Cells

15 pages, 886 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Lipocalin-2, Matrix Metalloproteinase-9, and MMP-9/NGAL Complex in Upper Aerodigestive Tract Carcinomas: A Pilot Study

by Luca Cavalcanti, Silvia Francati, Giampiero Ferraguti, Francesca Fanfarillo, Daniele Peluso, Christian Barbato, Antonio Greco, Antonio Minni and Carla Petrella

Cells 2025, 14(7), 506; https://doi.org/10.3390/cells14070506 - 29 Mar 2025

Viewed by 1078

Abstract

Upper aerodigestive tract (UADT) carcinomas have a high and rapidly increasing incidence, particularly in industrialized countries. The identification of diagnostic and prognostic biomarkers remains a key objective in oncological research. However, conflicting data have been reported regarding Lipocalin-2 (LCN-2 or NGAL), Matrix Metalloproteinase-9 [...] Read more.

Upper aerodigestive tract (UADT) carcinomas have a high and rapidly increasing incidence, particularly in industrialized countries. The identification of diagnostic and prognostic biomarkers remains a key objective in oncological research. However, conflicting data have been reported regarding Lipocalin-2 (LCN-2 or NGAL), Matrix Metalloproteinase-9 (MMP-9), and the MMP-9/NGAL complex in UADT carcinomas. For this reason, the primary aim of this study was to investigate the involvement and modulation of the LCN-2 system in UADT cancer by selecting patients at first diagnosis and excluding any pharmacological or interventional treatments that could act as confounding factors. In this clinical retrospective pilot study, we investigated LCN-2 and MMP-9 tissue gene expression, as well as circulating levels of LCN-2, MMP-9, and the MMP-9/NGAL complex. Our findings revealed a downregulation of LCN-2 and an upregulation of MMP-9 gene expression in tumor tissues compared to healthy counterparts. A similar trend was observed in circulating levels, with decreased LCN-2 and increased MMP-9 in cancer patients compared to healthy controls. Additionally, serum levels of the MMP-9/NGAL complex were significantly elevated in UADT cancer patients relative to controls. Our study suggests a potentially distinct role for the free form of LCN-2 and its conjugated form (MMP-9/NGAL complex) in UADT tumors. These findings not only provide new insights into the molecular mechanisms underlying tumor progression but also highlight the potential clinical relevance of these biomarkers. The differential expression patterns observed suggest that the LCN-2 and MMP-9/NGAL complex could serve as valuable tools for improving early diagnosis, monitoring disease progression, and potentially guiding therapeutic strategies. Further research is needed to validate their utility in clinical settings and to explore their prognostic and predictive value in personalized treatment approaches. Full article

(This article belongs to the Special Issue New Trends and Advances in Diagnosis and Prognosis of Head and Neck Cancer from Carcinogenesis to Future Molecular Targeted Therapies: 2nd Edition)

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21 pages, 8811 KB

Open AccessEditor’s ChoiceArticle

Empagliflozin Plays Vasoprotective Role in Spontaneously Hypertensive Rats via Activation of the SIRT1/AMPK Pathway

by Monika Kloza, Anna Krzyżewska, Hanna Kozłowska, Sandra Budziak and Marta Baranowska-Kuczko

Cells 2025, 14(7), 507; https://doi.org/10.3390/cells14070507 - 29 Mar 2025

Cited by 2 | Viewed by 1026

Abstract

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor tone via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways in spontaneously hypertensive rats [...] Read more.

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor tone via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways in spontaneously hypertensive rats (SHR) and controls (Wistar Kyoto rats, WKY). Functional (wire myography, organ bath) and biochemical (Western blot) studies were conducted on the third-order of the superior mesenteric arteries (sMAs) and/or aortas. EMPA induced concentration-dependent relaxation of preconstricted sMAs in both groups. In SHR, EMPA enhanced acetylcholine (Ach)-induced relaxation in sMAs and aortas and reduced constriction induced by phenylephrine (Phe) and U46619 in sMAs. The SIRT1 inhibitor (EX527) abolished EMPA’s effects on Ach-mediated relaxation and U46619-induced vasoconstriction, while AMPK inhibition reduced Ach-mediated relaxation and Phe-induced vasoconstriction. SHR showed increased SGLT2 and SIRT1 expression and decreased pAMPK/AMPK levels in sMAs. In conclusion, EMPA might exert vasoprotective effects in hypertension by enhancing endothelium-dependent relaxation and reducing constriction via AMPK/SIRT1 pathways. These properties could improve vascular health in patients with hypertension and related conditions. Further studies are needed to explore new indications for SGLT2 inhibitors. Full article

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32 pages, 1765 KB

Open AccessEditor’s ChoiceReview

Preclinical Models for Studying Fuchs Endothelial Corneal Dystrophy

by Fancheng Sun, Lexie W. Q. Xi, Wesley Luu, Myagmartsend Enkhbat, Dawn Neo, Jodhbir S. Mehta, Gary S. L. Peh and Evelyn K. F. Yim

Cells 2025, 14(7), 505; https://doi.org/10.3390/cells14070505 - 28 Mar 2025

Cited by 2 | Viewed by 2631

Abstract

Fuchs Endothelial Corneal Dystrophy (FECD) is a corneal endothelial disease that causes microenvironment alterations and endothelial cell loss, which leads to vision impairment. It has a high global prevalence, especially in elderly populations. FECD is also one of the leading indications of corneal [...] Read more.

Fuchs Endothelial Corneal Dystrophy (FECD) is a corneal endothelial disease that causes microenvironment alterations and endothelial cell loss, which leads to vision impairment. It has a high global prevalence, especially in elderly populations. FECD is also one of the leading indications of corneal transplantation globally. Currently, there is no clearly defined canonical pathway for this disease, and it has been proposed that the combinatorial effects of genetic mutations and exogenous factors cause FECD. Clinical studies and observations have provided valuable knowledge and understanding of FECD, while preclinical studies are essential for gaining insights into disease progression and mechanisms for the development and testing of regenerative medicine therapies. In this review, we first introduce the proposed genetic and molecular pathologies of FECD. Notably, we discuss the impact of abnormal extracellular matrix deposition (guttata), endothelial-to-mesenchymal transition, cell senescence, and oxidative stress on the pathology and etiology of FECD. We review and summarize the in vitro cell models, ex vivo tissues, and in vivo animal models used to study FECD. The benefits and challenges of each model are also discussed. Full article

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29 pages, 1740 KB

Open AccessEditor’s ChoiceReview

The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis

by Atsushi Nishida and Akira Andoh

Cells 2025, 14(7), 488; https://doi.org/10.3390/cells14070488 - 25 Mar 2025

Cited by 36 | Viewed by 8107

Abstract

Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion [...] Read more.

Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms of Chronic Inflammation-Associated Cancer)

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16 pages, 3864 KB

Open AccessEditor’s ChoiceArticle

Impact of a High-Fat Diet on the Gut Microbiome: A Comprehensive Study of Microbial and Metabolite Shifts During Obesity

by Md Abdullah Al Mamun, Ahmed Rakib, Mousumi Mandal and Udai P. Singh

Cells 2025, 14(6), 463; https://doi.org/10.3390/cells14060463 - 20 Mar 2025

Cited by 8 | Viewed by 5124

Abstract

Over the last few decades, the prevalence of metabolic diseases such as obesity, diabetes, non-alcoholic fatty liver disease, hypertension, and hyperuricemia has surged, primarily due to high-fat diet (HFD). The pathologies of these metabolic diseases show disease-specific alterations in the composition and function [...] Read more.

Over the last few decades, the prevalence of metabolic diseases such as obesity, diabetes, non-alcoholic fatty liver disease, hypertension, and hyperuricemia has surged, primarily due to high-fat diet (HFD). The pathologies of these metabolic diseases show disease-specific alterations in the composition and function of their gut microbiome. How HFD alters the microbiome and its metabolite to mediate adipose tissue (AT) inflammation and obesity is not well known. Thus, this study aimed to identify the changes in the gut microbiome and metabolomic signatures induced by an HFD to alter obesity. To explore the changes in the gut microbiota and metabolites, 16S rRNA gene amplicon sequencing and metabolomic analyses were performed after HFD and normal diet (ND) feeding. We noticed that, at taxonomic levels, the number of operational taxonomic units (OTUs), along with the Chao and Shannon indexes, significantly shifted in HFD-fed mice compared to those fed a ND. Similarly, at the phylum level, an increase in Firmicutes and a decrease in Bacteroidetes were noticed in HFD-fed mice. At the genus level, an increase in Lactobacillus and Ruminococcus was observed, while Allobaculum, Clostridium, and Akkermansia were markedly reduced in the HFD group. Many bacteria from the Ruminococcus genus impair bile acid metabolism and restrict weight loss. Firmicutes are efficient in breaking down complex carbohydrates into short-chain fatty acids (SCFAs) and other metabolites, whereas Bacteroidetes are involved in a more balanced or efficient energy extraction. Thus, an increase in Firmicutes over Bacteroidetes enhances the absorption of more calories from food, which may contribute to obesity. Taken together, the altered gut microbiota and metabolites trigger AT inflammation, which contributes to metabolic dysregulation and disease progression. Thus, this study highlights the potential of the gut microbiome in the development of therapeutic strategies for obesity and related metabolic disorders. Full article

(This article belongs to the Section Cellular Pathology)

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15 pages, 1619 KB

Open AccessEditor’s ChoiceArticle

Blockade of HSP70 Improves Vascular Function in a Mouse Model of Type 2 Diabetes

by Valentina Ochoa Mendoza, Amanda Almeida de Oliveira and Kenia Pedrosa Nunes

Cells 2025, 14(6), 424; https://doi.org/10.3390/cells14060424 - 13 Mar 2025

Viewed by 1134

Abstract

Type 2 diabetes (T2D) is a chronic disease that damages blood vessels and increases the risk of cardiovascular disease (CVD). Heat-shock protein 70 (HSP70), a family of chaperone proteins, has been recently reported as a key player in vascular reactivity that affects large [...] Read more.

Type 2 diabetes (T2D) is a chronic disease that damages blood vessels and increases the risk of cardiovascular disease (CVD). Heat-shock protein 70 (HSP70), a family of chaperone proteins, has been recently reported as a key player in vascular reactivity that affects large blood vessels like the aorta. Hyperglycemia, a hallmark of diabetes, correlates with the severity of vascular damage and circulating HSP70 levels. In diabetes, blood vessels often show impaired contractility, contributing to vascular dysfunction. However, HSP70’s specific role in T2D-related vascular contraction remains unclear. We hypothesized that blocking HSP70 would improve vascular function in a widely used diabetic mouse model (db/db). To test this, we measured both vascular intracellular and serum circulating HSP70 levels in control and diabetic male mice using immunofluorescence and Western blotting. We also examined the aorta’s contractile response using a wire myograph system, which measured the force produced in response to phenylephrine (PE), both with and without VER155008, a pharmacological inhibitor that targets the ATPase domain of HSP70, and after removing extracellular calcium. Our findings show that intracellular HSP70 (iHSP70) levels were similar in control and diabetic groups, while circulating HSP70 (eHSP70) levels were higher in the serum of diabetic mice, altering the iHSP70/eHSP70 ratio. Even though VER155008 attenuated both phases of the contractile curve in the diabetic and control groups, enhanced vasoconstriction to PE was only observed in the tonic phase of the curve in the db/db group, which was prevented by iHSP70 inhibition. This effect involved calcium mobilization, as both the maximal and total contraction forces to PE were restored in groups treated with VER155008. Additionally, internal calcium levels in aortic rings treated with VER155008 decreased, as observed in force generation upon calcium reintroduction, which was further corroborated using a biochemical calcium assay. In conclusion, our study demonstrates that blocking HSP70 improves vascular reactivity in the hyperglycemic state of T2D by restoring proper vascular contraction. Full article

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

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23 pages, 3082 KB

Open AccessEditor’s ChoiceReview

Metaboloepigenetics: Role in the Regulation of Flow-Mediated Endothelial (Dys)Function and Atherosclerosis

by Francisco Santos, Hashum Sum, Denise Cheuk Lee Yan and Alison C. Brewer

Cells 2025, 14(5), 378; https://doi.org/10.3390/cells14050378 - 5 Mar 2025

Cited by 4 | Viewed by 1832

Abstract

Endothelial dysfunction is the main initiating factor in atherosclerosis. Through mechanotransduction, shear stress regulates endothelial cell function in both homeostatic and diseased states. Accumulating evidence reveals that epigenetic changes play critical roles in the etiology of cardiovascular diseases, including atherosclerosis. The metabolic regulation [...] Read more.

Endothelial dysfunction is the main initiating factor in atherosclerosis. Through mechanotransduction, shear stress regulates endothelial cell function in both homeostatic and diseased states. Accumulating evidence reveals that epigenetic changes play critical roles in the etiology of cardiovascular diseases, including atherosclerosis. The metabolic regulation of epigenetics has emerged as an important factor in the control of gene expression in diseased states, but to the best of our knowledge, this connection remains largely unexplored in endothelial dysfunction and atherosclerosis. In this review, we (1) summarize how shear stress (or flow) regulates endothelial (dys)function; (2) explore the epigenetic alterations that occur in the endothelium in response to disturbed flow; (3) review endothelial cell metabolism under different shear stress conditions; and (4) suggest mechanisms which may link this altered metabolism to the regulation of the endothelial epigenome by modulations in metabolite availability. We believe that metabolic regulation plays an important role in endothelial epigenetic reprogramming and could pave the way for novel metabolism-based therapeutic strategies. Full article

(This article belongs to the Collection Cardiovascular Disease: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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15 pages, 746 KB

Open AccessEditor’s ChoiceReview

Diabetic Retinopathy (DR): Mechanisms, Current Therapies, and Emerging Strategies

by Hyewon Seo, Sun-Ji Park and Minsoo Song

Cells 2025, 14(5), 376; https://doi.org/10.3390/cells14050376 - 4 Mar 2025

Cited by 16 | Viewed by 4811

Abstract

Diabetic retinopathy (DR) is one of the most prevalent complications of diabetes, affecting nearly one-third of patients with diabetes mellitus and remaining a leading cause of blindness worldwide. Among the various diabetes-induced complications, DR is of particular importance due to its direct impact [...] Read more.

Diabetic retinopathy (DR) is one of the most prevalent complications of diabetes, affecting nearly one-third of patients with diabetes mellitus and remaining a leading cause of blindness worldwide. Among the various diabetes-induced complications, DR is of particular importance due to its direct impact on vision and the irreversible damage to the retina. DR is characterized by multiple pathological processes, primarily a hyperglycemia-induced inflammatory response and oxidative stress. Current gold standard therapies, such as anti-VEGF injections and photocoagulation, have shown efficacy in slowing disease progression. However, challenges such as drug resistance, partial therapeutic responses, and the reliance on direct eye injections—which often result in low patient compliance—remain unresolved. This review provides a comprehensive overview of the underlying molecular mechanisms in DR, the current therapies, and their unmet needs for DR treatment. Additionally, emerging therapeutic strategies for improving DR treatment outcomes are discussed. Full article

(This article belongs to the Special Issue Diabetes-Induced Organ Damage: Cellular Mechanisms and Therapeutic Opportunities)

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18 pages, 1457 KB

Open AccessEditor’s ChoiceReview

Sex Disparities in P53 Regulation and Functions: Novel Insights for Personalized Cancer Therapies

by Miriana Cardano, Giacomo Buscemi and Laura Zannini

Cells 2025, 14(5), 363; https://doi.org/10.3390/cells14050363 - 28 Feb 2025

Viewed by 1121

Abstract

Epidemiological studies have revealed significant sex differences in the incidence of tumors unrelated to reproductive functions, with females demonstrating a lesser risk and a better response to therapy than males. However, the reasons for these disparities are still unknown and cancer therapies are [...] Read more.

Epidemiological studies have revealed significant sex differences in the incidence of tumors unrelated to reproductive functions, with females demonstrating a lesser risk and a better response to therapy than males. However, the reasons for these disparities are still unknown and cancer therapies are generally sex-unbiased. The tumor-suppressor protein p53 is a transcription factor that can activate the expression of multiple target genes mainly involved in the maintenance of genome stability and tumor prevention. It is encoded by TP53, which is the most-frequently mutated gene in human cancers and therefore constitutes an attractive target for therapy. Recently, evidence of sex differences has emerged in both p53 regulations and functions, possibly providing novel opportunities for personalized cancer medicine. Here, we will review and discuss current knowledge about sexual disparities in p53 pathways, their role in tumorigenesis and cancer progression, and their importance in the therapy choice process, finally highlighting the importance of considering sex contribution in both basic research and clinical practice. Full article

(This article belongs to the Section Cell Signaling)

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16 pages, 1714 KB

Open AccessEditor’s ChoiceReview

Pro-Fibrotic Macrophage Subtypes: SPP1+ Macrophages as a Key Player and Therapeutic Target in Cardiac Fibrosis?

by Moritz Uhlig, Sebastian Billig, Jan Wienhold and David Schumacher

Cells 2025, 14(5), 345; https://doi.org/10.3390/cells14050345 - 27 Feb 2025

Cited by 1 | Viewed by 3176

Abstract

Cardiac fibrosis is a major driver of heart failure, a leading cause of morbidity and mortality worldwide. Advances in single-cell transcriptomics have revealed the pivotal role of SPP1+ macrophages in the pathogenesis of cardiac fibrosis, positioning them as critical mediators and promising therapeutic [...] Read more.

Cardiac fibrosis is a major driver of heart failure, a leading cause of morbidity and mortality worldwide. Advances in single-cell transcriptomics have revealed the pivotal role of SPP1+ macrophages in the pathogenesis of cardiac fibrosis, positioning them as critical mediators and promising therapeutic targets. SPP1+ macrophages, characterized by elevated expression of secreted phosphoprotein 1 (SPP1) and often co-expressing Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), localize to fibrotic niches in the heart and other organs. These cells interact with activated fibroblasts and myofibroblasts, driving extracellular matrix remodeling and fibrosis progression. Their differentiation is orchestrated by signals such as CXCL4, GM-CSF, and IL-17A, further emphasizing their regulatory complexity. Therapeutic strategies targeting SPP1+ macrophages have shown encouraging preclinical results. Approaches include silencing Spp1 using antibody–siRNA conjugates and modulating key pathways involved in macrophage differentiation. These interventions have effectively reduced fibrosis and improved cardiac function in animal models. The mechanisms underlying SPP1+ macrophage function in cardiac fibrosis provide a foundation for innovative therapies aimed at mitigating pathological remodeling and improving outcomes in patients with heart failure. This emerging field has significant potential to transform the treatment of fibrotic heart disease. Full article

(This article belongs to the Special Issue New Insights into Therapeutic Targets for Cardiovascular Diseases)

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20 pages, 4395 KB

Open AccessEditor’s ChoiceArticle

Sex Differences in Circulating Inflammatory, Immune, and Tissue Growth Markers Associated with Fabry Disease-Related Cardiomyopathy

by Margarita M. Ivanova, Julia Dao, Andrew Friedman, Neil Kasaci and Ozlem Goker-Alpan

Cells 2025, 14(5), 322; https://doi.org/10.3390/cells14050322 - 20 Feb 2025

Cited by 1 | Viewed by 1618

Abstract

Fabry disease (FD) is a lysosomal disorder due to alpha-galactosidase-A enzyme deficiency, accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which lead to proinflammatory effects. Males develop progressive hypertrophic cardiomyopathy (HCM) followed by fibrosis; females develop nonconcentric hypertrophy and/or early fibrosis. The inflammatory response [...] Read more.

Fabry disease (FD) is a lysosomal disorder due to alpha-galactosidase-A enzyme deficiency, accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which lead to proinflammatory effects. Males develop progressive hypertrophic cardiomyopathy (HCM) followed by fibrosis; females develop nonconcentric hypertrophy and/or early fibrosis. The inflammatory response to Gb3/lyso-Gb-3 accumulation is one of the suggested pathogenic mechanisms in FD cardiomyopathy when the secretion of inflammatory and transforming growth factors with infiltration of lymphocytes and macrophages into tissue promotes cardiofibrosis. This study aims to evaluate inflammation-driving cytokines and cardio-hypertrophic remodeling biomarkers contributing to sex-specific HCM progression. Biomarkers were studied in 20 healthy subjects and 45 FD patients. IL-2, IL-10, TNF-α, and IFN-γ were elevated in all patients, while IL-1α, MCP-1, and TNFR2 showed sex-specific differences. The increased cytokines were associated with the NF-kB pathway in FD males with HCM, revealing a correlation between MCP-1, IFN-γ, VEGF, GM-CSF, IL-10, and IL-2. In female patients, the impaired TNFα/TNFR2/TGFβ cluster with correlations to MCP-1, VEGF, GM-CSF, and IL-1α was observed. The activation of cytokines and the NF-kB pathway indicates significant inflammation during HCM remodeling in FD males. The TNFα/TNFR2/TGFβ signaling cluster may explain early fibrosis in females with FD cardiomyopathy. Sex-specific inflammatory responses in FD influence the severity and progression of HCM. Full article

(This article belongs to the Special Issue Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts)

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19 pages, 6384 KB

Open AccessEditor’s ChoiceArticle

A Critical Role of Intracellular PD-L1 in Promoting Ovarian Cancer Progression

by Rui Huang, Brad Nakamura, Rosemary Senguttuvan, Yi-Jia Li, Antons Martincuks, Rania Bakkar, Mihae Song, David K. Ann, Lorna Rodriguez-Rodriguez and Hua Yu

Cells 2025, 14(4), 314; https://doi.org/10.3390/cells14040314 - 19 Feb 2025

Viewed by 1942

Abstract

Disrupting the interaction between tumor-cell surface PD-L1 and T cell membrane PD-1 can elicit durable clinical responses. However, only about 10% of ovarian cancer patients respond to PD-1/PD-L1 blockade. Here, we show that PD-L1 expression in ovarian cancer-patient tumors is predominantly intracellular. Notably, [...] Read more.

Disrupting the interaction between tumor-cell surface PD-L1 and T cell membrane PD-1 can elicit durable clinical responses. However, only about 10% of ovarian cancer patients respond to PD-1/PD-L1 blockade. Here, we show that PD-L1 expression in ovarian cancer-patient tumors is predominantly intracellular. Notably, PARP inhibitor treatment highly increased intracellular PD-L1 accumulation in both ovarian cancer-patient tumor samples and cell lines. We investigated whether intracellular PD-L1 might play a critical role in ovarian cancer progression. Mutating the PD-L1 acetylation site in PEO1 and ID8^Brca1−/− ovarian cancer cells significantly decreased PD-L1 levels and impaired colony formation, which was accompanied by cell cycle G2/M arrest and apoptosis induction. PEO1 and ID8^Brca1−/− tumors with PD-L1 acetylation site mutation also exhibited significantly reduced growth in mice. Furthermore, targeting intracellular PD-L1 with a cell-penetrating antibody effectively decreased ovarian tumor-cell intracellular PD-L1 level and induced tumor-cell growth arrest and apoptosis, as well as enhanced DNA damage and STING activation, both in vitro and in vivo. In conclusion, we have shown the critical role of intracellular PD-L1 in ovarian cancer progression. Full article

(This article belongs to the Special Issue Ovarian Cancer and Endometriosis)

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22 pages, 4264 KB

Open AccessEditor’s ChoiceArticle

Seasonal Influences on Human Placental Transcriptomes Associated with Spontaneous Preterm Birth

by Khondoker M. Akram, Eleanor Dodd and Dilly O. C. Anumba

Cells 2025, 14(4), 303; https://doi.org/10.3390/cells14040303 - 18 Feb 2025

Viewed by 1641

Abstract

Demographic studies have revealed a strong association between exposure to high ambient temperatures during pregnancy and increased risks of preterm birth (PTB). The mechanism underlying this association is unclear, but it is plausible that altered placental function may contribute to it. In this [...] Read more.

Demographic studies have revealed a strong association between exposure to high ambient temperatures during pregnancy and increased risks of preterm birth (PTB). The mechanism underlying this association is unclear, but it is plausible that altered placental function may contribute to it. In this study, we conducted differential gene expression analysis, gene set enrichment analysis (GSEA), and gene ontology (GO) analysis on bulk RNA-seq data from human placentas delivered at term and preterm during the warmer months compared to placentas delivered at term and preterm during the colder months in the UK. We detected 48 differentially expressed genes in preterm placentas delivered during the warmer months compared to preterm placentas delivered during the colder months, the majority of which were inflammatory cytokines and chemokines, including SERPINA1, IL1B, CCL3, CCL3L3, CCL4, CCL4L2, CCL20, and CXCL8. The GSEA positively enriched 17 signalling pathways, including the NF-κB, IL17, Toll-like receptor, and chemokine signalling pathways in preterm placentas delivered during warmer months. These results were not observed in the placentas delivered at term during the same times of the year. The GO analysis revealed several enhanced biological processes, including neutrophil, granulocyte, monocyte, and lymphocyte chemotaxis, as well as inflammatory and humoral immune responses in preterm placentas, but not in placentas delivered at term in the summer. We conclude that maternal exposure to warm environmental temperatures during pregnancy likely alters the placental transcriptomes towards inflammation and immune regulation, potentially leading to PTB. Full article

(This article belongs to the Special Issue Molecular Insight into the Pathogenesis of Spontaneous Preterm Birth)

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14 pages, 2097 KB

Open AccessEditor’s ChoiceArticle

Angiotensin-(1-7) Provides Potent Long-Term Neurorepair/Neuroregeneration in a Rodent White Matter Stroke Model: Nonarteritic Ischemic Optic Neuropathy (rNAION)

by Kwang Min Woo, Yan Guo, Zara Mehrabian, Thomas Walther, Neil R. Miller and Steven L. Bernstein

Cells 2025, 14(4), 289; https://doi.org/10.3390/cells14040289 - 15 Feb 2025

Viewed by 1134

Abstract

Nonarteritic anterior ischemic optic neuropathy (NAION) is an ischemic lesion of the anterior optic nerve (ON), currently untreatable due to the length of time from symptom onset until treatment. We evaluated angiotensin-(1-7) (Ang-(1-7)): the MAS1-receptor ligand, as a possible NAION treatment using the [...] Read more.

Nonarteritic anterior ischemic optic neuropathy (NAION) is an ischemic lesion of the anterior optic nerve (ON), currently untreatable due to the length of time from symptom onset until treatment. We evaluated angiotensin-(1-7) (Ang-(1-7)): the MAS1-receptor ligand, as a possible NAION treatment using the rodent NAION model (rNAION). Long-Evans rats were unilaterally rNAION-induced. One-day post-induction, lesion severity was quantified via optic nerve head (ONH) edema using spectral domain optical coherence tomography. Animals meeting rNAION induction criteria were randomized into (1) Subcutaneous Ang-(1-7) infusion for 28 days and (2) Vehicle. Visual function was assessed using both visual acuity and flash visual evoked potentials (fVEP). Tissues were collected >30d and RGC neurons were quantified by stereology. ONs were histologically examined for inflammation. Ang-(1-7) improved post-rNAION visual function. Ang-(1-7)-treated animals showed improved visual acuity (ANCOVA: p = 0.0084) and improved fVEP amplitudes (ANCOVA: p = 0.0378) vs vehicle controls. The relative degree of improvement correlated with ONH edema severity. Treated animals showed trends towards increased RGC survival, and reduced optic nerve inflammatory cell infiltration. Ang-(1-7) is the first agent effective ≥1 day after rNAION induction. Ang-(1-7) type agonists may be useful in improving long-term function and neuronal survival in clinical NAION and other forms of white matter ischemia. Full article

(This article belongs to the Special Issue Novel and Experimental Strategies for the Treatment of Neurodegenerative Diseases)

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28 pages, 2721 KB

Open AccessEditor’s ChoiceReview

Autophagy in Tissue Repair and Regeneration

by Daniel Moreno-Blas, Teresa Adell and Cristina González-Estévez

Cells 2025, 14(4), 282; https://doi.org/10.3390/cells14040282 - 14 Feb 2025

Cited by 5 | Viewed by 4703

Abstract

Autophagy is a cellular recycling system that, through the sequestration and degradation of intracellular components regulates multiple cellular functions to maintain cellular homeostasis and survival. Dysregulation of autophagy is closely associated with the development of physiological alterations and human diseases, including the loss [...] Read more.

Autophagy is a cellular recycling system that, through the sequestration and degradation of intracellular components regulates multiple cellular functions to maintain cellular homeostasis and survival. Dysregulation of autophagy is closely associated with the development of physiological alterations and human diseases, including the loss of regenerative capacity. Tissue regeneration is a highly complex process that relies on the coordinated interplay of several cellular processes, such as injury sensing, defense responses, cell proliferation, differentiation, migration, and cellular senescence. These processes act synergistically to repair or replace damaged tissues and restore their morphology and function. In this review, we examine the evidence supporting the involvement of the autophagy pathway in the different cellular mechanisms comprising the processes of regeneration and repair across different regenerative contexts. Additionally, we explore how modulating autophagy can enhance or accelerate regeneration and repair, highlighting autophagy as a promising therapeutic target in regenerative medicine for the development of autophagy-based treatments for human diseases. Full article

(This article belongs to the Collection Feature Papers in Autophagy)

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19 pages, 3088 KB

Open AccessEditor’s ChoiceArticle

Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo

by Nabin Ghimire, Morgan Welch, Cassandra Secunda, Alexis Fink and Ahmed Lawan

Cells 2025, 14(4), 261; https://doi.org/10.3390/cells14040261 - 12 Feb 2025

Cited by 3 | Viewed by 973

Abstract

The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role [...] Read more.

The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role in the regulation of cell proliferation and the development of metabolic disorders. However, whether there is a causal relationship between MKP-2 and diabetes onset is unclear. The aim of this study was to determine the role of MKP-2 in the regulation of whole-body glucose homeostasis and the impact on pancreatic islet function using streptozotocin-induced pancreatic injury. Here, we show that female mice with whole-body deletion of MKP-2 exhibit hyperglycemia in mouse models treated with multiple low doses of streptozotocin (STZ). In comparison, both male MKP-2 wild-type and knockout mice were hyperglycemic. Consistent with the hyperglycemia, female MKP-2-deficient mice exhibited reduced islet size. Under T2D conditions, MKP-2-deficient mice display enhanced pancreatic JNK and ERK phosphorylation that is associated with the downregulation of genes important for pancreatic islet development and function, Pdx-1 and MafA. Furthermore, we found impaired metabolic flux in adipose tissue that is consistent with hyperglycemia and dysfunctional pancreas. MKP-2 deletion results in reduced Akt activation that is associated with increased adiposity and insulin resistance in female MKP-2 KO mice. These studies demonstrate the critical role of MKP-2 in the development of T2D diabetes in vivo. This suggests that MKP-2 may have a gender-specific role in diabetes development. This discovery raises the possibility that postmenopausal prevention of T2D may benefit from the activation of MKP-2 activity in islet cells. Full article

(This article belongs to the Section Cell Signaling)

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20 pages, 5182 KB

Open AccessEditor’s ChoiceArticle

Combinational Inhibition of MEK and AKT Synergistically Induces Melanoma Stem Cell Apoptosis and Blocks NRAS Tumor Growth

by Ryyan Alobaidi, Nusrat Islam, Toni Olkey, Yogameenakshi Haribabu, Mathew Shamo, Peter Sykora, Cynthia M. Simbulan-Rosenthal and Dean S. Rosenthal

Cells 2025, 14(4), 248; https://doi.org/10.3390/cells14040248 - 10 Feb 2025

Cited by 2 | Viewed by 1482

Abstract

Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MICs), implicated in tumorigenesis, invasion, and drug resistance, and characterized by an elevated expression of stem cell markers, including CD133. siRNA knockdown of CD133 has been previously shown to enhance apoptosis induced by [...] Read more.

Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MICs), implicated in tumorigenesis, invasion, and drug resistance, and characterized by an elevated expression of stem cell markers, including CD133. siRNA knockdown of CD133 has been previously shown to enhance apoptosis induced by the MEK inhibitor trametinib in melanoma cells. This study investigates the underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP melanoma, harboring the difficult-to-treat NRAS^Q61K driver mutation, after CRISPR-Cas9 CD133 knockout or Doxycycline (Dox)-inducible re-expression of CD133. CD133 knockout in BAKP cells increased trametinib-induced apoptosis by reducing anti-apoptotic p-AKT and p-BAD and increasing pro-apoptotic BAX. Conversely, Dox-induced CD133 expression diminished apoptosis in trametinib-treated cells, coincident with elevated p-AKT, p-BAD, and decreased activation of BAX and caspase-3. However, trametinib in combination with pan-AKT inhibitor capivasertib reduced cell survival as measured by XTT viability assays and apoptosis and colony formation assays, independent of CD133 status. CD133 may therefore activate a survival pathway wherein (1) increased AKT phosphorylation and activation induces (2) BAD phosphorylation and inactivation, which (3) decreases BAX activation, and (4) reduces caspases-3 activity and caspase-mediated PARP cleavage, leading to apoptosis suppression and drug resistance in melanoma. In vivo mouse xenograft studies using Dox-inducible melanoma cells revealed increased rates of tumor growth after induction of CD133 expression in trametinib-treated +Dox mice, an effect which was synergistically suppressed by combination treatment. Targeting nodes of the AKT and MAPK survival pathways with trametinib and capivasertib highlights the potential for combination therapies for NRAS-mutant melanoma stem cells for the development of more effective treatments for patients with high-risk melanoma. Full article

(This article belongs to the Section Cellular Pathology)

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13 pages, 9327 KB

Open AccessEditor’s ChoiceArticle

BCL-B Promotes Lung Cancer Invasiveness by Direct Inhibition of BOK

by Palaniappan Ramesh, Amal R. Al Kadi, Gaurav M. Borse, Maximilian Webendörfer, Gregor Zaun, Martin Metzenmacher, Fabian Doerr, Servet Bölükbas, Balazs Hegedüs, Smiths S. Lueong, Joelle Magne, Beiyun Liu, Greisly Nunez, Martin Schuler, Douglas R. Green and Halime Kalkavan

Cells 2025, 14(4), 246; https://doi.org/10.3390/cells14040246 - 9 Feb 2025

Viewed by 1615

Abstract

Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial [...] Read more.

Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial outer membrane permeabilization (MOMP) and consequently generate apoptosis-flatliners, which represent a source of drug-tolerant persister cells (DTPs). The engagement of endothelial-mesenchymal-transition (EMT) further promotes cancer cell invasiveness in such DTPs. Our results reveal that BCL-B fosters cancer cell aggressiveness by counteracting complete MOMP. Full article

(This article belongs to the Special Issue Mitophagy, Autophagy, Apoptosis and Senescence—the Roles of These Processes in Invasive Cancer Growth: Second Edition)

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15 pages, 1568 KB

Open AccessEditor’s ChoiceArticle

Telomere Length, Oxidative Stress, and Kidney Damage Biomarkers in Fabry Nephropathy

by Tina Levstek, Erazem Bahčič, Bojan Vujkovac, Andreja Cokan Vujkovac, Tine Tesovnik, Žiga Iztok Remec, Vanja Čuk and Katarina Trebušak Podkrajšek

Cells 2025, 14(3), 218; https://doi.org/10.3390/cells14030218 - 4 Feb 2025

Cited by 2 | Viewed by 1538

Abstract

Fabry nephropathy is a life-threatening complication of Fabry disease characterized by complex and incompletely understood pathophysiological processes possibly linked to premature aging. We aimed to investigate leukocyte telomere length (LTL), oxidative stress, and kidney damage biomarkers in relation to kidney function. The study [...] Read more.

Fabry nephropathy is a life-threatening complication of Fabry disease characterized by complex and incompletely understood pathophysiological processes possibly linked to premature aging. We aimed to investigate leukocyte telomere length (LTL), oxidative stress, and kidney damage biomarkers in relation to kidney function. The study included 35 Fabry patients and 35 age and sex-matched control subjects. Based on the estimated slope of the glomerular filtration rate, the patients were divided into two groups. Relative LTL was quantified by qPCR, urinary biomarkers 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) by UHPLC-MS/MS, and kidney damage biomarkers by flow cytometry. There was no statistically significant difference in LTL between Fabry patients and controls. However, a significant difference was observed in male patients compared to their matched control subjects (p = 0.013). Oxidative stress biomarkers showed no differences between patients and controls, while significant differences were observed in urinary IGFBP7, EGF, and OPN levels between Fabry patients with stable kidney function and those with progressive nephropathy (FDR = 0.021, 0.002, and 0.013, respectively). Significant differences were also observed in plasma levels of cystatin C, TFF3, and uromodulin between patients with progressive nephropathy and controls (all FDR = 0.039). Along with these biomarkers (FDR = 0.007, 0.017, and 0.010, respectively), NGAL also exhibited a significant difference between the two patient groups (FDR = 0.017). This study indicates accelerated telomere attrition, which may be related to disease burden in males. Furthermore, analyses of urinary oxidative stress markers revealed no notable disparities between the different kidney function groups, indicating their limited utility. However, promising differences were found in some biomarkers of kidney damage in urine and plasma. Full article

(This article belongs to the Special Issue Kidney Injury Biomarkers: From Early Detection to Transition to Chronic Kidney Disease)

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12 pages, 2279 KB

Open AccessEditor’s ChoiceArticle

Lactoferrin-Derived Peptide Chimera Induces Caspase-Independent Cell Death in Multiple Myeloma

by Young-Saeng Jang, Shima Barati Dehkohneh, Jaewon Lim, Jaehui Kim, Donghwan Ahn, Sun Shim Choi and Seung Goo Kang

Cells 2025, 14(3), 217; https://doi.org/10.3390/cells14030217 - 3 Feb 2025

Viewed by 1652

Abstract

Lactoferrin-derived peptide chimera is a synthetic peptide that mimics the functional unit of lactoferrin with antibacterial activity. Although LF has anticancer effects, to the best of our knowledge, its effects on multiple myeloma have not yet been studied. We explored the potential of [...] Read more.

Lactoferrin-derived peptide chimera is a synthetic peptide that mimics the functional unit of lactoferrin with antibacterial activity. Although LF has anticancer effects, to the best of our knowledge, its effects on multiple myeloma have not yet been studied. We explored the potential of a lactoferrin-derived chimera for multiple myeloma treatment, a malignant clonal plasma cell bone marrow disease. The lactoferrin-derived chimera effectively inhibited MM1S, MM1R, and RPMI8226 multiple myeloma cell growth, and induced the early and late phases of apoptosis, but not in normal peripheral blood mononuclear cells. Furthermore, the lactoferrin-derived chimera modulates the relative expression of genes involved in survival, apoptosis, and mitochondrial dysfunction at the transcriptional level. Mitochondrial analysis revealed that lactoferrin-derived chimera triggered oxidative stress in multiple myeloma cells, leading to reactive oxygen species generation and a decline in mitochondrial membrane potential, resulting in mitochondrial dysfunction. Although lactoferrin-derived chimera did not cause caspase-dependent cell death, it induced nuclear translocation of apoptosis-inducing factor and endonuclease G, indicating the initiation of caspase-independent apoptosis. Overall, the lactoferrin-derived chimera induces caspase-independent programmed cell death in multiple myeloma cell lines by increasing the nuclear translocation of apoptosis-inducing factor/endonuclease G. Therefore, it has potential for multiple myeloma cancer therapies. Full article

(This article belongs to the Special Issue Focus on Machinery of Cell Death)

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34 pages, 14955 KB

Open AccessEditor’s ChoiceArticle

Early Synapse-Specific Alterations of Photoreceptor Mitochondria in the EAE Mouse Model of Multiple Sclerosis

by Dalia R. Ibrahim, Karin Schwarz, Shweta Suiwal, Sofia Maragkou and Frank Schmitz

Cells 2025, 14(3), 206; https://doi.org/10.3390/cells14030206 - 30 Jan 2025

Cited by 1 | Viewed by 2170

Abstract

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) linked to many neurological disabilities. The visual system is frequently impaired in MS. In previous studies, we observed early malfunctions of rod photoreceptor ribbon synapses in the EAE mouse [...] Read more.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) linked to many neurological disabilities. The visual system is frequently impaired in MS. In previous studies, we observed early malfunctions of rod photoreceptor ribbon synapses in the EAE mouse model of MS that included alterations in synaptic vesicle cycling and disturbances of presynaptic Ca²⁺ homeostasis. Since these presynaptic events are highly energy-demanding, we analyzed whether synaptic mitochondria, which play a major role in synaptic energy metabolism, might be involved at that early stage. Rod photoreceptor presynaptic terminals contain a single large mitochondrion next to the synaptic ribbon. In the present study, we analyzed the expression of functionally relevant mitochondrial proteins (MIC60, ATP5B, COX1, PINK1, DRP1) by high-resolution qualitative and quantitative immunofluorescence microscopy, immunogold electron microscopy and quantitative Western blot experiments. We observed a decreased expression of many functionally relevant proteins in the synaptic mitochondria of EAE photoreceptors at an early stage, suggesting that early mitochondrial dysfunctions play an important role in the early synapse pathology. Interestingly, mitochondria in presynaptic photoreceptor terminals were strongly compromised in early EAE, whereas extra-synaptic mitochondria in photoreceptor inner segments remained unchanged, demonstrating a functional heterogeneity of photoreceptor mitochondria. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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18 pages, 3496 KB

Open AccessEditor’s ChoiceArticle

Heme-Oxygenase 1 Mediated Activation of Cyp3A11 Protects Against Non-Steroidal Pain Analgesics Induced Acute Liver Damage in Sickle Cell Disease Mice

by Ravi Vats, Ramakrishna Ungalara, Rikesh K. Dubey, Prithu Sundd and Tirthadipa Pradhan-Sundd

Cells 2025, 14(3), 194; https://doi.org/10.3390/cells14030194 - 28 Jan 2025

Viewed by 1409

Abstract

Pain constitutes a significant comorbidity associated with sickle cell disease (SCD). Analgesics serve as the primary method for pain management; however, the long-term effects of these drugs on the liver of SCD patients remain not completely understood. Using real-time intravital imaging, we analyzed [...] Read more.

Pain constitutes a significant comorbidity associated with sickle cell disease (SCD). Analgesics serve as the primary method for pain management; however, the long-term effects of these drugs on the liver of SCD patients remain not completely understood. Using real-time intravital imaging, we analyzed the effect of non-steroidal analgesics (NSA) in the liver of control and SS (SCD) mice. Remarkably, we found completely opposing effects in the liver of control and SS mice post-NSA treatment. Whereas SS mice were able to better tolerate the NSA treatment acutely compared to their littermate controls, in the long term, these mice showed delayed resolution of liver injury and exacerbated fibrosis compared to control mice. Mechanistically, we found that SS mice were protected from cytotoxicity caused by NSA at baseline due to the significant activation of hepatic Kupffer cells, which produced heme-oxygenase 1 (HO-1). HO-1 promoted the activation of the cytoprotective enzyme Cyp3A11, which inhibited hepatic damage caused by NSA. However, in the long term, depletion of hepatic Kupffer cells led to reduced expression of HO-1, which blocked the activation of Cyp3A11, resulting in fibrosis and a delay in the resolution of liver injury and inflammation. These preclinical data provide a strong proof-of-concept for HO-1 as well as Cyp3A11 as cytoprotectors against NSA-induced liver damage in the Townes model of SCD and support further development of these compounds as potential novel therapies for end-organ damage in SCD. Full article

(This article belongs to the Special Issue Sickle Cell Disease: Pathogenesis, Diagnosis and Treatment)

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23 pages, 4274 KB

Open AccessEditor’s ChoiceArticle

Investigation of the Roles of the Adenosine A(2A) and Metabotropic Glutamate Receptor Type 5 (mGlu5) Receptors in Prepulse Inhibition and CREB Signaling in a Heritable Rodent Model of Psychosis

by Anthony M. Cuozzo, Loren D. Peeters, Cristal D. Ahmed, Liza J. Wills, Justin T. Gass and Russell W. Brown

Cells 2025, 14(3), 182; https://doi.org/10.3390/cells14030182 - 24 Jan 2025

Cited by 2 | Viewed by 1183

Abstract

The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) [...] Read more.

The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) or an A(2A) agonist treatment could mitigate sensorimotor gating deficits and alter cyclic AMP response element-binding protein (CREB) levels in a rodent neonatal quinpirole (NQ) model of psychosis. F0 Sprague–Dawley rats were treated with neonatal saline or quinpirole (1 mg/kg) from postnatal day 1 to 21 and bred to produce an F1 generation. F1 offspring underwent prepulse inhibition (PPI) testing from postnatal day 44 to 48 to assess sensorimotor gating. The rats were treated with mGlu5 PAM 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) or A(2A) agonist CGS21680. Rats with at least one NQ-treated parent showed PPI deficits, which were alleviated by both CDPPB and CGS21680. Sex differences were noted across groups, with CGS21680 showing greater efficacy than CDPPB. Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis. Full article

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

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23 pages, 1685 KB

Open AccessEditor’s ChoiceReview

Crosstalk Between Abiotic and Biotic Stresses Responses and the Role of Chloroplast Retrograde Signaling in the Cross-Tolerance Phenomena in Plants

by Muhammad Kamran, Paweł Burdiak and Stanisław Karpiński

Cells 2025, 14(3), 176; https://doi.org/10.3390/cells14030176 - 23 Jan 2025

Cited by 4 | Viewed by 2046

Abstract

In the natural environment, plants are simultaneously exposed to multivariable abiotic and biotic stresses. Typical abiotic stresses are changes in temperature, light intensity and quality, water stress (drought, flood), microelements availability, salinity, air pollutants, and others. Biotic stresses are caused by other organisms, [...] Read more.

In the natural environment, plants are simultaneously exposed to multivariable abiotic and biotic stresses. Typical abiotic stresses are changes in temperature, light intensity and quality, water stress (drought, flood), microelements availability, salinity, air pollutants, and others. Biotic stresses are caused by other organisms, such as pathogenic bacteria and viruses or parasites. This review presents the current state-of-the-art knowledge on programmed cell death in the cross-tolerance phenomena and its conditional molecular and physiological regulators, which simultaneously regulate plant acclimation, defense, and developmental responses. It highlights the role of the absorbed energy in excess and its dissipation as heat in the induction of the chloroplast retrograde phytohormonal, electrical, and reactive oxygen species signaling. It also discusses how systemic- and network-acquired acclimation and acquired systemic resistance are mutually regulated and demonstrates the role of non-photochemical quenching and the dissipation of absorbed energy in excess as heat in the cross-tolerance phenomenon. Finally, new evidence that plants evolved one molecular system to regulate cell death, acclimation, and cross-tolerance are presented and discussed. Full article

(This article belongs to the Section Cell Signaling)

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35 pages, 2461 KB

Open AccessEditor’s ChoiceReview

Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer’s Disease

by Eunshil Lee and Yongmin Chang

Cells 2025, 14(3), 168; https://doi.org/10.3390/cells14030168 - 22 Jan 2025

Cited by 7 | Viewed by 6335

Abstract

The recent approval of lecanemab highlights that the amyloid beta (Aβ) protein is an important pathological target in Alzheimer’s disease (AD) and further emphasizes the significance of neuroinflammatory pathways in regulating Aβ accumulation. Indeed, Aβ accumulation triggers microglia activation, which are key mediators [...] Read more.

The recent approval of lecanemab highlights that the amyloid beta (Aβ) protein is an important pathological target in Alzheimer’s disease (AD) and further emphasizes the significance of neuroinflammatory pathways in regulating Aβ accumulation. Indeed, Aβ accumulation triggers microglia activation, which are key mediators in neuroinflammation. The inflammatory responses in this process can lead to neuronal damage and functional decline. Microglia secrete proinflammatory cytokines that accelerate neuronal death and release anti-inflammatory cytokines and growth factors contributing to neuronal recovery and protection. Thus, microglia play a dual role in neurodegeneration and neuroprotection, complicating their function in AD. Therefore, elucidating the complex interactions between Aβ protein, microglia, and neuroinflammation is essential for developing new strategies for treating AD. This review investigates the receptors and pathways involved in activating microglia and aims to enhance understanding of how these processes impact neuroinflammation in AD, as well as how they can be regulated. This review also analyzed studies reported in the existing literature and ongoing clinical trials. Overall, these studies will contribute to understanding the regulatory mechanisms of neuroinflammation and developing new therapies that can slow the pathological progression of AD. Full article

(This article belongs to the Special Issue Advances in the Study of Neuroinflammation)

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25 pages, 1440 KB

Open AccessFeature PaperEditor’s ChoiceReview

Circulating Tumor DNA Testing for Minimal Residual Disease and Its Application in Colorectal Cancer

by Oluseyi Abidoye, Daniel H. Ahn, Mitesh J. Borad, Christina Wu, Tanios Bekaii-Saab, Sakti Chakrabarti and Mohamad Bassam Sonbol

Cells 2025, 14(3), 161; https://doi.org/10.3390/cells14030161 - 22 Jan 2025

Cited by 5 | Viewed by 6401

Abstract

Colorectal cancer (CRC) represents a heterogeneous group of diseases that imposes a considerable global and national health burden. Although most CRC patients are diagnosed at an early stage and undergo potentially curative treatment, a significant proportion experience recurrence. Currently, adjuvant chemotherapy decisions are [...] Read more.

Colorectal cancer (CRC) represents a heterogeneous group of diseases that imposes a considerable global and national health burden. Although most CRC patients are diagnosed at an early stage and undergo potentially curative treatment, a significant proportion experience recurrence. Currently, adjuvant chemotherapy decisions are primarily based on clinicopathological characteristics, which have well-recognized limitations in accurately identifying patients harboring minimal residual disease (MRD), often resulting in unnecessary chemotherapy exposure. Circulating tumor DNA (ctDNA) has emerged as a promising surrogate marker for MRD, offering a more precise approach to identifying patients at risk of recurrence after curative-intent surgery and refining adjuvant chemotherapy decisions. Growing evidence from multiple studies has demonstrated that ctDNA outperforms traditional clinicopathological factors as a marker for MRD. This review synthesizes key studies supporting the role of ctDNA in MRD detection for CRC patients and evaluates clinical trials investigating the application of ctDNA in guiding adjuvant therapy decisions. This emerging strategy holds the potential to transform the adjuvant treatment paradigm in colorectal cancer by optimizing therapeutic precision and minimizing unnecessary treatment. Full article

(This article belongs to the Special Issue Current Status and Future Challenges of Liquid Biopsy)

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22 pages, 1949 KB

Open AccessEditor’s ChoiceReview

Mapping Human Uterine Disorders Through Single-Cell Transcriptomics

by Sandra Boldu-Fernández, Carolina Lliberos, Carlos Simon and Aymara Mas

Cells 2025, 14(3), 156; https://doi.org/10.3390/cells14030156 - 21 Jan 2025

Cited by 4 | Viewed by 3570

Abstract

Disruptions in uterine tissue function contribute to disorders such as endometriosis, adenomyosis, endometrial cancer, and fibroids, which all significantly impact health and fertility. Advances in transcriptomics, particularly single-cell RNA sequencing, have revolutionized uterine biological research by revealing the cellular heterogeneity and molecular mechanisms [...] Read more.

Disruptions in uterine tissue function contribute to disorders such as endometriosis, adenomyosis, endometrial cancer, and fibroids, which all significantly impact health and fertility. Advances in transcriptomics, particularly single-cell RNA sequencing, have revolutionized uterine biological research by revealing the cellular heterogeneity and molecular mechanisms underlying disease states. Single-cell RNA sequencing and spatial transcriptomics have mapped endometrial and myometrial cellular landscapes, which helped to identify critical cell types, signaling pathways, and phase-specific dynamics. Said transcriptomic technologies also identified stromal and immune cell dysfunctions, such as fibroblast-to-myofibroblast transitions and impaired macrophage activity, which drive fibrosis, chronic inflammation, and lesion persistence in endometriosis. For endometrial cancer, scRNA-seq uncovered tumor microenvironmental complexities, identifying cancer-associated fibroblast subtypes and immune cell profiles contributing to progression and therapeutic resistance. Similarly, studies on adenomyosis highlighted disrupted signaling pathways, including Wnt and VEGF, and novel progenitor cell populations linked to tissue invasion and neuroinflammation, while single-cell approaches characterized smooth muscle and fibroblast subpopulations in uterine fibroids, elucidating their roles in extracellular matrix remodeling and signaling pathways like ERK and mTOR. Despite challenges such as scalability and reproducibility, single-cell transcriptomic approaches may have potential applications in biomarker discovery, therapeutic target identification, and personalized medicine in gynecological disorders. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gynecological Disorders)

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17 pages, 702 KB

Open AccessEditor’s ChoiceReview

The Link Between Venous and Arterial Thrombosis: Is There a Role for Endothelial Dysfunction?

by Marco Paolo Donadini, Francesca Calcaterra, Erica Romualdi, Roberta Ciceri, Assunta Cancellara, Corrado Lodigiani, Monica Bacci, Silvia Della Bella, Walter Ageno and Domenico Mavilio

Cells 2025, 14(2), 144; https://doi.org/10.3390/cells14020144 - 20 Jan 2025

Cited by 10 | Viewed by 3848

Abstract

Venous thromboembolism (VTE) and arterial thrombosis (AT) are distinct yet closely related pathological processes. While traditionally considered separate entities, accumulating evidence suggests that they share common risk factors, such as inflammation and endothelial dysfunction (ED). This review explores the parallels and differences between [...] Read more.

Venous thromboembolism (VTE) and arterial thrombosis (AT) are distinct yet closely related pathological processes. While traditionally considered separate entities, accumulating evidence suggests that they share common risk factors, such as inflammation and endothelial dysfunction (ED). This review explores the parallels and differences between venous and arterial thrombosis, with particular attention to the role of unprovoked VTE and its potential links to atherosclerosis and systemic inflammation. A key focus is the role of ED, which is emerging as a critical factor in thrombogenesis across both the venous and arterial systems. We examine the current methods for clinically detecting ED, including the use of biomarkers and advanced imaging techniques. Additionally, we discuss novel research avenues, such as the potential of endothelial colony-forming cells and other innovative methodologies, to further unravel the complex mechanisms of thrombosis. Finally, we propose future clinical scenarios where targeting endothelial health could pave the way for more effective prevention and treatment strategies in thrombosis management. Full article

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

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18 pages, 815 KB

Open AccessEditor’s ChoiceReview

Impacts of Hyaluronan on Extracellular Vesicle Production and Signaling

by Melanie A. Simpson

Cells 2025, 14(2), 139; https://doi.org/10.3390/cells14020139 - 18 Jan 2025

Cited by 1 | Viewed by 1569

Abstract

Hyaluronan (HA) is a critical component of cell and tissue matrices and an important signaling molecule. The enzymes that synthesize and process HA, as well as the HA receptors through which the signaling properties of HA are transmitted, have been identified in extracellular [...] Read more.

Hyaluronan (HA) is a critical component of cell and tissue matrices and an important signaling molecule. The enzymes that synthesize and process HA, as well as the HA receptors through which the signaling properties of HA are transmitted, have been identified in extracellular vesicles and implicated in context-specific processes associated with health and disease. The goal of this review is to present a comprehensive summary of the research on HA and its related receptors and enzymes in extracellular vesicle biogenesis and the cellular responses to vesicles bearing these extracellular matrix modulators. When present in extracellular vesicles, HA is assumed to be on the outside of the vesicle and is sometimes found associated with CD44 or the HAS enzyme itself. Hyaluronidases may be inside the vesicles or present on the vesicle surface via a transmembrane domain or GPI linkage. The implication of presenting these signals in extracellular vesicles is that there is a greater range of systemic distribution and more complex delivery media than previously thought for secreted HA or hyaluronidase alone. Understanding the context for these HA signals offers new diagnostic and therapeutic insight. Full article

(This article belongs to the Special Issue Role of Hyaluronan in Human Health and Disease)

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17 pages, 1906 KB

Open AccessEditor’s ChoiceReview

Key Role of Phosphorylation in Small Heat Shock Protein Regulation via Oligomeric Disaggregation and Functional Activation

by Zachary B. Sluzala, Angelina Hamati and Patrice E. Fort

Cells 2025, 14(2), 127; https://doi.org/10.3390/cells14020127 - 17 Jan 2025

Cited by 5 | Viewed by 1768

Abstract

Heat shock proteins (HSPs) are essential molecular chaperones that protect cells by aiding in protein folding and preventing aggregation under stress conditions. Small heat shock proteins (sHSPs), which include members from HSPB1 to HSPB10, are particularly important for cellular stress responses. These proteins [...] Read more.

Heat shock proteins (HSPs) are essential molecular chaperones that protect cells by aiding in protein folding and preventing aggregation under stress conditions. Small heat shock proteins (sHSPs), which include members from HSPB1 to HSPB10, are particularly important for cellular stress responses. These proteins share a conserved α-crystallin domain (ACD) critical for their chaperone function, with flexible N- and C-terminal extensions that facilitate oligomer formation. Phosphorylation, a key post-translational modification (PTM), plays a dynamic role in regulating sHSP structure, oligomeric state, stability, and chaperone function. Unlike other PTMs such as deamidation, oxidation, and glycation—which are often linked to protein destabilization—phosphorylation generally induces structural transitions that enhance sHSP activity. Specifically, phosphorylation promotes the disaggregation of sHSP oligomers into smaller, more active complexes, thereby increasing their efficiency. This disaggregation mechanism is crucial for protecting cells from stress-induced damage, including apoptosis, inflammation, and other forms of cellular dysfunction. This review explores the role of phosphorylation in modulating the function of sHSPs, particularly HSPB1, HSPB4, and HSPB5, and discusses how these modifications influence their protective functions in cellular stress responses. Full article

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13 pages, 3393 KB

Open AccessEditor’s ChoiceArticle

Imaging Flow Cytometric Identification of Chromosomal Defects in Paediatric Acute Lymphoblastic Leukaemia

by Ana P. A. Simpson, Carly E. George, Henry Y. L. Hui, Ravi Doddi, Rishi S. Kotecha, Kathy A. Fuller and Wendy N. Erber

Cells 2025, 14(2), 114; https://doi.org/10.3390/cells14020114 - 14 Jan 2025

Cited by 1 | Viewed by 1743

Abstract

Acute lymphoblastic leukaemia is the most common childhood malignancy that remains a leading cause of death in childhood. It may be characterised by multiple known recurrent genetic aberrations that inform prognosis, the most common being hyperdiploidy and t(12;21) ETV6::RUNX1. We aimed to [...] Read more.

Acute lymphoblastic leukaemia is the most common childhood malignancy that remains a leading cause of death in childhood. It may be characterised by multiple known recurrent genetic aberrations that inform prognosis, the most common being hyperdiploidy and t(12;21) ETV6::RUNX1. We aimed to assess the applicability of a new imaging flow cytometry methodology that incorporates cell morphology, immunophenotype, and fluorescence in situ hybridisation (FISH) to identify aneuploidy of chromosomes 4 and 21 and the translocation ETV6::RUNX1. We evaluated this new “immuno-flowFISH” platform on 39 cases of paediatric ALL of B-lineage known to have aneuploidy of chromosomes 4 and 21 and the translocation ETV6::RUNX1. After identifying the leukaemic population based on immunophenotype (i.e., expression of CD34, CD10, and CD19 antigens), we assessed for copy numbers of loci for the centromeres of chromosomes 4 and 21 and the ETV6 and RUNX1 regions using fluorophore-labelled DNA probes in more than 1000 cells per sample. Trisomy 4 and 21, tetrasomy 21, and translocations of ETV6::RUNX1, as well as gains and losses of ETV6 and RUNX1, could all be identified based on FISH spot counts and digital imagery. There was variability in clonal makeup in individual cases, suggesting the presence of sub-clones. Copy number alterations and translocations could be detected even when the cell population comprised less than 1% of cells and included cells with a mature B-cell phenotype, i.e., CD19-positive, lacking CD34 and CD10. In this proof-of-principle study of 39 cases, this sensitive and specific semi-automated high-throughput imaging flow cytometric immuno-flowFISH method has been able to show that alterations in ploidy and ETV6::RUNX1 could be detected in the 39 cases of paediatric ALL. This imaging flow cytometric FISH method has potential applications for diagnosis and monitoring disease and marrow regeneration (i.e., distinguishing residual ALL from regenerating haematogones) following chemotherapy. Full article

(This article belongs to the Special Issue The Applications of Flow Cytometry: Advances, Challenges, and Trends)

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16 pages, 6880 KB

Open AccessEditor’s ChoiceReview

Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy

by Anna Piscone, Francesca Gorini, Susanna Ambrosio, Anna Noviello, Giovanni Scala, Barbara Majello and Stefano Amente

Cells 2025, 14(2), 112; https://doi.org/10.3390/cells14020112 - 14 Jan 2025

Cited by 3 | Viewed by 2074

Abstract

Genomic integrity is critical for cellular homeostasis, preventing the accumulation of mutations that can drive diseases such as cancer. Among the mechanisms safeguarding genomic stability, the Base Excision Repair (BER) pathway plays a pivotal role in counteracting oxidative DNA damage caused by reactive [...] Read more.

Genomic integrity is critical for cellular homeostasis, preventing the accumulation of mutations that can drive diseases such as cancer. Among the mechanisms safeguarding genomic stability, the Base Excision Repair (BER) pathway plays a pivotal role in counteracting oxidative DNA damage caused by reactive oxygen species. Central to this pathway are enzymes like 8-oxoguanine glycosylase 1 (OGG1), which recognize and excise 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) lesions, thereby initiating a series of repair processes that restore DNA integrity. BER inhibitors have recently been identified as a promising approach in cancer therapy, increasing the sensitivity of cancer cells to radiotherapy and chemotherapy. By exploiting tumor-specific DNA repair dependencies and synthetic lethal interactions, these inhibitors could be used to selectively target cancer cells while sparing normal cells. This review provides a robust reference for scientific researchers, offering an updated perspective on small-molecule inhibitors targeting the 8-oxodG-BER pathway and highlighting their potential role in expanding cancer treatment strategies. Full article

(This article belongs to the Special Issue DNA Damage and Repair for Targeted Cancer Therapy)

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16 pages, 12401 KB

Open AccessEditor’s ChoiceArticle

Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy

by Christopher R. Starr, Assylbek Zhylkibayev, Oleg Gorbatyuk, Alli M. Nuotio-Antar, James Mobley, Maria B. Grant and Marina Gorbatyuk

Cells 2025, 14(2), 107; https://doi.org/10.3390/cells14020107 - 13 Jan 2025

Cited by 1 | Viewed by 1326

Abstract

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in the lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in the pathogenesis of [...] Read more.

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in the lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in the pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBP^RP mice with constitutively active (ca) ChREBP. These mice underwent retinal functional testing, which was followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19^ChREBP) and subjected to global proteomics. Our results demonstrate that both proteins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photoreceptor degeneration, as we observed diminished scotopic ERG amplitudes in caChREBP^RP mice at P35. The retinal proteomic landscape revealed a decline in the KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific caChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19^ChREBP cells exhibit a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprogramming triggering retinal functional loss in mice. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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22 pages, 9006 KB

Open AccessEditor’s ChoiceArticle

Traumatic Brain Injury Promotes Neurogenesis and Oligodendrogenesis in Subcortical Brain Regions of Mice

by Olga Astakhova, Anna Ivanova, Ilia Komoltsev, Natalia Gulyaeva, Grigori Enikolopov and Alexander Lazutkin

Cells 2025, 14(2), 92; https://doi.org/10.3390/cells14020092 - 10 Jan 2025

Cited by 1 | Viewed by 3845

Abstract

Traumatic brain injury (TBI) is one of the major causes of severe neurological disorders and long-term dysfunction in the nervous system. Besides inducing neurodegeneration, TBI alters stem cell activity and neurogenesis within primary neurogenic niches. However, the fate of dividing cells in other [...] Read more.

Traumatic brain injury (TBI) is one of the major causes of severe neurological disorders and long-term dysfunction in the nervous system. Besides inducing neurodegeneration, TBI alters stem cell activity and neurogenesis within primary neurogenic niches. However, the fate of dividing cells in other brain regions remains unclear despite offering potential targets for therapeutic intervention. Here, we investigated cell division and differentiation in non-neurogenic brain regions during the acute and delayed phases of TBI-induced neurodegeneration. We subjected mice to lateral fluid percussion injury (LFPI) to model TBI and analyzed them 1 or 7 weeks later. To assess cellular proliferation and differentiation, we administered 5-ethinyl-2′-deoxyuridine (EdU) and determined the number and identity of dividing cells 2 h later using markers of neuronal precursors and astro-, micro-, and oligodendroglia. Our results demonstrated a significant proliferative response in several brain regions at one week post-injury that notably diminished by seven weeks, except in the optic tract. In addition to active astro- and microgliosis, we detected oligodendrogenesis in the striatum and optic tract. Furthermore, we observed trauma-induced neurogenesis in the striatum. These findings suggest that subcortical structures, particularly the striatum and optic tract, may possess a potential for self-repair through neuronal regeneration and axon remyelination. Full article

(This article belongs to the Section Cells of the Nervous System)

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17 pages, 4732 KB

Open AccessEditor’s ChoiceArticle

Anti-Inflammatory Effects of Cannabigerol In Vitro and In Vivo Are Mediated Through the JAK/STAT/NFκB Signaling Pathway

by Ga Hee Jeong, Ki Chan Kim and Ji Hyun Lee

Cells 2025, 14(2), 83; https://doi.org/10.3390/cells14020083 - 9 Jan 2025

Cited by 4 | Viewed by 6004

Abstract

Cannabinoid compounds have potential as treatments for a variety of conditions, with cannabigerol (CBG) being known for its anti-inflammatory properties. In this study, we investigated the effects of CBG in a cellular model of 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD). In the cellular model, [...] Read more.

Cannabinoid compounds have potential as treatments for a variety of conditions, with cannabigerol (CBG) being known for its anti-inflammatory properties. In this study, we investigated the effects of CBG in a cellular model of 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD). In the cellular model, we confirmed the cytotoxicity of CBG and downregulated the expression of inflammatory markers CCL26, IL1B, IL6, and TNF (p < 0.001). In the mouse model, clinical, histological, and immunological changes were analyzed. The results showed that CBG improved dermatitis severity score, epidermal thickness, and mast cell count and reduced inflammatory cytokines (Tslp, Il1b, Il4, Il6, Il13, Il17, Il18, Il22, and Il33) by qRT-PCR (p < 0.001). Western blot results showed modulated changes in JAK1, JAK2, TYK2, STAT1, STAT2, STAT3, p-STAT3, STAT6, and p-STAT6 (p < 0.05). Subsequently, p-IκBα, NF-κB, and p-NF-κB signaling factors were also reduced (p < 0.05), with corresponding changes in skin barrier factors. The results of this study indicate that CBG effectively alleviates AD-like symptoms and suggest the potential of CBG as a therapeutic agent. Full article

(This article belongs to the Special Issue Charming Micro-Insights into Health and Diseases)

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18 pages, 2095 KB

Open AccessEditor’s ChoiceArticle

miR-1233-3p Inhibits Angiopoietin-1-Induced Endothelial Cell Survival, Migration, and Differentiation

by Veronica Sanchez, Sharon Harel, Anas Khalid Sa’ub, Dominique Mayaki and Sabah N. A. Hussain

Cells 2025, 14(2), 75; https://doi.org/10.3390/cells14020075 - 8 Jan 2025

Cited by 1 | Viewed by 1208

Abstract

Angiopoietin-1 (Ang-1) and its receptor Tie-2 promote vascular integrity and angiogenesis. MicroRNAs (miRNAs) are involved in the regulation of many cellular functions, including endothelial cell (EC) survival, proliferation, and differentiation. Several reports indicate that these effects of miRNAs on EC functions are mediated [...] Read more.

Angiopoietin-1 (Ang-1) and its receptor Tie-2 promote vascular integrity and angiogenesis. MicroRNAs (miRNAs) are involved in the regulation of many cellular functions, including endothelial cell (EC) survival, proliferation, and differentiation. Several reports indicate that these effects of miRNAs on EC functions are mediated through the modulation of angiogenesis factor signaling including that of vascular endothelial growth factor (VEGF). To date, very little is known about the roles played by miRNAs in the signaling and angiogenesis promoted by the Ang-1–Tie-2 receptor axis. Our high-throughput screening of miRNAs regulated by Ang-1 exposure in human umbilical vein endothelial cells (HUVECs) has identified miR-1233-3p as a mature miRNA whose cellular levels are significantly downregulated in response to Ang-1 exposure. The expression of miR-1233-3p in these cells is also downregulated by other angiogenesis factors including VEGF, fibroblast growth factor 2 (FGF-2), transforming growth factor β (TGFβ), and angiopoietin-2 (Ang-2). The overexpression of miR-1233-3p in HUVECs using specific mimics significantly attenuated cell survival, migration, and capillary-like tube formation, and promoted apoptosis. Moreover, miR-1233-3p overexpression resulted in reversal of the anti-apoptotic, pro-migration, and pro-differentiation effects of Ang-1. Biotinylated miRNA pull-down assays showed that p53 and DNA damage-regulated 1 (PDRG1) is a direct target of miR-1233-3p in HUVECs. The exposure of HUVECs to Ang-1, angiopoietin-2 (Ang-2), fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), or transforming growth factor β (TGFβ) triggers the regulation of PDRG1 expression. This study highlights that miR-1233-3p exerts inhibitory effects on Ang-1-induced survival, migration, and the differentiation of cultured ECs. Full article

(This article belongs to the Collection microRNAs in Health and Diseases)

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25 pages, 2984 KB

Open AccessEditor’s ChoiceReview

TRIM25: A Global Player of Cell Death Pathways and Promising Target of Tumor-Sensitizing Therapies

by Wolfgang Eberhardt, Usman Nasrullah and Josef Pfeilschifter

Cells 2025, 14(2), 65; https://doi.org/10.3390/cells14020065 - 7 Jan 2025

Cited by 1 | Viewed by 3137

Abstract

Therapy resistance still constitutes a common hurdle in the treatment of many human cancers and is a major reason for treatment failure and patient relapse, concomitantly with a dismal prognosis. In addition to “intrinsic resistance”, e.g., acquired by random mutations, cancer cells typically [...] Read more.

Therapy resistance still constitutes a common hurdle in the treatment of many human cancers and is a major reason for treatment failure and patient relapse, concomitantly with a dismal prognosis. In addition to “intrinsic resistance”, e.g., acquired by random mutations, cancer cells typically escape from certain treatments (“acquired resistance”) by a large variety of means, including suppression of apoptosis and other cell death pathways via upregulation of anti-apoptotic factors or through inhibition of tumor-suppressive proteins. Therefore, ideally, the tumor-cell-restricted induction of apoptosis is still considered a promising avenue for the development of novel, tumor (re)sensitizing therapies. A growing body of evidence has highlighted the multifaceted role of tripartite motif 25 (TRIM25) in controlling different aspects of tumorigenesis, including chemotherapeutic drug resistance. Accordingly, overexpression of TRIM25 is observed in many tumors and frequently correlates with a poor patient survival. In addition to its originally described function in antiviral innate immune response, TRIM25 can play critical yet context-dependent roles in apoptotic- and non-apoptotic-regulated cell death pathways, including pyroposis, necroptosis, ferroptosis, and autophagy. The review summarizes current knowledge of molecular mechanisms by which TRIM25 can interfere with different cell death modalities and thereby affect the success of currently used chemotherapeutics. A better understanding of the complex repertoire of cell death modulatory effects by TRIM25 is an essential prerequisite for validating TRIM25 as a potential target for future anticancer therapy to surmount the high failure rate of currently used chemotherapies. Full article

(This article belongs to the Special Issue Apoptosis and Alternative Modes of Cell Death as Targets for Anticancer Therapy)

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18 pages, 2911 KB

Open AccessEditor’s ChoiceArticle

Flow Cytometric Assessment of FcγRIIIa-V158F Polymorphisms and NK Cell Mediated ADCC Revealed Reduced NK Cell Functionality in Colorectal Cancer Patients

by Phillip Schiele, Stefan Kolling, Stanislav Rosnev, Charlotte Junkuhn, Anna Luzie Walter, Jobst Christian von Einem, Sebastian Stintzing, Wenzel Schöning, Igor Maximilian Sauer, Dominik Paul Modest, Kathrin Heinrich, Lena Weiss, Volker Heinemann, Lars Bullinger, Marco Frentsch and Il-Kang Na

Cells 2025, 14(1), 32; https://doi.org/10.3390/cells14010032 - 31 Dec 2024

Cited by 2 | Viewed by 2332

Abstract

Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells is a key mechanism in anti-cancer therapies with monoclonal antibodies, including cetuximab (EGFR-targeting) and avelumab (PDL1-targeting). Fc gamma receptor IIIa (FcγRIIIa) polymorphisms impact ADCC, yet their clinical relevance in NK cell functionality remains debated. We developed [...] Read more.

Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells is a key mechanism in anti-cancer therapies with monoclonal antibodies, including cetuximab (EGFR-targeting) and avelumab (PDL1-targeting). Fc gamma receptor IIIa (FcγRIIIa) polymorphisms impact ADCC, yet their clinical relevance in NK cell functionality remains debated. We developed two complementary flow cytometry assays: one to predict the FcγRIIIa-V158F polymorphism using a machine learning model, and a 15-color flow cytometry panel to assess antibody-induced NK cell functionality and cancer-immune cell interactions. Samples were collected from healthy donors and metastatic colorectal cancer (mCRC) patients from the FIRE-6-Avelumab phase II study. The machine learning model accurately predicted the FcγRIIIa-V158F polymorphism in 94% of samples. FF homozygous patients showed diminished cetuximab-mediated ADCC compared to VF or VV carriers. In mCRC patients, NK cell dysfunctions were evident as impaired ADCC, decreased CD16 downregulation, and reduced CD137/CD107a induction. Elevated PD1+ NK cell levels, reduced lysis of PDL1-expressing CRC cells and improved NK cell activation in combination with the PDL1-targeting avelumab indicate that the PD1-PDL1 axis contributes to impaired cetuximab-induced NK cell function. Together, these optimized assays effectively identify NK cell dysfunctions in mCRC patients and offer potential for broader application in evaluating NK cell functionality across cancers and therapeutic settings. Full article

(This article belongs to the Special Issue Advances in the Study of Natural Killer (NK) Cells)

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17 pages, 2689 KB

Open AccessEditor’s ChoiceArticle

Ezrin Polarization as a Diagnostic Marker for Circulating Tumor Cells in Hepatocellular Carcinoma

by Ibrahim Büdeyri, Olaf Guckelberger, Elsie Oppermann, Dhruvajyoti Roy, Svenja Sliwinski, Felix Becker, Benjamin Struecker, Thomas J. Vogl, Andreas Pascher, Wolf O. Bechstein, Anna Lorentzen, Mathias Heikenwalder and Mazen A. Juratli

Cells 2025, 14(1), 6; https://doi.org/10.3390/cells14010006 - 25 Dec 2024

Viewed by 1567

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide, with no precise method for early detection. Circulating tumor cells (CTCs) expressing the dynamic polarity of the cytoskeletal membrane protein, ezrin, have been proposed to [...] Read more.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide, with no precise method for early detection. Circulating tumor cells (CTCs) expressing the dynamic polarity of the cytoskeletal membrane protein, ezrin, have been proposed to play a crucial role in tumor progression and metastasis. This study investigated the diagnostic and prognostic potential of polarized circulating tumor cells (p-CTCs) in HCC patients. CTCs were isolated from the peripheral blood of 20 HCC patients and 18 patients with nonmalignant liver disease (NMLD) via an OncoQuick^® kit and immunostained with Ezrin-Alexa Fluor 488^®, CD146-PE, and CD45-APC. A fluorescence microscopy was then performed for analysis. The HCC group exhibited significantly higher levels of p-CTCs, with median values of 0.56 p-CTCs/mL, compared to 0.02 p-CTCs/mL (p = 0.03) in the NMLD group. CTCs were detected in 95% of the HCC patients, with a sensitivity of 95% and specificity of 89%. p-CTCs were present in 75% of the HCC patients, with a sensitivity of 75% and a specificity of 94%. Higher p-CTC counts were associated with the significantly longer overall survival in HCC patients (p = 0.05). These findings suggest that p-CTCs could serve as valuable diagnostic and prognostic markers for HCC. The incorporation of p-CTCs into diagnostic strategies could enhance therapeutic decision-making and improve patient outcomes. Full article

(This article belongs to the Collection Current Understanding in Cancer Treatment and Monitoring Through Identification of Circulating Tumor Cells and Tumor-Derived Extracellular Vesicles)

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17 pages, 2859 KB

Open AccessFeature PaperEditor’s ChoiceArticle

The Tumor Metabolite 5′-Deoxy-5′Methylthioadenosine (MTA) Inhibits Maturation and T Cell-Stimulating Capacity of Dendritic Cells

by Christina Brummer, Katrin Singer, Frederik Henrich, Katrin Peter, Carolin Strobl, Bernadette Neueder, Christina Bruss, Kathrin Renner, Tobias Pukrop, Wolfgang Herr, Michael Aigner and Marina Kreutz

Cells 2024, 13(24), 2114; https://doi.org/10.3390/cells13242114 - 20 Dec 2024

Viewed by 1695

Abstract

Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5′-deoxy-5′methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it [...] Read more.

Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5′-deoxy-5′methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it is known to inhibit tumor-infiltrating T cells and NK cells. However, the impact of MTA on other intra-tumoral immune cells has not yet been fully elucidated. To study the effects of MTA on dendritic cells (DCs), human monocytes were maturated into DCs with (MTA-DC) or without MTA (co-DC) and analyzed for activation, differentiation, and T cell-stimulating capacity. MTA altered the cytokine secretion profile of monocytes and impaired their maturation into dendritic cells. MTA-DCs produced less IL-12 and showed a more immature-like phenotype characterized by decreased expression of the co-stimulatory molecules CD80, CD83, and CD86 and increased expression of the monocyte markers CD14 and CD16. Consequently, MTA reduced the capability of DCs to stimulate T cells. Mechanistically, the MTA-induced effects on monocytes and DCs were mediated by a mechanism beyond adenosine receptor signaling. These results provide new insights into how altered polyamine metabolism impairs the maturation of monocyte-derived DCs and impacts the crosstalk between T and dendritic cells. Full article

(This article belongs to the Collection Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications)

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15 pages, 3500 KB

Open AccessEditor’s ChoiceArticle

α-Synuclein Deletion Impairs Platelet Function: A Role for SNARE Complex Assembly

by Christopher Sennett, Wanzhu Jia, Jawad S. Khalil, Matthew S. Hindle, Charlie Coupland, Simon D. J. Calaminus, Julian D. Langer, Sean Frost, Khalid M. Naseem, Francisco Rivero, Natalia Ninkina, Vladimir Buchman and Ahmed Aburima

Cells 2024, 13(24), 2089; https://doi.org/10.3390/cells13242089 - 17 Dec 2024

Cited by 2 | Viewed by 1659

Abstract

Granule secretion is an essential platelet function that contributes not only to haemostasis but also to wound healing, inflammation, and atherosclerosis. Granule secretion from platelets is facilitated, at least in part, by Soluble N-ethylmaleimide-Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) complex-mediated granule fusion. [...] Read more.

Granule secretion is an essential platelet function that contributes not only to haemostasis but also to wound healing, inflammation, and atherosclerosis. Granule secretion from platelets is facilitated, at least in part, by Soluble N-ethylmaleimide-Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) complex-mediated granule fusion. Although α-synuclein is a protein known to modulate the assembly of the SNARE complex in other cells, its role in platelet function remains poorly understood. In this study, we provide evidence that α-synuclein is critical for haemostasis using α-synuclein-deficient (^−/−) mice. The genetic deletion of α-synuclein resulted in impaired platelet aggregation, secretion, and adhesion in vitro. In vivo haemostasis models showed that α-synuclein^−/− mice had prolonged bleeding times and activated partial thromboplastin times (aPTTs). Mechanistically, platelet activation induced α-synuclein serine (ser) 129 phosphorylation and re-localisation to the platelet membrane, accompanied by an increased association with VAMP 8, syntaxin 4, and syntaxin 11. This phosphorylation was calcium (Ca²⁺)- and RhoA/ROCK-dependent and was inhibited by prostacyclin (PGI₂). Our data suggest that α-synuclein regulates platelet secretion by facilitating SNARE complex formation. Full article

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20 pages, 3994 KB

Open AccessEditor’s ChoiceArticle

Discovery of Carbonic Anhydrase 9 as a Novel CLEC2 Ligand in a Cellular Interactome Screen

by Sebastian Hoffmann, Benedict-Tilman Berger, Liane Rosalie Lucas, Felix Schiele and John Edward Park

Cells 2024, 13(24), 2083; https://doi.org/10.3390/cells13242083 - 17 Dec 2024

Viewed by 1623

Abstract

Membrane proteins, especially extracellular domains, are key therapeutic targets due to their role in cell communication and associations. Yet, their functions and interactions often remain unclear. This study presents a general method to discover interactions of membrane proteins with immune cells and subsequently [...] Read more.

Membrane proteins, especially extracellular domains, are key therapeutic targets due to their role in cell communication and associations. Yet, their functions and interactions often remain unclear. This study presents a general method to discover interactions of membrane proteins with immune cells and subsequently to deorphanize their respective receptors. We developed a comprehensive recombinant protein library of extracellular domains of human transmembrane proteins and proteins found in the ER-Golgi-lysosomal systems. Using this library, we conducted a flow-cytometric screen that identified several cell surface binding events, including an interaction between carbonic anhydrase 9 (CAH9/CA9/CAIX) and CD14^high cells. Further analysis revealed this interaction was indirect and mediated via platelets bound to the monocytes. CA9, best known for its diverse roles in cancer, is a promising therapeutic target. We utilized our library to develop an AlphaLISA high-throughput screening assay, identifying CLEC2 as one robust CA9 binding partner. A five-amino-acid sequence (EDLPT) in CA9, identical to a CLEC2 binding domain in Podoplanin (PDPN), was found to be essential for this interaction. Like PDPN, CA9-induced CLEC2 signaling is mediated via Syk. A Hodgkin’s lymphoma cell line (HDLM-2) endogenously expressing CA9 can activate Syk-dependent CLEC2 signaling, providing enticing evidence for a novel function of CA9 in hematological cancers. In conclusion, we identified numerous interactions with monocytes and platelets and validated one, CA9, as an endogenous CLEC2 ligand. We provide a new list of other putative CA9 interaction partners and uncovered CA9-induced CLEC2 activation, providing new insights for CA9-based therapeutic strategies. Full article

(This article belongs to the Section Cellular Immunology)

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16 pages, 4686 KB

Open AccessEditor’s ChoiceArticle

Subset of DN Memory B Cells Expressing Low Levels of Inhibitory Receptor BTLA Is Enriched in SLE Patients

by Lucie Aubergeon, Renaud Felten, Jacques-Eric Gottenberg, Hélène Dumortier and Fanny Monneaux

Cells 2024, 13(24), 2063; https://doi.org/10.3390/cells13242063 - 13 Dec 2024

Cited by 2 | Viewed by 1714

Abstract

The dialogue between T and B cells can be regulated by different mechanisms, such as co-inhibitory receptors, which therefore play a crucial role in preventing autoimmune diseases such as systemic lupus erythematosus (SLE). B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor [...] Read more.

The dialogue between T and B cells can be regulated by different mechanisms, such as co-inhibitory receptors, which therefore play a crucial role in preventing autoimmune diseases such as systemic lupus erythematosus (SLE). B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor expressed on many myeloid and lymphoid cells. Although peripheral B cells express a very high amount of BTLA, previous works in the context of autoimmunity mainly focused on T cells, and whether BTLA expression on B cells plays a role in the lupus pathogenesis is still unclear. In the present study, we examine the expression of BTLA, as well as its ligand HVEM (Herpesvirus Entry Mediator), on various B cell subsets in lupus patients compared to healthy controls (HCs). We evidenced the existence of double-negative (DN; IgD⁻CD27⁻) memory B cells expressing very low levels of BTLA, which are enhanced in active lupus patients. An in-depth analysis revealed that these BTLA^low DN cells mainly correspond to the newly reported DN3 B cell subset, originally described in the context of SARS-CoV2 infection. These cells display an activated and antibody-secreting cell phenotype, and we propose that their low BTLA expression may favor their expansion and rapid differentiation into plasmablasts in lupus patients. Full article

(This article belongs to the Special Issue Immune Functions and Therapeutic Potential of B Lymphocytes in Autoimmune Disorders)

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17 pages, 10124 KB

Open AccessEditor’s ChoiceArticle

KSRP Deficiency Attenuates the Course of Pulmonary Aspergillosis and Is Associated with the Elevated Pathogen-Killing Activity of Innate Myeloid Immune Cells

by Vanessa Bolduan, Kim-Alicia Palzer, Frederic Ries, Nora Busch, Andrea Pautz and Matthias Bros

Cells 2024, 13(24), 2040; https://doi.org/10.3390/cells13242040 - 10 Dec 2024

Cited by 1 | Viewed by 1158

Abstract

The mRNA-binding protein KSRP (KH-type splicing regulatory protein) is known to modulate immune cell functions post-transcriptionally, e.g., by reducing the mRNA stability of cytokines. It is known that KSRP binds the AU-rich motifs (ARE) that are often located in the 3′-untranslated part of [...] Read more.

The mRNA-binding protein KSRP (KH-type splicing regulatory protein) is known to modulate immune cell functions post-transcriptionally, e.g., by reducing the mRNA stability of cytokines. It is known that KSRP binds the AU-rich motifs (ARE) that are often located in the 3′-untranslated part of mRNA species, encoding dynamically regulated proteins as, for example, cytokines. Innate myeloid immune cells, such as polymorphonuclear neutrophils (PMNs) and macrophages (MACs), eliminate pathogens by multiple mechanisms, including phagocytosis and the secretion of chemo- and cytokines. Here, we investigated the role of KSRP in the phenotype and functions of both innate immune cell types in the mouse model of invasive pulmonary aspergillosis (IPA). Here, KSRP^−/− mice showed lower levels of Aspergillus fumigatus conidia (AFC) and an increase in the frequencies of PMNs and MACs in the lungs. Our results showed that PMNs and MACs from KSRP^−/− mice exhibited an enhanced phagocytic uptake of AFC, accompanied by increased ROS production in PMNs upon stimulation. A comparison of RNA sequencing data revealed that 64 genes related to inflammatory and immune responses were shared between PMNs and MACs. The majority of genes upregulated in PMNs were involved in metabolic processes, cell cycles, and DNA repair. Similarly, KSRP-deficient PMNs displayed reduced levels of apoptosis. In conclusion, our results indicate that KSRP serves as a critical negative regulator of PMN and MAC anti-pathogen activity. Full article

(This article belongs to the Special Issue Innate Immunity in Health and Disease)

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25 pages, 6935 KB

Open AccessEditor’s ChoiceArticle

Clinical Potential of Novel Microbial Therapeutic LP51 Based on Xerosis-Microbiome Index

by Sukyung Kim, Md Abdur Rahim, Hanieh Tajdozian, Indrajeet Barman, Hyun-A Park, Youjin Yoon, Sujin Jo, Soyeon Lee, Md Sarower Hossen Shuvo, Sung Hae Bae, Hyunji Lee, Sehee Ju, Chae-eun Park, Ho-Kyoung Kim, Jeung Hi Han, Ji-Woong Kim, Sung geon Yoon, Jae Hong Kim, Yang Gyu Choi, Saebim Lee, Hoonhee Seo and Ho-Yeon Song Show full author list Hide full author list

Cells 2024, 13(23), 2029; https://doi.org/10.3390/cells13232029 - 9 Dec 2024

Viewed by 1748

Abstract

Xerosis, characterized by dry, rough skin, causes discomfort and aesthetic concerns, necessitating effective treatment. Traditional treatments often show limited efficacy, prompting the need for innovative therapies. This study highlights the efficacy of microbiome therapeutic LP51, derived from a healthy vaginal microbiome, in improving [...] Read more.

Xerosis, characterized by dry, rough skin, causes discomfort and aesthetic concerns, necessitating effective treatment. Traditional treatments often show limited efficacy, prompting the need for innovative therapies. This study highlights the efficacy of microbiome therapeutic LP51, derived from a healthy vaginal microbiome, in improving xerosis. A double-blind clinical trial involving 43 subjects with dry inner arm skin compared the effects of a 2.9% LP51 extract formulation to a placebo over 4 weeks. The LP51 group exhibited a significant increase in stratum corneum hydration (10.0 A.U.) compared to the placebo group (4.8 A.U.) and a 21.4% decrease in transepidermal water loss (TEWL), whereas the placebo group showed no significant change. LP51 also demonstrated benefits in enhancing skin hydration, improving the skin barrier, and exhibited anti-atopic, anti-inflammatory, and antioxidant properties. Safety was confirmed through in vitro cytotoxicity tests. These effects are attributed to the microbiome-safe component in LP51 and its role in improving xerosis, reflected by an increase in the xerosis-microbiome index, defined by the Firmicutes/Actinobacteria ratio. These findings position microbiome therapeutic LP51 as a promising novel treatment for xerosis. Full article

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17 pages, 5212 KB

Open AccessEditor’s ChoiceArticle

LINC01270 Regulates the NF-κB-Mediated Pro-Inflammatory Response via the miR-326/LDOC1 Axis in THP-1 Cells

by Imene Arab, Su-Geun Lim, Kyoungho Suk and Won-Ha Lee

Cells 2024, 13(23), 2027; https://doi.org/10.3390/cells13232027 - 8 Dec 2024

Cited by 1 | Viewed by 1627

Abstract

Long intergenic noncoding (LINC)01270 is a 2278 bp transcript belonging to the intergenic subset of long noncoding (lnc)RNAs. Despite increased reports of LINC01270’s involvement in different diseases, evident research on its effects on inflammation is yet to be achieved. In the present study, [...] Read more.

Long intergenic noncoding (LINC)01270 is a 2278 bp transcript belonging to the intergenic subset of long noncoding (lnc)RNAs. Despite increased reports of LINC01270’s involvement in different diseases, evident research on its effects on inflammation is yet to be achieved. In the present study, we investigated the potential role of LINC01270 in modulating the inflammatory response in the human monocytic leukemia cell line THP-1. Lipopolysaccharide treatment upregulated LINC01270 expression, and siRNA-mediated suppression of LINC01270 enhanced NF-κB activity and the subsequent production of cytokines IL-6, IL-8, and MCP-1. Interestingly, the knockdown of LINC01270 downregulated expression of leucine zipper downregulated in cancer 1 (LDOC1), a novel NF-κB suppressor. An analysis of the LINC01270/micro-RNA (miRNA)/protein interactome profile identified miR-326 as a possible mediator. Synthetic RNA agents that perturb the interaction among LINC01270, miR-326, and LDOC1 mRNA mitigated the changes caused by LINC01270 knockdown in THP-1 cells. Additionally, a luciferase reporter assay in HEK293 cells further confirmed that LINC01270 knockdown enhances NF-κB activation, while its overexpression has the opposite effect. This study provides insight into LINC01270’s role in modulating inflammatory responses to lipopolysaccharide stimulation in THP-1 cells via the miR-326/LDOC1 axis, which negatively regulates NF-κB activation. Full article

(This article belongs to the Special Issue Macrophage Activation and Regulation)

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16 pages, 1709 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Differential Infiltration of Key Immune T-Cell Populations Across Malignancies Varying by Immunogenic Potential and the Likelihood of Response to Immunotherapy

by Islam Eljilany, Sam Coleman, Aik Choon Tan, Martin D. McCarter, John Carpten, Howard Colman, Abdul Rafeh Naqash, Igor Puzanov, Susanne M. Arnold, Michelle L. Churchman, Daniel Spakowicz, Bodour Salhia, Julian A. Marin-Acevedo, Shridar Ganesan, Aakrosh Ratan, Craig Shriver, Patrick Hwu, William S. Dalton, George J. Weiner, Jose R. Conejo-Garcia, Paulo Rodriguez and Ahmad A. Tarhini Show full author list Hide full author list

Cells 2024, 13(23), 1993; https://doi.org/10.3390/cells13231993 - 3 Dec 2024

Cited by 1 | Viewed by 2449

Abstract

Background: Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate [...] Read more.

Background: Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate T-cell populations and their differential infiltration within different tumor types as estimated from mRNA co-expression levels of the corresponding cellular markers. Methods: We analyzed the mRNA co-expression levels of cellular biomarkers that define stem-like tumor-infiltrating lymphocytes (TILs), tissue-resident memory T-cells (TRM), early dysfunctional T-cells, late dysfunctional T-cells, activated-potentially anti-tumor (APA) T-cells and Butyrophilin 3A (BTN3A) isoforms, utilizing clinical and transcriptomic data from 1892 patients diagnosed with melanoma, bladder, ovarian, or pancreatic carcinomas. Real-world data were collected under the Total Cancer Care Protocol and the Avatar^® project (NCT03977402) across 18 cancer centers. Furthermore, we compared the survival outcomes following immune checkpoint inhibitors (ICIs) based on immune cell gene expression. Results: In melanoma and bladder cancer, the estimated infiltration of APA T-cells differed significantly (p = 4.67 × 10⁻¹² and p = 5.80 × 10⁻¹², respectively) compared to ovarian and pancreatic cancers. Ovarian cancer had lower TRM T-cell infiltration than melanoma, bladder, and pancreatic (p = 2.23 × 10⁻⁸, 3.86 × 10⁻²⁸, and 7.85 × 10⁻⁹, respectively). Similar trends were noted with stem-like, early, and late dysfunctional T-cells. Melanoma and ovarian expressed BTN3A isoforms more than other malignancies. Higher densities of stem-like TILs; TRM, early and late dysfunctional T-cells; APA T-cells; and BTN3A isoforms were associated with increased survival in melanoma (p = 0.0075, 0.00059, 0.013, 0.005, 0.0016, and 0.041, respectively). The TRM gene signature was a moderate predictor of survival in the melanoma cohort (AUROC = 0.65), with similar findings in testing independent public datasets of ICI-treated patients with melanoma (AUROC 0.61–0.64). Conclusions: Key cellular elements related to immune activation are more heavily infiltrated within ICI-responsive versus non-responsive malignancies, supporting a central role in anti-tumor immunity. In melanoma patients treated with ICIs, higher densities of stem-like TILs, TRM T-cells, early dysfunctional T-cells, late dysfunctional T-cells, APA T-cells, and BTN3A isoforms were associated with improved survival. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)

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18 pages, 2732 KB

Open AccessEditor’s ChoiceArticle

Deficiencies of Inducible Costimulator (ICOS) During Chronic Infection with Toxoplasma gondii Upregulate the CD28-Dependent Cytotoxicity of CD8⁺ T Cells and Their Effector Function Against Tissue Cysts of the Parasite

by Rajesh Mani, Kanal E. Balu and Yasuhiro Suzuki

Cells 2024, 13(23), 1998; https://doi.org/10.3390/cells13231998 - 3 Dec 2024

Cited by 1 | Viewed by 1053

Abstract

We recently identified that the cerebral mRNA expression of inducible costimulator (ICOS) and its ligand, ICOSL, both significantly increase during the elimination of Toxoplasma gondii cysts from the brains of infected mice by the perforin-mediated cytotoxic activity of CD8⁺ T cells. In [...] Read more.

We recently identified that the cerebral mRNA expression of inducible costimulator (ICOS) and its ligand, ICOSL, both significantly increase during the elimination of Toxoplasma gondii cysts from the brains of infected mice by the perforin-mediated cytotoxic activity of CD8⁺ T cells. In the present study, we examined the role of ICOS in activating the effector activity of CD8⁺ T cells in response to the presence of cysts in infected mice. Following the adoptive transfer of splenic CD8⁺ T cells from chronically infected ICOS-deficient (ICOS^−/−) and wild-type (WT) mice to infected SCID mice, fewer CD8⁺ T cells were detected in the brains of the recipients of ICOS^−/− CD8⁺ T cells than the recipients of WT CD8⁺ T cells. Interestingly, even with the lower migration rate of the ICOS^−/− CD8⁺ T cells, those T cells eliminated T. gondii cysts more efficiently than WT CD8⁺ T cells did in the brains of the recipient mice. Consistently, the ICOS^−/− CD8⁺ T cells secreted greater amounts of granzyme B in response to T. gondii antigens in vitro than WT CD8⁺ T cells did. We identified that CD8⁺ T cells of infected ICOS^−/− mice express significantly greater levels of CD28 on their surface than CD8⁺ T cells of infected WT mice, and the relative expression of CD28 mRNA to CD8β mRNA levels in the brains of the recipients of those CD8⁺ T cells were strongly correlated with their relative expression levels of mRNA for T-bet transcription factors and perforin. Furthermore, blocking CD28 signaling using a combination of anti-CD80 and anti-CD86 antibodies eliminated the increased cytotoxic activity of the ICOS^−/− CD8⁺ T cells in vitro. The present study uncovered notable compensatory interactions between ICOS and CD28, which protected the cytotoxic effector activity of CD8⁺ T cells against microbial infection in a murine model of chronic infection with T. gondii. Full article

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20 pages, 18147 KB

Open AccessEditor’s ChoiceArticle

CD38 Inhibitor 78c Attenuates Pro-Inflammatory Cytokine Expression and Osteoclastogenesis in Macrophages

by William Lory, Nityananda Chowdhury, Bridgette Wellslager, Subramanya Pandruvada, Yan Huang, Özlem Yilmaz and Hong Yu

Cells 2024, 13(23), 1971; https://doi.org/10.3390/cells13231971 - 28 Nov 2024

Cited by 3 | Viewed by 2238

Abstract

CD38, a nicotinamide adenine dinucleotide (NAD⁺) glycohydrolase, increases during infection or inflammation. Therefore, we aimed to evaluate the effects of a CD38 inhibitor (78c) on NAD⁺ levels, IL-1β, IL-6, TNF-α cytokine expressions, and osteoclastogenesis. The results show that treatment with [...] Read more.

CD38, a nicotinamide adenine dinucleotide (NAD⁺) glycohydrolase, increases during infection or inflammation. Therefore, we aimed to evaluate the effects of a CD38 inhibitor (78c) on NAD⁺ levels, IL-1β, IL-6, TNF-α cytokine expressions, and osteoclastogenesis. The results show that treatment with 78c on murine BMMs dose-dependently reduced CD38, reversed the decline of NAD⁺, and inhibited IL-1β, IL-6, and TNF-α pro-inflammatory cytokine levels induced by oral pathogen Porphyromonas gingivalis (Pg) or Aggregatibacter actinomycetemcomitans (Aa) or by advanced glycation end products (AGEs). Additionally, treatment with 78c dose-dependently suppressed osteoclastogenesis and bone resorption induced by RANKL. Treatment with 78c suppressed CD38, nuclear factor kappa-B (NF-κB), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs) induced by Pg, Aa, or AGEs, and suppressed podosome components (PI3K, Pyk2, Src, F-actin, integrins, paxillin, and talin) induced by RANKL. These results from our studies support the finding that the inhibition of CD38 by 78c is a promising therapeutic strategy to treat inflammatory bone loss diseases. However, treatment with a CD38 shRNA only significantly reduced IL-1β, IL-6, and TNF-α pro-inflammatory cytokine levels induced by AGEs. Compared with controls, it had limited effects on cytokine levels induced by Pg or Aa. Treatment with the CD38 shRNA enhanced RANKL-induced osteoclastogenesis, suggesting that 78c has some off-target effects. Full article

(This article belongs to the Collection Cell Biology in the United States: Latest Advances and Perspectives)

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30 pages, 7913 KB

Open AccessEditor’s ChoiceArticle

Peripheral Blood Leukocyte Subpopulation Changes in Reaction to an Acute Psychosocial Stressor as Compared to an Active Placebo-Stressor in Healthy Young Males: Mediating Effects of Major Stress-Reactive Endocrine Parameters

by Lisa-Marie Walther, Angelina Gideon, Christine Sauter, Marcel Leist and Petra H. Wirtz

Cells 2024, 13(23), 1941; https://doi.org/10.3390/cells13231941 - 22 Nov 2024

Cited by 2 | Viewed by 1689

Abstract

Psychosocial stress has been proposed to induce a redistribution of immune cells, but a comparison with an active placebo-psychosocial stress control condition is lacking so far. We investigated immune cell redistribution due to psychosocial stress compared to that resulting from an active placebo-psychosocial [...] Read more.

Psychosocial stress has been proposed to induce a redistribution of immune cells, but a comparison with an active placebo-psychosocial stress control condition is lacking so far. We investigated immune cell redistribution due to psychosocial stress compared to that resulting from an active placebo-psychosocial stress but otherwise identical control condition. Moreover, we tested for mediating effects of endocrine parameters and blood volume changes. The final study sample comprised 64 healthy young men who underwent either a psychosocial stress condition (Trier Social Stress Test; TSST; n = 38) or an active placebo-psychosocial stress control condition (PlacTSST; n = 26). Immune cell counts and hemoglobin, epinephrine, norepinephrine, ACTH, renin, and aldosterone levels, as well as those of saliva cortisol, were determined before and up to 30 min after the TSST/PlacTSST. The TSST induced greater increases in total leukocyte, monocyte, and lymphocyte levels as compared to the PlacTSST (p’s ≤ 0.001), but in not granulocyte counts. Neutrophil granulocyte counts increased in reaction to both the TSST and PlacTSST (p’s ≤ 0.001), while eosinophil and basophil granulocyte counts did not. The psychosocial stress-induced increases in immune cell counts from baseline to peak (i.e., +1 min after TSST cessation) were independently mediated by parallel increases in epinephrine (ab’s ≤ −0.43; 95% CIs [LLs ≤ −0.66; ULs ≤ −0.09]). Subsequent decreases in immune cell counts from +1 min to +10 min after psychosocial stress cessation were mediated by parallel epinephrine, renin, and blood volume decreases (ab’s ≥ 0.17; 95% CIs [LLs ≥ 0.02; ULs ≥ 0.35]). Our findings indicate that psychosocial stress specifically induces immune cell count increases in most leukocyte subpopulations that are not secondary to the physical or cognitive demands of the stress task. Increases in the number of circulating neutrophil granulocytes, however, are not psychosocial stress-specific and even occur in situations with a low probability of threat or harm. Our findings point to a major role of epinephrine in mediating stress-induced immune cell count increases and of epinephrine, renin, and blood volume changes in mediating subsequent immune cell count decreases from +1 min to +10 min after psychosocial stress cessation. Full article

(This article belongs to the Special Issue Innate Immunity in Health and Disease)

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