Current Issues in Molecular Biology

26 pages, 1342 KB

Open AccessEditor’s ChoiceReview

Current and Developing Therapeutics for Dry Eye Disease: Targeting Ion Channels

by Rebecca Jung, Emily Kao, Victor H. Guaiquil, Ali R. Djalilian and Mark I. Rosenblatt

Curr. Issues Mol. Biol. 2026, 48(3), 332; https://doi.org/10.3390/cimb48030332 - 21 Mar 2026

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Dry eye disease (DED) is an ocular surface disorder characterized by tear film instability, inflammation, epithelial damage, and neurosensory abnormalities. Due to its multifactorial etiology and pathophysiology, conventional therapies that focus on lubrication and immunosuppression often fall short in addressing the neuropathic component [...] Read more.

Dry eye disease (DED) is an ocular surface disorder characterized by tear film instability, inflammation, epithelial damage, and neurosensory abnormalities. Due to its multifactorial etiology and pathophysiology, conventional therapies that focus on lubrication and immunosuppression often fall short in addressing the neuropathic component of ocular pain experienced by a growing subset of patients. Recent developments in sensory neuroscience have highlighted the pivotal role of ion channels in mediating ocular surface homeostasis, pain signaling, and inflammation. This review examines the role of the following major ion channel families in the pathophysiology of DED and neuropathic ocular pain: transient receptor potential (TRP) channels, voltage-gated sodium (Nav) channels, and purinergic P2X receptors. The review details their anatomical distribution, molecular function, and responses to environmental stimuli such as heat, cold, osmolarity, and injury. Current treatments, such as artificial tears, anti-inflammatory drops, and systemic neuromodulators, are also reviewed in relation to their effects on ion channel modulation. Additionally, emerging therapies that directly target sensory transduction pathways are introduced. This review highlights the therapeutic potential of ion channel modulation in personalizing treatment for patients with ocular surface pain, particularly those with neuropathic features unresponsive to standard care. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2026)

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20 pages, 1827 KB

Open AccessEditor’s ChoiceArticle

Effects of Citicoline-Based Supplementation on Lipid Peroxidation Markers and Sirtuin-1 Expression in Ischemic Stroke

by Todorka Sokrateva, Bogdan Roussev, Daniela V. Vankova, Deyana G. Vankova, Diana Ivanova, Mihael Tsalta-Mladenov, Darina Georgieva, Miglena N. Nikolova, Galya Mihaylova and Milka A. Nashar

Curr. Issues Mol. Biol. 2026, 48(3), 314; https://doi.org/10.3390/cimb48030314 - 15 Mar 2026

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Abstract

Ischemic stroke (IS) is associated with pronounced oxidative stress and lipid peroxidation, which contribute to secondary neuronal damage. This study explored the effects of a six-month intervention with a new formulation containing citicoline, vitamin C, and extracts from green tea and aronia (Cytodeox™) [...] Read more.

Ischemic stroke (IS) is associated with pronounced oxidative stress and lipid peroxidation, which contribute to secondary neuronal damage. This study explored the effects of a six-month intervention with a new formulation containing citicoline, vitamin C, and extracts from green tea and aronia (Cytodeox™) on arachidonic acid (AA) metabolism, lipid peroxidation assessed by total 8-iso-prostaglandin F₂α (8-iso-PGF₂α), and Sirtuin-1 (SIRT1) expression in healthy controls (n = 43) and patients with IS (n = 53), both with and without comorbidities. AA and 8-iso-PGF₂α were quantified in serum using UPLC–MS and ELISA, respectively, and the fold change in SIRT1 expression was assessed in peripheral blood mononuclear cells (PBMCs) by RT-qPCR. In healthy controls, Cytodeox™ significantly lowered AA and 8-iso-PGF₂α levels. IS patients showed markedly increased baseline 8-iso-PGF₂α, indicating severe oxidative stress. Following supplementation, 8-iso-PGF₂α levels increased in patients with comorbidities, particularly diabetes mellitus (DM), whereas an exploratory analysis suggested a decreasing trend in patients without comorbidities. SIRT1 expression was significantly upregulated in IS patients, with the most pronounced increase observed in the DM subgroup, while remaining unchanged in controls. These findings suggest a protective, antioxidant, and membrane stabilising effect of Cytodeox™ under conditions of preserved or moderately impaired redox homeostasis, supporting its potential role as a preventive or early supportive intervention. Full article

(This article belongs to the Special Issue Repurposing and Innovation: Drug Research in Neuroprotection)

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12 pages, 3941 KB

Open AccessEditor’s ChoiceArticle

A Novel Anti-Cadherin-19 Monoclonal Antibody (Ca₁₉Mab-8) for Flow Cytometry, Western Blotting, and Immunohistochemistry

by Guanjie Li, Hiroyuki Suzuki, Mika K. Kaneko and Yukinari Kato

Curr. Issues Mol. Biol. 2026, 48(3), 307; https://doi.org/10.3390/cimb48030307 - 12 Mar 2026

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Abstract

The type II cadherin Cadherin-19 (CDH19) plays a crucial role in neural crest development. CDH19 regulates cell–cell junctions and migration by forming catenin–cytoskeleton complexes. Although anti-CDH19 monoclonal antibodies (mAbs) are used for specific applications such as Western blotting and immunohistochemistry (IHC), suitable anti-CDH19 [...] Read more.

The type II cadherin Cadherin-19 (CDH19) plays a crucial role in neural crest development. CDH19 regulates cell–cell junctions and migration by forming catenin–cytoskeleton complexes. Although anti-CDH19 monoclonal antibodies (mAbs) are used for specific applications such as Western blotting and immunohistochemistry (IHC), suitable anti-CDH19 mAbs for flow cytometry are limited. Therefore, developing mAbs that specifically recognize cell-surface-expressed CDH19 is essential for advancing both basic research and therapeutic strategies. Here, novel anti-human CDH19 mAbs (Ca₁₉Mabs) were created using flow cytometry-based high-throughput screening. One clone, Ca₁₉Mab-8 (IgG₁, κ), specifically recognized CDH19-overexpressed Chinese hamster ovary-K1 cells but did not bind to other 21 CDHs (including both type I and type II CDHs) in flow cytometry. Additionally, Ca₁₉Mab-8 recognized endogenous CDH19 in the human glioblastoma cell line LN229. The dissociation constant (K_D) of Ca₁₉Mab-8 for LN229/CDH19 was 9.0 × 10⁻⁹ M. Ca₁₉Mab-8 also detected endogenous CDH19 in Western blotting. Furthermore, Ca₁₉Mab-8 can detect CDH19 in IHC using human melanoma tissue. These findings suggest that Ca₁₉Mab-8 is a novel mAb that detects cell-surface-expressed CDH19 with high specificity and is suitable for various applications in basic research. Therefore, Ca₁₉Mab-8 has potential for clinical diagnosis and tumor therapy. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies, 3rd Volume)

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22 pages, 2019 KB

Open AccessEditor’s ChoiceArticle

Physicochemical and Proteolytic Barriers Limiting Activity of Cpl-1 and Pal Endolysins in Human Circulation

by Marek Adam Harhala, Katarzyna Gembara, Izabela Rybicka, Zuzanna Maria Kaźmierczak, Paulina Miernikiewicz and Krystyna Dąbrowska

Curr. Issues Mol. Biol. 2026, 48(2), 231; https://doi.org/10.3390/cimb48020231 - 21 Feb 2026

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Abstract

The growing prevalence of antibiotic-resistant bacterial infections poses a serious burden on healthcare systems worldwide. Endolysins are promising candidates for a new type of antibiotic due to their strong bacteriolytic activity. However, important limitations, including reduced activity and short persistence in the bloodstream, [...] Read more.

The growing prevalence of antibiotic-resistant bacterial infections poses a serious burden on healthcare systems worldwide. Endolysins are promising candidates for a new type of antibiotic due to their strong bacteriolytic activity. However, important limitations, including reduced activity and short persistence in the bloodstream, must still be addressed. We evaluated the key physicochemical and biological factors limiting the activity and stability of the endolysins Cpl-1 and Pal in blood. The analysis included ionic composition and strength, pH, bystander proteins, physiological temperature, and proteolytic activity. Our results indicate that the aforementioned factors significantly affect Cpl-1 and Pal, suggesting that physiological conditions in human circulation markedly restrict the anti-bacterial potential of endolysins. To overcome these limitations, we designed a set of Cpl-1 and Pal variants with modified amino acid compositions aimed at increasing their resistance to such physiological constraints. One variant demonstrated improved performance in an ex vivo mouse model and lacked a cleavage site for blood proteases. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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45 pages, 1122 KB

Open AccessEditor’s ChoiceReview

Phytochemical Quorum-Sensing Inhibitors Against Bacterial Pathogens: Mechanisms of Action and Translational Challenges

by Christos Papaneophytou

Curr. Issues Mol. Biol. 2026, 48(2), 214; https://doi.org/10.3390/cimb48020214 - 14 Feb 2026

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Abstract

Antimicrobial resistance is a critical global health challenge, driven by the rapid emergence of multidrug-resistant bacterial pathogens and exacerbated by extensive antibiotic use, which imposes intense selective pressure and disrupts host-associated microbial communities. In this context, quorum sensing (QS), a conserved molecular communication [...] Read more.

Antimicrobial resistance is a critical global health challenge, driven by the rapid emergence of multidrug-resistant bacterial pathogens and exacerbated by extensive antibiotic use, which imposes intense selective pressure and disrupts host-associated microbial communities. In this context, quorum sensing (QS), a conserved molecular communication system that coordinates population-level gene regulation, virulence expression, and biofilm development, has emerged as an attractive target for anti-virulence intervention. A growing body of evidence indicates that phytochemicals, such as curcumin, carvacrol, carnosol, eugenol, and chlorogenic acid, can modulate key QS pathways, including acyl-homoserine lactone-, autoinducing peptide-, and LuxS/AI-2-mediated signaling, thereby attenuating pathogenic behaviors at sub-inhibitory concentrations that do not directly impair bacterial viability. Despite this promise, the translational development of phytochemical-based QS inhibitors remains limited. Because QS also regulates cooperative and homeostatic functions in beneficial bacteria, QS-targeted interventions raise concerns about microbiome disruption and ecological imbalance. Furthermore, the literature is marked by substantial methodological heterogeneity, reliance on indirect phenotypic endpoints, limited molecular target validation, and insufficient assessment of toxicity, bioavailability, and pharmacokinetics. The predominance of simplified in vitro models further constrains extrapolation to complex host-associated and polymicrobial environments. This review critically examines the molecular mechanisms underlying phytochemical modulation of bacterial QS, synthesizes pathogen-focused experimental evidence, and evaluates key translational challenges arising from QS conservation, microbiome considerations, and methodological limitations. Addressing these barriers through mechanism-resolved experimentation, standardized evaluation frameworks, and microbiome-aware testing strategies will be essential for advancing phytochemical QS inhibitors toward clinically and industrially relevant anti-virulence applications. Full article

(This article belongs to the Special Issue Advances in Phytochemical Research: Molecular Pathways in Health and Disease)

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14 pages, 1726 KB

Open AccessEditor’s ChoiceArticle

Rhus coriaria Linn Extract as a Natural Inhibitor of Influenza A Virus Replication In Vitro

by Carla Prezioso, Maria Luisa Savo Sardaro, Flavio Frezza, Dolores Limongi, Salvatore Velotto, Leonardo Lupacchini, Giovanni D’Auria, Marta De Angelis, Lucia Nencioni and Paola Checconi

Curr. Issues Mol. Biol. 2026, 48(2), 207; https://doi.org/10.3390/cimb48020207 - 13 Feb 2026

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Abstract

Influenza A viruses remain a major public health threat due to their high mutation rates, antigenic variability, and the emergence of resistance to current antivirals, underscoring the need for novel therapeutic options. Natural compounds rich in polyphenols and flavonoids have attracted increasing attention [...] Read more.

Influenza A viruses remain a major public health threat due to their high mutation rates, antigenic variability, and the emergence of resistance to current antivirals, underscoring the need for novel therapeutic options. Natural compounds rich in polyphenols and flavonoids have attracted increasing attention as potential broad-spectrum antiviral agents. In this study, the activity of Rhus coriaria L. water extract against Influenza A virus in BEAS-2B human bronchial epithelial cells was investigated. Cell viability assay identified non-cytotoxic concentrations, up to 0.1 mg/mL, which were used in infection experiments. Viral replication was assessed at multiple levels by quantitative real-time PCR, western blotting, immunofluorescence and tissue culture infectious dose 50% (TCID₅₀). Treatment with R. coriaria extract resulted in a dose-dependent and statistically significant reduction of viral load. The extract decreased mRNA levels of Hemagglutin (HA), Neuraminidase (NA) and Matrix protein 2 (M2). Consistently, western blot analysis showed a decrease in major viral proteins HA, Nucleoprotein (NP), Matrix protein 1 (M1) and Polymerase Acidic protein (PA). Confocal images revealed a marked reduction in HA and PA signals, results that are statistically significant according to quantitative fluorescence evaluation. The convergence of results obtained through independent methodologies at both the transcriptional and protein levels highlight the robustness of the findings. These data provide the experimental evidence that Rhus coriaria interferes with influenza A virus replication in airway epithelial cells and support its further investigation as a promising phytochemical platform for the development of novel anti-influenza strategies. Full article

(This article belongs to the Special Issue Molecular and Real-World Evidence Research of Respiratory Diseases and Infections, 2nd Edition)

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22 pages, 2522 KB

Open AccessEditor’s ChoiceArticle

Oncological Safety of High Hydrostatic Pressure Treatment: Effects on Cancer-Associated Fibroblast-like Transdifferentiation of Adipose Stromal Cells

by Julia Kristin Brach, Vivica Freiin Grote, Anika Jonitz-Heincke, Rainer Bader, Daniel Strüder, Marco Hoffmann, Sven Gerlach, Petra Fischer, Markus Wirth, Tim Ruhl, Justus P. Beier, Agmal Scherzad and Stephan Hackenberg

Curr. Issues Mol. Biol. 2026, 48(1), 91; https://doi.org/10.3390/cimb48010091 - 16 Jan 2026

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Abstract

Oncological safety is essential for autologous reconstruction after resection of cartilage-infiltrating head and neck tumors. High hydrostatic pressure (HHP) enables complete devitalization of tumor-infiltrated tissue while preserving extracellular matrix integrity. However, residual soluble tumor-derived products may influence infiltrating stromal cells. This study examined [...] Read more.

Oncological safety is essential for autologous reconstruction after resection of cartilage-infiltrating head and neck tumors. High hydrostatic pressure (HHP) enables complete devitalization of tumor-infiltrated tissue while preserving extracellular matrix integrity. However, residual soluble tumor-derived products may influence infiltrating stromal cells. This study examined whether conditioned media (CM) from HHP-treated head and neck squamous cell carcinoma (HNSCC) cells induce cancer-associated fibroblast (CAF)-like transdifferentiation of human adipose stromal cells (hASCs). HASCs were exposed to CM from untreated or HHP-treated (300 MPa) HNSCC cells, tumor-CM (TCM), or TGF-β1. Morphological changes in hASCs were evaluated, and CAF marker expression was analyzed by qRT-PCR, immunofluorescence, Western blot, and ELISA. Cytokines were quantified via multiplex analysis. TGF-β1 induced a CAF-like phenotype with α-SMA upregulation, whereas TCM and 0 MPa-CM caused only modest increases in selected markers. Although 300 MPa-CM did not induce CAF-associated molecular signatures, hASCs exhibited morphological alterations, underscoring that morphology alone is insufficient to define CAF transdifferentiation. Cytokine secretion was elevated in response to all CM conditions. These findings indicate that HHP treatment at 300 MPa abolishes the paracrine CAF-inducing potential of tumor-derived mediators in vitro, supporting the oncological safety of HHP-treated tissues under these experimental condition, although further in vivo validation is warranted Full article

(This article belongs to the Section Molecular Medicine)

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16 pages, 1175 KB

Open AccessEditor’s ChoiceArticle

HERVs and Epigenetic Regulators Transcriptional Expression After Chondrogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells

by Ilaria Galliano, Cristina Calvi, Stefano Gambarino, Alice Dato, Anna Pau, Maddalena Dini, Anna Clemente, Carlotta Castagnoli and Massimiliano Bergallo

Curr. Issues Mol. Biol. 2026, 48(1), 37; https://doi.org/10.3390/cimb48010037 - 26 Dec 2025

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Abstract

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into various connective tissue cell types. Adipose tissue provides a rich source of MSCs (ADSCs), which can differentiate into osteoblasts, adipocytes, and chondroblasts. Pluripotency factors such as SOX2, NANOG, and OCT4 maintain MSC [...] Read more.

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into various connective tissue cell types. Adipose tissue provides a rich source of MSCs (ADSCs), which can differentiate into osteoblasts, adipocytes, and chondroblasts. Pluripotency factors such as SOX2, NANOG, and OCT4 maintain MSC stemness, whereas human endogenous retroviruses (HERVs) and their epigenetic regulators TRIM28 and SETDB1 have been implicated in transcriptional regulation and cell fate decisions. This study investigated the transcriptional expression of HERV-H, -K, and -W, TRIM28, SETDB1, and pluripotency markers (NANOG, OCT4, SOX2) during chondrogenic differentiation of ADSCs using Real-Time PCR. Chondrogenesis was confirmed by aggrecan (ACAN) upregulation and aggrecan immunostaining. Although no statistically significant differences were observed for HERV-H, HERV-K, or HERV-W, HERV-K and HERV-W showed a trend toward decreased expression in differentiated cells, consistent with the overall shift in transcriptional profile during lineage commitment. TRIM28 expression was significantly reduced, while SETDB1 showed a decreasing trend. Among pluripotency markers, OCT4 was significantly downregulated, whereas NANOG and SOX2 remained stable. Correlation analyses revealed that in differentiated ADSCs, HERV-W expression correlated negatively with TRIM28 and positively with SETDB1, while no correlations were found for HERV-H or HERV-K. These findings suggest that specific HERV families and their epigenetic regulators may undergo coordinated modulation during chondrogenic differentiation, supporting a complex and family-specific interplay between retroelement regulation, pluripotency factors, and MSC lineage commitment. Full article

(This article belongs to the Special Issue Innovative Approaches in Bone and Cartilage Regeneration: From Stem Cells to Organoids)

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19 pages, 5171 KB

Open AccessEditor’s ChoiceArticle

Interferon-Type-I Response and Autophagy Independently Regulate Radiation-Induced HLA-Class-I Molecule Expression in Lung Cancer

by Erasmia T. Xanthopoulou, Ioannis Lamprou, Ioannis M. Koukourakis, Achilleas G. Mitrakas, Georgios D. Michos, Anastasia Polyzoidou, Filippos G. Antoniadis, Alexandra Giatromanolaki and Michael I. Koukourakis

Curr. Issues Mol. Biol. 2026, 48(1), 28; https://doi.org/10.3390/cimb48010028 - 25 Dec 2025

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Abstract

Background/Objectives: The enhancement of antitumor immune responses by radiotherapy (RT) is partially attributed to the activation of the IFN-type-I pathway. However, the loss of HLA-class-I molecules, which occurs in a large percentage of non-small-cell lung cancers (NSCLCs), may block the cytotoxic effect [...] Read more.

Background/Objectives: The enhancement of antitumor immune responses by radiotherapy (RT) is partially attributed to the activation of the IFN-type-I pathway. However, the loss of HLA-class-I molecules, which occurs in a large percentage of non-small-cell lung cancers (NSCLCs), may block the cytotoxic effect of T-cells and immunotherapy (IO). Moreover, autophagy is also involved in HLA downregulation. We investigated the complex interactions between RT, HLA molecules, autophagy, and IFN-type-I responses. Methods: The A549, H1299, and ATG7-deficient NSCLC cell lines, along with the modified shLC3A H1299 cell line, were used for in vitro experiments. The effect of RT (8 and 3 × 8 Gy) on Interferon beta (IFNβ), IFN-stimulated genes (ISGs), and HLA-class-I expression in combination with IFN-type-I-response inhibitors (Ruxolitinib, Tofacitinib, Amlexanox) targeting the JAK and TBK1 was studied with Flow cytometry and RT-PCR. Results: RT significantly induced HLA-class-I expression. A parallel upregulation of IFNβ and ISGs mRNA levels was also documented. Although the IFN-type-I-response inhibitors suppressed the RT-induced IFNβ and ISGs expression, their effect on HLA-class-I expression was minimal. Blockage of LC3A autophagy (shLC3A cell line) significantly upregulated HLA-class-I basal levels, and RT further enhanced HLA expression. IFN-type-I-response inhibitors blocked the RT-inductive effect in the shLC3A H1299, but had no effect in the ATG7-deficient H1650 cell line. Conclusions: The current study supports the theory that baseline autophagy, RT-induced autophagy blockage, and IFN-type-I response enhancement define the HLA-class-I levels in NSCLC cells. This complex interplay emerges as a promising target for the development of radio-vaccination strategies to enhance the efficacy of radio-immunotherapy. Full article

(This article belongs to the Special Issue Molecular Insights into Radiation Oncology)

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22 pages, 1830 KB

Open AccessEditor’s ChoiceArticle

β-Arrestin 1 Differentially Modulates cAMP and ERK Pathways Downstream of the FSH Receptor

by Sei Hyun Park, Munkhzaya Byambaragchaa, Ye Rin Yu, Jae Won Lee, Min-Jeong Kwak, Seung-Bin Yoon, Ji-Su Kim, Myung-Hwa Kang and Kwan-Sik Min

Curr. Issues Mol. Biol. 2025, 47(12), 1051; https://doi.org/10.3390/cimb47121051 - 16 Dec 2025

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Abstract

This study compared the gonadotropin gene sequences (LH and FSH subunits) of Cynomolgus and Rhesus monkeys and produced recombinant single-chain LHβ/α and FSHβ/α proteins. The α- and FSHβ-subunit sequences were identical between species, while LHβ showed only minor synonymous differences. The recombinant hormones [...] Read more.

This study compared the gonadotropin gene sequences (LH and FSH subunits) of Cynomolgus and Rhesus monkeys and produced recombinant single-chain LHβ/α and FSHβ/α proteins. The α- and FSHβ-subunit sequences were identical between species, while LHβ showed only minor synonymous differences. The recombinant hormones were successfully expressed and shown to be mainly N-glycosylated. Recombinant monkey FSHβ/α activated cAMP signaling in human FSH receptor-expressing cells, confirming its biological activity. β-arrestin 1 was found to have dual roles: its absence increased cAMP signaling (negative regulation), but it was required for ERK1/2 activation. ERK activation depended mainly on the cAMP/PKA pathway. Human and rat FSH receptors displayed different ERK activation timing, indicating species-specific signaling behavior. Overall, the study establishes a reliable system for producing functional recombinant monkey gonadotropins and clarifies how β-arrestin 1 differentially regulates FSH receptor signaling. Full article

(This article belongs to the Collection Advancements in Molecular Biology and Pharmaceutical Science)

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14 pages, 741 KB

Open AccessEditor’s ChoiceReview

Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities

by Mi Eun Kim, Yeeun Lim and Jun Sik Lee

Curr. Issues Mol. Biol. 2025, 47(12), 1042; https://doi.org/10.3390/cimb47121042 - 14 Dec 2025

Cited by 6 | Viewed by 2610

Abstract

Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, [...] Read more.

Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2–KEAP1 antioxidant system, the cGAS–STING innate immune pathway, and the PINK1–Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD⁺ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Innovative Therapeutic Approaches in Inflammatory Diseases, Pioneering Precision Medicine Solutions)

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14 pages, 2214 KB

Open AccessEditor’s ChoiceArticle

Evaluation of the Role of AID-Induced Mutagenesis in Resistance to B-Cell Receptor Pathway Inhibitors in Chronic Lymphocytic Leukemia

by Chiara Pighi, Alessandro Gasparetto, Elisa Genuardi, Jianli Tao, Qi Wang, Candida Vitale, Valentina Griggio, Rocco Piazza, Sabino Ciavarella, Marta Coscia, Simone Ferrero, Alberto Zamò, Claudia Voena and Roberto Chiarle

Curr. Issues Mol. Biol. 2025, 47(12), 1031; https://doi.org/10.3390/cimb47121031 - 10 Dec 2025

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Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and B-cell receptor (BCR) pathway inhibitors such as idelalisib and ibrutinib are currently established therapies for CLL. Although effective, these drugs frequently lead to resistance, but the mechanisms are still not [...] Read more.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and B-cell receptor (BCR) pathway inhibitors such as idelalisib and ibrutinib are currently established therapies for CLL. Although effective, these drugs frequently lead to resistance, but the mechanisms are still not fully understood. Activation-induced cytidine deaminase (AID) is a B-cell enzyme essential for antibody diversification. However, it can also introduce off-target mutations, leading to genomic instability. This study investigates whether treatment with BCR pathway inhibitors increases AID activity in CLL and whether this activity contributes to the development of drug resistance. Peripheral blood samples from CLL patients were collected before and after treatment with idelalisib or ibrutinib. Targeted sequencing was used to identify mutations in known AID off-target genes. Concurrently, AID-wild type (AID-WT) and AID-knockout (AID-KO) CLL cell lines were established and subsequently exposed to escalating doses of BCR pathway inhibitors to develop drug-resistant models. In patient samples, treatment with BCR pathway inhibitors was associated with an increase in AID-dependent mutations in off-target genes, including BCL2, MYC, and IRF8. The in vitro models efficiently recapitulated the patients’ data, as only AID-WT CLL cells accumulated mutations in the same AID off-target genes after drug exposure. However, no mutations were detected in genes that could mediate drug resistance. We conclude that BCR pathway inhibitors enhance AID mutational activity in CLL, but this does not appear to be directly involved in driving drug resistance. AID-targeted loci may nonetheless serve as biomarkers for monitoring genomic instability during treatment and inform further study. Full article

(This article belongs to the Section Molecular Medicine)

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