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Curr. Issues Mol. Biol., Volume 48, Issue 6 (June 2026) – 103 articles

Cover Story (view full-size image): Inflammaging, the chronic low-grade inflammation associated with aging, is recognized as a dynamic biological process rather than a condition defined by circulating biomarkers. This review explores how diverse drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge toward key inflammatory signaling hubs such as NF-κB, NLRP3 inflammasome, cGAS-STING, JAK/STAT, and p38 MAPK. We highlight emerging evidence that these pathways are not only markers of aging but also actionable therapeutic targets. By shifting the focus from biomarker assessment to mechanism-based intervention, the concept of “druggable inflammaging” opens new opportunities for precision therapies aimed at promoting healthy aging and preventing age-related diseases. View this paper
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13 pages, 11891 KB  
Article
Exploring the Relationship Between Protein-Level Ratios (rQLTs) and Duodenal Ulcer
by Siwen Tang, Yongwei Li, Xi Yu, Ying Xiao and Tian Zhong
Curr. Issues Mol. Biol. 2026, 48(6), 643; https://doi.org/10.3390/cimb48060643 - 22 Jun 2026
Viewed by 180
Abstract
To explore the associations between protein-level ratios (rQLTs) and duodenal ulcer (DU) risk using Mendelian randomization (MR), colocalization, and pathway analysis approaches. A bidirectional MR approach was used to identify molecular targets linking rQLTs with DU, employing the inverse variance weighted (IVW) method [...] Read more.
To explore the associations between protein-level ratios (rQLTs) and duodenal ulcer (DU) risk using Mendelian randomization (MR), colocalization, and pathway analysis approaches. A bidirectional MR approach was used to identify molecular targets linking rQLTs with DU, employing the inverse variance weighted (IVW) method for causal estimation. Colocalization analysis ensured the reliability of inferred causal relationships. Gene interaction networks were constructed via STRING, and key regulatory hub-genes were identified through Cytoscape analysis. Significant inverse associations were found between rQLT-ACE2/GGT1 (Angiotensin-converting enzyme 2/γ-glutamyl transpeptidase 1) (IVW, OR (95% CI) = 0.754 (0.674–0.843), adjusted PIVW = 0.0005), and DU risk in the East Asian (Japanese) population. No statistically significant associations were observed in the European population. The findings indicate a genetic inverse association between rQLT-ACE2/GGT1 and DU risk in the East Asian (Japanese) population, while no corresponding association was observed in Europeans. These results provide genetic evidence consistent with a potential association rather than causal inference or biomarker validation. This study does not support conclusions regarding diagnostic or therapeutic utility at this stage. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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28 pages, 3354 KB  
Review
Metformin as an Innate Immune Modulator: Metabolic and Epigenetic Reprogramming of Innate Immune Cells and Therapeutic Implications
by Yunfeng Shi and Sheng Xia
Curr. Issues Mol. Biol. 2026, 48(6), 642; https://doi.org/10.3390/cimb48060642 - 22 Jun 2026
Viewed by 333
Abstract
Metformin, widely prescribed for type 2 diabetes mellitus (T2D), has emerged as a systemic immunomodulator with effects that extend far beyond glycemic control. Recent advances in immunometabolism reveal that metformin modulates innate immune responses through coordinated cellular metabolic reprogramming and epigenetic modification, which [...] Read more.
Metformin, widely prescribed for type 2 diabetes mellitus (T2D), has emerged as a systemic immunomodulator with effects that extend far beyond glycemic control. Recent advances in immunometabolism reveal that metformin modulates innate immune responses through coordinated cellular metabolic reprogramming and epigenetic modification, which collectively modulate the functional phenotype of innate immune cells. This narrative review summarizes current evidence regarding the immunomodulatory effects of metformin on the innate immune system, with a focus on immunometabolism and epigenetic regulation. It explores how metformin modulates innate immunity by altering cellular energy sensing, mitochondrial function, and nutrient utilization. Such metabolic changes and alterations further reshape chromatin structure and architecture, as well as transcriptional profiles and programs. Through the regulation of glycolysis, fatty acid oxidation, and histone modification landscapes, metformin regulates the phenotypes of innate immune cells, which can be pro-inflammatory, tolerogenic, or homeostatic. This conceptual framework presents a new understanding of metformin. As well as acting as an anti-inflammatory agent, it may regulate immune memory. Full article
(This article belongs to the Section Molecular Medicine)
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24 pages, 9848 KB  
Article
Comprehensive Bioinformatic Characterization of CD70, CD80, and TIGIT as Diagnostic, Prognostic, and Immune Biomarkers in Pan-Cancer
by Christos Panagiotis Rigopoulos, Ilias Georgakopoulos-Soares and Apostolos Zaravinos
Curr. Issues Mol. Biol. 2026, 48(6), 641; https://doi.org/10.3390/cimb48060641 - 21 Jun 2026
Viewed by 268
Abstract
Immunotherapy has transformed cancer treatment; however, clinical benefit remains limited to a subset of patients, underscoring the need for robust biomarkers that capture tumor-immune interactions across cancer types. In this study, we performed a comprehensive pan-cancer, multi-omics characterization of the immune checkpoint–related molecules [...] Read more.
Immunotherapy has transformed cancer treatment; however, clinical benefit remains limited to a subset of patients, underscoring the need for robust biomarkers that capture tumor-immune interactions across cancer types. In this study, we performed a comprehensive pan-cancer, multi-omics characterization of the immune checkpoint–related molecules CD70, CD80, and TIGIT to evaluate their diagnostic, prognostic, and immunological relevance. Using integrative analyses of transcriptomic, epigenomic, genomic, pharmacogenomic, and single-cell RNA-sequencing data from The Cancer Genome Atlas and complementary resources, we assessed expression patterns, DNA methylation, somatic mutations, copy number alterations, immune infiltration, tumor stemness, and drug sensitivity. CD70, CD80, and TIGIT were broadly dysregulated across multiple malignancies, with coordinated overexpression particularly evident in kidney renal clear-cell carcinoma. Elevated expression of these immune checkpoints was associated with advanced tumor stage, aggressive molecular subtypes, and unfavorable survival outcomes in selected cancers, including uveal melanoma and renal malignancies. Functional analyses revealed significant associations between checkpoint expression and key oncogenic pathways, including epithelial–mesenchymal transition, apoptosis, and hormone receptor signaling, suggesting links with tumor progression and immune activation states. Immune deconvolution analyses indicated that TIGIT expression is associated with a T-cell–inflamed microenvironment and reduced neutrophil infiltration, while CD80 exhibited methylation-dependent associations with immune cell composition. Genomic and epigenetic alterations were found to correlate with checkpoint expression patterns and immune phenotypes across tumor types. Pharmacogenomic profiling identified associations between checkpoint expression and sensitivity to multiple anticancer agents; however, these findings are based on cell line datasets and should be considered predictive. Single-cell transcriptomic analyses further resolved cell-type–specific expression patterns, distinguishing tumor-intrinsic from immune-restricted expression profiles. Collectively, our findings establish CD70, CD80, and TIGIT as integrative biomarkers of tumor progression, immune contexture, and therapeutic response, providing a rationale for their clinical exploitation in precision immuno-oncology. Full article
(This article belongs to the Collection Bioinformatics Approaches to Biomedicine)
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26 pages, 8022 KB  
Article
Genome-Wide Identification and Expression Analysis of the Thaumatin-like Protein Genes in Filipendula ulmaria under Bipolaris sorokiniana Infection
by Ekaterina A. Istomina, Marina P. Slezina and Tatyana I. Odintsova
Curr. Issues Mol. Biol. 2026, 48(6), 640; https://doi.org/10.3390/cimb48060640 - 20 Jun 2026
Viewed by 209
Abstract
Pathogenesis-related (PR) proteins are crucial for plant defense against pathogen infection. However, the specific role of thaumatin-like proteins (TLPs), which comprise the PR-5 family, in plant immune responses has not been thoroughly investigated. Filipendula ulmaria is a medicinal plant with valuable pharmacological properties, [...] Read more.
Pathogenesis-related (PR) proteins are crucial for plant defense against pathogen infection. However, the specific role of thaumatin-like proteins (TLPs), which comprise the PR-5 family, in plant immune responses has not been thoroughly investigated. Filipendula ulmaria is a medicinal plant with valuable pharmacological properties, including antimicrobial, anti-inflammatory, gastroprotective, immunomodulatory, and anticancer activities. The structure of the TLP family and its role in the immune system of meadowsweet have not been studied so far. The goal of this study was to analyze in detail the TLP gene family in meadowsweet and explore its response to fungal infection. In the meadowsweet genome, we identified 27 putative TLP genes, examined their structure and location on chromosomes, analyzed cis-regulatory elements in the promoter regions, predicted the structure and physicochemical characteristics of the encoded proteins, and performed a phylogenetic analysis. We also studied the differential expression of TLP genes under Bipolaris sorokiniana infection. Of six differentially expressed genes, three genes were up-regulated 48 h post-infection, suggesting their involvement in defense response to the fungus. The results obtained shed light on the role of the TLP gene family in the immune system of F. ulmaria and form the foundation for the creation of disease-resistant crops in agriculture and the development of bio-based antimicrobials in medicine. Full article
(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants, 4th Edition)
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24 pages, 5398 KB  
Article
Recent Dominant Transposition Events Affect Gene Regulatory Regions, but Not Coding Sequences, in Polar and Brown Bear Genomes
by Chris M. Njagi, James J. Kelley, Nikita Gulati, Naman S. Sijwali and Andrey Grigoriev
Curr. Issues Mol. Biol. 2026, 48(6), 639; https://doi.org/10.3390/cimb48060639 - 20 Jun 2026
Viewed by 205
Abstract
Transposable elements (TEs) are inserted into the genome and may change its properties; those occurring in or near regulatory regions may also alter gene expression. Given the challenges of detecting insertions in short-read sequencing, we analyzed structural variants in polar and brown bear [...] Read more.
Transposable elements (TEs) are inserted into the genome and may change its properties; those occurring in or near regulatory regions may also alter gene expression. Given the challenges of detecting insertions in short-read sequencing, we analyzed structural variants in polar and brown bear genomes by a reciprocal alignment of one species’ sample genomes to a reference sequence of the other species, thus inferring TE insertion as the other genome’s “deletions”. With this approach, we detected short interspersed elements (SINEs) belonging to the CAN SINE family as dominant fixed TEs. We observed a non-random distribution of CAN SINE insertion positions near both protein- and RNA-coding genes, where TEs often overlap UTRs or occur in their vicinity. In contrast, SINEs avoid coding sequences, suggesting TE insertions that would disrupt such sequences are under purifying selection. We used black bear as an outgroup and determined that most of the CAN SINE insertions in the polar bear genome were derived, since they are not present in black or brown bear, while there is no dominant trend for CAN SINE insertions in brown bear relative to the outgroup. Many of the genes with UTRs affected by CAN SINEs are potentially relevant to the differences between the species (body shape, size, etc.) or to Arctic-adaptation phenotypes such as fur color, metabolism, and the immune system. This supports a model that CAN SINEs have contributed to regulatory evolution in bears and provides further evidence of such events across carnivore genomes in the animal kingdom. Full article
(This article belongs to the Special Issue Emerging Trends for Genome-Wide Association Studies in Complex Disease Genetics)
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46 pages, 1662 KB  
Review
Cyanobacteria as a Photosynthetic Chassis for Metabolic Pathway Engineering with Heterologous Gene Expression
by Jessica Walshe and Sushanta Kumar Saha
Curr. Issues Mol. Biol. 2026, 48(6), 638; https://doi.org/10.3390/cimb48060638 - 19 Jun 2026
Viewed by 423
Abstract
Cyanobacteria are increasingly recognised as photosynthetic chassis for sustainable metabolic engineering because oxygenic photosynthesis generates ATP and NADPH via the photosynthetic electron transport chain, which drive CO2 fixation through the Calvin–Benson–Bassham cycle into carbon intermediates that can be redirected toward engineered heterologous [...] Read more.
Cyanobacteria are increasingly recognised as photosynthetic chassis for sustainable metabolic engineering because oxygenic photosynthesis generates ATP and NADPH via the photosynthetic electron transport chain, which drive CO2 fixation through the Calvin–Benson–Bassham cycle into carbon intermediates that can be redirected toward engineered heterologous pathways. Their genetic tractability, CO2-fixing capacity, ecological adaptability, and relatively simple cellular organisation make them attractive platforms for developing low-carbon biotechnological processes. This review explores recent progress in engineering cyanobacteria for heterologous pathway construction, critically evaluating genetic tools including transformation methods, genome integration strategies, promoter systems, and CRISPR-based editing, with specific emphasis on challenges of direct relevance to phototrophic chassis: host–pathway metabolic compatibility, precursor supply, cofactor balancing between photosynthetic output and heterologous pathway demand, and achieving genetic stability in polyploid cyanobacterial genomes. The review also addresses key limitations with mechanistic context: metabolic burden from multi-gene pathway expression reduces growth rate and selects against producing cells; polyploidy delays complete chromosomal segregation of engineered constructs; slow photoautotrophic growth constrains volumetric productivity; native regulatory networks resist carbon flux redirection; and cultivation constraints—including light attenuation in dense cultures and mismatches between photosynthetic ATP/NADPH supply and heterologous pathway demand—further limit achievable yields. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Plant Science 2026)
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20 pages, 1825 KB  
Article
Development of Chimeric Ribonuclease A Inhibitor for Molecular Biology Applications: SUMO Fusion as an Engineering Strategy
by Dmitry Sukhov, Tatyana Petrova, Daria Kruglova, Inna Kholoshenko, German Romanenko, Yuri Utkin, Pavel Pantyushenko, Dmitry Trofimov, Vladimir Korotkiy, Ekaterina Barsova and Yulia Kirillova
Curr. Issues Mol. Biol. 2026, 48(6), 637; https://doi.org/10.3390/cimb48060637 - 18 Jun 2026
Viewed by 268
Abstract
A chimeric RNase A inhibitor (SUMO-RI) was produced by fusing a SUMO domain to the N-terminus of the murine Rnh1 protein. Functional assays demonstrated that SUMO-RI effectively protects RNA from RNase A-mediated degradation under conditions mimicking real-time RT-PCR, with performance comparable to that [...] Read more.
A chimeric RNase A inhibitor (SUMO-RI) was produced by fusing a SUMO domain to the N-terminus of the murine Rnh1 protein. Functional assays demonstrated that SUMO-RI effectively protects RNA from RNase A-mediated degradation under conditions mimicking real-time RT-PCR, with performance comparable to that of commercial RNase inhibitors. The primary advantage of the chimeric design is its improved technological suitability: SUMO-RI exhibits markedly enhanced storage stability relative to the recombinant Rnh1 inhibitor. However, this benefit comes with a trade-off—SUMO fusion reduces thermostability at temperatures above approximately 47 °C. Together, these findings establish SUMO fusion as a rational engineering strategy for RNase inhibitors, offering improved practical handling at the expense of thermal resilience. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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29 pages, 5039 KB  
Article
In Vitro Evaluation of Combination Therapy with Doxorubicin and Quercetin for Uveal Melanoma
by Petra Fodor, Barbara Zsebik, Ferenc Fenyvesi, Zsuzsanna Szabó, Anna Vass and Gábor Halmos
Curr. Issues Mol. Biol. 2026, 48(6), 636; https://doi.org/10.3390/cimb48060636 - 18 Jun 2026
Viewed by 222
Abstract
Background: Uveal melanoma is the most common intraocular malignancy in adults with a poor prognosis. Although local therapies are effective, treatment options for advanced disease remain limited. Combination strategies using chemotherapeutic agents and natural compounds, such as quercetin, are in focus for their [...] Read more.
Background: Uveal melanoma is the most common intraocular malignancy in adults with a poor prognosis. Although local therapies are effective, treatment options for advanced disease remain limited. Combination strategies using chemotherapeutic agents and natural compounds, such as quercetin, are in focus for their potential to enhance antitumor efficiency and overcome resistance. Methods: The effects of doxorubicin, quercetin, and their combination were investigated in uveal melanoma cell lines. Cell viability was determined by an MTT assay, and apoptosis and cell cycle distribution by flow cytometry. Invasion assays were performed to evaluate metastatic potential, while modifications in signaling pathways were analyzed by Western blotting and qPCR. Results: Both doxorubicin and quercetin significantly reduced cell viability and induced apoptotic and necrotic cell death. The combination treatment demonstrated additional inhibitory effects in both cell lines, shown by increased SubG1 populations, reduced invasive capacity, and modulation of signaling pathways. Cell cycle analysis indicated treatment-induced growth inhibition. Notably, pathway modifications varied between cell lines, suggesting heterogeneous responses. Conclusions: Quercetin may potentiate certain antitumor effects of doxorubicin in uveal melanoma, particularly by reducing post-treatment invasiveness and modulating certain PI3K/AKT pathway-related proteins. These results support the possibility of quercetin-based combination therapies, although further molecular and in vivo studies are required. Full article
(This article belongs to the Special Issue Therapeutic Effects of Natural Bioactive Compounds in the Management of Human Diseases: 2nd Edition)
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10 pages, 2498 KB  
Article
Benincaside A Induces p53-Dependent Transactivation and Fas/CD95-Mediated Apoptosis in HCT 116 Human Colorectal Cancer Cells
by Jai-Sing Yang, Kun-Ching Cheng, Yu-Hsiu Chuang, Ping-Chung Kuo and Tian-Shung Wu
Curr. Issues Mol. Biol. 2026, 48(6), 635; https://doi.org/10.3390/cimb48060635 - 18 Jun 2026
Viewed by 209
Abstract
An undescribed seco-kaurane diterpenoid, benincaside A (BA), was isolated from the seeds of Benincasa hispida. The seeds of B. hispida have been traditionally used in folk medicine and previous studies have reported anti-tumor potential in B. hispida seed extracts. Accordingly, we investigated [...] Read more.
An undescribed seco-kaurane diterpenoid, benincaside A (BA), was isolated from the seeds of Benincasa hispida. The seeds of B. hispida have been traditionally used in folk medicine and previous studies have reported anti-tumor potential in B. hispida seed extracts. Accordingly, we investigated the cytotoxicity and underlying mechanisms of BA in colorectal cancer cells. BA inhibited growth in HT29, Colo205, HCT116, and CT26 colorectal cancer cells, as determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while showing no toxicity toward normal human umbilical vein endothelial cells (HUVEC) and human fibroblast WS-1 cells. In HCT116 cells, BA-induced deoxyribonucleic acid (DNA) damage and apoptosis, as evidenced by morphological changes, 4,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining, and assays of caspase-8 and caspase-3 activities. BA triggered apoptotic cell death via the extrinsic pathway, as indicated by elevated caspase-8 and caspase-3 activities. Intracellular reactive oxygen species (ROS) generation was observed in BA-treated HCT116 cells. The growth-inhibitory effects were significantly attenuated by pretreatment with N-acetylcysteine (NAC, an antioxidant), caffeine (an ATM kinase inhibitor), z-VAD-fmk (pan-caspase inhibitor), or z-IETD-fmk (caspase-8-specific inhibitor). Colorimetric assays confirmed increased caspase-8 and caspase-3 activities in BA-treated cells. This study is the first to report ROS-dependent signaling as a key mechanism underlying BA-induced cell death in HCT116 human colorectal cancer cells. Full article
(This article belongs to the Special Issue Advances in Phytochemical Research: Molecular Pathways in Health and Disease)
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30 pages, 5112 KB  
Article
Kombucha-Mediated Silver Nanoparticles with Fungicidal Activity Against WHO-Priority Candida Pathogens: In Vitro and Galleria mellonella Evaluation
by Razvan Vlad Opris, Dan Alexandru Toc, Alina Mihaela Baciu, Ioana Alina Colosi, Vlad Sever Neculicioiu, Anca Onaciu, Cristian-Silviu Moldovan, Ana-Maria Vlase, Carmen Costache and Adrian Florea
Curr. Issues Mol. Biol. 2026, 48(6), 634; https://doi.org/10.3390/cimb48060634 - 17 Jun 2026
Viewed by 277
Abstract
Invasive candidiasis caused by drug-resistant Candida species represents a critical global health challenge, with few novel therapeutic scaffolds under development. Here, silver nanoparticles were synthesized using a 21-day fermented Chun Mee kombucha tea extract (K-AgNPs) and characterized by UV-Vis spectroscopy, transmission electron microscopy, [...] Read more.
Invasive candidiasis caused by drug-resistant Candida species represents a critical global health challenge, with few novel therapeutic scaffolds under development. Here, silver nanoparticles were synthesized using a 21-day fermented Chun Mee kombucha tea extract (K-AgNPs) and characterized by UV-Vis spectroscopy, transmission electron microscopy, nanoparticle tracking analysis, and Fourier-transform infrared spectroscopy. LC-MS/MS profiling of the kombucha substrate documented a phytochemical landscape dominated by epigallocatechin (up to 122,631 µg/mL) and epigallocatechin gallate (up to 415 µg/mL), with a progressive ~80% decline in epicatechin and concomitant increases in gallic acid and chlorogenic acid across the 21-day fermentation. K-AgNPs obtained were spherical, 19.4 nm (±7.9 nm SD) in diameter, with a surface plasmon resonance peak at 415 nm. FTIR confirmed phenolic, carboxylate, and glycosidic surface capping. Antifungal susceptibility testing against eight Candida species, including the WHO critical–priority pathogen Candidozyma auris, showed concordant minimum inhibitory and minimum fungicidal concentrations of 0.80–1.60 µg/mL, confirming fungicidal activity. In vivo evaluation in Galleria mellonella larvae across six infection models demonstrated that K-AgNP treatment at the species-specific MIC significantly improved larval survival versus untreated infected controls (p < 0.01–0.001), while nanoparticle-only groups maintained ≥98% survival, indicating negligible toxicity. Co-treatment amplified total hemocyte mobilization, and K-AgNP-only larvae maintained hemocyte viability above 96% at all time points, indistinguishable from negative controls. Together, these findings demonstrate antifungal activity of K-AgNPs across the genus Candida in standardized in vitro and in vivo settings and provide justification for further investigation, including head-to-head comparison against licensed antifungals and physicochemical validation of nanoparticle stability under assay conditions. Full article
(This article belongs to the Special Issue Effects of Nanoparticles on Living Organisms, 3rd Edition)
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19 pages, 2938 KB  
Article
Plasma-Derived miRNAs as Fluid Biomarkers to Differentiate Alzheimer’s and Frontotemporal Dementia
by Rosalinda Di Gerlando, Francesca Dragoni, Evelyne Minucchi, Maria Garofalo, Giulia Perini, Alfredo Costa, Antonio Pisani, Carlo Morasso, Matteo Cotta Ramusino and Stella Gagliardi
Curr. Issues Mol. Biol. 2026, 48(6), 633; https://doi.org/10.3390/cimb48060633 - 17 Jun 2026
Viewed by 259
Abstract
Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD) are complex neurodegenerative disorders, often sharing overlapping symptoms. Non-coding RNAs may be involved in pathological processes in these conditions, hence the study of miRNAs isolated from plasma-derived extracellular vesicles (EVs) could provide exploratory insights into the [...] Read more.
Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD) are complex neurodegenerative disorders, often sharing overlapping symptoms. Non-coding RNAs may be involved in pathological processes in these conditions, hence the study of miRNAs isolated from plasma-derived extracellular vesicles (EVs) could provide exploratory insights into the molecular background. The main aim of this work was to identify shared deregulated miRNAs presenting different expression patterns in the two pathologies. A selection of the identified deregulated miRNAs was further studied with the purpose of identifying their mRNA targets and generating hypotheses on their potential pathological involvement. A total of 340 and 291 differentially expressed miRNAs were found in FTD and AD, respectively. Among the commonly deregulated miRNAs with opposite expression patterns between the two conditions, miR-638 emerged as a candidate of interest, showing consistent patterns across our experimental analyses. Nevertheless, these findings are preliminary and intended to be interpreted cautiously, requiring validation in larger cohorts. In addition, the expression of two of its predicted targets in peripheral blood mononuclear cells (PBMCs) appeared to align with miR-638 expression in the same cell type and may reflect potential differences in underlying brain pathological states. Full article
(This article belongs to the Special Issue Molecular Neuropsychiatry: Target Discovery for Mental Disorders)
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35 pages, 1294 KB  
Review
Transient Middle Cerebral Artery Occlusion in Rats as a Nonclinical Model of Ischemic Stroke: A Systematic Review
by Priscila Mendes, Joana Pinto, Carole Mateus, Inês Guerra and Vanessa Mateus
Curr. Issues Mol. Biol. 2026, 48(6), 632; https://doi.org/10.3390/cimb48060632 - 17 Jun 2026
Viewed by 289
Abstract
Background: Ischemic stroke remains a leading cause of mortality and disability worldwide. Despite extensive preclinical research, most neuroprotective strategies have failed to translate into clinical benefit, partly due to methodological variability. The transient intraluminal filament middle cerebral artery occlusion (tifMCAO) model is widely [...] Read more.
Background: Ischemic stroke remains a leading cause of mortality and disability worldwide. Despite extensive preclinical research, most neuroprotective strategies have failed to translate into clinical benefit, partly due to methodological variability. The transient intraluminal filament middle cerebral artery occlusion (tifMCAO) model is widely used, yet its implementation lacks consistency. This review aimed to characterize tifMCAO methodologies in adult rats and examine how experimental variability relates to reported outcomes. Methods: A systematic review was conducted following PRISMA guidelines. Studies using tifMCAO in adult rats were included. MEDLINE (PubMed), Web of Science, and Scopus were searched up to March 2025. Risk of bias was assessed using the SYRCLE tool and reporting quality using the ARRIVE checklist. The protocol was registered in PROSPERO (CRD420251140869). Results were synthesized narratively. Results: A total of 125 studies were included. A commonly used framework involved male Sprague–Dawley rats (6–12 weeks), silicone-coated monofilaments, occlusion durations of 60–120 min (most frequently 90 min), and isoflurane anesthesia, although this reflects methodological convergence rather than true standardization. Substantial variability was observed across methodological parameters. Variations in ischemia duration, filament properties, and anesthesia were associated with differences in infarct size, blood–brain barrier disruption, and functional outcomes. Conclusions: The tifMCAO model shows partial methodological convergence alongside significant variability influencing outcomes. Improved standardization and reporting are essential to enhance reproducibility and translational relevance. Full article
(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)
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15 pages, 2171 KB  
Article
Serotype-Specific Biochemical and Immunological Signatures of Dengue Virus Envelope Proteins
by Iasmin V. Costa, Ana Cecília R. Cruz and Carlos Alberto M. Carvalho
Curr. Issues Mol. Biol. 2026, 48(6), 631; https://doi.org/10.3390/cimb48060631 - 17 Jun 2026
Viewed by 267
Abstract
Dengue is an arboviral disease of global significance caused by Orthoflavivirus denguei (DENV), which has four antigenically distinct serotypes. The envelope (E) protein plays a critical role in viral entry and eliciting immune responses. This study aimed to compare the biochemical and immunological [...] Read more.
Dengue is an arboviral disease of global significance caused by Orthoflavivirus denguei (DENV), which has four antigenically distinct serotypes. The envelope (E) protein plays a critical role in viral entry and eliciting immune responses. This study aimed to compare the biochemical and immunological properties of the E protein across the four DENV serotypes using in silico approaches. E protein reference sequences were retrieved from RefSeq and analyzed with various bioinformatics tools. Sequence alignment revealed identities ranging from 63.08% to 77.69%. Biochemical analysis showed minimal variation in molecular weight and isoelectric point; however, the net charge of DENV-3 E protein was notably lower. Secondary structure predictions indicated a predominance of alpha-helices in DENVs-1/2, while DENVs-3/4 featured more beta-sheets. Post-translational modification analysis revealed mostly casein kinase II phosphorylation sites across all serotypes, with DENV-4 uniquely presenting also tyrosine kinase sites. Amino acids W231/D341 in DENV-1, Q86 in DENVs-2/4, and D87/D339 in DENV-3 showed maximum antigenicity scores in B cell recognition, while the human leukocyte antigen (HLA) alleles B*08:01/B*39:01 and DRB4*01:01, recognized by T cells, presented the highest number of predicted epitopes for the different DENV serotypes. Conservation analysis showed that the major antigenic regions highlighted in this study are highly conserved among contemporary DENV isolates despite the genetic variability observed within each serotype. These findings suggest that subtle structural differences in the E protein may contribute to distinct immunogenic profiles, highlighting candidate regions for future investigation. Full article
(This article belongs to the Section Molecular Microbiology)
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22 pages, 4238 KB  
Article
Bioactive Assessment of MMA-Based Dental Materials: Molecular Docking and Network Topology Analysis of Stress-Regulated Survival, Apoptosis, and Mechanotransduction Pathways
by Yağmur Dilber, Erhan Dilber and Kübra Yıldız Domaniç
Curr. Issues Mol. Biol. 2026, 48(6), 630; https://doi.org/10.3390/cimb48060630 - 17 Jun 2026
Viewed by 207
Abstract
Methyl methacrylate (MMA)-based materials are widely used in temporary and permanent prosthetic dentistry; the prolonged presence of these materials in the oral cavity and potential residual monomer release can affect local biological responses. This study aimed to evaluate the biocompatibility and toxicity profiles [...] Read more.
Methyl methacrylate (MMA)-based materials are widely used in temporary and permanent prosthetic dentistry; the prolonged presence of these materials in the oral cavity and potential residual monomer release can affect local biological responses. This study aimed to evaluate the biocompatibility and toxicity profiles of MMA, the monomeric unit of polymethyl methacrylate (PMMA), a key component of dental materials used in temporary prosthetic restorations. Molecular docking simulations were performed using CB-Dock2 and Autodock vina, while protein–protein interaction (PPI) analysis was performed using STRING and Cytoscape. In addition, Swiss ADME Target Prediction, toxicity prediction, and enrichment analyses were used to characterize the biological significance of selected targets in more detail. Molecular docking studies revealed promising interactions of MMA with valuable biomolecular targets relevant to biocompatibility. The toxicity profile revealed aspects of MMA that could be improved. Pharmacophore modeling, highlighting the importance of carbonyl and hydroxyl groups as pharmacophoric properties, revealed compounds with suitable biocompatibility profiles. Consequently, it emphasizes the interactions of MMA with biomolecules and safety considerations. It can guide the design and optimization of biocompatible materials as an exploratory avenue for future developments in dental biomaterials. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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33 pages, 2704 KB  
Review
Inflammaging Beyond Biomarkers: Molecular Mechanisms and Therapeutic Opportunities
by Amelia Tero-Vescan, Ruxandra Ștefănescu, Amalia Pușcaș, Mădălina Buț, Bianca-Eugenia Ősz and Mark Slevin
Curr. Issues Mol. Biol. 2026, 48(6), 629; https://doi.org/10.3390/cimb48060629 - 16 Jun 2026
Viewed by 438
Abstract
Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), [...] Read more.
Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP), fail to capture the complexity, tissue specificity, and causal architecture of inflammaging. Recent experimental evidence has demonstrated that diverse upstream drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge on a limited number of central inflammatory hubs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and p38 mitogen-activated protein kinase (p38 MAPK) signaling. These mechanistic nodes represent promising therapeutic targets, potentially modifiable biological processes, and support the emerging concept of ‘druggable inflammaging’, whereby senotherapeutics, inflammasome inhibitors, innate immune modulators, and metabolic interventions may actively modify aging-associated inflammatory biology rather than simply monitor it through biomarkers. This review highlights a paradigm shift from biomarker-based assessment toward mechanism-based intervention, where inflammaging can be characterized as a modifiable biological process and a central target for precision pharmacological strategies in aging-related diseases. Full article
(This article belongs to the Special Issue Targeted Therapies and Biomarker Discovery in Health and Disease)
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16 pages, 241 KB  
Article
Real-World Evaluation of Next-Generation Sequencing in Lung Cancer: Associations Between Histological Subtypes and Genomic Alterations
by Javier Azúa-Romeo, Maria Cabetas, Irene Rodriguez, Bárbara Angulo and Arantxa Andueza
Curr. Issues Mol. Biol. 2026, 48(6), 628; https://doi.org/10.3390/cimb48060628 - 16 Jun 2026
Viewed by 255
Abstract
Background: Lung cancer is a highly heterogeneous disease in which molecular characterization has become essential for guiding personalized therapies. The implementation of next-generation sequencing (NGS) allows for the simultaneous detection of multiple genomic alterations, improving tumor profiling and therapeutic decision-making. This study aimed [...] Read more.
Background: Lung cancer is a highly heterogeneous disease in which molecular characterization has become essential for guiding personalized therapies. The implementation of next-generation sequencing (NGS) allows for the simultaneous detection of multiple genomic alterations, improving tumor profiling and therapeutic decision-making. This study aimed to characterize the molecular landscape of lung cancer using NGS and to evaluate its association with histological subtypes and programmed death-ligand 1 (PD-L1) expression. Methods: A retrospective observational study was conducted on 96 patients diagnosed with lung cancer between 2023 and 2025. Molecular profiling was performed using the Action OncoKitDx panel. Associations between genetic alterations, histological subtypes, and PD-L1 expression were analyzed using Fisher’s exact test, with p < 0.05 considered statistically significant. Results: Adenocarcinoma was the most common histological subtype (67.7%), followed by squamous cell carcinoma (26%). The most common mutations were KRAS (34.4%), TP53 (29.2%), and EGFR (11.5%). KRAS mutations were significantly associated with adenocarcinoma (p = 0.001), while squamous cell carcinoma showed a higher frequency of cases without molecular alterations detected by the NGS panel (p = 0.002). Co-mutations were identified in 22.9% of cases, with KRAS–TP53 being the most common combination. Tumors harboring EGFR mutations showed a significantly lower frequency of co-mutations (p = 0.012). No significant associations were found between PD-L1 expression and either histological subtypes or the analyzed genetic alterations. Conclusions: Lung cancer exhibits marked molecular heterogeneity, with a predominance of KRAS mutations in adenocarcinoma. The low frequency of co-mutations in EGFR-mutated tumors supports their role as dominant driver alterations. The lack of association between PD-L1 expression and genomic alterations highlights the complexity of its regulation and suggests the involvement of multiple biological factors. These findings reinforce the clinical value of NGS in comprehensive tumor profiling and in the development of precision medicine strategies. Full article
(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era, 3rd Edition)
21 pages, 925 KB  
Review
MALDI-TOF Mass Spectrometry for Glioblastoma Secretome Biomarker Screening: A Review of Challenges and Perspectives
by David Aebisher, Klaudia Dynarowicz, Rostyslav Marunych, Izabela Rudy, Kacper Rogóż, Aleksandra Kawczyk-Krupka, Piotr Oleś and Dorota Bartusik-Aebisher
Curr. Issues Mol. Biol. 2026, 48(6), 627; https://doi.org/10.3390/cimb48060627 - 16 Jun 2026
Viewed by 278
Abstract
Glioblastoma (GBM) remains one of the most aggressive malignancies, characterized by profound heterogeneity and a dismal prognosis. While genomic and transcriptomic profiling have provided structural insights, they often fail to capture the dynamic interactions within the tumor microenvironment (TME). Secretome analysis—the study of [...] Read more.
Glioblastoma (GBM) remains one of the most aggressive malignancies, characterized by profound heterogeneity and a dismal prognosis. While genomic and transcriptomic profiling have provided structural insights, they often fail to capture the dynamic interactions within the tumor microenvironment (TME). Secretome analysis—the study of proteins actively secreted by tumor cells—offers a functional readout of these interactions and a reservoir for potential biomarkers. In this review, we critically evaluate the role of MALDI-TOF Mass Spectrometry as a strategic tool for GBM secretome profiling. While Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) remains the gold standard for deep protein discovery, we argue that MALDI-TOF’s speed, cost-effectiveness, and high-throughput capabilities position it as an ideal platform for clinical screening and “spectral phenotyping.” We discuss the technical hurdles, such as ion suppression and the “leakome” (intracellular contamination), and highlight how integrating MALDI with Extracellular Vesicle (EV) enrichment and Artificial Intelligence (AI) can bridge the gap between in vitro discovery and clinical application. Full article
(This article belongs to the Special Issue Molecular Markers of Tumor Response and Toxicity of Antitumor Therapy)
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56 pages, 3148 KB  
Review
Plant Bioactive Constituents and Their Potential Benefits in HPV-Positive Oropharyngeal Squamous Cell Carcinoma—A Narrative Review
by Violeta Popovici, Emma Adriana Ozon, Manuela Apetrei, Rodica Boca and Cerasela Elena Gîrd
Curr. Issues Mol. Biol. 2026, 48(6), 626; https://doi.org/10.3390/cimb48060626 - 16 Jun 2026
Viewed by 938
Abstract
Human papillomavirus (HPV) has become a leading cause of oropharyngeal cancers, alongside well-known risk factors such as tobacco and alcohol use. Currently, HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC) has increased significantly in developed countries, with HPV-16 being the most common high-risk subtype. [...] Read more.
Human papillomavirus (HPV) has become a leading cause of oropharyngeal cancers, alongside well-known risk factors such as tobacco and alcohol use. Currently, HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC) has increased significantly in developed countries, with HPV-16 being the most common high-risk subtype. Clinically, HPV+ OPSCC shows clear differences in prognosis compared to HPV-negative tumors, particularly regarding survival rates and treatment responses. Patients with HPV+ OPSCC tend to have notably better survival outcomes and a more favorable outlook. Strong evidence indicates that HPV-related oropharyngeal cancers represent a distinct epidemiological, clinical, and molecular group, setting them apart from non-HPV-related cancers. As a result, treatment strategies for these subtypes should follow specific clinical protocols to optimize outcomes. Additionally, the viral oncoproteins E6 and E7, which systematically disrupt host tumor-suppressor networks, provide strong reasons for targeted phytotherapeutic interventions. Therefore, there is increasing interest in exploring plant bioactive compounds with promising anti-HPV and anticancer effects that target key oncogenic pathways. This review aims to compile the latest data on bioactive phytochemicals with mechanistic evidence in HPV+ OPSCC, highlight their molecular interactions across oncogenic signaling pathways, and discuss evidence-based findings focusing on research published from 2000 to 2025. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2026)
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17 pages, 11952 KB  
Review
Microbial α-L-Rhamnosidases: Regioselective Biocatalysts for Flavonoid Biotransformation and Nutraceutical Applications
by Massimo Iorizzo
Curr. Issues Mol. Biol. 2026, 48(6), 625; https://doi.org/10.3390/cimb48060625 - 16 Jun 2026
Viewed by 228
Abstract
Microbial α-L-rhamnosidases are increasingly recognised as selective biocatalysts in food biotechnology, nutraceutical production, and health-related applications. These glycoside hydrolases catalyse the hydrolysis of terminal alpha-L-rhamnose residues from flavonoids, terpenoids, saponins, and other glycosylated natural products, thereby modulating sensory properties, solubility, intestinal absorption, and [...] Read more.
Microbial α-L-rhamnosidases are increasingly recognised as selective biocatalysts in food biotechnology, nutraceutical production, and health-related applications. These glycoside hydrolases catalyse the hydrolysis of terminal alpha-L-rhamnose residues from flavonoids, terpenoids, saponins, and other glycosylated natural products, thereby modulating sensory properties, solubility, intestinal absorption, and biological activity. While their traditional uses include debittering citrus juice and enhancing wine aroma, recent evidence demonstrates their wider value in selective flavonoid biotransformation, production of rare mono-glycosylated derivatives, probiotic fermentations, and microbiome-associated metabolism. This review summarises microbial sources, catalytic mechanisms, CAZy classification, substrate specificity, structure–function relationships, analytical methods, industrial process engineering, and emerging applications in functional foods and targeted nutraceutical applications. Particular attention is given to the distinction between alpha-(1→2)- and alpha-(1→6)-linked substrates, the production of isoquercitrin and prunin, recombinant enzyme platforms, immobilised biocatalysts, and potential future opportunities arising from metagenomics, synthetic biology, and AI-assisted protein engineering. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2026)
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23 pages, 2684 KB  
Article
Modulatory Activity of Uncaria tomentosa Extract in the Expression of Proteins Involved in the Unfolded Protein Response and Insulin Resistance
by Bruna Freitas Marchi, Vittoria de Lima Camandona, Athirson Moraes Chanavat, Gustavo Roncoli Reigado, Carla Roberta de Oliveira Carvalho, Felipe Santiago Chambergo and Viviane Abreu Nunes
Curr. Issues Mol. Biol. 2026, 48(6), 624; https://doi.org/10.3390/cimb48060624 - 16 Jun 2026
Viewed by 292
Abstract
Type 2 diabetes mellitus (T2D) is associated with dyslipidemia, characterized by elevated plasmatic triglycerides and free fatty acids, particularly palmitate (PA), which may cause lipotoxicity in skeletal muscle cells. This leads to inflammation, activation of the unfolded protein response (UPR), insulin resistance, and [...] Read more.
Type 2 diabetes mellitus (T2D) is associated with dyslipidemia, characterized by elevated plasmatic triglycerides and free fatty acids, particularly palmitate (PA), which may cause lipotoxicity in skeletal muscle cells. This leads to inflammation, activation of the unfolded protein response (UPR), insulin resistance, and cell death. Herbal medicines such as Uncaria tomentosa (UT) have shown potential as complementary treatments for T2D due to their protective effects. Purpose and study design: This study investigates the effect of UT aqueous extract on UPR and insulin resistance induced by PA in C2C12 myotubes. C2C12 myoblasts were grown in DMEM medium supplemented with 10% fetal bovine serum and differentiated into myotubes with 3.5% horse serum. The myotubes were incubated with 100 or 500 μM PA, 2–100 µM thapsigargin (Tg) or tunicamycin (Tn), in the presence or absence of 250 μg/mL UT extract or 100 µM TUDCA, for 2 or 6 h. The myotubes treated with UT extract for 6 h, after the incubation with 20 µM Tg, Tn or 500 µM PA, presented reduction in the expression of UPR-related genes ATF4 and CHOP by approximately 1.5-fold, and increased by 3-fold the expression of IRS-1, an insulin-signaling protein, when compared to myotubes incubated with only 20 µM Tg, Tn or 500 µM PA. These findings suggest that UT extract may serve as a modulator against skeletal muscle dyslipidemia by downregulating ATF4 and CHOP, reducing cell stress and death, while enhancing IRS-1 expression, which supports the use of the UT extract in managing insulin resistance and T2D. Full article
(This article belongs to the Special Issue Natural Phytochemicals as Modulators of Cellular Pathways and Therapeutic Targets in Disease Models)
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15 pages, 2735 KB  
Article
Evaluation of the Individual Effects of Melatonin and Umbilical Cord-Derived Mesenchymal Stem Cell Exosomes on Cell Viability and Apoptosis in BE(2)-C Neuroblastoma Cells In Vitro
by Ahmet Şengül, Dilek Kaan, Hatice Güler and Hüseyin Yiğit
Curr. Issues Mol. Biol. 2026, 48(6), 623; https://doi.org/10.3390/cimb48060623 - 16 Jun 2026
Viewed by 254
Abstract
The study aimed to investigate the individual therapeutic effects of melatonin and umbilical cord-derived mesenchymal stem cell exosomes (UC-MSC-Exo) separately on BE(2)-C neuroblastoma cells. Melatonin is recognized for its anti-cancer, antioxidant, and apoptosis-inducing properties, and its ability to cross the blood–brain barrier. UC-MSC-Exos [...] Read more.
The study aimed to investigate the individual therapeutic effects of melatonin and umbilical cord-derived mesenchymal stem cell exosomes (UC-MSC-Exo) separately on BE(2)-C neuroblastoma cells. Melatonin is recognized for its anti-cancer, antioxidant, and apoptosis-inducing properties, and its ability to cross the blood–brain barrier. UC-MSC-Exos are nanovesicles from mesenchymal stem cells that can also cross the blood–brain barrier and transport biologically active molecules. The potential therapeutic benefits of each independent agent in treating BE(2)-C neuroblastoma cells were investigated. Melatonin and UC-MSC-Exos were examined on BE(2)-C neuroblastoma cells at varying concentrations and time intervals to evaluate cell viability and apoptosis. Both melatonin and UC-MSC-Exo independently reduced cell viability and induced apoptosis in a manner that depended on the dosage and duration of exposure. Melatonin had an IC50 of 2.68 mM after 24 h, while UC-MSC-Exo showed an IC50 of 25.3 μg/mL after 48 h, with no cytotoxic effects observed at 24 h. Specifically, individual concentrations of 2.5 mM and 5 mM of melatonin, as well as 50 µg/mL and 100 µg/mL of UC-MSC-Exo, led to significant levels of apoptotic and necrotic cells at 48 and 72 h (p < 0.001). Our findings suggest that the individual administration of melatonin and UC-MSC-Exo may hold therapeutic potential for neuroblastoma cells, particularly given their ability to cross the blood–brain barrier. Further in vivo research is required to evaluate their clinical utility. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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22 pages, 2397 KB  
Article
FuDiCo: Gene Fusion-Initiated Path Propagation for Disease Comorbidity Prediction
by Ashwag Altayyar and Li Liao
Curr. Issues Mol. Biol. 2026, 48(6), 622; https://doi.org/10.3390/cimb48060622 - 16 Jun 2026
Viewed by 181
Abstract
Disease comorbidity—the co-occurrence of two or more diseases in the same individual—has gained growing attention due to its association with adverse clinical outcomes and increased treatment complexity. Recent subgraph-based approaches for disease comorbidity prediction model disease modules as subgraphs induced by disease-associated genes [...] Read more.
Disease comorbidity—the co-occurrence of two or more diseases in the same individual—has gained growing attention due to its association with adverse clinical outcomes and increased treatment complexity. Recent subgraph-based approaches for disease comorbidity prediction model disease modules as subgraphs induced by disease-associated genes in the protein–protein interaction (PPI) network and learn disease representations from subgraph topology. However, these approaches are constrained by incomplete disease–gene annotations, which may obscure important molecular relationships between diseases. Accordingly, disease comorbidity may also be influenced by molecular events beyond annotated disease genes, such as gene fusion events that have emerged as important contributors to disease mechanisms. Motivated by the role of gene fusions in disease development, we introduce Gene Fusion-Initiated Path Propagation for Disease Comorbidity Prediction (FuDiCo), a framework that models comorbidity through influence propagation over the PPI network. FuDiCo represents fusion-associated genes as localized perturbation sources and learns how their influence propagates along interaction paths toward disease subgraphs, thereby capturing propagation patterns that link related diseases and contribute to their comorbidity. Experiments on a benchmark disease comorbidity dataset show that FuDiCo outperforms state-of-the-art methods, achieving statistically significant improvements. These results shed light on the importance of gene fusion events in understanding disease relationships. Full article
(This article belongs to the Special Issue Bioinformatics in Human Disease Network Analysis)
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27 pages, 6328 KB  
Article
Screening of Natural Product-Derived USP7 Inhibitors for Cancer Therapy via Integrated Machine Learning and Molecular Simulations
by Faris Alrumaihi
Curr. Issues Mol. Biol. 2026, 48(6), 621; https://doi.org/10.3390/cimb48060621 - 16 Jun 2026
Viewed by 241
Abstract
Ubiquitination, a crucial cellular protein regulation process, is linked to various diseases, including cancer. Deubiquitinases (DUBs) can reverse ubiquitination, offering a therapeutic strategy. USP7, a DUB, is a key target in oncology due to its role in destabilizing p53, and small-molecule inhibitors could [...] Read more.
Ubiquitination, a crucial cellular protein regulation process, is linked to various diseases, including cancer. Deubiquitinases (DUBs) can reverse ubiquitination, offering a therapeutic strategy. USP7, a DUB, is a key target in oncology due to its role in destabilizing p53, and small-molecule inhibitors could restore p53 activity and combat tumor growth. In this study, we integrated a machine learning (ML)-based screening approach with molecular docking and molecular dynamics (MD) simulations in order to identify potential small-molecule inhibitors of USP7. ML-based screening identified 22 active molecules from a library of 2301 natural compounds. Among the 22 active compounds, only fifteen compounds fulfilled the drug-likeness criteria. Subsequently, molecular docking found three compounds, PubChem 162957515, 114917, and 442879 as potential inhibitors based on binding affinity and interactions. Further, MD simulations and MM-PBSA analyses were performed to evaluate the stability and dynamic behavior of the complexes. Binding energy calculations Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) revealed that compounds PubChem 114917 and 162957515 exhibited strong binding affinities of −20.98 kcal/mol and −18.68 kcal/mol, respectively, implying that these compounds could serve as promising inhibitors for the development of anticancer therapeutics. Full article
(This article belongs to the Special Issue Emerging Trends in Bioinformatics and Computational Biology)
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11 pages, 1308 KB  
Article
β-Hydroxybutyrate Attenuates Cardiac Inflammation and Hepatic Fibrosis in Dahl Salt-Sensitive Rats
by Satoyasu Ito, Eri Manabe, Toshiyuki Shikata, Kojiro Takamoto and Shuhei Kobuchi
Curr. Issues Mol. Biol. 2026, 48(6), 620; https://doi.org/10.3390/cimb48060620 - 16 Jun 2026
Viewed by 210
Abstract
Hypertension remains a major driver of multi-organ damage, including cardiac remodeling and hepatic complications. The ketone body β-hydroxybutyrate (BHB) has emerged as a potential metabolic signaling molecule with anti-inflammatory properties. This study investigated whether BHB attenuates cardiac stress and hepatic injury in a [...] Read more.
Hypertension remains a major driver of multi-organ damage, including cardiac remodeling and hepatic complications. The ketone body β-hydroxybutyrate (BHB) has emerged as a potential metabolic signaling molecule with anti-inflammatory properties. This study investigated whether BHB attenuates cardiac stress and hepatic injury in a salt-sensitive hypertensive model. Dahl salt-sensitive (DS) rats were fed a high-salt (HS) diet combined with a choline-deficient diet to induce cardiac inflammation and hepatic fibrosis. Rats received either BHB or a control vehicle. We found that BHB significantly suppressed hepatic lipid accumulation and fibrotic markers, including TGF-β and collagen III mRNA, even under severe dietary stress. In the heart, BHB attenuated the expression of inflammatory markers (TNF-α and ANP) despite the persistence of high systolic blood pressure. These results demonstrate that BHB exerts direct organ-protective effects through anti-inflammatory and anti-fibrotic actions that are independent of robust blood pressure reduction. Our findings suggest that BHB could be a promising metabolic intervention for managing multi-organ complications in hypertensive patients with metabolic comorbidities. Full article
(This article belongs to the Section Molecular Pharmacology)
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15 pages, 2373 KB  
Article
Identification and Transcriptome Resource of the Mite Orthogalumna cf. terebrantis (Acari: Galumnidae) in China
by Menghui Yang, Xiaochuan Ma, Konglin Zhou, Sheng Lin, Jianming Chen and Zhenyue Lin
Curr. Issues Mol. Biol. 2026, 48(6), 619; https://doi.org/10.3390/cimb48060619 - 15 Jun 2026
Viewed by 209
Abstract
The genus Orthogalumna (Oribatida: Galumnidae) has been recognized for its phytophagous associations with aquatic plants, particularly its potential role in the biocontrol of the invasive weed Water hyacinth (Eichhornia crassipes). Despite its ecological significance, this genus remains poorly studied in terms [...] Read more.
The genus Orthogalumna (Oribatida: Galumnidae) has been recognized for its phytophagous associations with aquatic plants, particularly its potential role in the biocontrol of the invasive weed Water hyacinth (Eichhornia crassipes). Despite its ecological significance, this genus remains poorly studied in terms of its micromorphological architecture, phylogenetics, and genomic resources. In this study, we report Orthogalumna cf. terebrantis from China, providing the first comprehensive characterization of an Orthogalumna species by integrating morphology, phylogeny, and transcriptomics. This record represents the first documented occurrence of O. cf. terebrantis in China, pending confirmation by voucher-based morphological comparison and molecular data. This work provides critical microstructural evidence to complement traditional morphological identification and establishes a foundational molecular dataset for future studies on the systematics, comparative genomics, and environmental adaptation of oribatid mites. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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25 pages, 3645 KB  
Article
Temporal Effects of Cigarette Smoke and Phytochemical-Based E-Liquid Aerosols on Tracheo-Alveolar Histopathology and the IL-6/TNF-α Molecular Signaling Axis
by Awal Prasetyo, Dora Maftikhati, Levina Athaya Anarizta, Nazhira Ghina Setyawan, Anindha Waradita Putri Yuwono, Maria Meutia Saleha, Farahdita Ramadhanti Annisa Mukti, Hermawan Istiadi, Udadi Sadhana and Fathur Nur Kholis
Curr. Issues Mol. Biol. 2026, 48(6), 618; https://doi.org/10.3390/cimb48060618 - 15 Jun 2026
Viewed by 253
Abstract
This study compared the temporal effects of traditional cigarettes and e-cigarettes on lung health in male Rattus norvegicus over 8- and 12-week periods. Thirty rats were evaluated for tracheal/alveolar histopathology and systemic markers (IL-6, TNF-α, SOD-3, MDA). Chronic cigarette exposure (12 weeks) and [...] Read more.
This study compared the temporal effects of traditional cigarettes and e-cigarettes on lung health in male Rattus norvegicus over 8- and 12-week periods. Thirty rats were evaluated for tracheal/alveolar histopathology and systemic markers (IL-6, TNF-α, SOD-3, MDA). Chronic cigarette exposure (12 weeks) and nicotine aerosol (8 weeks) significantly suppressed weight gain, while ascorbic acid aerosol caused less growth inhibition. At 8 weeks, cigarette exposure (K3) induced adaptive tracheal mucosal thickening (66.88 ± 17.92 µm vs. 52.40 ± 2.63 µm in control K1), increased goblet cells (4.2 ± 2.44 N/mm), elevated SOD-3 (12.75 ± 1.10 pg/mL), and initiated emphysematous alveolar expansion (469.77 ± 91.31 µm vs. 202.03 ± 29.38 µm in K1 in K1). Conversely, 12-week cigarette smoke (K4) triggered epithelial exhaustion, significantly thinning the tracheal mucosa (34.65 ± 6.55 µm) and elevating systemic IL-6 (11.45 ± 1.17 pg/mL vs. 8.43 ± 0.88 pg/mL in control K2). Notably, chronic electronic ascorbic acid aerosolization (K6) preserved localized alveolar structural layouts and limited septal thickening compared with nicotine groups. However, it failed to suppress systemic inflammation, as evidenced by elevated IL-6 levels. In conclusion, while ascorbic acid aerosols moderate localized parenchymal destruction compared to nicotine, chronic aerosol exposure accelerates systemic immune activation. Full article
(This article belongs to the Special Issue Advances in Phytochemical Research: Molecular Pathways in Health and Disease)
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13 pages, 5667 KB  
Article
Analysis of Chloroplast Genome Characteristics and Codon Usage Bias of Styphnolobium japonicum f. oligophyllum
by Zhi-Qiang Mu, Xiao Zhang, Jing-Jing Yan, Bao-Ping Chen and Hong-Wei Wang
Curr. Issues Mol. Biol. 2026, 48(6), 617; https://doi.org/10.3390/cimb48060617 - 15 Jun 2026
Viewed by 193
Abstract
To investigate the codon usage bias (CUB) and its influencing factors in the chloroplast genome of Styphnolobium japonicum f. oligophyllum, we sequenced, assembled and annotated the genome using Illumina high-throughput sequencing, and systematically analyzed 52 protein-coding sequences. The chloroplast genome is 158,739 [...] Read more.
To investigate the codon usage bias (CUB) and its influencing factors in the chloroplast genome of Styphnolobium japonicum f. oligophyllum, we sequenced, assembled and annotated the genome using Illumina high-throughput sequencing, and systematically analyzed 52 protein-coding sequences. The chloroplast genome is 158,739 bp with a typical quadripartite structure, containing 129 functional genes. It presents a mean GC3 content of 28.26% and a mean ENC value of 45.40, indicating weak CUB and low gene expression. Among 31 preferred codons (RSCU > 1), 29 (93.5%) end with A/U. Neutrality plot, ENC-plot and PR2-plot analyses reveal that natural selection is the primary regulator of CUB. A total of 19 optimal codons were identified. These results provide fundamental reference data that may facilitate future genetic engineering efforts in S. japonicum f. oligophyllum. Full article
(This article belongs to the Section Molecular Plant Sciences)
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38 pages, 1537 KB  
Review
Photoreceptor Vulnerability to Ferroptosis: Membrane Phospholipid Peroxidation, Mitochondrial Homeostasis, and RPE–Photoreceptor Coupling
by Yue Sun, Zhaorui Xu, Yanxia Wu, Mingxu Zhang and Xuejing Lu
Curr. Issues Mol. Biol. 2026, 48(6), 616; https://doi.org/10.3390/cimb48060616 - 15 Jun 2026
Viewed by 340
Abstract
Photoreceptor (PR) degeneration is a shared pathological feature of multiple blinding retinal diseases. This narrative review examines the mechanisms underlying PR vulnerability to ferroptosis-associated lipid-peroxidation injury, with emphasis on three interconnected features: the marked enrichment of docosahexaenoic acid (DHA) and other polyunsaturated fatty [...] Read more.
Photoreceptor (PR) degeneration is a shared pathological feature of multiple blinding retinal diseases. This narrative review examines the mechanisms underlying PR vulnerability to ferroptosis-associated lipid-peroxidation injury, with emphasis on three interconnected features: the marked enrichment of docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) in PR outer-segment disc membranes; the chronically high metabolic demand of PRs and the specialized spatial organization of their mitochondria; and retinal pigment epithelium (RPE)–PR metabolic coupling, including outer-segment renewal and phagocytic turnover, glucose transport and lactate shuttling, and visual-cycle–related all-trans-retinal (atRAL) clearance and bisretinoid accumulation. We also summarize antioxidant defense systems centered on the cystine/glutamate antiporter (xCT)–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis and mitochondrial GPX4 (mtGPX4), which restricts iron-dependent lipid peroxidation in PRs. We propose that highly oxidizable membrane phospholipid substrates, mitochondrial homeostatic imbalance, and impaired RPE–PR metabolic coupling may collectively shape PR susceptibility to ferroptosis-associated injury. From a therapeutic perspective, this framework supports multitarget strategies designed to interrupt lipid-peroxidation propagation, stabilize mitochondrial redox homeostasis and quality-control mechanisms, and restore RPE–PR metabolic support and local iron-buffering capacity. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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40 pages, 949 KB  
Review
Advancements in Immune Checkpoint-Based Immunotherapy for Triple-Negative Breast Cancer
by Dexian Wei, Yuan Zhang, Yanlin Wu, Liqun Ren and Qing He
Curr. Issues Mol. Biol. 2026, 48(6), 615; https://doi.org/10.3390/cimb48060615 - 12 Jun 2026
Viewed by 427
Abstract
Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular [...] Read more.
Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular targets, surgery combined with chemotherapy remains the mainstay of clinical treatment. In recent years, immunotherapy has provided new strategies for TNBC management. Immune checkpoints are key regulatory molecules that maintain immune homeostasis, and blocking these checkpoints can restore T cell activity and enhance tumor cell killing. Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit, particularly in combination with chemotherapy for patients with locally advanced or metastatic TNBC. This review focuses on immune checkpoint–based immunotherapy in TNBC, providing an overview from mechanistic insights to clinical applications and emerging therapeutic strategies. In addition to ICIs, we discuss alternative approaches, such as bispecific antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor T cell (CAR-T) therapy, tumor vaccines, and oncolytic viruses (OVs), highlighting their current research progress and clinical applications in TNBC treatment. Full article
(This article belongs to the Special Issue Tumor Immunotherapy: Mechanisms and Translation)
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16 pages, 7872 KB  
Article
Assembly and Comparative Analysis of the Complete Mitochondrial Genome of Corydalis ophiocarpa (Papaveraceae)
by Ming Lei, Cui Li, Jing Wang, Mei Qin, Li-Rong Huang, Xia-Lian Ou, Liang Kang, Han Liu and Zhan-Jiang Zhang
Curr. Issues Mol. Biol. 2026, 48(6), 614; https://doi.org/10.3390/cimb48060614 - 12 Jun 2026
Viewed by 262
Abstract
Corydalis ophiocarpa is a medicinally valuable plant, noted for its abundant alkaloid content. Despite its significance, the mitochondrial (mt) genome of this plant has not been characterized, which impedes both the phylogenetic understanding within the Corydalis genus and the comprehension of its full [...] Read more.
Corydalis ophiocarpa is a medicinally valuable plant, noted for its abundant alkaloid content. Despite its significance, the mitochondrial (mt) genome of this plant has not been characterized, which impedes both the phylogenetic understanding within the Corydalis genus and the comprehension of its full genetic potential. In this research, we successfully assembled the complete mitogenome of C. ophiocarpa by employing a hybrid method that integrates Oxford Nanopore long reads with Illumina short reads. The assembled genome forms a circular structure of 600,064 bp, with a GC content of 46.49%, and includes 63 genes, comprising 40 unique protein-coding genes (PCGs), 20 tRNAs, and three rRNAs. Through assembly and coverage analysis, we identified a 6383 bp forward repeat associated with a contig having approximately double the depth, indicating a repeat-mediated multipartite structure where the main circle may coexist with two smaller subgenomic forms. We discovered 775 C-to-U RNA editing sites across the 40 PCGs, with 95.4% being non-synonymous and favoring hydrophobic amino acid substitutions, particularly in Complex I subunits. Furthermore, we identified sixteen mt plastid DNA fragments constituting 2.43% of the mitogenome, a proportion more than double that found in the closely related C. saxicola. Phylogenetic analysis confirms that C. ophiocarpa is most closely related to C. saxicola, with C. pauciovulata as another close relative. This study presents the first complete mitogenome of C. ophiocarpa, providing a genomic basis for investigating the relationships between mt genome structure, post-transcriptional regulation, and specialized metabolism in the Corydalis genus. Full article
(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants, 4th Edition)
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