Karolina Szafranska, Izabela Czyzynska-Cichon, Sara Metwally, Konrad Szymanowski, Wolfgang Hübner, Jerzy Kotlinowski, Ewelina Dobosz, Peter McCourt, Thomas Huser, Malgorzata Lekka and Bartlomiej Zapotoczny

Cells 2025, 14(8), 621; https://doi.org/10.3390/cells14080621 - 21 Apr 2025

Abstract

Liver sinusoidal endothelial cells (LSECs) play a crucial role in hepatic homeostasis, clearance, and microcirculatory regulation. Their fenestrations—patent transcellular pores—are essential for proper liver function, yet disappear in pathological conditions such as liver fibrosis and inflammation through a process known as defenestration. Defenestrated [...] Read more.

Liver sinusoidal endothelial cells (LSECs) play a crucial role in hepatic homeostasis, clearance, and microcirculatory regulation. Their fenestrations—patent transcellular pores—are essential for proper liver function, yet disappear in pathological conditions such as liver fibrosis and inflammation through a process known as defenestration. Defenestrated sinusoids are often linked to the liver stiffening that occurs through mechanotransduction-regulated processes. We performed a detailed characterization of polyacrylamide (PAA) hydrogels using atomic force microscopy (AFM), rheometry, scanning electron microscopy, and fluorescence microscopy to assess their potential as biomimetic substrates for LSECs. We additionally implemented AFM; quantitative fluorescence microscopy, including high-resolution structured illumination microscopy (HR-SIM); and an endocytosis assay to characterize the morphology and function of LSECs. Our results revealed significant local variations in hydrogel stiffness and differences in pore sizes. The primary LSECs cultured on these substrates had a range of stiffnesses and were analyzed with regard to their number of fenestrations, cytoskeletal organization, and endocytic function. To explore mechanotransduction in inflammatory liver disease, we investigated LSECs from a genetic model of systemic inflammation triggered by the deletion of Mcpip1 in myeloid leukocytes and examined their ability to restore their fenestrations on soft substrates. Our study demonstrates the beneficial effect of soft hydrogels on LSECs. Control cells exhibited a similar fenestrated morphology and function compared to cells cultured on plastic substrates. However, the pathological LSECs from the genetic model of systemic inflammation regained their fenestrations when cultured on soft hydrogels. This observation supports previous findings on the beneficial effects of soft substrates on LSEC fenestration status. Full article

(This article belongs to the Section Cell Microenvironment)

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24 pages, 6557 KiB

Open AccessArticle

LFA-1/ICAM-1 Interactions Between CD8⁺ and CD4⁺ T Cells Promote CD4⁺ Th1-Dominant Differentiation and CD8⁺ T Cell Cytotoxicity for Strong Antitumor Immunity After Cryo-Thermal Therapy

by Yichen Yao, Zelu Zhang, Shicheng Wang, Junjun Wang, Yuankai Hao, Ke Wang and Ping Liu

Cells 2025, 14(8), 620; https://doi.org/10.3390/cells14080620 - 21 Apr 2025

Abstract

CD4⁺ T cells have been well-regarded as “helper” cells in activating the cytotoxicity of CD8⁺ T cells for effective tumor eradication, while few studies have focused on whether CD8⁺ T cells regulate CD4⁺ T cells. Our previous studies provided [...] Read more.

CD4⁺ T cells have been well-regarded as “helper” cells in activating the cytotoxicity of CD8⁺ T cells for effective tumor eradication, while few studies have focused on whether CD8⁺ T cells regulate CD4⁺ T cells. Our previous studies provided evidence for an interaction between CD4⁺ and CD8⁺ T cells after cryo-thermal therapy, but the mechanism remains unclear, especially pertaining to how CD8⁺ T cells promote the Th1 differentiation of CD4⁺ T cells. This study revealed that activated CD4⁺ and CD8⁺ T cells are critical for CTT-induced antitumor immunity, and the interaction between activated T cells is enhanced. The reciprocal regulation of activated CD8⁺ and CD4⁺ T cells was through LFA-1/ICAM-1 interactions, in which CD8⁺ T cells facilitate Notch1-dependent CD4⁺ Th1-dominant differentiation and promote IL-2 secretion of CD4⁺ T cells. Meanwhile, IL-2 derived from CD4⁺ T cells enhances the cytotoxicity of CD8⁺ T cells and establishes a positive feedback loop via increasing the expression of LFA-1 and ICAM-1 on T cells. Clinical analyses further validated that LFA-1/ICAM interactions between CD4⁺ and CD8⁺ T cells are correlated with clinical outcomes. Our study extends the functions of the LFA-1/ICAM-1 adhesion pathway, indicating its novel role in the interaction of CD4⁺ and CD8⁺ T cells. Full article

(This article belongs to the Section Cell Signaling)

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48 pages, 5608 KiB

Open AccessReview

Induced Pluripotent Stem Cells-Based Regenerative Therapies in Treating Human Aging-Related Functional Decline and Diseases

by Peijie Yu, Bin Liu, Cheng Dong and Yun Chang

Cells 2025, 14(8), 619; https://doi.org/10.3390/cells14080619 - 21 Apr 2025

Abstract

A significant increase in life expectancy worldwide has resulted in a growing aging population, accompanied by a rise in aging-related diseases that pose substantial societal, economic, and medical challenges. This trend has prompted extensive efforts within many scientific and medical communities to develop [...] Read more.

A significant increase in life expectancy worldwide has resulted in a growing aging population, accompanied by a rise in aging-related diseases that pose substantial societal, economic, and medical challenges. This trend has prompted extensive efforts within many scientific and medical communities to develop and enhance therapies aimed at delaying aging processes, mitigating aging-related functional decline, and addressing aging-associated diseases to extend health span. Research in aging biology has focused on unraveling various biochemical and genetic pathways contributing to aging-related changes, including genomic instability, telomere shortening, and cellular senescence. The advent of induced pluripotent stem cells (iPSCs), derived through reprogramming human somatic cells, has revolutionized disease modeling and understanding in humans by addressing the limitations of conventional animal models and primary human cells. iPSCs offer significant advantages over other pluripotent stem cells, such as embryonic stem cells, as they can be obtained without the need for embryo destruction and are not restricted by the availability of healthy donors or patients. These attributes position iPSC technology as a promising avenue for modeling and deciphering mechanisms that underlie aging and associated diseases, as well as for studying drug effects. Moreover, iPSCs exhibit remarkable versatility in differentiating into diverse cell types, making them a promising tool for personalized regenerative therapies aimed at replacing aged or damaged cells with healthy, functional equivalents. This review explores the breadth of research in iPSC-based regenerative therapies and their potential applications in addressing a spectrum of aging-related conditions. Full article

(This article belongs to the Special Issue The Potential of Induced Pluripotent Stem Cells)

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24 pages, 1421 KiB

Open AccessReview

Mitochondrial Dysfunction: A New Hallmark in Hereditable Thoracic Aortic Aneurysm Development

by Daniel Marcos-Ríos, Antonio Rochano-Ortiz, Irene San Sebastián-Jaraba, María José Fernández-Gómez, Nerea Méndez-Barbero and Jorge Oller

Cells 2025, 14(8), 618; https://doi.org/10.3390/cells14080618 - 21 Apr 2025

Abstract

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension [...] Read more.

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension and hereditary genetic mutations. Among the hereditary causes, Marfan syndrome is the most prevalent, characterized as a connective tissue disorder driven by FBN1 mutations that lead to life-threatening thoracic aortic ruptures. Similarly, mutations affecting the TGF-β pathway underlie Loeys–Dietz syndrome, while mutations in genes encoding extracellular or contractile apparatus proteins, such as ACTA2, are linked to non-syndromic familial TAA. Despite differences in genetic origin, these hereditary conditions share central pathophysiological features, including aortic medial degeneration, smooth muscle cell dysfunction, and extracellular remodeling, which collectively weaken the aortic wall. Recent evidence highlights mitochondrial dysfunction as a crucial contributor to aneurysm formation in Marfan syndrome. Disruption of the extracellular matrix–mitochondrial homeostasis axis exacerbates aortic wall remodeling, further promoting aneurysm development. Beyond its structural role in maintaining vascular integrity, the ECM plays a pivotal role in supporting mitochondrial function. This intricate relationship between extracellular matrix integrity and mitochondrial homeostasis reveals a novel dimension of TAA pathophysiology, extending beyond established paradigms of extracellular matrix remodeling and smooth muscle cell dysfunction. This review summarizes mitochondrial dysfunction as a potential unifying mechanism in hereditary TAA and explores how understanding mitochondrial dysfunction, in conjunction with established mechanisms of TAA pathogenesis, opens new avenues for developing targeted treatments to address these life-threatening conditions. Mitochondrial boosters could represent a new clinical opportunity for patients with hereditary TAA. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Marfan Syndrome)

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16 pages, 5298 KiB

Open AccessArticle

Neuregulin-1 (NRG1) Binds to the Allosteric Binding Site (Site 2) and Suppresses Allosteric Integrin Activation by Inflammatory Cytokines: A Potential Mechanism of Anti-Inflammatory and Anti-Fibrosis Action of NRG1

by Yoko K. Takada and Yoshikazu Takada

Cells 2025, 14(8), 617; https://doi.org/10.3390/cells14080617 - 21 Apr 2025

Abstract

We showed that multiple inflammatory cytokines (e.g., CCL5, CXCL12, CX3CL1, CD40L, and FGF2) bind to the allosteric site (site 2) of integrins, distinct from the classical RGD-binding site (site 1), and allosterically activate integrins. A major inflammatory lipid mediator 25-hydroxycholesterol is known to [...] Read more.

We showed that multiple inflammatory cytokines (e.g., CCL5, CXCL12, CX3CL1, CD40L, and FGF2) bind to the allosteric site (site 2) of integrins, distinct from the classical RGD-binding site (site 1), and allosterically activate integrins. A major inflammatory lipid mediator 25-hydroxycholesterol is known to bind to site 2 and allosterically activates integrins and induces inflammatory signals (e.g., IL-6 and TNF secretion). Thus, site 2 is involved in inflammatory signaling. Neuregulin-1 (NRG1) is known to suppresses the progression of inflammatory diseases, fibrosis, and insulin resistance. But, the mechanism of anti-inflammatory action of NRG1 is unclear. We previously showed that NRG1 binds to the classical RGD-binding site (site 1). Mutating the 3 Lys residues that are involved in site 1 binding (NRG1 3KE mutant) is defective in binding to site 1 and in ErbB3-mediated mitogenic signals. Docking simulation predicted that NRG1 binds to site 2. We hypothesized that NRG1 acts as an antagonist of site 2 and blocks allosteric activation by multiple cytokines. Here, we describe that NRG1 binds to site 2 but does not activate soluble αvβ3 or αIIbβ3 in 1 mM Ca²⁺, unlike inflammatory cytokines. Instead, NRG1 suppressed integrin activation by several inflammatory cytokines, suggesting that NRG1 acts as a competitive inhibitor of site 2. Wild-type NRG1 is not suitable for long-term treatment due to its mitogenicity. We showed that the non-mitogenic NRG1 3KE mutant still bound to site 2 and inhibited allosteric activation of soluble and cell-surface integrins, suggesting that NRG1 3KE may have potential as a therapeutic. Full article

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18 pages, 2372 KiB

Open AccessReview

LncRNAs Regulate Vasculogenic Mimicry in Human Cancers

by Eloísa Ibarra-Sierra, Mercedes Bermúdez, Carlos Esteban Villegas-Mercado, Macrina B. Silva-Cázares and César López-Camarillo

Cells 2025, 14(8), 616; https://doi.org/10.3390/cells14080616 - 20 Apr 2025

Abstract

Vasculogenic mimicry (VM) has recently been discovered as an alternative mechanism for nourishing cancer cells in vivo. During VM, tumor cells align and organize themselves into three-dimensional (3D) channel-like structures to transport nutrients and oxygen to the internal layers of tumors. This mechanism [...] Read more.

Vasculogenic mimicry (VM) has recently been discovered as an alternative mechanism for nourishing cancer cells in vivo. During VM, tumor cells align and organize themselves into three-dimensional (3D) channel-like structures to transport nutrients and oxygen to the internal layers of tumors. This mechanism mainly occurs in aggressive solid tumors and has been associated with poor prognosis in oncologic patients. Long non-coding RNAs (lncRNAs) are essential regulators of protein-encoding genes involved in cancer development and progression. These single-stranded RNA molecules regulate critical cellular functions in cancer cells including cell proliferation, apoptosis, angiogenesis, VM, therapy response, migration, invasion, and metastasis. Recently, high-throughput RNA-sequencing technologies have identified thousands of lncRNAs, but only a small percentage of them have been functionally characterized in human cancers. The vast amount of data about its genomic expression in tumors can allow us to dissect their functions in cancer biology and make them suitable biomarkers for cancer diagnosis and prognosis. In this study, we reviewed the current knowledge about the role of lncRNAs in regulating VM in cancer. We also examined the molecular mechanisms of lncRNAs and highlight several commonalities in the cellular functions associated with VM between diverse cancer types. Future directions for research focused on deciphering their function in VM are delineated. Finally, the potential of selected lncRNAs as novel therapeutic targets in RNA-based molecular interventions is also discussed. Full article

(This article belongs to the Special Issue Non-Coding and Coding RNAs in Targeted Cancer Therapy)

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24 pages, 2785 KiB

Open AccessArticle

A Mimetic Assay of Neutrophil Extracellular Trap Degradation Using YOYO-1-Stained DNA-Histone Surface Webs

by Katherine H. Nguyen, Midori L. Wasielewski, Srilakshmi Yalavarthi, Xianggui Qu, Jason S. Knight and Shuichi Takayama

Cells 2025, 14(8), 615; https://doi.org/10.3390/cells14080615 - 19 Apr 2025

Viewed by 48

Abstract

Neutrophil extracellular traps (NETs) are not only promising biomarkers of disease, but also potential therapeutic targets. Overproduction or the improper clearance of NETs has been linked to disease severity. In vitro NET degradation assays can reveal mechanisms and degradation efficiency differences in diseased [...] Read more.

Neutrophil extracellular traps (NETs) are not only promising biomarkers of disease, but also potential therapeutic targets. Overproduction or the improper clearance of NETs has been linked to disease severity. In vitro NET degradation assays can reveal mechanisms and degradation efficiency differences in diseased serum samples. There is a need for more convenient assays to increase the speed of NET degradation studies. This paper describes a simplified, lower variability mimetic assay with DNA–histone structures, referred to as surface webs, that performs functionally similarly to traditional NET degradation assays with increased scalability, ease of use, shorter preparation time, and lowered costs. The surface webs are created and dehydrated in a 96-well microplate that is shelf-stable, transportable, and viable for 30 days of storage at room temperature. The surface webs, compared to NETs, have similar shapes and distribution but lower intraplate variability while degrading with healthy serum and DNase I within the same timeframe. The assay can identify patient serum with reduced degradation capabilities. This assay opens new opportunities for NET-targeted drug discovery and studies on the role of NETs as modulators of disease. Full article

(This article belongs to the Special Issue Formation, Aggregation, Persistence, and Maturation of NETs)

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33 pages, 2137 KiB

Open AccessReview

REDOX Imbalance and Oxidative Stress in the Intervertebral Disc: The Effect of Mechanical Stress and Cigarette Smoking on ER Stress and Mitochondrial Dysfunction

by Hui Li, Joshua Kelley, Yiqing Ye, Zhi-Wei Ye, Danyelle M. Townsend, Jie Zhang and Yongren Wu

Cells 2025, 14(8), 613; https://doi.org/10.3390/cells14080613 - 19 Apr 2025

Viewed by 63

Abstract

Low back pain is a widespread condition that significantly impacts quality of life, with intervertebral disc degeneration (IDD) being a major contributing factor. However, the underlying mechanisms of IDD remain poorly understood, necessitating further investigation. Environmental risk factors, such as mechanical stress and [...] Read more.

Low back pain is a widespread condition that significantly impacts quality of life, with intervertebral disc degeneration (IDD) being a major contributing factor. However, the underlying mechanisms of IDD remain poorly understood, necessitating further investigation. Environmental risk factors, such as mechanical stress and cigarette smoke, elevate reactive oxygen species levels from both endogenous and exogenous sources, leading to redox imbalance and oxidative stress. The endoplasmic reticulum (ER) and mitochondria, two key organelles responsible for protein folding and energy production, respectively, are particularly vulnerable to oxidative stress. Under oxidative stress conditions, ER stress and mitochondrial dysfunction occur, resulting in unfolded protein response activation, impaired biosynthetic processes, and disruptions in the tricarboxylic acid cycle and electron transport chain, ultimately compromising energy metabolism. Prolonged and excessive ER stress can further trigger apoptosis through ER–mitochondrial crosstalk. Given the unique microenvironment of the intervertebral disc (IVD)—characterized by hypoxia, glucose starvation, and region-specific cellular heterogeneity—the differential effects of environmental stressors on distinct IVD cell populations require further investigation. This review explores the potential mechanisms through which environmental risk factors alter IVD cell activities, contributing to IDD progression, and discusses future therapeutic strategies aimed at mitigating disc degeneration. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress Signaling Pathway: From Bench to Bedside)

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16 pages, 4274 KiB

Open AccessArticle

Proportions of Basement Membrane Proteins in Cerebrovascular Smooth Muscle Cells After Exposure to Hypercapnia and Amyloid Beta

by Jennifer M. Dewing, Abby Keable, Alexandru Laslo, Laura Chinezu, Adrian Ivanescu, J. Arjuna Ratnayaka, Raj Kalaria, Mark Slevin, Ajay Verma and Roxana O. Carare

Cells 2025, 14(8), 614; https://doi.org/10.3390/cells14080614 - 18 Apr 2025

Viewed by 133

Abstract

Vascular basement membranes (BMs), composed of laminins, collagen IV, fibronectin, and perlecan, are secreted by endothelial cells, pericytes, smooth muscle cells (SMCs), and astrocytes. In the brain, amyloid beta (Aβ) is eliminated along cerebrovascular BMs of capillaries and arteries as intramural periarterial drainage [...] Read more.

Vascular basement membranes (BMs), composed of laminins, collagen IV, fibronectin, and perlecan, are secreted by endothelial cells, pericytes, smooth muscle cells (SMCs), and astrocytes. In the brain, amyloid beta (Aβ) is eliminated along cerebrovascular BMs of capillaries and arteries as intramural periarterial drainage (IPAD). Ageing modifies vascular BMs, impairing IPAD and leading to Aβ deposition as cerebral amyloid angiopathy. To better understand the molecular determinants of IPAD in ageing, we quantified the relative abundance of BMs secreted by human-derived cerebral endothelial cells, pericytes, brain vascular SMCs, and astrocytes in vitro. We then assessed BM protein levels in SMCs under hypercapnia (8% CO₂) as a model of vascular ageing, with and without Aβ exposure. Of the four cell types, we found SMCs secreted the highest levels of fibronectin, laminin, and perlecan, whilst pericytes secreted the highest levels of collagen IV. Hypercapnia increased the expression of collagen IV and fibronectin in SMCs but decreased the expression of laminin. The expression of perlecan increased under hypercapnia, but only in the presence of Aβ. This work highlights the varying compositions of vascular BMs and the dynamic differential responses of SMCs to Aβ and hypercapnia, helping to elucidate the age-related changes that impair IPAD in cerebral vessels. Full article

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14 pages, 1878 KiB

Open AccessArticle

The miR-146a Single Nucleotide Polymorphism rs2910164 Promotes Proliferation, Chemoresistance, Migration, Invasion, and Apoptosis Suppression in Breast Cancer Cells

by Sarai Morales-González, Gloria M. Calaf, Mónica Acuña, Julio C. Tapia and Lilian Jara

Cells 2025, 14(8), 612; https://doi.org/10.3390/cells14080612 - 18 Apr 2025

Viewed by 66

Abstract

Breast cancer (BC) is the most common malignant disease in women worldwide. Several studies have reported that microRNA-146a (miR-146a) dysregulation plays a role in multiple cancers, including BC. However, the mechanism underlying this association is controversial, possibly reflecting diverse roles for this miR [...] Read more.

Breast cancer (BC) is the most common malignant disease in women worldwide. Several studies have reported that microRNA-146a (miR-146a) dysregulation plays a role in multiple cancers, including BC. However, the mechanism underlying this association is controversial, possibly reflecting diverse roles for this miR in different types of cancer. The SNP rs2910164:G>C, located within the miR-146a precursor, has been linked to a BC risk. Our group previously showed a specific association between rs2910164:G>C and an increased BC risk in patients with early-onset sporadic BC. There are no studies in the literature that evaluate the functional consequences of the rs2910164 polymorphism in the BC process. Therefore, the goal of the present study was to evaluate in vitro the effect of the SNP rs2910164:G>C on BC progression in luminal A and triple-negative cell lines. We found that rs2910164:G>C upregulated the expression of two mature miR-146a sequences, 3p and 5p. Furthermore, pre-miR-146a-C enhanced proliferation, migration, and invasion in luminal A and triple-negative breast cells, as well as decreasing cisplatin-induced apoptosis. Interestingly, the pre-miR-146a C allele decreased cisplatin resistance in MCF-7 cells but increased cisplatin resistance in MDA-MB-231 cells. We propose that the rs2910164 C allele promotes miR-146a overexpression, which is causally involved in proliferation, migration, invasion, apoptosis, and cisplatin resistance. Full article

(This article belongs to the Collection MicroRNAs in Cancer: From Molecular Mechanisms to Applications in Diagnostic and Therapeutic Opportunities)

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19 pages, 6672 KiB

Open AccessArticle

Substrate Stiffness Modulates TGF-β1-Induced Lineage Specification in Multipotent Vascular Stem Cells

by Yujie Yan, Yuhang Wang, Julia S. Chu, Li Yang, Xian Li and Song Li

Cells 2025, 14(8), 611; https://doi.org/10.3390/cells14080611 - 17 Apr 2025

Viewed by 114

Abstract

Multipotent vascular stem cells (MVSCs) are found in the vascular wall and surrounding tissues and possess the ability to differentiate into mesenchymal lineages. Previous studies have shown that MVSCs can be activated in response to vascular injury and differentiate into vascular smooth muscle [...] Read more.

Multipotent vascular stem cells (MVSCs) are found in the vascular wall and surrounding tissues and possess the ability to differentiate into mesenchymal lineages. Previous studies have shown that MVSCs can be activated in response to vascular injury and differentiate into vascular smooth muscle cells (SMCs), contributing to vascular remodeling and microvessel formation. However, it remains unclear as to whether and how microenvironmental changes in the extracellular matrix, such as substrate stiffness, modulates MVSC differentiation under pathological conditions. This study demonstrated that MVSCs cultured on stiff substrates exhibited increased cell spreading, stronger cell adhesion, and a higher expression of SMC markers, including myosin heavy chain (MHC), myocardin (MYCD), calponin 1 (CNN1), and smooth muscle α-actin (SMA). In contrast, MVSCs on soft substrates showed an elevated expression of the chondrogenic markers aggrecan 1 (AGC1) and collagen-II (COL2A1). The presence of TGF-β1 further increased the expression of SMC markers on stiff substrates and chondrogenic markers on the soft substrates. Collectively, these results establish substrate stiffness as a key regulator of MVSC lineage commitment through cytoskeletal reorganization, with TGF-β1 acting as a biochemical amplifier. Our findings highlight the substrate-stiffness-dependent differentiation of MVSCs and provide mechanistic insights into the role of MVSCs in vascular remodeling during atherosclerosis development and blood vessel regeneration. Full article

(This article belongs to the Section Stem Cells)

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23 pages, 1493 KiB

Open AccessReview

Psoriasis in Obese Adolescents with Diabetes—From Common Molecular Background to Vicious Circle of Metabolic Syndrome—Case Report and Review of Literature

by Angelika Bielach-Bazyluk, Filip Bossowski, Magdalena Skorupska, Hanna Mysliwiec, Artur Tadeusz Bossowski and Iwona Flisiak

Cells 2025, 14(8), 610; https://doi.org/10.3390/cells14080610 - 17 Apr 2025

Viewed by 88

Abstract

Psoriasis and type 1 diabetes mellitus (T1DM) are chronic autoimmune diseases sharing common immunological pathways, particularly the involvement of interleukin 17 (IL-17), driving Th17-mediated inflammation. This review explores the overlap between psoriasis, obesity, T1DM, and necrobiosis lipoidica (NL), a skin condition associated with [...] Read more.

Psoriasis and type 1 diabetes mellitus (T1DM) are chronic autoimmune diseases sharing common immunological pathways, particularly the involvement of interleukin 17 (IL-17), driving Th17-mediated inflammation. This review explores the overlap between psoriasis, obesity, T1DM, and necrobiosis lipoidica (NL), a skin condition associated with diabetes. Obesity exacerbates inflammation through immune cell activation in adipose tissue and the release of proinflammatory adipokines, such as leptin, resistin, and IL-18, which enhance autoimmune responses and insulin resistance. Leptin promotes the differentiation of Th1 and Th17 cells, which are central to autoimmune responses in both psoriasis and T1DM. The coexistence of psoriasis, T1DM, and insulin resistance further complicates metabolic control, increasing the risk of complications like diabetic nephropathy and cardiovascular disease. Biologic treatments targeting IL-17A and IL-17F offer promising therapeutic options for managing both skin and metabolic symptoms. The early identification and management of metabolic risk factors, along with personalized interventions, are essential to improve clinical outcomes in patients with psoriasis and T1DM, particularly in obese individuals. This case report and review highlight the complex interplay of these conditions and emphasize the need for integrated treatment strategies. Full article

(This article belongs to the Special Issue Cellular and Clinical Mechanisms of Obesity and Diabetes and Their Complications)

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24 pages, 1380 KiB

Open AccessReview

The Role of Oxidative Stress and Inflammation in the Pathogenesis and Treatment of Vascular Dementia

by Aseel Y. Altahrawi, Antonisamy William James and Zahoor A. Shah

Cells 2025, 14(8), 609; https://doi.org/10.3390/cells14080609 - 17 Apr 2025

Viewed by 225

Abstract

Vascular dementia (VaD) is a heterogeneous group of brain disorders caused by cerebrovascular pathologies and the second most common cause of dementia, accounting for over 20% of cases and posing an important global health concern. VaD can be caused by cerebral infarction or [...] Read more.

Vascular dementia (VaD) is a heterogeneous group of brain disorders caused by cerebrovascular pathologies and the second most common cause of dementia, accounting for over 20% of cases and posing an important global health concern. VaD can be caused by cerebral infarction or injury in critical brain regions, including the speech area of the dominant hemisphere or arcuate fasciculus of the dominant hemisphere, leading to notable cognitive impairment. Although the exact causes of dementia remain multifactorial and complex, oxidative stress (reactive oxygen species), neuroinflammation (TNFα, IL-6, and IL-1β), and inflammasomes are considered central mechanisms in its pathology. These conditions contribute to neuronal damage, synaptic dysfunction, and cognitive decline. Thus, antioxidants and anti-inflammatory agents have emerged as potential therapeutic targets in dementia. Recent studies emphasize that cerebrovascular disease plays a dual role: first, as a primary cause of cognitive impairment and then as a contributor to the manifestation of dementia driven by other factors, such as Alzheimer’s disease and other neurodegenerative conditions. This comprehensive review of VaD focuses on molecular mechanisms and their consequences. We provided up-to-date knowledge about epidemiology, pathophysiological mechanisms, and current therapeutic approaches for VaD. Full article

(This article belongs to the Special Issue Molecular Pathways and Potential Therapeutic Targets of Vascular Dysfunction)

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19 pages, 1388 KiB

Open AccessReview

SASP Modulation for Cellular Rejuvenation and Tissue Homeostasis: Therapeutic Strategies and Molecular Insights

by Saud Alqahtani, Taha Alqahtani, Krishnaraju Venkatesan, Durgaramani Sivadasan, Rehab Ahmed, Nizar Sirag, Hassabelrasoul Elfadil, Hanem Abdullah Mohamed, Haseena T.A., Rasha Elsayed Ahmed, Pooja Muralidharan and Premalatha Paulsamy

Cells 2025, 14(8), 608; https://doi.org/10.3390/cells14080608 - 17 Apr 2025

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Abstract

Cellular senescence regulates aging, tissue maintenance, and disease progression through the Senescence-Associated Secretory Phenotype (SASP), a secretory profile of cytokines, chemokines, growth factors, and matrix-remodeling enzymes. While transient SASP aids wound healing, its chronic activation drives inflammation, fibrosis, and tumorigenesis. This review examines [...] Read more.

Cellular senescence regulates aging, tissue maintenance, and disease progression through the Senescence-Associated Secretory Phenotype (SASP), a secretory profile of cytokines, chemokines, growth factors, and matrix-remodeling enzymes. While transient SASP aids wound healing, its chronic activation drives inflammation, fibrosis, and tumorigenesis. This review examines SASP’s molecular regulation, dual roles in health and pathology, and therapeutic potential. The following two main strategies are explored: senescence clearance, which eliminates SASP-producing cells, and SASP modulation, which refines secretion to suppress inflammation while maintaining regenerative effects. Key pathways, including NF-κB, C/EBPβ, and cGAS-STING, are discussed alongside pharmacological, immunotherapeutic, gene-editing, and epigenetic interventions. SASP heterogeneity necessitates tissue-specific biomarkers for personalized therapies. Challenges include immune interactions, long-term safety, and ethical considerations. SASP modulation emerges as a promising strategy for aging, oncology, and tissue repair, with future advancements relying on multi-omics and AI-driven insights to optimize clinical outcomes. Full article

(This article belongs to the Special Issue Cell Death: Cell–Cell Interactions and Signaling Networks)

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24 pages, 1430 KiB

Open AccessReview

Immune Dysregulation in Depression and Anxiety: A Review of the Immune Response in Disease and Treatment

by Christopher Hole, Akash Dhamsania, Cassandra Brown and Rebecca Ryznar

Cells 2025, 14(8), 607; https://doi.org/10.3390/cells14080607 - 17 Apr 2025

Viewed by 270

Abstract

Rates of depression and anxiety have increased significantly in recent decades, with many patients experiencing treatment-resistant symptoms. Beyond psychiatric manifestations, these conditions are associated with heightened risks of suicide, cardiovascular disease, chronic pain, and fatigue. Emerging research suggests that neuroinflammation, immune dysregulation, and [...] Read more.

Rates of depression and anxiety have increased significantly in recent decades, with many patients experiencing treatment-resistant symptoms. Beyond psychiatric manifestations, these conditions are associated with heightened risks of suicide, cardiovascular disease, chronic pain, and fatigue. Emerging research suggests that neuroinflammation, immune dysregulation, and hypothalamic–pituitary–adrenal axis dysfunction contribute to their pathophysiology, often interacting bidirectionally with stress. While current first-line treatments primarily target neurotransmitter imbalances, many patients do not achieve symptom resolution, highlighting the need for novel approaches. This review explores the role of immune dysfunction, cytokine activity, and neurotransmitter interactions in depression and anxiety. Additionally, we examine how existing pharmacological and non-pharmacological interventions influence inflammation and immune responses. Understanding these mechanisms may pave the way for more integrative treatment strategies that combine immune modulation with traditional psychiatric therapies. Full article

(This article belongs to the Special Issue Inflammatory Pathways in Psychiatric Disorders)

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47 pages, 1310 KiB

Open AccessReview

Impact of High-Efficacy Therapies for Multiple Sclerosis on B Cells

by Federica Galota, Simone Marcheselli, Sara De Biasi, Lara Gibellini, Francesca Vitetta, Alessia Fiore, Krzysztof Smolik, Giulia De Napoli, Martina Cardi, Andrea Cossarizza and Diana Ferraro

Cells 2025, 14(8), 606; https://doi.org/10.3390/cells14080606 - 17 Apr 2025

Viewed by 333

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative autoimmune disorder of the central nervous system characterized by demyelination and neurodegeneration. Traditionally considered a T-cell-mediated disease, the crucial role of B lymphocytes in its pathogenesis, through different mechanisms contributing to inflammation and autoreactivity, [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative autoimmune disorder of the central nervous system characterized by demyelination and neurodegeneration. Traditionally considered a T-cell-mediated disease, the crucial role of B lymphocytes in its pathogenesis, through different mechanisms contributing to inflammation and autoreactivity, is increasingly recognized. The risk of long-term disability in MS patients can be reduced by an early treatment initiation, in particular with high-efficacy therapies. The aim of this review is to provide an overview of the mechanisms of action of high-efficacy therapies for MS, with a focus on their impact on B cells and how this contributes to the drugs’ efficacy and safety profiles. Anti-CD20 monoclonal antibodies, Alemtuzumab, Cladribine and sequestering therapies encompassing Natalizumab and S1P receptors modulators will be discussed and emerging therapies, including Bruton’s Tyrosine Kinase inhibitors, will be presented. Full article

(This article belongs to the Special Issue Cell Biology: State of the Art and Perspectives in Italy 2025)

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19 pages, 10222 KiB

Open AccessArticle

L-Tryptophan-Rich Diet Alleviates High-Intensity-Exercise-Induced Liver Dysfunction via the Metabolite Indole-3-Acetic Acid and AhR Activation

by Dawei Wang, Pengfei Hou, Hedong Lang, Yundong Xia, Qian Bai, Yu Yao, Long Yi and Mantian Mi

Cells 2025, 14(8), 605; https://doi.org/10.3390/cells14080605 - 16 Apr 2025

Viewed by 173

Abstract

High-intensity exercise (HIE) induces liver dysfunction and is detrimental to exercise performance. The underlying mechanism and preventive strategy urgently need to be explored. We increased the amount of tryptophan appropriately in the diet and explored the effect of an L-tryptophan-rich diet on the [...] Read more.

High-intensity exercise (HIE) induces liver dysfunction and is detrimental to exercise performance. The underlying mechanism and preventive strategy urgently need to be explored. We increased the amount of tryptophan appropriately in the diet and explored the effect of an L-tryptophan-rich diet on the alleviation of HIE-induced liver dysfunction and the underlying mechanism. In this work, by establishing a C57BL/6 mouse model of high-intensity swimming exercise, the results demonstrated an L-tryptophan-rich diet significantly attenuated HIE-induced liver dysfunction, which was associated with increased levels of the tryptophan metabolite indole-3-acetic acid (IAA). Furthermore, IAA indeed exerted a protective effect against HIE-induced liver dysfunction in vivo and LPS-induced hepatocyte dysfunction in vitro. In conclusion, an L-tryptophan-rich diet may be a promising strategy to prevent HIE-induced liver dysfunction and metabolic disturbance via the metabolite indole-3-acetic acid and AhR activation. Full article

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16 pages, 3922 KiB

Open AccessArticle

Memory T Cell Subsets Expressing Tissue Homing Receptors and Chemokine Levels in Human Tegumentary Leishmaniasis

by Julia Pimentel, M. Fernanda García Bustos, Paula Ragone, Jorge D. Marco, Paola Barroso, Andrea Cecilia Mesías, Mercedes Basombrío, María Occhionero, Federico Ramos, Susana Adriana Laucella, Cecilia Pérez Brandán and Cecilia Parodi

Cells 2025, 14(8), 604; https://doi.org/10.3390/cells14080604 - 16 Apr 2025

Viewed by 164

Abstract

Tegumentary leishmaniasis (TL) presents two main clinical forms: cutaneous (CL) and mucosal (ML) leishmaniasis affecting skin and nasopharyngeal mucosa. Due to parasite localization through disease stages, recruitment of T cells expressing chemokine receptors and their ligands will influence the generated host responses. The [...] Read more.

Tegumentary leishmaniasis (TL) presents two main clinical forms: cutaneous (CL) and mucosal (ML) leishmaniasis affecting skin and nasopharyngeal mucosa. Due to parasite localization through disease stages, recruitment of T cells expressing chemokine receptors and their ligands will influence the generated host responses. The aim of this work was to characterize differential profiles of T cells expressing chemokine receptors and their plasma ligands by flow cytometry and ELISA. CL patients showed increased numbers of effector memory CD4⁺ T cells expressing skin homing receptors (CLA, CCR4), with the reversion of this effector phenotype observed after achieving clinical recovery. Meanwhile, ML patients showed higher frequencies of effector memory/terminal effector CD4⁺ and CD8⁺ T cells expressing chemokine receptors directed to skin (CLA, CCR4, CCR10) and mucosal (CCR6) tissues. Additionally, we reported that plasma amounts of ligands (CCL17, CCL20) vary according to the clinical form of TL. Finally, we demonstrated the ability of Leishmania spp. to modulate chemokine production (CCL17) in vitro. This work highlights the effector T cell response directed to skin and mucosal tissues in TL, emphasizing the role of cytotoxic functions in ML. The studied chemokine receptors could contribute to predicting disease progression and guiding future studies targeting relevant receptors to diminish pathogenic effector functions. Full article

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12 pages, 1190 KiB

Open AccessReview

ESCRT Machinery in HBV Life Cycle: Dual Roles in Autophagy and Membrane Dynamics for Viral Pathogenesis

by Jia Li, Reinhild Prange and Mengji Lu

Cells 2025, 14(8), 603; https://doi.org/10.3390/cells14080603 - 16 Apr 2025

Viewed by 166

Abstract

The endosomal sorting complexes required for transport (ESCRT) comprise a fundamental cellular machinery with remarkable versatility in membrane remodeling. It is multifunctional in the multivesicular body (MVB) biogenesis, exosome formation and secretion, virus budding, cytokinesis, plasma membrane repair, neuron pruning, and autophagy. ESCRT’s [...] Read more.

The endosomal sorting complexes required for transport (ESCRT) comprise a fundamental cellular machinery with remarkable versatility in membrane remodeling. It is multifunctional in the multivesicular body (MVB) biogenesis, exosome formation and secretion, virus budding, cytokinesis, plasma membrane repair, neuron pruning, and autophagy. ESCRT’s involvement in cellular mechanisms extends beyond basic membrane trafficking. By directly interacting with autophagy-related (ATG) proteins and facilitating autophagosome-lysosome fusion, ESCRT ensures cellular homeostasis. Dysregulation in ESCRT function has been implicated in cancer, neurodegenerative disorders, and infectious diseases, underscoring its critical role in numerous pathologies. Hepatitis B virus (HBV) is an enveloped virus that exploits ESCRT and autophagy pathways for viral replication, assembly, and secretion. This review synthesizes recent mechanistic insights into ESCRT’s multifaceted roles, particularly focusing on its interactions with autophagy formation and the HBV lifecycle. Full article

(This article belongs to the Section Autophagy)

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22 pages, 8508 KiB

Open AccessArticle

Combining AdipoRon with Paclitaxel Unveils Synergistic Potential in Non-Small Cell Lung Cancer Cells via AMPK-ERK1/2 Signaling

by Sanober Kafeel, Giuseppina Palmiero, Alessia Salzillo, Angela Ragone, Silvio Naviglio and Luigi Sapio

Cells 2025, 14(8), 602; https://doi.org/10.3390/cells14080602 - 16 Apr 2025

Viewed by 126

Abstract

As part of chemotherapy regimens, Paclitaxel improves the overall survival of many non-small cell lung cancer (NSCLC) patients. However, the development of drug resistance and adverse events limits its clinical usage, reinforcing the need for further advancements in NSCLC therapeutics. We recently recognized [...] Read more.

As part of chemotherapy regimens, Paclitaxel improves the overall survival of many non-small cell lung cancer (NSCLC) patients. However, the development of drug resistance and adverse events limits its clinical usage, reinforcing the need for further advancements in NSCLC therapeutics. We recently recognized the adiponectin receptor agonist AdipoRon as a promising anticancer compound in NSCLC. Consequently, this study aimed to evaluate the therapeutic potential of combining AdipoRon with Paclitaxel (Combo) in NSCLC cells. With respect to individual treatments, Combo triggered a stronger inhibition of both cell growth and clonogenic potential, as well as a greater induction of cell death. The Combo-mediated cytotoxicity was also corroborated by cleavage of poly-ADP ribose polymerase (PARP) and caspase-3 apoptotic markers. Notably, AMP-activated protein kinase (AMPK) emerged as a critical sensor in Combo efficacy, as its inhibition by Compound-C unveiled a significant rescue in cell growth. Although Combo caused a gradual downregulation of extracellular signal-regulated kinase 1/2 (ERK1/2), the hindrance in the upstream cascade by PD98059 partially counteracted the Combo outcomes. In conclusion, our findings designate AdipoRon as an effective candidate in Paclitaxel-based therapy. Nevertheless, future studies aimed at exploring the Combo aptitude in overcoming the Paclitaxel-related restraints need to be investigated in NSCLC. Full article

(This article belongs to the Special Issue Emerging Targets and Therapeutic Potential Drugs in Tumor Progression and Therapeutic Resistance)

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15 pages, 2859 KiB

Open AccessArticle

The Influence of Sedimentation on the Composition of the Lipoaspirate and the Effects on Further Mechanical Processing

by Andreas Eigenberger, Oliver Felthaus, Alexander Bartsch, Tom Schimanski, Kirsten Utpatel and Lukas Prantl

Cells 2025, 14(8), 601; https://doi.org/10.3390/cells14080601 - 16 Apr 2025

Viewed by 167

Abstract

Manual processing of lipoaspirate can enhance stem cell concentration, thereby improving the take rate, which still represents a major challenge in autologous fat transfer. However, since the preparation consists of many manual steps that are difficult to standardize, we investigated the influence of [...] Read more.

Manual processing of lipoaspirate can enhance stem cell concentration, thereby improving the take rate, which still represents a major challenge in autologous fat transfer. However, since the preparation consists of many manual steps that are difficult to standardize, we investigated the influence of residual tumescent solution on the macroscopic and microscopic outcome of the mechanically processed lipoaspirate. Additionally, we investigated whether sedimentation followed by vacuum filtration of the aqueous phase could accelerate processing by replacing the initial centrifugation step. Samples with more than 5% remaining aqueous phase show no clearly defined oil phase, preventing any volume reduction. In contrast, all centrifuged samples produced a clear oil phase. The remaining tissue, as confirmed by both histology and viability assays, was superior to nanofat. Although sedimentation and filtration in the LipoCollector did not sufficiently separate enough aqueous phase from the lipoaspirate, tissue viability was significantly higher compared to our control container. Our findings indicate that centrifugation remains essential for effective aqueous phase separation and further mechanical processing, while the automatic filtration may enhance processing efficiency. These results indicate that further work is needed to simplify mechanical processing, as the outcome can be significantly influenced by parameters such as tumescent impurities. Full article

(This article belongs to the Section Tissues and Organs)

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19 pages, 889 KiB

Open AccessReview

Therapeutic Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Treatment of Parkinson’s Disease

by Ana Volarevic, Carl Randall Harrell, Aleksandar Arsenijevic, Valentin Djonov and Vladislav Volarevic

Cells 2025, 14(8), 600; https://doi.org/10.3390/cells14080600 - 16 Apr 2025

Viewed by 235

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the gradual loss of dopamine-producing neurons. Oxidative stress, mitochondrial dysfunction, detrimental immune response, and neuroinflammation are mainly responsible for the injury and degeneration of dopaminergic neurons in the brains of patients suffering from [...] Read more.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the gradual loss of dopamine-producing neurons. Oxidative stress, mitochondrial dysfunction, detrimental immune response, and neuroinflammation are mainly responsible for the injury and degeneration of dopaminergic neurons in the brains of patients suffering from PD. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic approach for treating PD due to their ability to suppress the activation of inflammatory immune cells and enhance the viability and function of dopamine-producing neurons. MSC-EVs can easily bypass the blood-brain barrier and deliver their cargo (neuroprotective factors, immunosuppressive proteins, and microRNAs) to injured dopamine-producing neurons and brain-infiltrated inflammatory immune cells. A large number of recently published experimental studies demonstrated that MSC-EVs efficiently alleviated PD-related motor and behavioral deficits in animal models, indicating that MSC-EVs should be considered as potentially new therapeutic agents for the treatment of PD. Accordingly, in this review article, we summarized current knowledge about the therapeutic potential of MSCs-EVs in the treatment of PD, paving the way for their future clinical use in the treatment of neurodegenerative and neuroinflammatory disorders. Full article

(This article belongs to the Special Issue Molecular Therapeutic Advances for Neurodegenerative Diseases)

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15 pages, 2571 KiB

Open AccessArticle

Dual Role of HNF4α in Colorectal Adenocarcinoma During Carcinogenesis and Metastasis

by Ju Seok Kim, Kyung-Hee Kim, Jun Young Heo, Min Kyung Choi and Min-Kyung Yeo

Cells 2025, 14(8), 599; https://doi.org/10.3390/cells14080599 - 15 Apr 2025

Viewed by 220

Abstract

Hepatocyte nuclear factor 4α (HNF4α), a highly conserved member of the nuclear receptor superfamily of transcription factors, has been identified as a promising therapeutic candidate for colorectal adenocarcinoma (CRAC). This study was to investigate the significance of HNF4α in CRAC and mechanisms governing [...] Read more.

Hepatocyte nuclear factor 4α (HNF4α), a highly conserved member of the nuclear receptor superfamily of transcription factors, has been identified as a promising therapeutic candidate for colorectal adenocarcinoma (CRAC). This study was to investigate the significance of HNF4α in CRAC and mechanisms governing its function. The expression patterns and clinical relevance of HNF4α were evaluated in relation to nuclear factor kappa B (NF-κb), Yes-associated protein (YAP), and epithelial–mesenchymal transition markers. HNF4α exhibited upregulation during carcinogenesis compared to normal and precancerous lesions. The overexpression and inhibition of HNF4α were correlated with the modulation of CRAC cell migration and invasion, either promoting or suppressing these processes. Notably, levels of HNF4α were significantly diminished in metastatic and poorly differentiated CRAC relative to primary CRAC samples. Moreover, reduced HNF4α levels were associated with unfavorable prognostic factors. The inhibition of HNF4A induced a decrease in NF-κb protein levels, concomitant with an increase in YAP. Our results indicate a dual role of HNF4α in tumor progression, either as a promotor or inhibitor, depending on the pathologic condition of CRAC and the related signaling pathways. HNF4α exhibits a complex role, whereby its overexpression is linked to early carcinogenesis and reduced expression is associated with the progression and metastasis of CRAC. Full article

(This article belongs to the Collection The Research of Biomarkers in Colorectal Cancer and Gastric Cancer)

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19 pages, 1311 KiB

Open AccessFeature PaperReview

Deciphering the Controversial Role of TP53 Inducible Glycolysis and Apoptosis Regulator (TIGAR) in Cancer Metabolism as a Potential Therapeutic Strategy

by Fatima I. AlMaazmi, Lara J. Bou Malhab, Leen ElDohaji and Maha Saber-Ayad

Cells 2025, 14(8), 598; https://doi.org/10.3390/cells14080598 - 15 Apr 2025

Viewed by 266

Abstract

Tumor metabolism has emerged as a critical target in cancer therapy, revolutionizing our understanding of how cancer cells grow, survive, and respond to treatment. Historically, cancer research focused on genetic mutations driving tumorigenesis, but in recent decades, metabolic reprogramming has been recognized as [...] Read more.

Tumor metabolism has emerged as a critical target in cancer therapy, revolutionizing our understanding of how cancer cells grow, survive, and respond to treatment. Historically, cancer research focused on genetic mutations driving tumorigenesis, but in recent decades, metabolic reprogramming has been recognized as a hallmark of cancer. The TP53 inducible glycolysis and apoptosis regulator, or TIGAR, affects a wide range of cellular and molecular processes and plays a key role in cancer cell metabolism by regulating the balance between glycolysis and antioxidant defense mechanisms. Cancer cells often exhibit a shift towards aerobic glycolysis (the Warburg effect), which allows rapid energy production and gives rise to biosynthetic intermediates for proliferation. By inhibiting glycolysis, TIGAR can reduce the proliferation rate of cancer cells, particularly in early-stage tumors or specific tissue types. This metabolic shift may limit the resources available for rapid cell division, thereby exerting a tumor-suppressive effect. However, this metabolic shift also leads to increased levels of reactive oxygen species (ROS), which can damage the cell if not properly managed. TIGAR helps protect cancer cells from excessive ROS by promoting the pentose phosphate pathway (PPP), which generates NADPH—a key molecule involved in antioxidant defense. Through its actions, TIGAR decreases the glycolytic flux while increasing the diversion of glucose-6-phosphate into the PPP. This reduces ROS levels and supports biosynthesis and cell survival by maintaining the balance of nucleotides and lipids. The role of TIGAR has been emerging as a prognostic and potential therapeutic target in different types of cancers. This review highlights the role of TIGAR in different types of cancer, evaluating its potential role as a diagnostic marker and a therapeutic target. Full article

(This article belongs to the Topic Cancer Cell Metabolism (2nd Edition))

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14 pages, 1144 KiB

Open AccessReview

MMP3 as a Molecular Link: Unraveling the Connection Between Ankylosing Spondylitis and Acute Coronary Syndrome

by Iliannis Y. Roa-Bruzón, Luis F. Duany-Almira, Yeminia M. Valle-Delgadillo, Héctor E. Flores-Salinas, Emmanuel Valdés-Alvarado and Jorge R. Padilla-Gutiérrez

Cells 2025, 14(8), 597; https://doi.org/10.3390/cells14080597 - 15 Apr 2025

Viewed by 191

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the joints, limiting patients’ mobility and quality of life. Recent studies have shown that patients with AS have a significantly higher risk of developing severe cardiovascular complications, such as acute coronary syndrome [...] Read more.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the joints, limiting patients’ mobility and quality of life. Recent studies have shown that patients with AS have a significantly higher risk of developing severe cardiovascular complications, such as acute coronary syndrome (ACS). A comprehensive review (2014–2024) included a study evaluating the significance of matrix metalloproteinase 3 (MMP-3) in cardiovascular risk among AS patients. The findings indicate that chronic inflammation in AS not only damages the joints but also contributes to the progression of cardiovascular diseases. At the molecular level, MMP-3 is instrumental in degrading the extracellular matrix, leading to instability in the atherosclerotic plaques and increasing the risk of ACS. Additionally, MMP-3 activation is related to the inflammatory pathways, such as tumor necrosis factor-alpha (TNF-α) and NF-κB, which amplify its effect on both joint destruction and vascular damage. This molecular approach offers new perspectives for understanding and treating AS and its cardiovascular complications, suggesting that MMP-3 inhibition could be a promising therapeutic strategy to mitigate cardiovascular risk in these patients. Full article

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28 pages, 9850 KiB

Open AccessReview

Primary Cilia, Hypoxia, and Liver Dysfunction: A New Perspective on Biliary Atresia

by Patrícia Quelhas, Diogo Morgado and Jorge dos Santos

Cells 2025, 14(8), 596; https://doi.org/10.3390/cells14080596 - 15 Apr 2025

Viewed by 525

Abstract

Ciliopathies are disorders that affect primary or secondary cellular cilia or structures associated with ciliary function. Primary cilia (PC) are essential for metabolic regulation and embryonic development, and pathogenic variants in cilia-related genes are linked to several pediatric conditions, including renal-hepatic diseases and [...] Read more.

Ciliopathies are disorders that affect primary or secondary cellular cilia or structures associated with ciliary function. Primary cilia (PC) are essential for metabolic regulation and embryonic development, and pathogenic variants in cilia-related genes are linked to several pediatric conditions, including renal-hepatic diseases and congenital defects. Biliary atresia (BA) is a progressive infantile cholangiopathy and the leading cause of pediatric liver transplantation. Although the exact etiology of BA remains unclear, evidence suggests a multifactorial pathogenesis influenced by both genetic and environmental factors. Patients with BA and laterality defects exhibit genetic variants associated with ciliopathies. Interestingly, even isolated BA without extrahepatic anomalies presents morphological and functional ciliary abnormalities, suggesting that environmental triggers may disrupt the ciliary function. Among these factors, hypoxia has emerged as a potential modulator of this dysfunction. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a central role in hepatic responses to oxygen deprivation, influencing bile duct remodeling and fibrosis, which are key processes in BA progression. This review explores the crosstalk between hypoxia and hepatic ciliopathies, with a focus on BA. It discusses the molecular mechanisms through which hypoxia may drive disease progression and examines the therapeutic potential of targeting hypoxia-related pathways. Understanding how oxygen deprivation influences ciliary function may open new avenues for treating biliary ciliopathies and improving patient outcomes. Full article

(This article belongs to the Special Issue The Role of Cilia in Health and Diseases—2nd Edition)

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30 pages, 2369 KiB

Open AccessReview

Phenotyping the Chemical Communications of the Intestinal Microbiota and the Host: Secondary Bile Acids as Postbiotics

by Ginevra Urbani, Elena Rondini, Eleonora Distrutti, Silvia Marchianò, Michele Biagioli and Stefano Fiorucci

Cells 2025, 14(8), 595; https://doi.org/10.3390/cells14080595 - 15 Apr 2025

Viewed by 646

Abstract

The current definition of a postbiotic is a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the [...] Read more.

The current definition of a postbiotic is a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health. Full article

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18 pages, 944 KiB

Open AccessReview

The Importance of Cancer Stem Cells and Their Pathways in Endometrial Cancer: A Narrative Review

by Laura Georgiana Caravia, Melinda Ildiko Mitranovici, Ioan Emilian Oala, Andreea Taisia Tiron, Anca Angela Simionescu, Alina Maria Borcan and Marius Craina

Cells 2025, 14(8), 594; https://doi.org/10.3390/cells14080594 - 14 Apr 2025

Viewed by 260

Abstract

Endometrial cancer is one of the most common malignancies seen in women in developed countries. While patients in the early stages of this cancer show better responses to surgery, adjuvant hormonal therapy, and chemotherapy, patients with recurrence show treatment resistance. Researchers have recently [...] Read more.

Endometrial cancer is one of the most common malignancies seen in women in developed countries. While patients in the early stages of this cancer show better responses to surgery, adjuvant hormonal therapy, and chemotherapy, patients with recurrence show treatment resistance. Researchers have recently focused on cancer stem cells (CSCs) in the treatment of gynecologic cancer in general but also specifically in endometrial cancer. CSCs have been investigated because of their resistance to conventional therapies, such as chemo- and radiotherapy, and their ability to induce the progression and recurrence of malignancy. The activation of alternative pathways, such as WNT, PI3K, NF-kB, or NOTCH, could be the basis of the acquisition of these abilities of CSCs. Their specific markers and signaling pathways could be treatment targets for CSCs. In this article, we discuss the importance of obtaining a better understanding of the molecular basis and pathways of CSCs in endometrial cancer and the role of CSCs, aiming to discover more specific therapeutic approaches. Full article

(This article belongs to the Special Issue Signaling Pathways in Endometrial Cancer Cells)

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21 pages, 9781 KiB

Open AccessArticle

LRG1 Alters Pericyte Phenotype and Compromises Vascular Maturation

by Alexandra E. Hoeh, Jui-Hsien Chang, Ronja S. Mueller, Mark Basche, Alessandro Fantin, Anastasios Sepetis, Giulia De Rossi, Athina Dritsoula, Robin R. Ali, Patric Turowski, Stephen E. Moss and John Greenwood

Cells 2025, 14(8), 593; https://doi.org/10.3390/cells14080593 - 14 Apr 2025

Viewed by 294

Abstract

Upregulation of leucine-rich alpha-2-glycoprotein-1 (LRG1) contributes to aberrant neovascularization in many different diseases. In contrast, LRG1 is not involved in developmental angiogenesis. Here, we investigated the vasculopathic properties of LRG1 by examining its effect on developing retinal blood vessels. By injecting recombinant protein [...] Read more.

Upregulation of leucine-rich alpha-2-glycoprotein-1 (LRG1) contributes to aberrant neovascularization in many different diseases. In contrast, LRG1 is not involved in developmental angiogenesis. Here, we investigated the vasculopathic properties of LRG1 by examining its effect on developing retinal blood vessels. By injecting recombinant protein or an expression vector into the mouse retina during vascular development, we showed that exogenous LRG1 reduces pericyte coverage and NG2 expression. It leads to diminished collagen IV sheathing, fewer adhesion and gap junctions, and reduced vessel calibre and vascular density. Moreover, in mouse retinae containing exogenous LRG1, the developing blood–retinal barrier remains more permeable with significantly higher numbers of transcytotic vesicles present in microvascular endothelial cells. These results reveal that exogeneous LRG1 is sufficient to interfere with the maturation of developing retinal vessels and drive vessel development towards a dysfunctional phenotype. These observations deliver further evidence that LRG1 is an angiopathic factor and highlight the therapeutic potential of blocking LRG1 in diseases characterized by pathogenic angiogenesis or vascular remodelling. Full article

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18 pages, 3222 KiB

Open AccessArticle

Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells

by Amanda L. Johnson, Harmon S. Khela, Jack Korleski, Sophie Sall, Yunqing Li, Weiqiang Zhou, Karen Smith-Connor, John Laterra and Hernando Lopez-Bertoni

Cells 2025, 14(8), 592; https://doi.org/10.3390/cells14080592 - 14 Apr 2025

Viewed by 147

Abstract

Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are [...] Read more.

Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and the molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We showed that this immunosuppressive Treg-like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGFβ type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a six-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2^high GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics. Full article

(This article belongs to the Special Issue The Pivotal Role of Tumor Stem Cells in Glioblastoma)

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