Current Issues in Molecular Biology

35 pages, 635 KB

Open AccessReview

Redox-Regulated Mitophagy and Lysosomal Dysfunction as a Convergent Mechanism in Female Infertility: Molecular Insights and Therapeutic Perspectives

by Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Athanasios Karpouzos, Ioannis Papapanagiotou, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Christina Trakateli, Nana Kojo Koranteng, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis

Curr. Issues Mol. Biol. 2026, 48(4), 429; https://doi.org/10.3390/cimb48040429 - 21 Apr 2026

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Abstract

Conventional hormonal and clinical models inadequately clarify the complex and diverse aspects of female infertility, resulting in poor reproductive outcomes and reduced egg viability. A growing body of research indicates that female reproductive failure is mostly due to disruptions in cellular homeostasis, especially [...] Read more.

Conventional hormonal and clinical models inadequately clarify the complex and diverse aspects of female infertility, resulting in poor reproductive outcomes and reduced egg viability. A growing body of research indicates that female reproductive failure is mostly due to disruptions in cellular homeostasis, especially concerning organelle quality control. Oxidative stress has emerged as a crucial mediator connecting metabolic, inflammatory, and ageing-related processes to ovarian failure, however its downstream impacts on intracellular organelle turnover remain insufficiently clarified. Our narrative review encapsulates the existing data for a unified pathogenic concept focused on the redox-regulated mitochondria–lysosome axis. We examine the interaction of oxidative stress, mitochondrial malfunction, compromised mitophagy, and lysosomal deficiency in granulosa cells and oocytes. Prolonged oxidative stress may disrupt this equilibrium, leading to defective mitochondria accumulation and impaired mitophagy. This self-perpetuating cycle may ultimately jeopardises reproductive viability and oocyte integrity. The integrated axis offers a shared molecular foundation for various infertility-related diseases, such as inadequate ovarian response, obesity-associated infertility, polycystic ovary syndrome, and ovarian ageing. Ultimately, we analyse new findings suggesting that specific antioxidant chemicals modify mitophagy and lysosomal function while also neutralising reactive oxygen species, highlighting their potential use in precision fertility treatments. Our research redefines female infertility as a condition of redox-dependent organelle quality control, thereby introducing novel avenues for identifying biomarkers, categorising patients, and targeting treatments in assisted reproduction. Full article

(This article belongs to the Special Issue Molecular Research on Free Radicals and Oxidative Stress—2nd Edition)

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23 pages, 2364 KB

Open AccessArticle

The Influence of TDP1 Inhibitor Usnic Acid Derivative OL9-116 on the Effects of Topotecan in Human Cells

by Tatyana E. Kornienko, Arina A. Chepanova, Maria V. Kolobenko, Irina A. Chernyshova, Alexandra L. Zakharenko, Artur S. Venzel, Nadezhda S. Dyrkheeva, Andrey V. Markov, Rashid O. Anarbaev, Konstantin N. Naumenko, Olga A. Luzina, Nariman F. Salakhutdinov, Vladimir A. Ivanisenko and Olga I. Lavrik

Curr. Issues Mol. Biol. 2026, 48(4), 428; https://doi.org/10.3390/cimb48040428 - 21 Apr 2026

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Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoi-somerase 1 (TOP1)-DNA complexes. We have previously developed a TDP1 inhibitor, compound OL9-116, which is capable of enhancing the action of the anticancer drug topotecan (TPC), a TOP1 poison, in [...] Read more.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoi-somerase 1 (TOP1)-DNA complexes. We have previously developed a TDP1 inhibitor, compound OL9-116, which is capable of enhancing the action of the anticancer drug topotecan (TPC), a TOP1 poison, in vitro and in vivo. In this study, the inhibition mode of OL9-116 (uncompetitive) was investigated. We have shown that N-terminal domain of TDP1, which is important for the cell function of TDP1 but is not involved in catalysis directly, reduced the inhibitory potency of OL9-116 probably by influencing the conformation of the enzyme. OL9-116 did not reduce cell viability and did not affect mitochondrial membrane potential. OL9-116 enhanced the cytotoxic/antiproliferative effect of TPC on the panel of tumor cells. This effect was not observed on nontumor cells or TDP1-deficient cells. OL9-116 and TPC had different effects on TDP1 and TOP1 gene expression detected by PCR depending on the cell type and the presence of functional TDP1. The direct relation between the effects of the compounds on the gene expression and cell survival was not found. The obtained data indicated a synergistic effect of OL9-116 and TPC, which appeared to be mediated by TDP1 inhibition rather than by an effect on TDP1 gene expression. Full article

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

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15 pages, 1502 KB

Open AccessArticle

Association of Serum ELMO-3 Levels with Metastatic Status and Survival Outcomes in Non-Small Cell Lung Cancer

by Hilal Oğuz Soydinç, Murat Serilmez, Ceren Tilgen Yasasever, Elif Bilgin Doğru, Uğur Gezer, Şule Karaman, Nergiz Dağoğlu Sakin and Derya Duranyıldız

Curr. Issues Mol. Biol. 2026, 48(4), 427; https://doi.org/10.3390/cimb48040427 - 21 Apr 2026

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Abstract

Non-small cell lung cancer remains one of the leading causes of cancer-related mortality worldwide, and identifying molecular markers associated with tumor progression and metastasis is important for improving patient management. This study investigated serum ELMO-3 levels in patients with NSCLC and evaluated their [...] Read more.

Non-small cell lung cancer remains one of the leading causes of cancer-related mortality worldwide, and identifying molecular markers associated with tumor progression and metastasis is important for improving patient management. This study investigated serum ELMO-3 levels in patients with NSCLC and evaluated their relationship with clinicopathological characteristics. Serum samples from 50 NSCLC patients and 20 healthy controls were analyzed. ELMO-3 concentrations were measured using an enzyme-linked immunosorbent assay. Statistical analyses included non-parametric group comparisons, receiver operating characteristic curve analysis, Kaplan–Meier survival analysis, and multivariate Cox proportional hazards regression. The mean ELMO-3 level was 0.409 ± 0.543, which was used as the cutoff value to categorize patients into low- and high-ELMO-3 groups; 76% of patients were classified as low-ELMO-3 and 24% as high-ELMO-3. The results showed that serum ELMO-3 levels did not differ significantly between NSCLC patients and healthy controls and were not associated with metastatic status. However, a significant association was observed between ELMO-3 expression status and tumor histopathology. Survival analysis demonstrated that distant metastasis and radiotherapy were significantly associated with overall survival. In multivariate analysis, age, operability, distant metastasis, and serum ELMO-3 levels were identified as independent factors associated with survival. These findings suggest that circulating ELMO-3 may have potential prognostic relevance; however, the results should be interpreted with caution and require validation in larger, independent cohorts. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers, 3rd Edition)

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27 pages, 1575 KB

Open AccessReview

Microglial Innate Immune Memory: Implications and Research Advances in Central Nervous System Disorders

by Yaru Song, Shiyi Shu, Xiansi Zeng, Manli Xia, Junru Liu and Li Li

Curr. Issues Mol. Biol. 2026, 48(4), 426; https://doi.org/10.3390/cimb48040426 - 21 Apr 2026

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Abstract

The central nervous system (CNS), comprising the brain and spinal cord, represents the core regulatory hub of the body. Damage to the CNS often leads to irreversible structural and functional impairments of neural tissues, posing a major global public health challenge. Immune memory [...] Read more.

The central nervous system (CNS), comprising the brain and spinal cord, represents the core regulatory hub of the body. Damage to the CNS often leads to irreversible structural and functional impairments of neural tissues, posing a major global public health challenge. Immune memory encompasses two states: immune training and immune tolerance, which are characterized by enhanced or attenuated immune responses, respectively, following initial exposure to external stimuli in immune cells such as monocytes and macrophages. Microglia, the resident immune cells of the CNS, can be rapidly activated by external stimuli. Accumulating evidence indicates that microglial immune memory plays a critical role in sustaining states and neuroinflammatory responses in CNS disorders. Specifically, the immune training state promotes amyloid-β (Aβ) accumulation in the brains of Alzheimer’s disease (AD) model mice, thereby exacerbating neuronal damage, whereas the immune tolerance state suppresses pro-inflammatory cytokine expression and alleviates neuroinflammation. This review focuses on two immune memory states in microglia—training and tolerance—and what triggers them. We summarize their roles and mechanisms in CNS diseases. Specifically, we break down how epigenetic and metabolic reprogramming control microglial immune memory, with an emphasis on how these two processes interact during memory formation and maintenance. Our goal is to fill key knowledge gaps about their combined effects and to suggest new therapeutic targets. Evidence shows that immune memory acts as a “double-edged sword” in the CNS: it can either fuel harmful inflammation and worsen damage, or, when moderately activated, protect nerves. Therefore, precisely balancing these two states could help reduce harmful inflammation while preserving the protective functions of microglia, offering a new, reversible immunotherapy for CNS diseases. Full article

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

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24 pages, 1500 KB

Open AccessReview

Epigenetic and Transcriptomic Pathways Underlying Animal Models of Cognitive and Psychiatric Disorders: A Scoping Review

by Jaishriram Rathored, Ajay Pal and Deepika Sai Painkra

Curr. Issues Mol. Biol. 2026, 48(4), 425; https://doi.org/10.3390/cimb48040425 - 21 Apr 2026

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Abstract

Background: Cognitive and psychiatric disorders are caused by a complex interplay between genetic predisposition, environmental exposures, and dynamic molecular regulation in the brain. Animal models provide a controlled environment for examining these mechanisms, and advances in transcriptome and epigenomic technologies have greatly expanded [...] Read more.

Background: Cognitive and psychiatric disorders are caused by a complex interplay between genetic predisposition, environmental exposures, and dynamic molecular regulation in the brain. Animal models provide a controlled environment for examining these mechanisms, and advances in transcriptome and epigenomic technologies have greatly expanded our knowledge of disease-relevant pathways. Objective: This scoping review systematically maps and synthesizes the epigenetic and transcriptomic findings from the established animal models of four neuropsychiatric conditions—autism spectrum disorder (ASD), schizophrenia, depression, and Rett syndrome—drawing on a PRISMA-ScR-guided literature search. The review characterizes the breadth of evidence, identifies convergent and divergent molecular pathways, and highlights the translational gaps and therapeutic implications. Methods: Research employing chromatin accessibility testing, genome-wide DNA methylation mapping, single-cell and bulk RNA sequencing, histone modification profiling, and multi-omics integration in mouse and other validated animal models was thoroughly reviewed. A quality appraisal of the primary experimental studies (n = 63) was performed using a modified CAMARADES checklist. Results: Beyond generalized cellular stress responses, multi-omics analysis emphasizes the cell-type- and context-dependent nature of epigenetic changes in animal models, including isoform-specific histone modifications and model-dependent binding of HDAC/MeCP2 complexes to genes involved in synaptic plasticity. Single-cell RNA sequencing analyses have uniformly shown transcriptional changes in parvalbumin-positive (PV+) interneurons. Conclusions: The specific convergence of epigenetic disruptions in neural circuits involved in synaptic structure and inhibitory function could play a role in the generation of neuropsychiatric phenotypes in animal models, highlighting the importance of circuit- and cell-type-specific epigenetics while pointing to potential therapeutic avenues. Full article

(This article belongs to the Special Issue Molecular Neuropsychiatry: Target Discovery for Mental Disorders)

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28 pages, 7721 KB

Open AccessArticle

Coptis chinensis Franch. Suppresses Invasive Pulmonary Aspergillosis by Augmenting NADPH-Dependent Neutrophil Extracellular Traps via Dual Modulation of Complement Activation and Gut Microbiota

by Zhuqiao Jiang, Lingmei Zhou, Jinping Wang, Hao Sun, Liwen Cai, Hanqi Yin, Hui Zhu, Ming Li and Zhuoya Wang

Curr. Issues Mol. Biol. 2026, 48(4), 424; https://doi.org/10.3390/cimb48040424 - 20 Apr 2026

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Abstract

Invasive pulmonary aspergillosis (IPA) poses a serious threat to immunocompromised hosts, with limited therapeutic options highlighting the need for novel strategies. Coptis chinensis Franch. (CCF), a traditional Chinese herb containing antimicrobial alkaloids like berberine, was investigated for its therapeutic efficacy and immunological effects [...] Read more.

Invasive pulmonary aspergillosis (IPA) poses a serious threat to immunocompromised hosts, with limited therapeutic options highlighting the need for novel strategies. Coptis chinensis Franch. (CCF), a traditional Chinese herb containing antimicrobial alkaloids like berberine, was investigated for its therapeutic efficacy and immunological effects in a murine IPA model. Immunosuppressed female KM mice infected with Aspergillus fumigatus AF293 were treated with CCF or amphotericin B (AmB). CCF significantly improved survival, reduced fungal burden, and alleviated lung pathology, without inducing hepatotoxicity or nephrotoxicity. Transcriptomic profiling revealed a time-dependent immune response. Complement-related pathways were enriched at 2 days post-infection, whereas neutrophil recruitment and NET-related pathways became more prominent by day 4. Hub gene analysis identified Syk, Rac2, Ncf1, and Cybb as key nodes associated with the NADPH oxidase complex. Western blot and inhibitor experiments further supported the involvement of this pathway in CCF-mediated protection. Additionally, 16S rDNA sequencing indicated enrichment of Clostridium species in the gut microbiota of CCF-treated mice, which was positively correlated with the expression of NADPH oxidase-related genes, suggesting a potential gut–lung association. In conclusion, these findings support the antifungal efficacy of CCF in IPA and suggest that its protective effects may involve coordinated changes in complement-related responses, NADPH oxidase-associated neutrophil activity, and gut microbiota composition. Full article

(This article belongs to the Special Issue Natural Product Drug Activity and Biomedicine Application)

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24 pages, 3486 KB

Open AccessArticle

Mining and Analysis of Salt Tolerance Genes in Maize at the Seedling Stage

by Zhenping Ren, Zelong Zhuang, Jianwen Bian, Wanling Ta, Xiaojia Hao, Lei Zhang and Yunling Peng

Curr. Issues Mol. Biol. 2026, 48(4), 423; https://doi.org/10.3390/cimb48040423 - 20 Apr 2026

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Abstract

Salt stress represents a significant abiotic stress factor that adversely affects plant growth and development. It directly inhibits both vegetative and reproductive growth, resulting in substantial reductions in crop yield and quality. Consequently, the identification of salt tolerance genes and the elucidation of [...] Read more.

Salt stress represents a significant abiotic stress factor that adversely affects plant growth and development. It directly inhibits both vegetative and reproductive growth, resulting in substantial reductions in crop yield and quality. Consequently, the identification of salt tolerance genes and the elucidation of their underlying molecular mechanisms are crucial for improving crop salt tolerance and ensuring agricultural productivity. To investigate the molecular basis underlying differential salt tolerance between Zheng58 and PH4CV, we employed pooled sequencing (BSA-seq) using extreme phenotypic individuals from their F₂ population and conducted a comparative transcriptome analysis at the seedling stage of the two genotypes. Phenotypic, physiological, biochemical, and ion content analyses revealed that Zheng58 exhibited significantly superior performance compared to PH4CV under salt stress conditions. BSA-seq analysis identified six genomic regions associated with salt tolerance, encompassing a total of 391 genes. Functional annotation enabled the screening of 151 candidate genes potentially involved in salt stress responses. Transcriptome profiling indicated that differentially expressed genes were significantly enriched in biological processes, particularly plant hormone signal transduction and MAPK signaling pathways. Integrating BSA-seq and transcriptome data, key candidate gene ZmACC2 (Zm00001eb419400) was identified as potentially involved in the regulation of salt tolerance in maize. This gene may modulate Na⁺/K⁺/Ca²⁺ homeostasis and reactive oxygen species metabolism through defense responses mediated by ethylene (ETH) and hydrogen peroxide, as well as through ion homeostasis regulatory pathways. This study provides valuable candidate genes and a theoretical foundation for further dissection of the molecular mechanisms governing salt tolerance in maize. Full article

(This article belongs to the Special Issue Plant Hormones, Development, and Stress Tolerance)

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21 pages, 777 KB

Open AccessReview

Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

by Lina Zhu, Yang Li and Yiyao Bao

Curr. Issues Mol. Biol. 2026, 48(4), 422; https://doi.org/10.3390/cimb48040422 - 19 Apr 2026

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Abstract

Bartter syndrome (BS) represents a group of rare, autosomal recessive renal tubular disorders characterized by hypokalemic hypochloremic metabolic alkalosis, secondary hyperaldosteronism, and normal to low blood pressure. The underlying pathophysiology is primarily driven by defects in critical ion transport proteins or channels localized [...] Read more.

Bartter syndrome (BS) represents a group of rare, autosomal recessive renal tubular disorders characterized by hypokalemic hypochloremic metabolic alkalosis, secondary hyperaldosteronism, and normal to low blood pressure. The underlying pathophysiology is primarily driven by defects in critical ion transport proteins or channels localized within the thick ascending limb of the loop of Henle, leading to impaired salt reabsorption. Recent advances in molecular genetics have refined the classification of Bartter syndrome. Current evidence supports SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 as the core disease genes within the contemporary BS spectrum, with MAGED2 causing a distinct X-linked transient antenatal form. In contrast, gain-of-function CASR variants, historically labeled “type V Bartter syndrome”, are now more appropriately described as CaSR-associated Bartter-like phenotypes within the broader spectrum of disorders of calcium homeostasis. Despite significant progress, two primary research limitations remain. First, fully elucidating genotype–phenotype correlations and overcoming diagnostic complexities continues to be highly challenging due to substantial phenotypic overlap and genetic heterogeneity. Compounding these diagnostic hurdles is the equally critical challenge of understanding mutation-driven pathogenic mechanisms to develop viable clinical interventions. This review systematically summarizes the current molecular genetic landscape of BS to address these gaps. We highlight the relationships between specific genetic variants and clinical manifestations, delve into molecular pathophysiology including protein misfolding and trafficking defects, and explore emerging therapeutic approaches such as molecular chaperones. By integrating genetic and clinical data, this work aims to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome. Full article

(This article belongs to the Special Issue Molecular Biology in Drug Design and Precision Therapy, 2nd Edition)

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22 pages, 584 KB

Open AccessEditor’s ChoiceReview

Management of Pregnancy in Women with Inflammatory Bowel Disease: Positioning Janus Kinase Inhibitors Within Current Evidence

by Dario Colacurci, Raffaele Pellegrino, Alessia Lamart, Davide Staiano, Ilaria De Costanzo, Michele Izzo, Giuseppe Imperio, Fabio Landa, Giulia Scamardella, Enrica Di Lella, Alessandro Federico, Laura Sarno and Antonietta Gerarda Gravina

Curr. Issues Mol. Biol. 2026, 48(4), 421; https://doi.org/10.3390/cimb48040421 - 19 Apr 2026

Viewed by 379

Abstract

Inflammatory bowel diseases (IBD) frequently affect women of reproductive age. Disease activity may arise during pregnancy, at times in severe forms, thereby generating complex clinical scenarios. Adequate control of disease activity throughout pregnancy and the achievement of a safe delivery with a healthy [...] Read more.

Inflammatory bowel diseases (IBD) frequently affect women of reproductive age. Disease activity may arise during pregnancy, at times in severe forms, thereby generating complex clinical scenarios. Adequate control of disease activity throughout pregnancy and the achievement of a safe delivery with a healthy newborn, therefore, represent vital objectives in therapeutic management. In recent years, the therapeutic armamentarium for moderate to severe IBD has expanded exponentially, with the introduction of biological agents and small molecules. However, although these therapies have largely superseded conventional treatment in complex settings, they do not share the same safety profile in pregnancy. Concerns persist regarding potential transplacental transfer and possible teratogenic effects, which justify mandatory caution in their use during pregnancy. Nonetheless, clinicians may readily encounter scenarios of active IBD during pregnancy in patients who have previously experienced failure of the biological agents most extensively studied in this context, thus necessitating an evaluation of the safety of more novel therapeutic options. This review examines the available evidence on Janus kinase inhibitors. Current data, which are highly heterogeneous and of low quality, preclude any recommendation for the use of these small molecules during pregnancy. Prospective registries and large-scale observational studies are mandatory, pending the feasibility of dedicated trials, to better characterise these inhibitors, which could prove valuable, should the evidence ultimately support their use, in women with biologic multi-failure active IBD during pregnancy. Full article

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14 pages, 1370 KB

Open AccessArticle

Genome-Wide Association Study Suggests rrp44 Is a Key Regulator of Growth Traits in Channel Catfish (Ictalurus punctatus)

by Shiyong Zhang, Hongyan Liu, Yongqiang Duan, Minghua Wang and Xiaohui Chen

Curr. Issues Mol. Biol. 2026, 48(4), 420; https://doi.org/10.3390/cimb48040420 - 18 Apr 2026

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Abstract

Understanding the genetic architecture underlying growth variation is central to improving aquaculture species through genomic selection. Here, we performed a genome-wide association study (GWAS) on 303 individuals from a G₂ breeding population of channel catfish (Ictalurus punctatus) using whole-genome resequencing [...] Read more.

Understanding the genetic architecture underlying growth variation is central to improving aquaculture species through genomic selection. Here, we performed a genome-wide association study (GWAS) on 303 individuals from a G₂ breeding population of channel catfish (Ictalurus punctatus) using whole-genome resequencing data. After stringent quality control, 5.64 million high-confidence single nucleotide polymorphisms (SNPs) were retained for association analyses of two key growth traits—monthly weight gain (MWG) and body depth (BH). We identified 15 and 28 loci significantly associated with MWG and BH, respectively, with the majority concentrated on chromosome 20. Two SNPs (Chr20:14,657,971 and Chr20:14,658,012) located in exon 9 of the rrp44 gene were significantly associated with both traits. Functional annotation and enrichment analyses revealed that the rrp44 gene, encoding an exoribonuclease subunit of the RNA exosome complex, participates in mitotic spindle regulation and post-transcriptional RNA decay, processes critical for cellular growth and metabolic homeostasis. We propose that rrp44 may influence growth through the modulation of feeding rhythm and circadian regulation, providing a potential molecular basis for growth heterogeneity in channel catfish. These findings enrich our understanding of growth-related genomic variation and offer valuable molecular markers for precision breeding and genetic improvement of catfish. Full article

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

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16 pages, 268 KB

Open AccessReview

Challenges and Limitations in Molecular Testing of Resected Non-Small Cell Lung Cancer Specimens

by Nikolaos Korodimos, Ioannis Tomos, Periklis Foukas, Konstantinos Kontzoglou, Anna Koumarianou, Ilias Santaitidis, Konstantinos Kostopanagiotou, Sofoklis Mitsos, Anastasios Moisiadis and Periklis Tomos

Curr. Issues Mol. Biol. 2026, 48(4), 419; https://doi.org/10.3390/cimb48040419 - 18 Apr 2026

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Abstract

Non-small cell lung cancer (NSCLC) accounts for nearly 85% of lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Advances in molecular diagnostics and targeted therapies have transformed treatment paradigms, yet the integration of molecular testing into routine care for [...] Read more.

Non-small cell lung cancer (NSCLC) accounts for nearly 85% of lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Advances in molecular diagnostics and targeted therapies have transformed treatment paradigms, yet the integration of molecular testing into routine care for resected NSCLC specimens continues to face significant challenges. This review outlines the technical, clinical, and systemic barriers that limit the effectiveness of molecular testing. Key considerations include tissue quality, the limitations of formalin-fixed paraffin-embedded (FFPE) samples, and the comparative roles of conventional methods—such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR)—versus next-generation sequencing (NGS). We also discuss the prevalence and clinical relevance of common genomic alterations, including TP53, KRAS, EGFR, and ALK, as well as their impact on prognosis and treatment selection. Real-world obstacles such as accessibility, reimbursement, delays in testing, interdisciplinary coordination, and sample adequacy are critically examined. Emerging innovations—including multi-omics integration, spatial profiling, liquid biopsy, artificial intelligence, and novel targeted therapies—offer opportunities to overcome current limitations and improve patient outcomes. Finally, practical recommendations are proposed to optimize tissue handling, testing algorithms, and access to precision-guided therapies. By addressing these challenges, molecular testing in NSCLC can be more effectively leveraged to personalize treatment strategies and enhance survival outcomes. Full article

(This article belongs to the Special Issue Molecular Biology of Lung Cancer: Pathogenesis and New Therapeutic Strategies)

21 pages, 9644 KB

Open AccessArticle

Brain-Derived Cystathionine β-Synthase-Generated H₂S Attenuates Cerebral Ischemia–Reperfusion Injury via VEGFR₂-Mediated Angiogenesis in MCAO/R Rats

by Shuai Liang, La Jiang, Yu Jiang, Shan Wang, Jia-Rong Jiang, Ji-Yue Wen, Zhi-Wu Chen and Shuo Chen

Curr. Issues Mol. Biol. 2026, 48(4), 418; https://doi.org/10.3390/cimb48040418 - 18 Apr 2026

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Abstract

Ischemic stroke (IS) remains a major cause of global disability and mortality. While exogenous H₂S has demonstrated neuroprotective potential, the role of endogenous H₂S generated by cystathionine β-synthase (CBS) in cerebral ischemia–reperfusion injury (CIRI) remains incompletely elucidated. L-Cysteine (L-Cys), [...] Read more.

Ischemic stroke (IS) remains a major cause of global disability and mortality. While exogenous H₂S has demonstrated neuroprotective potential, the role of endogenous H₂S generated by cystathionine β-synthase (CBS) in cerebral ischemia–reperfusion injury (CIRI) remains incompletely elucidated. L-Cysteine (L-Cys), as a substrate for CBS, serves as a key precursor for endogenous H₂S. Using the established pre-clinical model of CIRI—middle cerebral artery occlusion/reperfusion (MCAO/R) in rats—we investigated the neuroprotective effects of brain-derived CBS-generated H₂S through neurological function scoring, 2,3,5-triphenylchlorotetrazole (TTC) staining, enzyme-linked immunosorbent assay (ELISA), and histopathological examination. Immunofluorescence, Western blot, and laser speckle contrast imaging were utilized to analyze the protein expression of ZO-1, claudin-5, CBS, vascular endothelial growth factor receptor-2 (VEGFR₂) and CD31, as well as cerebral blood flux changes. L-Cys treatment ameliorated neurological deficits, reduced cerebral infarct volume, decreased serum lactate dehydrogenase (LDH) and neuron-specific enolase (NSE) levels, attenuated histopathological damage, alleviated cerebral edema, and restored blood–brain barrier integrity via upregulation of tight junction proteins ZO-1 and claudin-5. Additionally, L-Cys improved MCAO/R-induced cognitive impairment and behavioral deficits. Furthermore, L-Cys upregulated CBS and VEGFR₂ expression, enhanced endogenous H₂S production, promoted post-ischemic cerebral angiogenesis, and improved cerebral blood flux recovery. CBS-derived H₂S promoted post-ischemic angiogenesis mediated by VEGFR₂, enhances cerebral reperfusion flux, and consequently ameliorated MCAO/R-induced CIRI in rats, providing experimental evidence for clinical translation. Full article

(This article belongs to the Section Molecular Pharmacology)

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34 pages, 1600 KB

Open AccessReview

Psychedelics and Autism Therapy: A Review of Current Research and Future Directions

by Christopher S. Gondi, Manu Gnanamony, Tarun P. Gondi, Lilyt Nersesyan and Lusine Demirkhanyan

Curr. Issues Mol. Biol. 2026, 48(4), 417; https://doi.org/10.3390/cimb48040417 - 18 Apr 2026

Viewed by 4529

Abstract

Autism Spectrum Disorder (ASD) is a lifelong condition marked by challenges in social communication and repetitive behaviors. Current treatments, primarily behavioral therapies, often fail to address the core symptoms. Recent research has explored the potential of psychedelics, such as LSD, psilocybin, and MDMA, [...] Read more.

Autism Spectrum Disorder (ASD) is a lifelong condition marked by challenges in social communication and repetitive behaviors. Current treatments, primarily behavioral therapies, often fail to address the core symptoms. Recent research has explored the potential of psychedelics, such as LSD, psilocybin, and MDMA, as a new therapeutic approach. While these substances primarily modulate the serotonin 5-HT_2A receptor, their therapeutic effects also involve interactions with other serotonergic, dopaminergic, and glutamatergic pathways, collectively promoting neuroplasticity—the brain’s ability to change and adapt. The specific receptors’ activation leads to structural and functional changes in the brain that can enhance social behavior and emotional regulation. Studies show that psychedelics may reduce symptoms of conditions like treatment-resistant depression and PTSD, highlighting their therapeutic potential. For ASD specifically, psychedelics may improve psychological flexibility, reduce distress, and enhance social interaction. While promising, the use of these substances requires careful consideration. Psychedelics can induce intense experiences and altered states of consciousness, necessitating strict monitoring and support during therapy. Ethical guidelines, including informed consent, are crucial, especially for vulnerable populations. In conclusion, psychedelics hold significant promise for treating ASD and other psychiatric disorders by promoting neuroplasticity and modulating complex signaling pathways. Continued research and clinical trials, conducted with strong ethical oversight, are essential to realizing their full therapeutic potential. Full article

(This article belongs to the Section Molecular Medicine)

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20 pages, 65875 KB

Open AccessArticle

Identification of Key Genes Regulated by Lactylation Modification and Associated with Tumor Immune Microenvironment in Breast Cancer

by Yaohong Xie, Yi Ge, Na Miao, Pengxia Zhang and Jiaqi Xia

Curr. Issues Mol. Biol. 2026, 48(4), 416; https://doi.org/10.3390/cimb48040416 - 17 Apr 2026

Viewed by 308

Abstract

Breast cancer (BRCA) is the most common cancer worldwide, with an incidence exceeding that of lung cancer. Protein lactylation, a newly identified post-translational modification involving the binding of lactic acid to lysine residues, plays an important role in BRCA. However, its role in [...] Read more.

Breast cancer (BRCA) is the most common cancer worldwide, with an incidence exceeding that of lung cancer. Protein lactylation, a newly identified post-translational modification involving the binding of lactic acid to lysine residues, plays an important role in BRCA. However, its role in BRCA progression remains largely unexplored. This study aims to identify and characterize the lactylation-related genes involved in BRCA biology. Transcriptomic and clinical data of BRCA and normal breast tissues were obtained from TCGA and GEO. Lactylation-related genes were curated from literature and intersected with BRCA datasets to identify candidates. A prognostic risk model was constructed using LASSO and Cox regression. Functional enrichment was performed using KEGG, GSVA, and GSEA. Immune correlations were evaluated by ESTIMATE, CIBERSORT. Single-cell RNA-seq data were integrated to assess gene expression heterogeneity across tumor and immune compartments. In vitro, MDA-MB-231 cells were treated with sodium L-lactate and lactylation-inducing agents, and gene expression was validated by Western blot and RT-qPCR, while EdU and wound healing assays evaluated proliferation and migration. We identified six hub genes associated with the immune microenvironment. Notably, S100A4 is significantly underexpressed, suggesting their potential regulatory roles in BRCA. Further analysis demonstrated that lactylation-related genes are closely linked to immune regulation in BRCA, indicating a possible crosstalk between metabolic modification and tumor immunity. Additionally, we found that lactylation significantly influences gene expression patterns and immune infiltration in BRCA. Importantly, lactic acid ions were shown to upregulate lactylation levels in BRCA cells, underscoring the functional impact of metabolic signals on post-translational modifications in tumorigenesis. Our findings indicate a potential mechanism wherein lactylation affects BRCA progression via lactic acid-driven regulation of the immune microenvironment; they also highlight the possible involvement of S100A4 in this process and offer new insights that could contribute to the diagnosis and treatment of BRCA. Full article

(This article belongs to the Section Molecular Medicine)

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11 pages, 1844 KB

Open AccessArticle

Rapid and Efficient Creation of Sweet–Waxy Maize Germplasm via CRISPR/Cas9-Mediated Gene Editing of Sh2 and Wx

by Xiaolan Yan, Junnan Li, Huijian Liu, Wenfei Jia, Guojun Gao, Yongtian Qin, Longxiang Guan, Xiaxia Duan, Jialu Xu, Pingliang Zhou, Yucai Guo, Xuguang Li, Ling Yang, Hongyu Chen, Weihua Li, Pengshuai Yan, Qingqian Zhou, Zhiyuan Fu, Jihua Tang and Hongqiu Wang

Curr. Issues Mol. Biol. 2026, 48(4), 415; https://doi.org/10.3390/cimb48040415 - 17 Apr 2026

Viewed by 370

Abstract

Sweet–waxy maize is a highly valuable specialty maize type with an increasing market demand, but conventional breeding methods for producing sweet–waxy maize are restricted by severe bottlenecks, such as long breeding cycles and linkage drag. This study was conducted to rapidly create sweet–waxy [...] Read more.

Sweet–waxy maize is a highly valuable specialty maize type with an increasing market demand, but conventional breeding methods for producing sweet–waxy maize are restricted by severe bottlenecks, such as long breeding cycles and linkage drag. This study was conducted to rapidly create sweet–waxy maize germplasm using CRISPR/Cas9 genome-editing technology. We used a CRISPR/Cas9 system to target maize Sh2 (regulating the super-sweet kernel trait) and Wx (controlling the waxy kernel trait), which are two key genes in the starch biosynthesis pathway. Two small-guide RNAs (sgRNAs) designed for each gene were incorporated into CRISPR/Cas9 vectors, which were then introduced into maize via Agrobacterium-mediated transformation. We obtained Cas9-free T₃ homozygous sh2 and wx mutant lines with significant increases in kernel soluble sugar and amylopectin contents, respectively, but no adverse changes to major agronomic traits. Using these Cas9-free lines, we developed a new type of sweet–waxy maize germplasm, in which waxy and sweet kernels on the same ear segregated at a 3:1 ratio. Our results indicate that CRISPR/Cas9-mediated editing of Sh2 and Wx can efficiently generate sweet–waxy maize germplasm with no detectable linkage drag. The study methods would be useful for optimizing the molecular breeding of novel and innovative maize germplasm. Full article

(This article belongs to the Special Issue Advances in Molecular Plant Physiology and Genomic Breeding of Cereals)

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35 pages, 2719 KB

Open AccessReview

Long Non-Coding RNAs in Human Disease: An Overview of Biogenesis, Molecular Mechanism and Therapeutic Opportunities

by Arvind Kumar Dubey, Anil Kumar, Zhadyrassyn Nurbekova and Navin Kumar

Curr. Issues Mol. Biol. 2026, 48(4), 414; https://doi.org/10.3390/cimb48040414 - 17 Apr 2026

Viewed by 399

Abstract

LncRNAs, defined as transcripts longer than 200 nucleotides with limited protein-coding potential, have emerged as important regulators of gene expression across multiple levels of cellular regulation. These molecules influence chromatin organization, transcriptional activity, and post-transcriptional processes through diverse interactions with DNA, RNA, and [...] Read more.

LncRNAs, defined as transcripts longer than 200 nucleotides with limited protein-coding potential, have emerged as important regulators of gene expression across multiple levels of cellular regulation. These molecules influence chromatin organization, transcriptional activity, and post-transcriptional processes through diverse interactions with DNA, RNA, and protein complexes. Although initially considered transcriptional byproducts, accumulating evidence now indicates that lncRNAs participate in a wide range of physiological processes and are implicated in numerous human diseases, including cancer, cardiovascular disorders, neurological diseases, and immune related conditions. However, the strength of mechanistic evidence varies substantially across the field, with robust functional validation currently limited to a relatively small number of well-characterized lncRNAs. In many cases, proposed regulatory roles remain supported primarily by expression correlations or limited perturbation studies, highlighting the need for careful evaluation of reproducibility, context dependence, and locus-specific effects. In addition, translating lncRNA discoveries into therapeutic strategies faces several practical challenges, including efficient tissue-specific delivery, subcellular localization constraints, isoform complexity, and potential off-target effects. This review provides an overview of current knowledge on lncRNA classification, biogenesis, and molecular mechanisms, evaluates their roles in human disease, and discusses emerging therapeutic approaches in the context of translational feasibility. By integrating mechanistic insights with current limitations and unresolved questions, we highlight priorities for future research aimed at harnessing lncRNAs for diagnostic and therapeutic applications in precision medicine. Full article

(This article belongs to the Special Issue Molecular Functions of Long Non-Coding RNAs: Implications for Diseases and Therapy)

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17 pages, 5435 KB

Open AccessEditor’s ChoiceArticle

Curcumin Attenuates LPS-Induced Migration/EMT and LPS/ATP-Associated IL-1β Release in Androgen-Independent Prostate Cancer Cells

by Mon-Der Cho, Shang-Yu Chou, Yu-Ming Hsu, Chi-Ying Li, Yi-Hong Tsai and Fang-Rong Chang

Curr. Issues Mol. Biol. 2026, 48(4), 413; https://doi.org/10.3390/cimb48040413 - 17 Apr 2026

Viewed by 279

Abstract

Inflammation can promote aggressive phenotypes in prostate cancer, including enhanced migration/EMT-like changes and inflammasome-associated cytokine release. Here, we examined whether curcumin modulates these inflammation-driven responses in androgen-independent prostate cancer cells. PC-3 and DU145 cells were treated with curcumin (10 or 25 μM) or [...] Read more.

Inflammation can promote aggressive phenotypes in prostate cancer, including enhanced migration/EMT-like changes and inflammasome-associated cytokine release. Here, we examined whether curcumin modulates these inflammation-driven responses in androgen-independent prostate cancer cells. PC-3 and DU145 cells were treated with curcumin (10 or 25 μM) or N-acetylcysteine (NAC; 2 mM). Sub-cytotoxic dosing was defined by CCK-8 viability assays. LPS (0.5 μg/mL) was used to induce motility-, invasion-, and EMT-associated responses, assessed by wound-healing assay, Matrigel-coated Transwell invasion assay, and RT–qPCR of SNAI1, CDH1, and VIM. Intracellular ROS was quantified by CM-H₂DCFDA flow cytometry. Inflammasome-associated and EMT-related protein changes were evaluated under LPS priming (24 h) followed by ATP triggering (5 mM, 1 h), with NLRP3, cleaved caspase-1, cleaved IL-1β, vimentin, and E-cadherin assessed by immunoblotting and IL-1β secretion measured by ELISA. Curcumin at 10–25 μM did not cause overt cytotoxicity and significantly reduced LPS-induced wound closure and invasive activity in both cell lines, accompanied by attenuation of EMT-associated transcriptional changes and a decrease in ROS-positive events. Under LPS priming/ATP triggering, inflammasome-associated protein signals and IL-1β secretion were robustly induced; curcumin suppressed IL-1β release and attenuated NLRP3, cleaved caspase-1, and cleaved IL-1β signals, while reversing vimentin/E-cadherin changes. NAC produced similar inhibitory patterns, supporting a redox-linked contribution to these responses. Collectively, curcumin dampens inflammation-driven motility/invasion, EMT-associated changes, and inflammasome-associated responses in androgen-independent prostate cancer cells. Full article

(This article belongs to the Section Bioorganic Chemistry and Medicinal Chemistry)

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8 pages, 873 KB

Open AccessBrief Report

Angelic Acid Prevents RANKL-Induced Osteoclastogenesis Through Pathway-Biased Inhibition of MAPK–NFATc1 Signaling

by Lifang Zhang, Mojtaba Tabandeh and Vishwa Deepak

Curr. Issues Mol. Biol. 2026, 48(4), 412; https://doi.org/10.3390/cimb48040412 - 17 Apr 2026

Viewed by 233

Abstract

Excessive osteoclast activity drives inflammatory bone loss in osteoporosis, rheumatoid arthritis, and periodontitis. Natural compounds represent promising therapeutic candidates with favorable safety profiles; however, few exhibit pathway-biased mechanisms of action. Here, we report that angelic acid (AA), a naturally occurring unsaturated monocarboxylic acid, [...] Read more.

Excessive osteoclast activity drives inflammatory bone loss in osteoporosis, rheumatoid arthritis, and periodontitis. Natural compounds represent promising therapeutic candidates with favorable safety profiles; however, few exhibit pathway-biased mechanisms of action. Here, we report that angelic acid (AA), a naturally occurring unsaturated monocarboxylic acid, potently inhibits RANKL-induced osteoclastogenesis. This effect occurs with an IC₅₀ of 1.9 µM without cytotoxicity. Mechanistically, AA selectively suppressed RANKL-activated phosphorylation of ERK1/2, p38, and JNK (all three MAPK branches), while leaving NF-κB transcriptional activity unaffected. This preferential MAPK suppression disrupted downstream NFATc1 nuclear translocation, thereby preventing NFATc1-driven transcription of osteoclast-specific effector genes including TRAP, cathepsin K, and Atp6v0d2. These findings identify AA as a novel inhibitor of the RANKL–MAPK–NFATc1 axis, providing a mechanistic foundation for its therapeutic development in osteoporosis and other osteolytic diseases. Full article

(This article belongs to the Special Issue The Role of Bioactives in Inflammation, 2nd Edition)

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20 pages, 9626 KB

Open AccessArticle

MD Simulation of Vector–Receptor Pharmacologic Pairs for Tumor-Specific Drug Delivery: Transfer of Boron Atoms by RGD Peptide to αvβ3 Integrin Receptor

by Ivan Baigunov, Kholmirzo Kholmurodov, Jaloliddin Gafurzoda, Mirzoaziz Husenzoda, Elena Gribova, Pavel Gladyshev, Dara Slobodova, Raisa Gorshkova and Alexey Lipengolts

Curr. Issues Mol. Biol. 2026, 48(4), 411; https://doi.org/10.3390/cimb48040411 - 16 Apr 2026

Viewed by 452

Abstract

We utilized molecular dynamics (MD) simulations to explore the interaction of the RGD peptide with the αvβ3 integrin receptor, a key process for targeted drug delivery to tumors. The goal of these simulations was to model the transport of boron atoms by the [...] Read more.

We utilized molecular dynamics (MD) simulations to explore the interaction of the RGD peptide with the αvβ3 integrin receptor, a key process for targeted drug delivery to tumors. The goal of these simulations was to model the transport of boron atoms by the RGD peptide and to characterize the binding event between this vector and its receptor. The study focused on the interaction processes and spatial arrangements of the solvated RGD–integrin system. Simulations were run for 100 ns to achieve relaxed-state configurations. Our model featured two RGD peptides: one pre-localized within the integrin’s binding site and another initially positioned externally. The external peptide was observed to diffuse freely and subsequently bind to the αvβ3 integrin. This spontaneous binding event provides valuable insights into the pharmacological specificity and mechanisms of the RGD–integrin interaction, informing the design of effective drug delivery systems. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Peptides and Molecular Conjugates for Targeted Drug Delivery)

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26 pages, 8478 KB

Open AccessArticle

Integrative Multi-Omics Analysis Reveals the Immunoregulatory Effects of Sepia Ink on ADHD-like Phenotypes

by Baohong Wei, Jiayi Yin, Wenmin Yuan, Peiling Cai, Qiaoling Song, Zhe Li, Xiaoqing Ma, Xue Yang, Lejia Hong, Huashi Guan, Guanhua Du and Wenzhe Yang

Curr. Issues Mol. Biol. 2026, 48(4), 410; https://doi.org/10.3390/cimb48040410 - 16 Apr 2026

Viewed by 345

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD), affecting 5–10% of children globally, faces treatment limitations due to adverse effects and uncertain long-term risks of current pharmacotherapies. This study investigated the therapeutic potential of sepia ink (SI), a marine-derived natural complex from cuttlefish, in a scopolamine-induced ADHD-like mouse [...] Read more.

Attention-Deficit/Hyperactivity Disorder (ADHD), affecting 5–10% of children globally, faces treatment limitations due to adverse effects and uncertain long-term risks of current pharmacotherapies. This study investigated the therapeutic potential of sepia ink (SI), a marine-derived natural complex from cuttlefish, in a scopolamine-induced ADHD-like mouse model. The chemical constituents of SI were characterized via Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). The behavioral assessments, histopathological examinations, flow cytometry, and complete blood counts were utilized to evaluate its effects on ADHD-like phenotypes, neuroinflammation, and immune function. Integrated transcriptomic, plasma metabolomic, and 16S rRNA sequencing were used to explore the underlying mechanisms. SI significantly alleviated hyperactivity and improved spatial learning and memory deficits. It reduced hippocampal neuronal damage, attenuated neuroinflammation, and reversed scopolamine-induced immunosuppression in spleen and thymus. SI also restored the balance of immune cell subsets in both mesenteric lymph nodes and spleen, and the peripheral blood cell counts. Multi-omics analyses suggested that the beneficial effects of SI were associated with reduced neuroinflammation, rebalanced systemic immune responses, partial correction of lipid metabolic disturbances, and restoration of gut microbiota homeostasis. Collectively, our findings indicate that SI effectively mitigates the in vivo ADHD-like impairments by coordinating immune, metabolic, and gut microbiota-related processes, thereby supporting its potential as a marine-derived therapeutic candidate for further ADHD treatment. Full article

(This article belongs to the Special Issue The Modulatory Effects of Plants with Therapeutic Potential in Neuropsychiatric Disorder)

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15 pages, 6504 KB

Open AccessArticle

A Preliminary Investigation of the Anti-Salmonella Enteritidis Potential of Quercetin in Chickens Using Network Pharmacology, Molecular Docking, and In Vitro Antibacterial Assays

by Qi Xiao, Yufeng Yan, Zihao Zhao, Xinyue Zhang, Tengfei Jiang and Fanzhi Kong

Curr. Issues Mol. Biol. 2026, 48(4), 409; https://doi.org/10.3390/cimb48040409 - 16 Apr 2026

Viewed by 263

Abstract

Salmonella Enteritidis is a major threat to poultry health and food safety, underscoring the need for safe alternatives to conventional antibiotics. In this study, quercetin, a natural flavonoid with antibacterial and immunomodulatory properties, was evaluated using an integrated approach combining network pharmacology, molecular [...] Read more.

Salmonella Enteritidis is a major threat to poultry health and food safety, underscoring the need for safe alternatives to conventional antibiotics. In this study, quercetin, a natural flavonoid with antibacterial and immunomodulatory properties, was evaluated using an integrated approach combining network pharmacology, molecular docking, in vitro antibacterial assays, and preliminary in vivo validation. Potential targets of quercetin and Salmonella Enteritidis were identified from the TCMSP and GeneCards databases, followed by protein–protein interaction analysis, topological screening, and GO/KEGG enrichment analyses. Five core targets, namely IL1B, IL6, STAT1, PTGS2, and IFNG, were identified and were mainly enriched in immune- and inflammation-related pathways. Molecular docking suggested favorable interactions between quercetin and these predicted targets. In vitro, quercetin showed moderate antibacterial activity against Salmonella Enteritidis, with a minimum inhibitory concentration of 256 μg/mL and a minimum bactericidal concentration of 512 μg/mL. In vivo, quercetin alleviated intestinal histopathological damage and reduced the transcriptional expression of the five target genes in infected chicks in a dose-dependent manner, with more evident effects at doses of 512 mg/kg or higher. These findings provide preliminary evidence that quercetin may exert both direct antibacterial and host-associated protective effects against Salmonella Enteritidis, although the underlying mechanisms require further validation. Full article

(This article belongs to the Section Molecular Pharmacology)

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22 pages, 2372 KB

Open AccessReview

Natural Products in Endometrial Cancer: Molecular Mechanisms, Preclinical Evidence, and Clinical Perspectives

by Hsien-Chang Wu, Chung-Che Tsai and Chan-Yen Kuo

Curr. Issues Mol. Biol. 2026, 48(4), 408; https://doi.org/10.3390/cimb48040408 - 16 Apr 2026

Viewed by 507

Abstract

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence linked to obesity and metabolic dysfunction. While early-stage EC is often curable, advanced and recurrent disease remains difficult to treat due to resistance and limited therapeutic options. Natural [...] Read more.

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence linked to obesity and metabolic dysfunction. While early-stage EC is often curable, advanced and recurrent disease remains difficult to treat due to resistance and limited therapeutic options. Natural products derived from traditional Chinese medicine have attracted attention as complementary strategies in EC management. These compounds exhibit multi-target effects, including modulation of estrogen signaling, inhibition of proliferation, induction of apoptosis, and regulation of immune and inflammatory pathways. This review summarizes current evidence on natural products in EC, integrating preclinical findings, emerging clinical data, and mechanistic insights from molecular and systems biology approaches. Key challenges, including variability, bioavailability, and insufficient clinical validation, are discussed. Future directions emphasize the integration of natural products into precision oncology frameworks. Full article

(This article belongs to the Special Issue Pharmacological Activities and Mechanisms of Action of Natural Products, 2nd Edition)

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31 pages, 9123 KB

Open AccessArticle

Exploring the Biological Potency of Carotenoids Against Alzheimer’s Disease: An Integrated Approach of Molecular Docking and Molecular Dynamics

by Meriem Khedraoui, El Mehdi Karim, Imane Yamari, Abdelkbir Errougui, Doni Dermawan, Nasser Alotaiq and Samir Chtita

Curr. Issues Mol. Biol. 2026, 48(4), 407; https://doi.org/10.3390/cimb48040407 - 16 Apr 2026

Viewed by 418

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, amyloid-β aggregation, mitochondrial stress, and aberrant kinase activity. Carotenoids, naturally occurring pigments with antioxidant and neuroprotective properties, have emerged as promising candidates for AD intervention. In this study, we performed a [...] Read more.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, amyloid-β aggregation, mitochondrial stress, and aberrant kinase activity. Carotenoids, naturally occurring pigments with antioxidant and neuroprotective properties, have emerged as promising candidates for AD intervention. In this study, we performed a systematic stepwise computational screening of a large carotenoid library (n = 1191) to identify multitarget candidates against AD–related proteins. The workflow consisted of predefined ADMET filtering (oral absorption > 90%, Caco-2 > 0.9, logBB > −1, and absence of major CYP inhibition and toxicity alerts), reducing the dataset to 61 compounds, followed by multi-target molecular docking against AChE, BChE, BACE-1, MAO-B, and GSK3-β. Compounds were ranked using an aggregated mean docking score across all five targets, and the top-performing candidate was subjected to detailed mechanistic analyses. Hopkinsiaxanthin emerged as the highest-ranked multitarget carotenoid and was further evaluated using frontier molecular orbital (FMO) analysis, pharmacophore modeling, 100 ns molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and per-residue decomposition. Docking predicted favorable estimated binding affinities toward all targets. MD simulations confirmed stable receptor–ligand complexes with low RMSD values (0.278–0.285 nm). MM/PBSA analysis indicated favorable binding free energies, particularly for GSK3-β (−22.73 kcal/mol) and AChE (−21.50 kcal/mol). Per-residue decomposition identified key hotspot residues driving stabilization. Overall, this structured computational framework identifies Hopkinsiaxanthin as a promising multitarget scaffold and supports its prioritization for experimental validation in AD models. Full article

(This article belongs to the Special Issue Emerging Trends in Bioinformatics and Computational Biology)

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20 pages, 10570 KB

Open AccessArticle

Precision Intervention of Isorhamnetin Total Flavonoids in Ischemic Heart Failure: Mechanistic Exploration Based on Signature Gene Targets

by Li-Juan Zhang, Xu Hu, Kader Kaderyea, Wen-Ling Su, Yue Wang, Di-Wei Liu, Rui-Fang Zheng and Jian-Guo Xing

Curr. Issues Mol. Biol. 2026, 48(4), 406; https://doi.org/10.3390/cimb48040406 - 15 Apr 2026

Viewed by 288

Abstract

Early identification of ischemic heart failure (IHF) is critical for improving patient prognosis and clinical outcomes. However, effective diagnostic biomarkers and targeted therapeutic strategies for IHF remain limited. Total flavonoids from Dracocephalum moldavica L. (TFDM) exert potential cardioprotective effects; however, the molecular mechanisms [...] Read more.

Early identification of ischemic heart failure (IHF) is critical for improving patient prognosis and clinical outcomes. However, effective diagnostic biomarkers and targeted therapeutic strategies for IHF remain limited. Total flavonoids from Dracocephalum moldavica L. (TFDM) exert potential cardioprotective effects; however, the molecular mechanisms by which TFDM acts against IHF have not been fully elucidated. Therefore, this study aims to identify diagnostic biomarkers for IHF and explore the potential therapeutic mechanism of TFDM targeting these key genes. Given the small sample size (n = 17) of the clinical dataset, LASSO regression and Random Forest were employed due to their superior performance in feature selection, noise reduction, and stability in small-sample scenarios. In this study, we screened key characteristic genes of IHF through bioinformatics analysis and further investigated the binding potential between these key genes and active components of TFDM using molecular docking, thus providing new targets for the early diagnosis of IHF and new evidence for the intervention mechanism of TFDM in IHF. Full article

(This article belongs to the Special Issue Pharmacological Activities and Mechanisms of Action of Natural Products, 2nd Edition)

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20 pages, 5261 KB

Open AccessArticle

Formulation of Blumea balsamifera, Anredera cordifolia, and Phyllanthus niruri Extracts as Potential Anti-Inflammatory Agents

by Siti Martinah Pajriah, Dyah Iswantini, Henny Purwaningsih, Banaz Jalil, Min Rahminiwati and Novriyandi Hanif

Curr. Issues Mol. Biol. 2026, 48(4), 405; https://doi.org/10.3390/cimb48040405 - 15 Apr 2026

Viewed by 306

Abstract

Inflammation is an immune response to foreign substances, pathogens, and cellular damage, characterized by redness, pain, and swelling. The use of synthetic anti-inflammatory drugs may cause adverse side effects, prompting the need for natural alternatives. This study aimed to evaluate the total flavonoid [...] Read more.

Inflammation is an immune response to foreign substances, pathogens, and cellular damage, characterized by redness, pain, and swelling. The use of synthetic anti-inflammatory drugs may cause adverse side effects, prompting the need for natural alternatives. This study aimed to evaluate the total flavonoid content and anti-inflammatory activity of single and combined extracts of sembung (Blumea balsamifera) [S], binahong (Anredera cordifolia) [B], and meniran (Phyllanthus niruri) [M] leaves. Extraction was performed using a 70% ethanol and water solution. Total flavonoid content was determined spectrophotometrically using quercetin as the standard. LC-HR-MS/MS results showed the presence of flavonoids, terpenoids, phenolics, and amino acids in each single extract (S, B, and M). Anti-inflammatory activity was assessed through the inhibition of albumin denaturation and the inhibition of cyclooxygenase-2 (COX-2). The highest flavonoid content (35.27 mg QE/g DW) in single extracts was found in B of the ethanolic extract, while the highest flavonoid content (40.24 mg QE/g DW) in all formulations was discovered in a combination of the ethanolic extract S:B:M (1:0:1). Moreover, the ethanolic extract S:B:M (1:0:1) gave the strongest inhibition (76.47%) of the albumin denaturation at 300 µg/mL and the strongest inhibition (98.5%) of the COX-2 inhibition at 100 µg/mL. Sembung extract was highest for reducing the expression of pro-inflammatory cytokines and TNF-α was 97.66% at an extract concentration of 15.625 ppm. As for S, S:B:M (1:0:1) and S:B:M (1:1:1) can reduce the expression of pro-inflammatory cytokines, as IL-6 was 100% in 0 pg/mL at an extract concentration of 15.625 ppm. Full article

(This article belongs to the Special Issue The Role of Bioactives in Inflammation, 2nd Edition)

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19 pages, 5504 KB

Open AccessArticle

Identification of Potential Pancreatic Lipase Inhibitors from Traditional Chinese Medicines via Molecular Docking, Molecular Dynamics Simulation and In Vitro Validation

by Zixuan Zhang, Jinhua Long, Tingting Li, Nan Xu, Zhili Xu, Yuedan Wang, Ming Chu and Mingbo Zhang

Curr. Issues Mol. Biol. 2026, 48(4), 404; https://doi.org/10.3390/cimb48040404 - 15 Apr 2026

Viewed by 338

Abstract

Obesity represents one of the most critical global public health challenges. Pancreatic lipase (PL) serves as a key therapeutic target for obesity control, whereas clinical synthetic PL inhibitors are greatly restricted by adverse reactions. Traditional Chinese medicines (TCMs) have a long-standing history in [...] Read more.

Obesity represents one of the most critical global public health challenges. Pancreatic lipase (PL) serves as a key therapeutic target for obesity control, whereas clinical synthetic PL inhibitors are greatly restricted by adverse reactions. Traditional Chinese medicines (TCMs) have a long-standing history in regulating lipid metabolism and ameliorating obesity-related disorders, and are characterized by remarkable structural diversity, low toxicity, and mild side effects, thus representing a promising source for developing safe and efficient PL inhibitors. In this work, an integrated strategy combining in silico screening and in vitro validation was employed to identify potential PL inhibitors from TCM components, including molecular docking, molecular dynamics simulation, MM/PBSA binding free energy computation, and in vitro enzymatic assay. Six compounds with docking scores ranging from −9.9 to −9.0 kcal/mol were selected for further investigation. Molecular dynamics simulations verified the favorable structural stability of the corresponding ligand–PL complexes, and MM/PBSA calculations demonstrated negative binding free energies from −21.24 ± 0.39 to −12.03 ± 0.40 kcal/mol. In vitro experiments indicated that three compounds (Hydroxygenkwanin, Atractylenolide I, and Peiminine) showed effective PL inhibitory activity, with IC₅₀ values of 0.128 ± 0.009, 0.584 ± 0.031, and 0.748 ± 0.042 mM, respectively. These values are comparable to quercetin (0.231 ± 0.034 mM) but significantly higher than orlistat (0.481 ± 0.023 μM), which is attributed to their non-covalent binding pattern. Collectively, this study validated the reliability of the integrated in silico and in vitro screening strategy, identified three effective pancreatic lipase inhibitors derived from TCMs, established a robust paradigm for the discovery of natural PL inhibitors, and laid a solid foundation for subsequent research on natural anti-obesity agents. Full article

(This article belongs to the Special Issue Pharmacological Activities and Mechanisms of Action of Natural Products, 2nd Edition)

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19 pages, 3837 KB

Open AccessArticle

TRIM24 Regulates Adaptation to Glucose Deprivation in Association with Aspartate Accumulation and Impaired AMPK Signaling

by Xiaochen Yu, Duopeng An, Dadui Ren, Peng He, Yunkai Yang, Nanye Chen, Rui Wang, Shan Wu, Jun Feng and Meiqing Feng

Curr. Issues Mol. Biol. 2026, 48(4), 403; https://doi.org/10.3390/cimb48040403 - 14 Apr 2026

Viewed by 281

Abstract

Glucose deprivation is a major metabolic stress that requires coordinated adaptive responses to maintain cellular homeostasis and survival, yet the role of tripartite motif-containing 24 (TRIM24) in this process remains unclear. To address this question, we generated CRISPR-Cas9-mediated TRIM24-knockout MCF-7 and HEK293 cell [...] Read more.

Glucose deprivation is a major metabolic stress that requires coordinated adaptive responses to maintain cellular homeostasis and survival, yet the role of tripartite motif-containing 24 (TRIM24) in this process remains unclear. To address this question, we generated CRISPR-Cas9-mediated TRIM24-knockout MCF-7 and HEK293 cell lines, performed targeted metabolomic profiling and aspartate assays, used 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), aminooxyacetic acid (AOA), aspartate supplementation, and glutamic-oxaloacetic transaminase 2 (GOT2) knockdown to probe AMPK signaling and aspartate metabolism, and examined starvation responses in constitutive Trim24 knockout mice on a C57BL/6 background. Loss of TRIM24 sensitized cells to glucose deprivation. Re-expression of TRIM24 partially restored cell viability under glucose deprivation in both MCF-7 and HEK293 cells. Under glucose-free conditions, TRIM24 deficiency was associated with impaired AMP-activated protein kinase (AMPK) pathway activation, increased intracellular aspartate accumulation, and altered ATP/AMP levels. Pharmacological reactivation of AMPK by AICAR improved the survival of TRIM24-deficient cells under glucose deprivation. Reducing intracellular aspartate by AOA treatment or GOT2 knockdown restored AMPK pathway activation and improved adaptation to glucose deprivation, whereas exogenous aspartate suppressed AMPK signaling and increased ATP/AMP levels. In vivo, starvation of Trim24-deficient mice was associated with reduced AMPK pathway activation and increased aspartate levels. Together, these findings support a model in which TRIM24 contributes to adaptation to glucose deprivation and in which abnormal aspartate accumulation contributes to impaired AMPK pathway activation in TRIM24-deficient cells. Full article

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

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23 pages, 32795 KB

Open AccessArticle

Genome-Wide Identification and Expression Profiling of HD-Zip Family Genes in Flax (Linum usitatissimum L.)

by Yamin Niu, Yanni Qi, Limin Wang, Wenjuan Li, Zhao Dang, Yaping Xie, Wei Zhao, Gang Wang, Zuyu Hu, Nan Lu, Xiaoyan Zhu, Jing Zheng, Junyan Wu and Jianping Zhang

Curr. Issues Mol. Biol. 2026, 48(4), 402; https://doi.org/10.3390/cimb48040402 - 14 Apr 2026

Viewed by 272

Abstract

The homeodomain-leucine zipper (HD-Zip) transcription factor family is conserved in land plants and is critical for regulating growth, development, and stress responses. Flax (Linum usitatissimum L.) is an economically valuable dual-purpose crop valued for its high nutrition and notable drought tolerance; however, [...] Read more.

The homeodomain-leucine zipper (HD-Zip) transcription factor family is conserved in land plants and is critical for regulating growth, development, and stress responses. Flax (Linum usitatissimum L.) is an economically valuable dual-purpose crop valued for its high nutrition and notable drought tolerance; however, its HD-Zip gene family has not been systematically characterized. In this study, a comprehensive genome-wide analysis was performed to identify and characterize the HD-Zip family in flax. A total of 34 LuHD-Zip genes were identified, which were unevenly distributed across 15 chromosomes and exhibited substantial variation in physicochemical properties. The encoded proteins ranged from 200 to 372 amino acids in length, with molecular weights of 22.7–40.3 kDa and theoretical isoelectric points (pI) of 4.49–9.46. All LuHD-Zip proteins were predicted to be hydrophilic and localized to the nucleus. Phylogenetic analysis divided these proteins into two major subfamilies (Group 1 and Group 2), a classification strongly supported by conserved gene structures and motif compositions, implying potential functional redundancy within each group. Gene duplication analysis revealed that segmental duplication events (29 pairs) were the primary drivers of family expansion. Comparative syntenic analysis further indicated that the LuHD-Zip gene family has remained relatively conserved throughout evolution. Promoter cis-element analysis identified multiple regulatory elements associated with hormone signaling and abiotic stress responses, suggesting complex transcriptional control in response to environmental stimuli. Expression profiling via quantitative real-time PCR (qRT-PCR) demonstrated that LuHD-Zip genes exhibit tissue-specific expression patterns and are differentially regulated by various phytohormone treatments and abiotic stresses. This study provides the first genome-wide characterization of the HD-Zip gene family in flax, offering valuable insights into its evolution and potential functions. These findings establish a solid foundation for future functional investigations of the LuHD-Zip gene family. Full article

(This article belongs to the Special Issue Molecular Breeding and Genetics Research in Plants—3rd Edition)

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19 pages, 2981 KB

Open AccessArticle

A Comparative Bioinformatics Analysis of the Transcriptomic Profiles of Peri-Implantitis and Periodontitis and Their Common Signaling Pathways with Atherosclerosis

by Aleksandr V. Guskov, Anatoliy S. Utyuzh, Aleksandr A. Oleynikov, Aleksandr A. Nikiforov and Stanislav N. Kotlyarov

Curr. Issues Mol. Biol. 2026, 48(4), 401; https://doi.org/10.3390/cimb48040401 - 14 Apr 2026

Viewed by 356

Abstract

(1) Objective. To conduct a comparative bioinformatics analysis of the transcriptomic profiles of peri-implantitis and periodontitis to identify common and specific molecular signatures underlying their pathogenesis, as well as molecular parallels with atherosclerosis. (2) Methods: We used datasets from the Gene Expression Omnibus [...] Read more.

(1) Objective. To conduct a comparative bioinformatics analysis of the transcriptomic profiles of peri-implantitis and periodontitis to identify common and specific molecular signatures underlying their pathogenesis, as well as molecular parallels with atherosclerosis. (2) Methods: We used datasets from the Gene Expression Omnibus (GEO) database: dataset GSE223924 (30 gingival tissue samples from patients with peri-implantitis, periodontitis, and healthy subjects) and GSE100927 (atherosclerotic and control tissue; n = 104). Differentially expressed genes (DEGs) were identified based on the criteria: |logFC| > 1 and FDR < 0.05. To quantitatively assess the relative abundance of immune cells, we used the xCell deconvolution algorithm. (3) Results: In the peri-implantitis group, 3669 DEGs with upregulated expression and 3106 with downregulated expression were identified; in the periodontitis group, 1968 and 1250 DEGs, respectively. Functional analysis of the upregulated DEGs revealed activation of inflammatory processes, cell adhesion, and angiogenesis in both diseases. Key differences lay in the activation of adaptive immune mechanisms in peri-implantitis (enrichment of the “graft rejection” and “T-cell receptor signaling”) and innate immunity in periodontitis (enrichment of the “lipopolysaccharide response” and “Toll-like receptors (TLR) signaling” pathways). Analysis of downregulated DEGs revealed more profound disruptions in cytoskeletal organization and epithelial differentiation in periodontitis, as well as suppression of xenobiotic and lipid metabolism in both diseases. xCell deconvolution confirmed a significant increase in B cells, neutrophils, monocytes, M1 macrophages, and dendritic cells in peri-implantitis, and also revealed a trend toward an increase in these cells in periodontitis (p > 0.05), which is consistent with the activation of TLR signaling. In periodontitis, a significant increase in M2 macrophages and a decrease in Th1 cells were observed. Comparison with atherosclerosis revealed 272 common DEGs with peri-implantitis and 173 common DEGs with periodontitis. Functional analysis of the common genes confirmed their role in leukocyte transendothelial migration, cytokine production, and the “Lipids and Atherosclerosis” pathway. (4) Conclusions: Functional analysis and immune deconvolution consistently demonstrate that peri-implantitis is characterized by statistically significant activation of both adaptive and innate immunity, whereas in periodontitis, the activation of innate immunity manifests primarily at the level of signaling pathways. The significant overlap found between the transcriptional profiles of both diseases and atherosclerosis may indicate the presence of common pathogenetic links. Full article

(This article belongs to the Special Issue Bioinformatics in Human Disease Network Analysis)

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Open AccessArticle

Molecular Analysis of miR-155 and MIR155HG Mutations in Conjunction with TLR4 Variants in Inflammatory Joint Disease

by Wissam Albeer Nooh, Raya Kh. Yashooa, Abdullah W. Khaleel, Treska S. Hassan, Shawnim M. Maaruf, Safa M. Salim, Abd Al-Bar Al-Farha, Suhad A. Mustafa and Dara K. Mohammad

Curr. Issues Mol. Biol. 2026, 48(4), 400; https://doi.org/10.3390/cimb48040400 - 14 Apr 2026

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Abstract

Inflammatory joint diseases, including osteoarthritis, are multifactorial disorders in which dysregulated innate immune signaling and non-coding RNA (ncRNA)-mediated regulation of gene expression play essential roles. MicroRNA-155 (miR-155), its host gene MIR155HG, and Toll-like receptor 4 (TLR4) form a tightly linked inflammatory signaling axis, [...] Read more.

Inflammatory joint diseases, including osteoarthritis, are multifactorial disorders in which dysregulated innate immune signaling and non-coding RNA (ncRNA)-mediated regulation of gene expression play essential roles. MicroRNA-155 (miR-155), its host gene MIR155HG, and Toll-like receptor 4 (TLR4) form a tightly linked inflammatory signaling axis, yet their combined genetic variability in chronic joint inflammation remains insufficiently characterized. The aim of this study was to investigate genetic variants in MIR155HG exon 3, mature miR-155, and TLR4 exon 3 and assess their potential synergistic role in chronic inflammatory joint disease. A case–control study was conducted with 100 cases (50 osteoarthritis patients and 50 matched healthy controls). Genomic DNA was analysed using polymerase chain reaction (PCR) and Sanger sequencing. Variant alleles and genotypes were identified, and their allele frequencies and genotypes were calculated using Mutation Surveyor. Detected variants were compared with public databases, and in silico tools were used to estimate the structural impact of TLR4 missense mutations. Sixteen heterozygous variants were identified in MIR155HG exon 3, most of them novel and population-specific. Interestingly, the highest variant frequencies for MIR155HG exon 3 were observed at positions 12448G>GC and 12481T>TA (both 64.3%), followed by 12442T>TC (57.1%). Additionally, two novel variants were detected in the miR-155 gene (chr21:29,694,314 G>A and chr21:29,646,351 T>C), each present at an allele frequency of 7.1% and absent from current external variant databases. Moreover, two rare TLR4 exon-3 variants were identified; a synonymous variant, c.147C>A (Pro49Pro; rs375037549), and a missense mutation, c.148G>A (Asp50Asn; rs776561489). Notably, in silico analyses and molecular dynamic simulations indicated that the Asp50Asn (D50N) substitution destabilizes the TLR4 protein. Conclusion: Concurrent variants in MIR155HG, miR-155, and TLR4 suggest a convergent regulatory molecular axis that may contribute to disease susceptibility and inflammatory progression. Full article

(This article belongs to the Section Molecular Medicine)

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Curr. Issues Mol. Biol., Volume 48, Issue 4 (April 2026) – 91 articles

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