Current Issues in Molecular Biology最新文献

{"title":"Genome-Wide Association Study Suggests <i>rrp44</i> Is a Key Regulator of Growth Traits in Channel Catfish (<i>Ictalurus punctatus</i>).","authors":"Shiyong Zhang, Hongyan Liu, Yongqiang Duan, Minghua Wang, Xiaohui Chen","doi":"10.3390/cimb48040420","DOIUrl":"https://doi.org/10.3390/cimb48040420","url":null,"abstract":"<p><p>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 (<i>Ictalurus punctatus</i>) 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 <i>rrp44</i> gene were significantly associated with both traits. Functional annotation and enrichment analyses revealed that the <i>rrp44</i> 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 <i>rrp44</i> 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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychedelics and Autism Therapy: A Review of Current Research and Future Directions.","authors":"Christopher S Gondi, Manu Gnanamony, Tarun P Gondi, Lilyt Nersesyan, Lusine Demirkhanyan","doi":"10.3390/cimb48040417","DOIUrl":"https://doi.org/10.3390/cimb48040417","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13115131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-Derived Cystathionine β-Synthase-Generated H₂S Attenuates Cerebral Ischemia-Reperfusion Injury via VEGFR₂-Mediated Angiogenesis in MCAO/R Rats.","authors":"Shuai Liang, La Jiang, Yu Jiang, Shan Wang, Jia-Rong Jiang, Ji-Yue Wen, Zhi-Wu Chen, Shuo Chen","doi":"10.3390/cimb48040418","DOIUrl":"https://doi.org/10.3390/cimb48040418","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angelic Acid Prevents RANKL-Induced Osteoclastogenesis Through Pathway-Biased Inhibition of MAPK-NFATc1 Signaling.","authors":"Lifang Zhang, Mojtaba Tabandeh, Vishwa Deepak","doi":"10.3390/cimb48040412","DOIUrl":"https://doi.org/10.3390/cimb48040412","url":null,"abstract":"<p><p>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 <i>TRAP</i>, <i>cathepsin K</i>, and <i>Atp6v0d2</i>. 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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid and Efficient Creation of Sweet-Waxy Maize Germplasm via CRISPR/Cas9-Mediated Gene Editing of <i>Sh2</i> and <i>Wx</i>.","authors":"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, Hongqiu Wang","doi":"10.3390/cimb48040415","DOIUrl":"https://doi.org/10.3390/cimb48040415","url":null,"abstract":"<p><p>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 <i>Sh2</i> (regulating the super-sweet kernel trait) and <i>Wx</i> (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 <i>Agrobacterium</i>-mediated transformation. We obtained Cas9-free T₃ homozygous <i>sh2</i> and <i>wx</i> 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 <i>Sh2</i> and <i>Wx</i> 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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13115123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin Attenuates LPS-Induced Migration/EMT and LPS/ATP-Associated IL-1β Release in Androgen-Independent Prostate Cancer Cells.","authors":"Mon-Der Cho, Shang-Yu Chou, Yu-Ming Hsu, Chi-Ying Li, Yi-Hong Tsai, Fang-Rong Chang","doi":"10.3390/cimb48040413","DOIUrl":"https://doi.org/10.3390/cimb48040413","url":null,"abstract":"<p><p>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 <i>SNAI1</i>, <i>CDH1</i>, and <i>VIM</i>. 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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Key Genes Regulated by Lactylation Modification and Associated with Tumor Immune Microenvironment in Breast Cancer.","authors":"Yaohong Xie, Yi Ge, Na Miao, Pengxia Zhang, Jiaqi Xia","doi":"10.3390/cimb48040416","DOIUrl":"https://doi.org/10.3390/cimb48040416","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long Non-Coding RNAs in Human Disease: An Overview of Biogenesis, Molecular Mechanism and Therapeutic Opportunities.","authors":"Arvind Kumar Dubey, Anil Kumar, Zhadyrassyn Nurbekova, Navin Kumar","doi":"10.3390/cimb48040414","DOIUrl":"https://doi.org/10.3390/cimb48040414","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Preliminary Investigation of the Anti-<i>Salmonella Enteritidis</i> Potential of Quercetin in Chickens Using Network Pharmacology, Molecular Docking, and In Vitro Antibacterial Assays.","authors":"Qi Xiao, Yufeng Yan, Zihao Zhao, Xinyue Zhang, Tengfei Jiang, Fanzhi Kong","doi":"10.3390/cimb48040409","DOIUrl":"https://doi.org/10.3390/cimb48040409","url":null,"abstract":"<p><p><i>Salmonella Enteritidis</i> 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 <i>Salmonella Enteritidis</i> 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 <i>Salmonella Enteritidis</i>, 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 <i>Salmonella Enteritidis</i>, although the underlying mechanisms require further validation.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Biological Potency of Carotenoids Against Alzheimer's Disease: An Integrated Approach of Molecular Docking and Molecular Dynamics.","authors":"Meriem Khedraoui, El Mehdi Karim, Imane Yamari, Abdelkbir Errougui, Doni Dermawan, Nasser Alotaiq, Samir Chtita","doi":"10.3390/cimb48040407","DOIUrl":"https://doi.org/10.3390/cimb48040407","url":null,"abstract":"<p><p>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 (<i>n</i> = 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.</p>","PeriodicalId":10839,"journal":{"name":"Current Issues in Molecular Biology","volume":"48 4","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}