International Journal of Molecular Sciences

14 pages, 1044 KiB

Open AccessArticle

Cytokines from Macrophages Activated by Spike S1 of SARS-CoV-2 Cause eNOS/Arginase Imbalance in Endothelial Cells

by Giulia Recchia Luciani, Rossana Visigalli, Valeria Dall’Asta, Bianca Maria Rotoli and Amelia Barilli

Int. J. Mol. Sci. 2025, 26(12), 5916; https://doi.org/10.3390/ijms26125916 - 19 Jun 2025

Viewed by 651

Abstract

Multiple lines of evidence suggest that endothelial dysfunction is a key player in the pathogenesis of COVID-19, with cytokine storm as one of the main primary causes. Among the mechanisms underlying endothelial damage, clinical findings identify alterations in arginine metabolism, as patients with [...] Read more.

Multiple lines of evidence suggest that endothelial dysfunction is a key player in the pathogenesis of COVID-19, with cytokine storm as one of the main primary causes. Among the mechanisms underlying endothelial damage, clinical findings identify alterations in arginine metabolism, as patients with severe COVID-19 exhibit lower levels of nitric oxide synthase (eNOS) and upregulated arginase. In this study, we investigated, in human endothelial cells (HUVECs), the effect of conditioned medium from macrophages activated with SARS-CoV-2 Spike protein (CM_S1) on arginine metabolism. The results indicate that CM_S1 causes a marked decrease in eNOS and an increase in arginase, along with a greater intracellular arginine content and the induction of the CAT2 transporter. These effects are ascribable to the inflammatory mediators released by macrophages in CM_S1, mainly TNFα and IL-1β. Since infliximab, an antibody targeting TNFα, and baricitinib, an inhibitor of the JAK/STAT pathway, correct the observed imbalance between eNOS and arginase, our findings suggest the potential efficacy of a combined therapy to counteract endothelial dysfunction in COVID-19. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection)

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15 pages, 2256 KiB

Open AccessBrief Report

Tear Cytokine Changes up to One Year After Allogeneic Hematopoietic Stem Cell Transplant: Effect of Daily Topical Cyclosporine-A 0.1% Emulsion

by Louis Tong, Yu-Chi Liu, Sharon Wan Jie Yeo, Chang Liu, Isabelle Xin Yu Lee, Yeh Ching Linn, Aloysius Ho, Hein Than, Jeffrey Kim Siang Quek, William Ying Khee Hwang, Francesca Lorraine Wei Inng Lim and Li Lim

Int. J. Mol. Sci. 2025, 26(12), 5915; https://doi.org/10.3390/ijms26125915 - 19 Jun 2025

Viewed by 530

Abstract

Purpose: To profile tear cytokine changes in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) patients after instillation of daily topical cyclosporine-A 0.1% cationic emulsion. Methods: Participants in a longitudinal study were given cyclosporine eyedrops daily from 3 to 5 weeks before and 3 months, [...] Read more.

Purpose: To profile tear cytokine changes in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) patients after instillation of daily topical cyclosporine-A 0.1% cationic emulsion. Methods: Participants in a longitudinal study were given cyclosporine eyedrops daily from 3 to 5 weeks before and 3 months, 6 months, and 12 months post-HSCT. The outcomes included tear cytokine concentration assayed by the Proximity Extension Assay O-linked target 96 platform. The patients were divided into two groups: Group 1 (n = 8 conjunctival CD4 cells responding to cyclosporine) and Group 2 (n = 5 conjunctival CD4 cells not suppressed after cyclosporine, where patients were non-compliant with cyclosporine). All participants had a standardized clinical examination, including meibomian gland evaluation and tear breakup times. Results: The levels of 38 cytokines/chemokines showed significant changes (p < 0.05) over time, and in many, the elevation was marked at one year. These include gamma-interferon, CXCL9, CCL3, and CCL4 (all p < 0.0001). For gamma-interferon, there was significant interaction between group and time at 1 year (p = 0.022), where the cytokine was significantly suppressed in Group 1. Four other cytokines showed significant group and time interaction at 1 year: FGF23, FGF5, LIFR, and Enrage (all p < 0.05). All patients had either withdrawal or a reduction in systemic immunomodulation between 6 months and 1 year. We found several cytokines to be associated with changes in tear osmolarity or symptom scores. Conclusions: HSCT induces significant elevation of 38 tear cytokines/chemokines even without the occurrence of ocular graft-versus-host disease when systemic immunosuppression is reduced within the first year. Topical daily cyclosporine eyedrops can reduce some pro-inflammatory tear cytokines. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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16 pages, 3385 KiB

Open AccessArticle

Effects of C-Ring Structural Differences on the Inhibition of N^ε-(Carboxyethyl)lysine in the Methylglyoxal-Lysine System by Flavonoids

by Yating Ling, Linlin Zhang, Bangzhu Peng and Zhuo Zhang

Int. J. Mol. Sci. 2025, 26(12), 5914; https://doi.org/10.3390/ijms26125914 - 19 Jun 2025

Viewed by 381

Abstract

This study investigated the effects of taxifolin (Tax), quercetin (Que), (+)-catechin (Cat) and luteolin (Lute) on the advanced Maillard reaction stage in the methylglyoxal-lysine (MGO-Lys) system. Since the four flavonoids share identical A- and B-ring structures, the inhibitory effects and molecular [...] Read more.

This study investigated the effects of taxifolin (Tax), quercetin (Que), (+)-catechin (Cat) and luteolin (Lute) on the advanced Maillard reaction stage in the methylglyoxal-lysine (MGO-Lys) system. Since the four flavonoids share identical A- and B-ring structures, the inhibitory effects and molecular mechanisms of flavonoids with different C-ring structures on N^ε-(carboxyethyl)lysine (CEL) formation were revealed. The results demonstrated that Cat exhibited the best inhibitory effect on CEL with an inhibition rate of 53.78%, while Lute showed the lowest inhibition rate of 3.97%. The flavonoids (i.e., Tax, Que, Cat and Lute) inhibited the formation of non-fluorescent CEL, where hydroxylation at C³ on the C-ring favored the enhancement of the inhibitory effect of the flavonoids on CEL, while the C²-C³ double bond and the carbonyl group at the C⁴ position reduced their inhibitory ability. The alkaline environment favored the enhancement of the inhibition of CEL by Tax, Que, Cat and Lute. Notably, Tax, Que, Cat and Lute can inhibit CEL formation by competitively capturing MGO to form mono- or di-adducts and reducing lysine consumption. This study provides innovative strategies and a theoretical foundation for developing effective CEL inhibitors in food thermal processing. Full article

(This article belongs to the Section Physical Chemistry and Chemical Physics)

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18 pages, 4352 KiB

Open AccessReview

LncRNA-Encoded Micropeptides: Expression Validation, Translational Mechanisms, and Roles in Cellular Metabolism

by Chul Woong Ho, Ji Won Lee, Chang Hoon Shin and Kyung-Won Min

Int. J. Mol. Sci. 2025, 26(12), 5913; https://doi.org/10.3390/ijms26125913 - 19 Jun 2025

Viewed by 618

Abstract

The discovery of functional micropeptides encoded by long noncoding RNAs (lncRNAs) has challenged the traditional view that these transcripts lack coding potential. With the advancement of high-resolution translation profiling combined with enhanced MS-based techniques, numerous lncRNAs have been found to harbor small open [...] Read more.

The discovery of functional micropeptides encoded by long noncoding RNAs (lncRNAs) has challenged the traditional view that these transcripts lack coding potential. With the advancement of high-resolution translation profiling combined with enhanced MS-based techniques, numerous lncRNAs have been found to harbor small open reading frames (sORFs) that give rise to bioactive micropeptides. These peptides participate in diverse biological processes, particularly in cellular metabolism, by modulating enzymatic activity and metabolic pathways. However, the identification and functional characterization of these micropeptides remain technically challenging due to their small size, low abundance, and the need for rigorous downstream validation studies. This review encompasses a comprehensive overview of the biogenesis of lncRNA-derived micropeptides, methodologies for detecting and validating their expression, the molecular mechanisms governing their translation, and their emerging roles in metabolic regulation. By integrating current findings and technological advancements, we highlight the potential physiological and pathological implications of these micropeptides and outline future research directions in the field. Full article

(This article belongs to the Special Issue Latest Review Papers in Macromolecules 2025)

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15 pages, 2958 KiB

Open AccessArticle

Isostrictiniin Alleviates LPS-Induced Acute Lung Injury via the Regulation of the Keap1-Nrf2/HO-1 and MAPK/NF-κB Signaling Pathways

by Wanting Ding, Yuan Sun, Wulipan Tuohudaali, Chenyang Li, Yuhan Yao and Jun Zhao

Int. J. Mol. Sci. 2025, 26(12), 5912; https://doi.org/10.3390/ijms26125912 - 19 Jun 2025

Viewed by 506

Abstract

This study aimed to investigate the preventive effects of isostrictiniin (ITN) from Nymphaea candida against acute lung injury (ALI) through lipopolysaccharide (LPS)-induced ALI mice and LPS-induced A549 cells. Compared with the model group, ITN (50 and 100 mg/kg) significantly reduced the lung indexes, [...] Read more.

This study aimed to investigate the preventive effects of isostrictiniin (ITN) from Nymphaea candida against acute lung injury (ALI) through lipopolysaccharide (LPS)-induced ALI mice and LPS-induced A549 cells. Compared with the model group, ITN (50 and 100 mg/kg) significantly reduced the lung indexes, W/D rates, BALF WBC counts, and total protein contents in ALI mice (p < 0.05), as well as the blood neu counts (p < 0.01), while increasing the blood lym counts (p < 0.01). ITN (50 and 100 mg/kg) also markedly decreased the lung tissue TNF-α, IL-6, IL-1β, MDA, and MPO activities in ALI mice (p < 0.01) and enhanced the SOD and GSH levels (p < 0.01). Additionally, ITN (50 and 100 mg/kg) significantly improved lung histopathological damage in ALI mice. Moreover, ITN (10 and 25 µM) significantly reduced the NO, PGE2, IL-1β, IL-6, TNF-α, and MDA levels in LPS-induced A549 cells (p < 0.01) while significantly increasing the SOD and GSH activities (p < 0.01). After LPS-induced A549 cells, the Keap1, p-JNK/JNK, p-ERK1/2/ERK1/2, p-P38/P38, p-IκBα/IκBα, and p-NF-κBp65/NF-κB p65 levels were significantly upregulated (p < 0.05), whereas the Nrf2 and HO-1 protein expressions were downregulated (p < 0.05). After treatment with ITN (25 μM), the changes in these relative protein expressions in LPS-induced A549 cells were significantly reversed (p < 0.05). The above results indicate that ITN has a better preventive effect against ALI, and its mechanisms are related to the regulation of the Keap1-Nrf2/HO-1 and MAPK/NF-κB signaling pathways. Full article

(This article belongs to the Special Issue Antioxidants: The Molecular Guardians Against Oxidative Stress)

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18 pages, 1331 KiB

Open AccessReview

Spectral Flow Cytometry: The Current State and Future of the Technology

by E. A. Astakhova, A. S. Gubaeva, D. A. Naumova, A. E. Egorova, A. A. Maznina, I. G. Rybkina, I. M. Osmanov, D. V. Tabakov, O. N. Mityaeva and P. Yu. Volchkov

Int. J. Mol. Sci. 2025, 26(12), 5911; https://doi.org/10.3390/ijms26125911 - 19 Jun 2025

Viewed by 557

Abstract

Flow cytometry is a powerful and widely used tool for the analysis of various cell populations, but its capabilities are severely limited by the need to apply correction of fluorescent signals from near or similar fluorochromes when analyzing multicolor panels. Spectral flow cytometry [...] Read more.

Flow cytometry is a powerful and widely used tool for the analysis of various cell populations, but its capabilities are severely limited by the need to apply correction of fluorescent signals from near or similar fluorochromes when analyzing multicolor panels. Spectral flow cytometry extends the capabilities of classical cytometry by reading the full fluorescence spectrum of fluorophores and their subsequent spectral separation. This significantly increases the number of markers analyzed in a single panel and thus allows for more in-depth studies of cell populations. In the age of big data analysis, this represents a serious advantage of spectral cytometry and can significantly increase its use in scientific and clinical practice. This review describes the principle of spectral cytometry, advantages and limitations of the method, and summarizes the newest deep immunophenotyping panels developed and validated for spectral cytometry. Full article

(This article belongs to the Special Issue Flow Cytometry: Applications and Challenges)

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31 pages, 7349 KiB

Open AccessArticle

Melatonin Alleviates MBP-Induced Oxidative Stress and Apoptosis in TM3 Cells via the SIRT1/PGC-1α Signaling Pathway

by Jingjing Liu, Qingcan Guan, Shuang Li, Qi Qi and Xiaoyan Pan

Int. J. Mol. Sci. 2025, 26(12), 5910; https://doi.org/10.3390/ijms26125910 - 19 Jun 2025

Viewed by 443

Abstract

This study investigates the role of melatonin in alleviating the oxidative stress and apoptosis of TM3 Leydig cells induced by 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the primary active metabolite of Bisphenol A, and clarifies its potential mechanisms involving the SIRT1/PGC-1α pathway. We found that melatonin effectively [...] Read more.

This study investigates the role of melatonin in alleviating the oxidative stress and apoptosis of TM3 Leydig cells induced by 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the primary active metabolite of Bisphenol A, and clarifies its potential mechanisms involving the SIRT1/PGC-1α pathway. We found that melatonin effectively mitigated MBP-induced cytotoxicity in TM3 cells (p < 0.05). The testosterone levels and steroid hormone synthesis proteins were significantly restored by melatonin. Furthermore, there was a significant reduction in apoptosis after melatonin treatment both in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues (p < 0.05), along with a significant decrease in the pro-apoptotic markers Bax and cleaved caspase 3, and a significant increase in the anti-apoptotic Bcl-2 level and the Bcl-2/Bax ratio in TM3 cells (p < 0.05). Additionally, the mitochondrial membrane potential improved significantly, ROS and MDA levels were down-regulated, and ATP production was elevated following melatonin treatment in TM3 cells. Mechanistically, melatonin promoted PGC-1α expression and activated the SIRT1 signaling pathway in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues. This leads to increased expression of NRF2 and its downstream antioxidant genes, mitochondrial respiratory chain complex-related genes, mitochondrial biogenesis genes, and mitochondrial fusion genes while significantly reducing mitochondrial fission genes (p < 0.05). The PGC-1α inhibitor SR-18292 reversed these protective effects, confirming the critical role of this pathway. Conclusively, melatonin exerts a protective effect against MBP-induced oxidative stress and apoptosis in TM3 cells through the SIRT1/PGC-1α pathway, indicating its potential as a therapeutic agent for improving male reproductive health compromised by environmental toxins. Full article

(This article belongs to the Special Issue Molecular, Cellular Mechanism of Oxidative Stress in Physiological and Pathophysiological Conditions)

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25 pages, 1794 KiB

Open AccessReview

When Your Body Tells You to Not Breastfeed—The Connivance of Oxytocin, Prolactin, and Dopamine

by Vladimír Kraus, Jr., Beáta Čižmárová and Anna Birková

Int. J. Mol. Sci. 2025, 26(12), 5909; https://doi.org/10.3390/ijms26125909 - 19 Jun 2025

Viewed by 968

Abstract

Breastfeeding is universally recognized for its extensive health benefits for both infants and mothers. However, for some women, the experience of breastfeeding can be complicated by intense negative emotional and physical reactions, including phenomena such as dysphoric milk ejection reflex and breastfeeding aversion/agitation. [...] Read more.

Breastfeeding is universally recognized for its extensive health benefits for both infants and mothers. However, for some women, the experience of breastfeeding can be complicated by intense negative emotional and physical reactions, including phenomena such as dysphoric milk ejection reflex and breastfeeding aversion/agitation. This review explores the neuroendocrine underpinnings of these conditions, emphasizing the interplay between oxytocin, prolactin, and dopamine. Oxytocin, traditionally viewed as a hormone promoting bonding and emotional regulation, can paradoxically provoke a stress response in vulnerable individuals. Prolactin, a key hormone for lactation and maternal behaviors, is implicated in stress resilience and mood regulation, but its dysregulation may contribute to depressive states. Dopamine, critical for reward processing and emotional stability, may underlie the acute emotional dysregulation seen in dysphoric milk ejection reflex. Together, disturbances in these neurohormonal systems may explain the aversive emotional experiences during breastfeeding. An improved understanding of these mechanisms offers critical insights into maternal mental health during lactation and underscores the importance of supportive clinical approaches for affected women. Full article

(This article belongs to the Special Issue Effects of Stressors During Pregnancy and Breastfeeding on the Child: Molecular Perspectives)

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16 pages, 6075 KiB

Open AccessArticle

Combination of Slightly Acidic Electrolyzed Water and Hydrogel to Enhance Stability, Increase Antibacterial Efficacy, and Promote Infectious Wound Healing

by Nanxin Li, Chao Li, Dongbo Li, Awn Abbas, Xingyu Chen, Xiaoyang Ai, Wei Zhang, Gang Shu, Juchun Lin, Haohuan Li, Funeng Xu, Guangneng Peng and Hualin Fu

Int. J. Mol. Sci. 2025, 26(12), 5908; https://doi.org/10.3390/ijms26125908 - 19 Jun 2025

Cited by 1 | Viewed by 410

Abstract

Wound infections remain significant challenges for current tissue adhesives, primarily due to their poor adhesion in moist environments, slow bonding, cytotoxicity, and limited antibacterial properties. Slightly acidic electrolyzed water (SAEW), a potent disinfectant, suffers from limited stability due to chlorine loss. This study [...] Read more.

Wound infections remain significant challenges for current tissue adhesives, primarily due to their poor adhesion in moist environments, slow bonding, cytotoxicity, and limited antibacterial properties. Slightly acidic electrolyzed water (SAEW), a potent disinfectant, suffers from limited stability due to chlorine loss. This study developed a novel SAEW-based hydrogel (SAEW-gel) by combining SAEW with chitosan and β-glycerol disodium phosphate to improve its stability and therapeutic potential. SAEW-gel demonstrated high water absorption, long-term water retention, and enhanced antibacterial activity against S. aureus and E. coli compared to SAEW alone. It maintained germicidal efficacy after prolonged storage and significantly accelerated wound healing in a rat model, achieving a 95.41% healing rate by the 12th day of treatment. Mechanistically, SAEW-gel reduced inflammatory cell infiltration, promoted granulation and collagen formation, and regulated inflammatory markers (IL-6, IL-1β, TNF-α, MPO, HYP). These findings highlight SAEW-gel as a promising biomaterial for treating infectious wounds and support its potential for future clinical application. Full article

(This article belongs to the Special Issue Drug Delivery Systems in Veterinary Medicine: Innovations and Applications)

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13 pages, 1291 KiB

Open AccessArticle

Retinal BMI1 Expression Preserves Photoreceptors in Sodium-Iodate-Induced Oxidative Stress Models

by Zhongyang Lu, Shufeng Liu, Maria G. Morales, Andy Whitlock, Ram Ramkumar and Hema L. Ramkumar

Int. J. Mol. Sci. 2025, 26(12), 5907; https://doi.org/10.3390/ijms26125907 - 19 Jun 2025

Viewed by 476

Abstract

Dry age-related macular degeneration (AMD) is a leading cause of vision loss in individuals over 50, yet no approved therapies exist for early or intermediate stages of the disease. Oxidative stress is a central driver of retinal degeneration in AMD, and sodium iodate [...] Read more.

Dry age-related macular degeneration (AMD) is a leading cause of vision loss in individuals over 50, yet no approved therapies exist for early or intermediate stages of the disease. Oxidative stress is a central driver of retinal degeneration in AMD, and sodium iodate (NaIO₃)-induced injury serves as a well-characterized model of oxidative damage to the retinal pigment epithelium (RPE) and photoreceptors. BMI1, a poly-comb group protein involved in DNA repair, mitochondrial function, and cellular renewal, has emerged as a promising therapeutic target for retinal neuroprotection. We evaluated the efficacy of AAV-mediated BMI1 gene delivery in murine models using two administration routes: subretinal (SR) and suprachoroidal (SC). AAV5.BMI1 (1 × 10⁹ vg/eye) was delivered SR in Balb/c mice and evaluated at 4 and 15 weeks post-injection. AAV8.BMI1 (5 × 10⁹ or 1 × 10¹⁰ vg/eye) was administered SC in C57BL/6 mice and assessed at 4 weeks. Control groups received BSS or AAV8.stuffer. Following NaIO₃ exposure, retinal structure and function were analyzed by optical coherence tomography (OCT), electroretinography (ERG), histology, and molecular assays. SC delivery of AAV8.BMI1 achieved the highest levels of retinal BMI1 expression with no evidence of local or systemic toxicity. Treated eyes showed dose-dependent preservation of outer nuclear layer (ONL) thickness and significantly improved ERG responses indicating structural and functional protection. These findings support SC AAV.BMI1 gene therapy as a promising, minimally invasive, and translatable approach for early intervention in intermediate AMD. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Retinal Diseases)

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24 pages, 17226 KiB

Open AccessArticle

Comparison Bioinformatic Analysis of Extracellular Vesicles-Related Genes and MicroRNAs in Breast Cancer

by Durmus Ayan, Serife Buket Bozkurt Polat, Esma Ozmen and Mehmet Ali Gul

Int. J. Mol. Sci. 2025, 26(12), 5906; https://doi.org/10.3390/ijms26125906 - 19 Jun 2025

Viewed by 537

Abstract

Breast cancer (BC) remains a leading cause of cancer-related mortality in women, with treatment challenges due to the lack of targeted therapies. Extracellular vesicles (EVs) play a crucial role in BC progression by carrying bioactive molecules. This study analyzed EV-associated molecules (ENPEP, TIMP1, [...] Read more.

Breast cancer (BC) remains a leading cause of cancer-related mortality in women, with treatment challenges due to the lack of targeted therapies. Extracellular vesicles (EVs) play a crucial role in BC progression by carrying bioactive molecules. This study analyzed EV-associated molecules (ENPEP, TIMP1, CD36, MARCKS, DAB2, CXCL14, miR-181b-5p, miR-222-3p) using bioinformatics tools. We used GEPIA2; Human Protein Atlas (HPA) 24.0; bc-GenExMiner v5.1; UALCAN 2022; Kaplan–Meier plotter 2025; ENCORI database v2.0; Enrichr-KG web tool 2021; Cancer Hallmark Enrichment tool 2025; Tumor, Normal, and Metastatic (TNM) plot database 2025; MicroRNA Target Prediction Database 6.0; TargetScan 8.0; and STRING database 12.0. CD36, DAB2, and CXCL14 were significantly downregulated, while TIMP1 was upregulated in BC tissues (p < 0.05). CD36, CXCL14, and DAB2 were predominantly low in triple-negative and basal-like subtypes, whereas TIMP1 was higher in HER2+, ER+, and PR+ tumors (p < 0.01). These changes correlated with promoter methylation patterns. Higher TIMP1, DAB2, and CXCL14 levels were associated with improved overall survival (p < 0.05). miR-222-3p was downregulated and positively correlated with TIMP1 and DAB2, while miR-181b-5p was upregulated and negatively correlated with CXCL14. TNM analysis confirmed these expression changes. Functional enrichment linked these molecules to key cancer hallmarks, including proliferation and angiogenesis. CD36, DAB2, CXCL14, TIMP1, miR-222-3p, and miR-181b-5p may serve as biomarkers for BC pathogenesis and potential therapeutic targets. Further studies are needed to validate these findings. Full article

(This article belongs to the Special Issue Extracellular Vesicles (EVs) in Cancer Progression and Metastasis: Molecular Insights and Clinical Outlook)

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41 pages, 1013 KiB

Open AccessReview

Neurobiological Mechanisms of Electroconvulsive Therapy: Molecular Perspectives of Brain Stimulation

by Ermin Fetahovic, Vladimir Janjic, Maja Muric, Nemanja Jovicic, Branimir Radmanovic, Gvozden Rosic, Dragica Selakovic, Milos Filipovic and Nemanja Muric

Int. J. Mol. Sci. 2025, 26(12), 5905; https://doi.org/10.3390/ijms26125905 - 19 Jun 2025

Viewed by 661

Abstract

Electroconvulsive therapy (ECT) remains one of the most effective interventions for treatment-resistant psychiatric disorders, particularly major depressive disorder and bipolar disorder. Despite extensive clinical and preclinical investigations, the precise neurobiological mechanisms underlying ECT’s therapeutic effects are not fully understood. This review explores the [...] Read more.

Electroconvulsive therapy (ECT) remains one of the most effective interventions for treatment-resistant psychiatric disorders, particularly major depressive disorder and bipolar disorder. Despite extensive clinical and preclinical investigations, the precise neurobiological mechanisms underlying ECT’s therapeutic effects are not fully understood. This review explores the molecular and cellular pathways involved in ECT, emphasizing its impact on neurotrophic signaling, oxidative stress, apoptosis, and neuroplasticity. Evidence suggests that ECT modulates brain-derived neurotrophic factor and other neurotrophic factors, promoting synaptic plasticity and neuronal survival. Additionally, ECT influences the hypothalamic–pituitary–adrenal axis, reduces neuroinflammation, and alters neurotransmitter systems, contributing to its antidepressant effects. Recent findings also highlight the role of mitochondrial function and oxidative stress regulation in ECT-induced neural adaptation. By synthesizing current molecular insights, this review provides a comprehensive perspective on the neurobiological mechanisms of ECT, offering potential directions for future research and therapeutic advancements in brain stimulation. Full article

(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy—2nd Edition)

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18 pages, 279 KiB

Open AccessArticle

Steroidomic Changes in the Cerebrospinal Fluid of Women with Multiple Sclerosis

by Radmila Kancheva, Eva Kubala Havrdová, Marta Velíková, Ludmila Kancheva, Josef Včelák, Radek Ampapa, Michal Židó, Ivana Štětkářová, Tereza Škodová and Martin Hill

Int. J. Mol. Sci. 2025, 26(12), 5904; https://doi.org/10.3390/ijms26125904 - 19 Jun 2025

Viewed by 273

Abstract

Multiple sclerosis (MS) is a long-term disease that causes inflammation and damage to the nervous system. This study evaluated steroidomic alterations related to MS in 57 female MS patients during the follicular phase and 17 during the luteal phase, as well as in [...] Read more.

Multiple sclerosis (MS) is a long-term disease that causes inflammation and damage to the nervous system. This study evaluated steroidomic alterations related to MS in 57 female MS patients during the follicular phase and 17 during the luteal phase, as well as in age- and phase-matched controls. The data showed that (1) unconjugated and conjugated steroids were strongly linked between the blood and CSF. (2) MS patients have lower levels of unconjugated steroids compared to controls. However, unchanged levels of conjugated steroids suggest a possible increase in steroid sulfotransferase functioning. (3) MS patients show altered levels of steroids linked to 11β-hydroxylase (CYP11B1) function. While direct enzyme activity was not measured, disrupted cortisol biosynthesis—potentially linked to reduced functioning of both CYP11B1 and 17α-hydroxylase/17,20-lyase—is associated with more severe cases of MS. (4) Reduced levels of 5α/β-steroids and protective GABAergic 3α-hydroxy-5α/β-steroids in MS patients might be linked to the pathophysiology of MS. (5) A potential increase in AKR1C3 function in MS could contribute to inflammation, as this enzyme catalyzes the synthesis of both steroids and prostaglandins. However, direct measurements of enzyme activity are needed to confirm this hypothesis. (6) Lower pregnenolone levels in MS patients might weaken neuroprotection, while higher pregnenolone sulfate levels could support cognitive function. (7) Lower levels of protective pregnenolone, DHEA, and androstenediol were associated with worse MS, suggesting these steroids may help shield against the disease. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

25 pages, 2579 KiB

Open AccessArticle

Exploring Carboxamide Derivatives as Promising Anticancer Agents: Design, In Vitro Evaluation, and Mechanistic Insights

by Manal M. Al-Najdawi, Maysaa M. Saleh, Dima A. Sabbah, Rima Hajjo, Hiba Zalloum, Suha M. Abudoleh, Duaa A. Abuarqoub, Yusuf M. Al-Hiari, Mohammad Yasin Mohammad, Husam ALSalamat, Hebah Mansour, Nawzat D. Aljbour and Aktham H. Mestareehi

Int. J. Mol. Sci. 2025, 26(12), 5903; https://doi.org/10.3390/ijms26125903 - 19 Jun 2025

Viewed by 574

Abstract

Carboxamide derivatives are a promising class of compounds in anticancer drug discovery, owing to their ability to interact with multiple oncogenic targets and their favorable pharmacological profiles. In this study, we report the design, synthesis, and biological evaluation of a series of N [...] Read more.

Carboxamide derivatives are a promising class of compounds in anticancer drug discovery, owing to their ability to interact with multiple oncogenic targets and their favorable pharmacological profiles. In this study, we report the design, synthesis, and biological evaluation of a series of N-substituted 1H-indole-2-carboxamides as potential anticancer agents. The synthesized compounds were assessed for antiproliferative activity using the MTT assay against MCF-7 (breast cancer), K-562 (leukemia), and HCT-116 (colon cancer) cell lines, with normal human dermal fibroblasts included as a non-cancerous control. Several compounds demonstrated notable cytotoxicity and selectivity. Compounds 12, 14, and 4 exhibited potent activity against K-562 cells, with IC₅₀ values of 0.33 µM, 0.61 µM, and 0.61 µM, respectively. Compound 10 showed the most significant activity against HCT-116 cells (IC₅₀ = 1.01 µM) with a high selectivity index (SI = 99.4). Moderate cytotoxicity was observed against MCF-7 cells. To elucidate the mechanism of action, molecular docking and induced-fit docking studies were conducted against key cancer-related targets, including topoisomerase–DNA (PDB ID: 5ZRF), PI3Kα (4L23), and EGFR (3W32), revealing favorable binding interactions. Additionally, principal component analysis of molecular descriptors indicated that the compounds possess promising drug-like and lead-like properties, particularly compound 10. Overall, this study highlights N-substituted indole-2-carboxamides as promising scaffolds for further optimization. The integration of synthetic chemistry, biological assays, and computational modeling provides a robust foundation for the continued development of these compounds as potential anticancer agents. Full article

(This article belongs to the Special Issue Biological Hallmarks and Therapeutic Strategies in Cancer)

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21 pages, 374 KiB

Open AccessReview

Complement System Inhibitors in Nephrology: An Update—Narrative Review

by Mugurel Apetrii, Alexandru Dan Costache, Irina Iuliana Costache Enache, Luminita Voroneanu, Andreea Simona Covic, Mehmet Kanbay and Adrian Covic

Int. J. Mol. Sci. 2025, 26(12), 5902; https://doi.org/10.3390/ijms26125902 - 19 Jun 2025

Viewed by 781

Abstract

Complement system inhibitors are emerging as promising therapies in nephrology, particularly for diseases where complement dysregulation is central to pathogenesis. This review summarizes the role of complement activation in kidney diseases and current evidence supporting complement-targeted treatments. As the complement system can be [...] Read more.

Complement system inhibitors are emerging as promising therapies in nephrology, particularly for diseases where complement dysregulation is central to pathogenesis. This review summarizes the role of complement activation in kidney diseases and current evidence supporting complement-targeted treatments. As the complement system can be involved in the pathogenesis of different diseases to varying degrees, several research works have been conducted. These research efforts aim, firstly, to understand the mechanisms and role of complement cascade components in the most prevalent nephrological diseases and, secondly, to explore the potential of complement system inhibitors in these conditions and their possible clinical applications. Clinical trials demonstrate that complement inhibitors are most effective in conditions with significant complement involvement, such as C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), and immune complex membranoproliferative glomerulonephritis (IC-MPGN). These agents show variable benefits in diseases with partial complement activation, including lupus nephritis and ANCA-associated vasculitis, while their role in disorders like diabetic nephropathy and focal–segmental glomerulosclerosis remains limited. Complement inhibition offers a targeted strategy to prevent disease progression and improve outcomes in selected nephrological disorders. Full article

(This article belongs to the Special Issue Recent Molecular Trends and Prospects in Kidney Diseases)

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44 pages, 4143 KiB

Open AccessReview

Condensation Reactions of 2-Aminothiophenoles to Afford 2-Substituted Benzothiazoles of Biological Interest: A Review (2020–2024)

by Itzia I. Padilla-Martínez, Alejandro Cruz, Efrén V. García-Báez, Jessica E. Mendieta-Wejebe and Martha C. Rosales-Hernández

Int. J. Mol. Sci. 2025, 26(12), 5901; https://doi.org/10.3390/ijms26125901 - 19 Jun 2025

Viewed by 634

Abstract

Several benzothiazole (BT) derivatives have recently been explored in medicinal chemistry, and they are frequently reported in the literature. The interest in this kind of heterocyclic compounds and their structural hybrids has been increasing, as shown by several reviews reported over the last [...] Read more.

Several benzothiazole (BT) derivatives have recently been explored in medicinal chemistry, and they are frequently reported in the literature. The interest in this kind of heterocyclic compounds and their structural hybrids has been increasing, as shown by several reviews reported over the last decade. In this context, we found that about 70 articles related to the synthesis of BT derivatives that studied their biological activities were published in the last five years. From this, we prepared a review on the synthesis and biological activity studies about this topic. In this bibliographic review it was found that medicinal chemists also explore BT derivatives in search of anticancer and anti-Alzheimer’s candidates. This review comprehends 70 articles, published between 2020 and 2024, related to the synthesis of BT derivatives with the purpose of assessing their biological activities. On the other hand, BT derivatives have been explored as molecular species that perform two or more biological actions, called multifunctional drugs. Some accounts related to the structure–activity relationship which provide a framework for drug discovery and design are also discussed. The synthetic methods of BT synthesis include the use of biocatalysts, solvent-free conditions, photocatalysts, and catalysts supported on nanoparticles. Studies also explore renewable energy sources such as microwave, UV, and visible-light and mechanochemical sources. Full article

(This article belongs to the Special Issue Advances in Organic Synthesis in Drug Discovery)

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12 pages, 1876 KiB

Open AccessCase Report

A Unique Case of a Child with Two Rare Hereditary Diseases: Familial Dilated Cardiomyopathy and Arterial Calcification

by Yulia Burykina, Daria Chudakova, Olga Zharova, Elena Basargina, Irina Silnova, Natalia Sdvigova, Leila Gandaeva, Yulia Davydova, Valentina Kaverina, Ilya Zhanin, Alexander Pushkov, Andrey Fisenko and Kirill Savostyanov

Int. J. Mol. Sci. 2025, 26(12), 5900; https://doi.org/10.3390/ijms26125900 - 19 Jun 2025

Viewed by 487

Abstract

Here, we present a unique case of the combination of two rare hereditary diseases—a familial form of dilated cardiomyopathy (DCM) and arterial calcification (AC)—in a 10-month-old boy. DCM was caused by a novel pathogenic nucleotide variant (NV) c.542G>T in the MYH7 gene, and [...] Read more.

Here, we present a unique case of the combination of two rare hereditary diseases—a familial form of dilated cardiomyopathy (DCM) and arterial calcification (AC)—in a 10-month-old boy. DCM was caused by a novel pathogenic nucleotide variant (NV) c.542G>T in the MYH7 gene, and AC was caused by biallelic nucleotide variants c.3421C>T and c.4015C>T in the ABCC6 gene. NVs were identified by the next-generation sequencing (NGS) of a broad panel of 404 genes potentially involved in cardiovascular disorders and subsequently validated by Sanger sequencing in the proband and his parents. Cardiologic examinations confirmed the familial nature of cardiomyopathy and the pathogenicity of variant c.542G>T in MYH7 gene. This case highlights the clinical utility of NGS in identifying complex co-existing hereditary conditions and emphasizes the need for the comprehensive genetic testing of patients with atypical clinical presentations. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

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37 pages, 18599 KiB

Open AccessArticle

Diclofenac Immune-Mediated Hepatitis: Identification of Innate and Adaptive Immune Responses at Clinically Relevant Doses

by Jürgen Borlak and Reinhard Spanel

Int. J. Mol. Sci. 2025, 26(12), 5899; https://doi.org/10.3390/ijms26125899 - 19 Jun 2025

Viewed by 547

Abstract

Diclofenac is an effective medication for pain and inflammation. However, its use has been linked to hepatitis. To gain insight into diclofenac’s ability to cause hepatitis, we investigated the regulation of major effectors of the immune system following daily treatment of minipigs at [...] Read more.

Diclofenac is an effective medication for pain and inflammation. However, its use has been linked to hepatitis. To gain insight into diclofenac’s ability to cause hepatitis, we investigated the regulation of major effectors of the immune system following daily treatment of minipigs at 3 and 15 mg/kg for 28 days. Histopathology evidenced lobular inflammation, and through a combination of immunogenomics and immunopathology, we detected marked innate and adaptive immune responses. We identified 109 significantly regulated genes linked to neutrophil, monocyte, Kupffer cell, and lymphocyte responses and 32 code for cytokine- and interferon-γ-signaling. In support of wound repair, immunopathology evidenced manifest upregulation of macrophage migration inhibitory factor and CD74. Furthermore, the strong expression of IgG and IgM underscored humoral immune responses. Diclofenac caused an activation of the complement system, especially the C1 inhibitor of the classical pathway and C3 with critical functions in liver regeneration. The marked expression of complement factor B and H of the alternate pathway modulated B-cell responses. Likely, the upregulation of factor H protected hepatocytes from injury by limiting complement-mediated damage of inflamed cells. Additionally, diclofenac treatment elicited marked hepatic expression of lysozyme and KLF6. The latter earmarks M1-polarized Kupffer cells. We observed an extraordinary induction of calprotectin/S100A9 and of the monocyte/macrophage CD163 scavenger receptor, and therefore, we detected innate immune sensing of damaged cells. Lastly, we noted an unprecedented induction of the acute phase reactant SAA1 and DEC-205, which recognize apoptotic and necrotic cells. Together, our results offer mechanistic insights into immune-mediated liver injury patterns following diclofenac treatment. Full article

(This article belongs to the Section Molecular Toxicology)

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18 pages, 1844 KiB

Open AccessReview

A Bridge Too Far? Towards Medical Therapy for Clinically Nonfunctioning Pituitary Tumors

by Nikita Mogar, Dongyun Zhang and Anthony P. Heaney

Int. J. Mol. Sci. 2025, 26(12), 5898; https://doi.org/10.3390/ijms26125898 - 19 Jun 2025

Viewed by 352

Abstract

Clinically nonfunctioning pituitary tumors (CNFPTs) typically do not cause hormonal excess, progress insidiously, and are often large and invasive at presentation. Complete resection is frequently not attainable; radiotherapy (RT) may effectively limit growth but carries a significant risk of hypopituitarism. Medical therapy with [...] Read more.

Clinically nonfunctioning pituitary tumors (CNFPTs) typically do not cause hormonal excess, progress insidiously, and are often large and invasive at presentation. Complete resection is frequently not attainable; radiotherapy (RT) may effectively limit growth but carries a significant risk of hypopituitarism. Medical therapy with dopamine D2 receptor agonists and/or somatostatin analogs has been explored in CNFPTs but have yielded inconsistent results, and there is an unmet need for novel efficacious and safe medical therapies. The authors used the PubMed database to identify and review articles published from January 1982 to July 2024, that discussed the medical treatment of CNFPTs. The most commonly studied medical therapies were somatostatin receptor ligands (SRLs) and dopamine D2 receptor agonists. Of 111 patients with CNFPTs treated with SRLs, 31 (28%) exhibited tumor shrinkage. Following dopamine agonist treatment in 355 patients, tumor shrinkage occurred in 113 (32%), tumor stabilization in 182 (51%), and tumor growth in 60 (17%). The efficacy of other less commonly employed therapies such as GnRH analogs, PRRT, and temozolomide was also reviewed. Efficacious and safe medical therapies evaluated in robust randomized placebo-controlled clinical trials are needed to improve the management of CNFPTs. Full article

(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)

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24 pages, 5303 KiB

Open AccessArticle

Pro-Apoptotic Activity of 1-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-2-one, an Intracellular Inhibitor of PIM-1 Kinase in Acute Lymphoblastic Leukemia and Breast Cancer Cells

by Patrycja Wińska, Monika Wielechowska, Łukasz Milewski, Paweł Siedlecki and Edyta Łukowska-Chojnacka

Int. J. Mol. Sci. 2025, 26(12), 5897; https://doi.org/10.3390/ijms26125897 - 19 Jun 2025

Viewed by 437

Abstract

Inhibition of CK2 and/or PIM-1 kinases has been shown to induce apoptosis in a variety of cancer cell lines, underscoring their potential as valuable targets in anti-cancer drug development. In this study, a series of N-substituted derivatives of 4,5,6,7-tetrabromo-1H-benzimidazole, including [...] Read more.

Inhibition of CK2 and/or PIM-1 kinases has been shown to induce apoptosis in a variety of cancer cell lines, underscoring their potential as valuable targets in anti-cancer drug development. In this study, a series of N-substituted derivatives of 4,5,6,7-tetrabromo-1H-benzimidazole, including 2-oxopropyl/2-oxobutyl substituents and their respective hydroxyl analogues, were synthesized and evaluated for anti-cancer activity. The compounds’ ability to inhibit CK2α and PIM-1 kinases was assessed through enzymatic assays, complemented by comprehensive in silico enzyme–substrate docking analyses. Cytotoxicity was evaluated using the MTT assay in human cancer cell lines—including acute lymphoblastic leukemia (CCRF-CEM) and breast cancer (MCF-7, MDA-MB-231)—as well as in normal Vero cells. Apoptosis induction in the two most responsive cell lines (CCRF-CEM and MCF-7) was further examined using flow cytometry-based assays, including annexin V binding, mitochondrial membrane potential disruption, caspase-3 activation, and cell cycle analysis. Intracellular inhibition of CK2 and PIM-1 kinases was confirmed in CCRF-CEM and MCF-7 cells using Western blot and phospho-flow cytometry. Among the synthesized compounds, we identified a novel TBBi derivative exhibiting pronounced pro-apoptotic activity and the ability to inhibit PIM-1 kinase intracellularly. These findings support the hypothesis that PIM-1 kinase represents a promising molecular target for the treatment of leukemia. Full article

(This article belongs to the Special Issue Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition)

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Graphical abstract

13 pages, 857 KiB

Open AccessReview

Extracellular Vesicles as Targeted Communicators in Complementary Medical Treatments

by Keehyun Earm, Yung E. Earm and Denis Noble

Int. J. Mol. Sci. 2025, 26(12), 5896; https://doi.org/10.3390/ijms26125896 - 19 Jun 2025

Viewed by 496

Abstract

The supposed meridians of traditional oriental medicine have been a cause of conflict between traditional and modern medical science. A possible resolution has been proposed: That extracellular vesicles, including exosomes, may be the transmitters of traditional therapies such as massage and acupuncture. This [...] Read more.

The supposed meridians of traditional oriental medicine have been a cause of conflict between traditional and modern medical science. A possible resolution has been proposed: That extracellular vesicles, including exosomes, may be the transmitters of traditional therapies such as massage and acupuncture. This article develops that idea by proposing that the pathways between surface and deep structures may be laid down during the embryonic migration of cells from one region of the developing body to distant regions. This hypothesis depends on the proven targeting of vesicular communication via cell surface binding molecules and their complementary binding sites on target cells. The hypothesis is therefore experimentally testable. The article also draws attention to a strong analogy with Charles Darwin’s theory of pangenesis for particulate communication between the soma and germline. Full article

(This article belongs to the Special Issue Extracellular Vesicles in the Pathogenesis of Disease and Their Potential Role as Therapeutic Targets)

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14 pages, 5450 KiB

Open AccessCase Report

Extramedullary Relapse of CBFA2T3::GLIS2-Positive Megakaryoblastic Leukemia Mimicking Secondary Ewing Sarcoma: An Exemplary Case for the Diagnostic Trap

by Svetlana Lebedeva, Ekaterina Mikhailova, Sophia Bogacheva, Dmitry Abramov, Svetlana Kashpor, Alexander Druy, Alexandra Semchenkova, Marina Gaskova, Olga Lotonina, Ilya Sidorov, Galina Tereschenko, Yulia Olshanskaya, Galina Novichkova, Alexey Maschan, Elena Zerkalenkova and Alexander Popov

Int. J. Mol. Sci. 2025, 26(12), 5895; https://doi.org/10.3390/ijms26125895 - 19 Jun 2025

Viewed by 406

Abstract

In children without Down syndrome who have acute megakaryoblastic leukemia (AMKL), inv(16)(p13q24)/CBFA2T3::GLIS2 is the most frequent genetic aberration. Pediatric CBFA2T3::GLIS2-positive AMKL is strongly associated with a poor prognosis and a high cumulative incidence of relapse. One of the key laboratory signs [...] Read more.

In children without Down syndrome who have acute megakaryoblastic leukemia (AMKL), inv(16)(p13q24)/CBFA2T3::GLIS2 is the most frequent genetic aberration. Pediatric CBFA2T3::GLIS2-positive AMKL is strongly associated with a poor prognosis and a high cumulative incidence of relapse. One of the key laboratory signs of CBFA2T3::GLIS2-positive AMKL is the RAM immunophenotype, which looks very similar to that of solid-tumor bone marrow (BM) infiltration. For this reason, in cases of isolated extramedullary involvement of CBFA2T3::GLIS2-positive AMKL, excluding solid tumors may be challenging. We report a case of a girl with isolated extramedullary CBFA2T3::GLIS2-positive AMKL relapse, which was misdiagnosed as secondary Ewing sarcoma. The morphological differential diagnosis between Ewing sarcoma and AMKL presented significant challenges owing to their overlapping histological features (small, round blue-cell morphology and similar growth patterns). The tumor cells’ immunophenotype completely mirrored that at the initial diagnosis of AMKL. Additional cytogenetic and molecular studies confirmed the presence of the CBFA2T3::GLIS2 fusion, but no Ewing sarcoma-specific EWSR1, FUS and CIC fusion transcripts were found. Thus, extramedullary CBFA2T3::GLIS2-positive AMKL relapse was confirmed. The presented case demonstrates the difficulties in differential diagnosis between AMKL relapse and the development of a secondary tumor. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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19 pages, 2936 KiB

Open AccessArticle

Association of Gene Expression Profiles in HPV-Positive Head and Neck Squamous Cell Carcinoma with Patient Outcome: In Search of Prognostic Biomarkers

by J. Noé García-Chávez, Adriana Contreras-Paredes, Claudia González-Espinosa, Imelda Martínez-Ramírez, Elizabeth Langley, Marcela Lizano and J. Omar Muñoz-Bello

Int. J. Mol. Sci. 2025, 26(12), 5894; https://doi.org/10.3390/ijms26125894 - 19 Jun 2025

Viewed by 650

Abstract

Head and Neck Squamous Cell Carcinoma (HNSCC) ranks sixth in incidence and seventh in cancer mortality worldwide. Approximately 30% of HNSCC cases are related to human papillomavirus (HPV) infection, the oropharynx being the anatomical subsite most associated with HPV infection. Traditionally, HPV-positive HNSCC [...] Read more.

Head and Neck Squamous Cell Carcinoma (HNSCC) ranks sixth in incidence and seventh in cancer mortality worldwide. Approximately 30% of HNSCC cases are related to human papillomavirus (HPV) infection, the oropharynx being the anatomical subsite most associated with HPV infection. Traditionally, HPV-positive HNSCC has been considered to have better treatment response and clinical outcome. However, HPV-positive HNSCC is a heterogeneous group since 30% of the cases present early relapse, which implies that there are differences in molecular profiles within HPV-positive patients. In this study, we used bioinformatic data analysis from open-access repositories to compare molecular profiles differentially expressed between HPV-positive and -negative HNSCC patients. Using the TCGA HNSCC transcriptomic data, we identified a group of genes, whose expression is related to clinical outcome in patients. Our findings were validated in an independent cohort confirming that the expression levels of FABP4, HMGA2, S100A10, GDNF, SLC7A,2 and GPR18 genes were associated with overall survival (OS) exclusively in HPV-positive HNSCC patients, while ST6GALNAC1 expression was associated with OS in HPV-negative HNSCC. The expression of OS-related genes was independent of tumor stage and history of alcoholism. Our findings suggest that transcriptional profiles in HPV-positive HNSCC are an excellent source of information for the search for potential prognostic biomarkers. Full article

(This article belongs to the Special Issue Viral Infections and Cancer: Recent Advances and Future Perspectives)

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19 pages, 3202 KiB

Open AccessArticle

Identification of Proteins Associated with Ovarian Cancer Chemotherapy Resistance Using MALDI-MSI

by Tannith M. Noye, Parul Mittal, Zoe K. Price, Annie Fewster, Georgia Williams, Tara L. Pukala, Manuela Klingler-Hoffmann, Peter Hoffmann, Martin K. Oehler, Noor A. Lokman and Carmela Ricciardelli

Int. J. Mol. Sci. 2025, 26(12), 5893; https://doi.org/10.3390/ijms26125893 - 19 Jun 2025

Viewed by 467

Abstract

Ovarian cancer is the most lethal gynecological cancer. Up to 75% of cases are high-grade serous ovarian cancer (HGSOC) that have high chemosensitivity to first-line platinum-based therapies. However, 75% of patients will become chemoresistant following relapse. The underlying mechanism for developing resistance to [...] Read more.

Ovarian cancer is the most lethal gynecological cancer. Up to 75% of cases are high-grade serous ovarian cancer (HGSOC) that have high chemosensitivity to first-line platinum-based therapies. However, 75% of patients will become chemoresistant following relapse. The underlying mechanism for developing resistance to chemotherapy in HGSOC is poorly understood. In this study, we employed Matrix-Assisted Laser Desorption/Ionization–Mass Spectrometry Imaging (MALDI-MSI) on matching formalin-fixed paraffin-embedded (FFPE) HGSOC tissues at the time of diagnosis and following relapse with chemotherapy-resistant disease (n = 4). We identified m/z values that were differentially abundant in the matching diagnosis and relapse HGSOC tissues. These were matched to proteins using nano-liquid chromatography tandem mass spectrometry (LC-MS/MS). We identified upregulated proteins in the HGSOC relapse tissues, including COL12A1, FUBP1, PLEC, SLC4A1, and TKT. These proteins were validated by immunohistochemistry (IHC) and gene expression using online databases. IHC showed COL12A1, FUBP1, PLEC, SLC4A1, and TKT protein abundance were significantly elevated in HGSOC relapse tissues compared to matching tissues at diagnosis. COL12A1, FUBP1, PLEC, and TKT mRNA expression levels were significantly increased in HGSOC compared to normal ovary and associated with poor prognosis in HGSOC. We confirmed that higher protein abundance of both COL12A1 and PLEC correlated with reduced progression-free survival in HGSOC patients. Furthermore, both COL12A1 and PLEC mRNA and protein levels were significantly associated with chemotherapy resistance. In summary, using MALDI-MSI, we have identified proteins, including COL12A1 and PLEC, associated with chemotherapy resistance to be further evaluated as HGSOC biomarkers and/or therapeutic targets. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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23 pages, 2915 KiB

Open AccessArticle

Analysis of the Expression Patterns of Tumor Necrosis Factor Alpha Signaling Pathways and Regulatory MicroRNAs in Astrocytic Tumors

by Klaudia Skóra, Damian Strojny, Dawid Sobański, Rafał Staszkiewicz, Paweł Gogol, Mateusz Miller and Beniamin Oskar Grabarek

Int. J. Mol. Sci. 2025, 26(12), 5892; https://doi.org/10.3390/ijms26125892 - 19 Jun 2025

Viewed by 463

Abstract

Chronic inflammation is increasingly recognized as a driver of glioma progression, with tumor necrosis factor-alpha (TNF-α) playing a central role in modulating the tumor microenvironment. This study aimed to investigate the expression profiles and regulatory mechanisms of TNF-α and its downstream mediators—including interleukin-1 [...] Read more.

Chronic inflammation is increasingly recognized as a driver of glioma progression, with tumor necrosis factor-alpha (TNF-α) playing a central role in modulating the tumor microenvironment. This study aimed to investigate the expression profiles and regulatory mechanisms of TNF-α and its downstream mediators—including interleukin-1 beta (IL-1β), Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8), and Mitogen-activated protein kinase kinase 7 (MAP2K7)—in astrocytic tumors of varying malignancy. We conducted an integrative molecular analysis of 60 human astrocytic tumor samples (20 G2, 12 G3, 28 G4) using transcriptomic microarrays, Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR), Enzyme-Linked Immunosorbent Assay (ELISA), Western blotting, immunohistochemistry, methylation-specific PCR, and miRNA profiling. Prognostic associations were evaluated using Kaplan–Meier survival and Cox regression analyses. TNF-α, IL-1β, and MAP3K8 were significantly upregulated in high-grade tumors, with log₂ fold changes ranging from 5.56 to 8.76 (p < 0.001). High expression of TNF-α (HR = 2.10, 95% CI: 1.27–3.46, p = 0.004), IL-1β (HR = 2.35, 95% CI: 1.45–3.82, p = 0.001), and MAP3K8 (Hazard Ratio; HR = 1.88, 95% confidence interval; 95% CI: 1.12–3.16, p = 0.015) was associated with poorer overall survival. miR-34a-3p and miR-30 family members, predicted to target TNF-α and IL-1β, were markedly downregulated in G3/G4 tumors (e.g., miR-30e-3p fold change: –3.78, p < 0.01). Promoter hypomethylation was observed in G3/G4 tumors, supporting epigenetic activation. Our findings establish a multi-layered regulatory mechanism of TNF-α signaling in astrocytic tumors. These data highlight the TNF-α/IL-1β/MAP3K8 axis as a critical driver of glioma aggressiveness and a potential therapeutic target. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases 2.0)

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3 pages, 151 KiB

Open AccessEditorial

The Therapeutic Potential of Antioxidants in the Prevention of Human Diseases

by Kota V. Ramana

Int. J. Mol. Sci. 2025, 26(12), 5891; https://doi.org/10.3390/ijms26125891 - 19 Jun 2025

Viewed by 298

Abstract

The recent surge in various chronic infectious and non-infectious diseases worldwide has created an urgent need for safe and effective prevention and treatment options to control and manage these diseases [...] Full article

(This article belongs to the Special Issue Therapeutic Potential of Antioxidants in the Prevention of Human Diseases)

23 pages, 6728 KiB

Open AccessArticle

Identification and Expression Analysis of G-Protein-Coupled Receptors Provide Insights into Functional and Mechanistic Responses to Herbivore-Induced Plant Volatiles of Paracarophenax alternatus

by Ruiheng Lin, Xu Chu, Yangming Zhang, Sikai Ke, Yunfeng Zheng, Wei Yu, Feiping Zhang and Songqing Wu

Int. J. Mol. Sci. 2025, 26(12), 5890; https://doi.org/10.3390/ijms26125890 - 19 Jun 2025

Viewed by 335

Abstract

Herbivore-induced plant volatiles (HIPVs) play a pivotal role in mediating tritrophic interactions between plants, herbivores, and their natural enemies. Paracarophenax alternatus, a parasitic mite targeting the egg stage of Monochamus alternatus, has emerged as a promising biocontrol agent. However, its ability [...] Read more.

Herbivore-induced plant volatiles (HIPVs) play a pivotal role in mediating tritrophic interactions between plants, herbivores, and their natural enemies. Paracarophenax alternatus, a parasitic mite targeting the egg stage of Monochamus alternatus, has emerged as a promising biocontrol agent. However, its ability to detect Pinus massoniana-derived HIPVs for host insect localization remains unclear. G-protein-coupled receptors (GPCRs) may play a role in mediating the perception of HIPVs and associated chemosensory signaling pathways in mites. In this study, a total of 85 GPCRs were identified from P. alternatus. All GPCRs exhibited conserved transmembrane domains and stage-specific expression patterns, with 21 receptors significantly upregulated in viviparous mites. Combined with two previously identified odorant receptors (ORs), six candidate chemosensory receptors were selected for molecular dynamics simulations to validate their binding stability with key volatile compounds. The results demonstrate that specific GPCRs likely facilitate HIPV detection in mites, enabling precise host localization within dynamic ecological niches. Our findings provide critical insights into the molecular basis of mite–host interactions and establish a framework for optimizing P. alternatus-based biocontrol strategies against pine wilt disease vectors. Full article

(This article belongs to the Section Molecular Biology)

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10 pages, 1123 KiB

Open AccessArticle

Indoleamine 2,3-Dioxygenase Regulates Placental Trophoblast Cell Invasion

by Yoshiki Kudo and Jun Sugimoto

Int. J. Mol. Sci. 2025, 26(12), 5889; https://doi.org/10.3390/ijms26125889 - 19 Jun 2025

Viewed by 276

Abstract

To clarify the physiological importance of the tryptophan catabolizing enzyme, indoleamine 2,3-dioxygenase, in human pregnancy, we have studied how the expression of this enzyme controls extravillous cytotrophoblast invasion into the decidua. We have generated an Ishikawa cell line stably transfected with a plasmid [...] Read more.

To clarify the physiological importance of the tryptophan catabolizing enzyme, indoleamine 2,3-dioxygenase, in human pregnancy, we have studied how the expression of this enzyme controls extravillous cytotrophoblast invasion into the decidua. We have generated an Ishikawa cell line stably transfected with a plasmid encoding indoleamine 2,3-dioxygenase under the control of a tetracycline inducible promoter. Using this Ishikawa cell line and extravillous cytotrophoblast cell line, HTR-8/SVneo, we developed a quantitative in vitro trophoblast invasion assay. When trophoblast cells were cultured on a layer of Ishikawa cells expressing indoleamine 2,3-dioxygenase, tryptophan degradation was enhanced and trophoblast cell invasion was suppressed. These findings suggest that indoleamine 2,3-dioxygenase expressed in the decidua may play a role in regulating trophoblast invasion. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Physiology and Endocrinology)

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23 pages, 3841 KiB

Open AccessArticle

The Prognostic Value of the Hedgehog Signaling Pathway in Ovarian Cancer

by Noor D. Salman, Lars C. Hanker, Balázs Győrffy, Áron Bartha, Louisa Proppe and Martin Götte

Int. J. Mol. Sci. 2025, 26(12), 5888; https://doi.org/10.3390/ijms26125888 - 19 Jun 2025

Viewed by 439

Abstract

The hedgehog pathway is a major regulator of cell growth and differentiation during embryogenesis and early development. The literature suggests that variations in this pathway’s genes play a role in tumor progression and response to therapy. This study aimed to assess the correlation [...] Read more.

The hedgehog pathway is a major regulator of cell growth and differentiation during embryogenesis and early development. The literature suggests that variations in this pathway’s genes play a role in tumor progression and response to therapy. This study aimed to assess the correlation between the expression levels of selected genes of this pathway and the progression-free and overall survival of ovarian cancer patients. Using the database Kaplan–Meier plotter, which includes the gene expression and survival data of 1565 ovarian cancer patients, higher expression levels of the genes SHH, PTCH1, PTCH2, and GLI1 displayed better survival correlations, while GLI, GLI3, and SUFU correlated with adverse outcomes. Further dissection revealed a differential impact of the genes in specific clinical-histopathological categories. Notably, higher expression levels of SUFU were associated with a negative impact on ovarian cancer patients under many clinical–histopathological aspects. These results shed new light on the role of these genes in the chemoresponsiveness of ovarian cancer, especially SUFU, which could be considered a novel indicator for poor prognosis in epithelial ovarian cancer. Full article

(This article belongs to the Special Issue Gynecological Oncology: From Molecular Basis to Therapy)

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30 pages, 1486 KiB

Open AccessSystematic Review

Comparison of the Mediterranean Diet and Other Therapeutic Strategies in Metabolic Syndrome: A Systematic Review and Meta-Analysis

by Alejandro Bruna-Mejias, Jessica San Martin, Danna Arciniegas-Diaz, Trinidad Meneses-Caroca, Amelia Salamanca-Cerda, Antonia Beas-Gambi, Jessica Paola-Loaiza-Giraldo, Cynthia Ortiz-Ahumada, Pablo Nova-Baeza, Gustavo Oyanedel-Amaro, Mathias Orellana-Donoso, Alejandra Suazo-Santibáñez, Juan Sanchis-Gimeno and Juan José Valenzuela-Fuenzalida

Int. J. Mol. Sci. 2025, 26(12), 5887; https://doi.org/10.3390/ijms26125887 - 19 Jun 2025

Cited by 1 | Viewed by 1048

Abstract

The Mediterranean diet (MD) is one of the healthiest diets, high in fiber, antioxidants, and unsaturated fats. MD improves lipid profiles, reduces inflammation, controls blood pressure, decreases insulin resistance, and enhances the sensitivity to this hormone, lowering the risks of Metabolic syndrome (MS). [...] Read more.

The Mediterranean diet (MD) is one of the healthiest diets, high in fiber, antioxidants, and unsaturated fats. MD improves lipid profiles, reduces inflammation, controls blood pressure, decreases insulin resistance, and enhances the sensitivity to this hormone, lowering the risks of Metabolic syndrome (MS). MS is characterized by central obesity, hypertension, insulin resistance, and dyslipidemia, increasing the risk of cardiovascular disease and type II diabetes. The objective of this study was to know the effectiveness of the MD versus other treatments in patients with MS. A systematic search across multiple databases, Medline, Embase, Web of Science, Scopus, Google Scholar, and Cinahl, was conducted using keywords such as “Mediterranean diet”, “Mediterranean food”, “eat mediterranean”, “Metabolic syndrome”, and “x syndrome”. A total of 12 studies met the inclusion criteria. Mediterranean diet at different doses versus other diets or other treatments showed significant improvements in clinical parameters, including BMI (mean difference of −0.83 95% CI: −0.93 to −0.74; p < 0.00001),waist circumference (mean difference = −1.81, CI = −2.63 to −0.99, p < 0.00001) triglycerides (mean difference = −22.38, CI = −32.86 to −11.90, p < 0.00001), Glucose (mean difference = −4.28, CI = −7.64 to −0.93, p = 0.005) and, HOMA IR (mean difference = −0.72, CI = −0.78 to −0.65, p < 0.00001), and Insulin resistance (mean difference = −2.98, CI = −3.27 to −2.69, p < 0.00001), all of which improved, Although there were more outcomes, these are the most important changes for patients with metabolic syndrome. MD improves metabolic and cardiovascular health, but study heterogeneity limits the results’ generalizability. Because of that, further research is needed to standardize approaches and explore their mechanisms. MD should be part of an optimized strategy that includes education and physical activity. The strength of the evidence was very low according to the GRADE approach. Further research is needed to support the efficacy of the Mediterranean diet in patients with MS. Full article

(This article belongs to the Special Issue Molecular Therapeutics for Diabetes and Related Complications, 2nd Edition)

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Int. J. Mol. Sci., Volume 26, Issue 12 (June-2 2025) – 491 articles

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