NAFLD is a major cause of morbidity and mortality worldwide. The present study aims to investigate the therapeutic potential of selected lignans, including 6-hydroxy enterodiol and secoisolariciresinol, against the key molecular targets involved in the pathogenesis of the disease. A network pharmacology approach was employed to elucidate the interaction between the proteins of bioactive compounds and disease targets, while docking and density functional theory (DFT) calculations were conducted to assess the electronic properties and reactivity profiles of the ligands. GO and KEGG pathway enrichment analysis was done to understand the core targets that are involved in various biological pathways and biological functions. Furthermore, dynamic validation of the stability and conformational behavior of the protein-ligand complexes under the physiological condition was done through MM-GBSA free energy calculations, Free Energy Landscape (FEL) mapping, and Principal Component Analysis (PCA). AKT1, CASP3, and IL6 exhibited highly favorable binding free energies, which range from 75.0196 to 75.2026 kcal/mol, indicating the stability and binding of the proteins. Moreover, CASP3 exhibited a low energy gap and a high electrophilicity index, underscoring its potential as an effective electron acceptor. In conclusion, the present computational study provides substantial evidence for the efficacy of a group of peptides as natural therapies for the treatment of nonalcoholic fatty liver disease.
{"title":"Computational investigation of lignans as potential target for non-alcoholic fatty liver disease: Insights from network pharmacology, docking, DFT, and dynamics simulation analysis","authors":"Rajappan Chandra Satish Kumar , Akash Jayaraman , Ramesh Venkatachalapathy","doi":"10.1016/j.humgen.2025.201457","DOIUrl":"10.1016/j.humgen.2025.201457","url":null,"abstract":"<div><div>NAFLD is a major cause of morbidity and mortality worldwide. The present study aims to investigate the therapeutic potential of selected lignans, including 6-hydroxy enterodiol and secoisolariciresinol, against the key molecular targets involved in the pathogenesis of the disease. A network pharmacology approach was employed to elucidate the interaction between the proteins of bioactive compounds and disease targets, while docking and density functional theory (DFT) calculations were conducted to assess the electronic properties and reactivity profiles of the ligands. GO and KEGG pathway enrichment analysis was done to understand the core targets that are involved in various biological pathways and biological functions. Furthermore, dynamic validation of the stability and conformational behavior of the protein-ligand complexes under the physiological condition was done through MM-GBSA free energy calculations, Free Energy Landscape (FEL) mapping, and Principal Component Analysis (PCA). AKT1, CASP3, and IL6 exhibited highly favorable binding free energies, which range from 75.0196 to 75.2026 kcal/mol, indicating the stability and binding of the proteins. Moreover, CASP3 exhibited a low energy gap and a high electrophilicity index, underscoring its potential as an effective electron acceptor. In conclusion, the present computational study provides substantial evidence for the efficacy of a group of peptides as natural therapies for the treatment of nonalcoholic fatty liver disease.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201457"},"PeriodicalIF":0.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The reduction of serum low-density lipoprotein cholesterol (LDL-C) remains a cornerstone in the prevention and management of atherosclerotic cardiovascular disease (ASCVD). Over the past decades, substantial progress has been made in elucidating the molecular mechanisms regulating cholesterol homeostasis, leading to the development of effective LDL-lowering therapies. A pivotal advancement in this field was the identification of proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that plays a critical role in lipid metabolism. PCSK9 promotes the degradation of hepatic LDL receptors (LDL-R), thereby impairing the clearance of circulating LDL-C. The discovery that loss-of-function mutations in PCSK9 confer protection against cardiovascular events has spurred the development of PCSK9-targeted therapies, particularly monoclonal antibodies, which have demonstrated robust efficacy in reducing LDL-C levels and cardiovascular risk. Despite these clinical successes, the intricate regulatory networks governing PCSK9 expression, especially at the post-transcriptional level, remain incompletely understood. Emerging evidence implicates microRNAs (miRNAs) as key modulators of lipid metabolism, including the regulation of PCSK9. These small, non-coding RNAs orchestrate complex gene regulatory circuits and have the potential to fine-tune PCSK9 expression, offering novel therapeutic avenues beyond current pharmacological inhibitors. This review critically examines the current understanding of miRNA-mediated regulation of PCSK9, highlights key miRNAs implicated in this process, and discusses their potential as therapeutic targets or biomarkers in the context of dyslipidemia and cardiovascular disease. Unraveling the interplay between miRNAs and PCSK9 may pave the way for next-generation lipid-lowering strategies with enhanced specificity and efficacy.
{"title":"Post-transcriptional targeting of PCSK9 by microRNAs: From mechanisms to therapeutic potential","authors":"Maryam Mahjoubin-Tehran , Samaneh Rezaei , Tannaz Jamialahmadi , Prashant Kesharwani , Amirhossein Sahebkar","doi":"10.1016/j.humgen.2025.201456","DOIUrl":"10.1016/j.humgen.2025.201456","url":null,"abstract":"<div><div>The reduction of serum low-density lipoprotein cholesterol (LDL-C) remains a cornerstone in the prevention and management of atherosclerotic cardiovascular disease (ASCVD). Over the past decades, substantial progress has been made in elucidating the molecular mechanisms regulating cholesterol homeostasis, leading to the development of effective LDL-lowering therapies. A pivotal advancement in this field was the identification of proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that plays a critical role in lipid metabolism. PCSK9 promotes the degradation of hepatic LDL receptors (LDL-R), thereby impairing the clearance of circulating LDL-C. The discovery that loss-of-function mutations in PCSK9 confer protection against cardiovascular events has spurred the development of PCSK9-targeted therapies, particularly monoclonal antibodies, which have demonstrated robust efficacy in reducing LDL-C levels and cardiovascular risk. Despite these clinical successes, the intricate regulatory networks governing PCSK9 expression, especially at the post-transcriptional level, remain incompletely understood. Emerging evidence implicates microRNAs (miRNAs) as key modulators of lipid metabolism, including the regulation of PCSK9. These small, non-coding RNAs orchestrate complex gene regulatory circuits and have the potential to fine-tune PCSK9 expression, offering novel therapeutic avenues beyond current pharmacological inhibitors. This review critically examines the current understanding of miRNA-mediated regulation of PCSK9, highlights key miRNAs implicated in this process, and discusses their potential as therapeutic targets or biomarkers in the context of dyslipidemia and cardiovascular disease. Unraveling the interplay between miRNAs and PCSK9 may pave the way for next-generation lipid-lowering strategies with enhanced specificity and efficacy.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201456"},"PeriodicalIF":0.5,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recent research has focused on the link between phase separation genes and immunity, alongside their potential role in insulin signaling modulation. Autoimmune insulin receptoropathy (AIR), characterized by sporadic hypoglycemia, lacks reliable molecular markers for early detection.
Methods
Phase separation genes associated with AIR were analyzed using differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) explored biological differences. A protein-protein interaction (PPI) network and machine learning (SVM-REF, RandomForest) identified core phase separation genes. Functional insights were gained through correlation, differential expression, and single-gene GSEA analyses. Marker gene activity was assessed via single-sample GSEA. Mendelian randomization (MR) examined potential causal links between DO results and the disease, validating associations with phase separation genes. Unsupervised machine learning reinforced the findings.
Results
Differential gene expression and WGCNA identified 2944 differentially expressed genes and 18 co-expression modules in AIR. The darkturquoise module, showing a potential inverse relationship with disease status, was selected for further analysis. GSEA revealed up-regulated pathways such as Inositol phosphate metabolism and down-regulated pathways like Drug metabolism. PPI network and machine learning analyses identified 10 core genes closely linked to AIR, demonstrating significant predictive capability and potential as early diagnostic biomarkers.
Conclusions
The phase separation genes linked to AIR show strong disease associations, offering potential for early prediction and improved clinical management.
{"title":"Enhancing network analysis with supervised machine learning and mendelian randomization with unsupervised machine learning to identify core phase separation biomarkers in autoimmune insulin receptoropathy","authors":"Chuyu Liang , Zhaoxia Yu , Qiuyi Liang , Ziran Zeng , Rongguan Ma , Wenyan Xie , Xiao Zhu","doi":"10.1016/j.humgen.2025.201455","DOIUrl":"10.1016/j.humgen.2025.201455","url":null,"abstract":"<div><h3>Background</h3><div>Recent research has focused on the link between phase separation genes and immunity, alongside their potential role in insulin signaling modulation. Autoimmune insulin receptoropathy (AIR), characterized by sporadic hypoglycemia, lacks reliable molecular markers for early detection.</div></div><div><h3>Methods</h3><div>Phase separation genes associated with AIR were analyzed using differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) explored biological differences. A protein-protein interaction (PPI) network and machine learning (SVM-REF, RandomForest) identified core phase separation genes. Functional insights were gained through correlation, differential expression, and single-gene GSEA analyses. Marker gene activity was assessed via single-sample GSEA. Mendelian randomization (MR) examined potential causal links between DO results and the disease, validating associations with phase separation genes. Unsupervised machine learning reinforced the findings.</div></div><div><h3>Results</h3><div>Differential gene expression and WGCNA identified 2944 differentially expressed genes and 18 co-expression modules in AIR. The darkturquoise module, showing a potential inverse relationship with disease status, was selected for further analysis. GSEA revealed up-regulated pathways such as Inositol phosphate metabolism and down-regulated pathways like Drug metabolism. PPI network and machine learning analyses identified 10 core genes closely linked to AIR, demonstrating significant predictive capability and potential as early diagnostic biomarkers.</div></div><div><h3>Conclusions</h3><div>The phase separation genes linked to AIR show strong disease associations, offering potential for early prediction and improved clinical management.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201455"},"PeriodicalIF":0.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-23DOI: 10.1016/j.humgen.2025.201454
Rajesh Kumar, Srividya Shivakumar
Breast cancer (BC) continues to be the world's leading cause of mortality for women. Despite advancements in cancer treatments such as radiation, hormone therapy, chemotherapy, and targeted therapy, these methods often have significant adverse effects and damage healthy cells. Keeping in view these limitations, there is an urgent need to produce safe, accessible, and efficient breast anticancer treatments. Apigenin (API), a flavonoid derived from edible plants, has garnered considerable attention in recent years. In silico, in vitro, and in vivo investigations, API has shown encouraging chemopreventive properties. In particular, it has been demonstrated that API inhibits the growth of cancer cells, trigger apoptosis, and alter key signaling pathways that involved to the onset of cancer. With regard to BC and cancer stem cells (CSCs), the objective of this review is to present a comprehensive outline of the recent study on API, clarifying its mechanisms of action, pharmacokinetics, therapeutic efficacy, bioavailability, cytotoxicity and potential as a supplement to conventional cancer therapies. The information provided will be helpful to researchers and medical professionals who are interested in learning more about alternative cancer treatments.
{"title":"Harnessing apigenin for breast cancer treatment: Current insights","authors":"Rajesh Kumar, Srividya Shivakumar","doi":"10.1016/j.humgen.2025.201454","DOIUrl":"10.1016/j.humgen.2025.201454","url":null,"abstract":"<div><div>Breast cancer (BC) continues to be the world's leading cause of mortality for women. Despite advancements in cancer treatments such as radiation, hormone therapy, chemotherapy, and targeted therapy, these methods often have significant adverse effects and damage healthy cells. Keeping in view these limitations, there is an urgent need to produce safe, accessible, and efficient breast anticancer treatments. Apigenin (API), a flavonoid derived from edible plants, has garnered considerable attention in recent years. In silico, in vitro, and in vivo investigations, API has shown encouraging chemopreventive properties. In particular, it has been demonstrated that API inhibits the growth of cancer cells, trigger apoptosis, and alter key signaling pathways that involved to the onset of cancer. With regard to BC and cancer stem cells (CSCs), the objective of this review is to present a comprehensive outline of the recent study on API, clarifying its mechanisms of action, pharmacokinetics, therapeutic efficacy, bioavailability, cytotoxicity and potential as a supplement to conventional cancer therapies. The information provided will be helpful to researchers and medical professionals who are interested in learning more about alternative cancer treatments.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201454"},"PeriodicalIF":0.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-23DOI: 10.1016/j.humgen.2025.201453
Muhammad Masroor , Zeba Haque , Haya Anwar , Farina Hanif , Waqas Ahmed Farooqui
Background
NAFLD occurs in many individuals without obesity, metabolic syndrome, or diabetes, indicating other factors like genetic predisposition play a significant role.
Objective
This study investigates the association between genetic polymorphisms (PNPLA3 and APOC3) and metabolic markers, including liver enzymes and HbA1c, in predicting NAFLD within a Pakistani population.
Methods
This case-control study was conducted at Dow University of Health Sciences from 2015 to 2021. This reports part of the data from a larger project exploring risk factors for NAFLD. Data from 60 participants including gender and age matched 43 NAFLD cases and 17 controls were analyzed for genetic polymorphisms (PNPLA3 rs738408, rs738409; APOC3 rs2845116, rs2845117) with power estimates ranging from 71.6 to 90 % for genetic parameters. Anthropometric, biochemical, and liver enzyme measurements and DNA sequencing were performed. Categorical variables were analyzed using chi-square or Fisher's exact tests, for continuous variables independent t-tests (normally distributed) and Mann-Whitney U tests for non-normal liver parameters were applied. Genetic associations were evaluated through chi-square tests with Monte Carlo simulation (for small cell counts) and effect sizes calculated using Cramer's V.
Results
Significant associations were found between NAFLD and polymorphisms APOC3 rs2845117 (C allele, p = 0.027 and APOC3 rs2845116 (T allele, p = 0.039). A significant association was also observed for PNPLA3 10109C > G (p = 0.00.030) but not PNPLA3 rs738408; 10,112C > T (p = 0.073). Cases showed significantly higher BMI, HbA1c, fasting blood glucose, serum triglycerides, and liver enzymes (ALT, Alkaline phosphatase, Gamma GT) compared to controls (p < 0.05).
Conclusions
Metabolic and anthropometric factors were strongly associated with NAFLD. Genetic variants in APOC3 (rs2845117, rs2845116) and PNPLA3 (rs738409) but not rs738408 showed significant associations with NAFLD. APOC3 rs2845117 CC conferring the highest risk for NAFLD. These markers may aid early detection and guide targeted prevention.
{"title":"Association of APOC3 and PNPLA3 genetic polymorphism in adult Pakistani population with non-alcoholic fatty liver disease","authors":"Muhammad Masroor , Zeba Haque , Haya Anwar , Farina Hanif , Waqas Ahmed Farooqui","doi":"10.1016/j.humgen.2025.201453","DOIUrl":"10.1016/j.humgen.2025.201453","url":null,"abstract":"<div><h3>Background</h3><div>NAFLD occurs in many individuals without obesity, metabolic syndrome, or diabetes, indicating other factors like genetic predisposition play a significant role.</div></div><div><h3>Objective</h3><div>This study investigates the association between genetic polymorphisms (PNPLA3 and APOC3) and metabolic markers, including liver enzymes and HbA1c, in predicting NAFLD within a Pakistani population.</div></div><div><h3>Methods</h3><div>This case-control study was conducted at Dow University of Health Sciences from 2015 to 2021. This reports part of the data from a larger project exploring risk factors for NAFLD. Data from 60 participants including gender and age matched 43 NAFLD cases and 17 controls were analyzed for genetic polymorphisms (PNPLA3 rs738408, rs738409; APOC3 rs2845116, rs2845117) with power estimates ranging from 71.6 to 90 % for genetic parameters. Anthropometric, biochemical, and liver enzyme measurements and DNA sequencing were performed. Categorical variables were analyzed using chi-square or Fisher's exact tests, for continuous variables independent <em>t</em>-tests (normally distributed) and Mann-Whitney <em>U</em> tests for non-normal liver parameters were applied. Genetic associations were evaluated through chi-square tests with Monte Carlo simulation (for small cell counts) and effect sizes calculated using Cramer's V.</div></div><div><h3>Results</h3><div>Significant associations were found between NAFLD and polymorphisms APOC3 rs2845117 (C allele, <em>p</em> = 0.027 and APOC3 rs2845116 (T allele, <em>p</em> = 0.039). A significant association was also observed for PNPLA3 10109C > G (<em>p</em> = 0.00.030) but not PNPLA3 rs738408; 10,112C > T (<em>p</em> = 0.073). Cases showed significantly higher BMI, HbA1c, fasting blood glucose, serum triglycerides, and liver enzymes (ALT, Alkaline phosphatase, Gamma GT) compared to controls (<em>p</em> < 0.05).</div></div><div><h3>Conclusions</h3><div>Metabolic and anthropometric factors were strongly associated with NAFLD. Genetic variants in <em>APOC3</em> (rs2845117, rs2845116) and <em>PNPLA3</em> (rs738409) but not rs738408 showed significant associations with NAFLD. <em>APOC3</em> rs2845117 CC conferring the highest risk for NAFLD. These markers may aid early detection and guide targeted prevention.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201453"},"PeriodicalIF":0.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Single nucleotide polymorphisms (SNPs) are prevalent genetic variations that can alter protein structure and function, contributing to disease susceptibility and progression. Among SNPs, non-synonymous SNPs (nsSNPs) occurring in coding regions lead to amino acid substitutions, potentially altering protein properties. Interleukin 18 (IL-18), a pro-inflammatory cytokine, plays a significant role in maintaining immune responses, inflammation, and cell signaling and has been associated with various inflammatory diseases and cancer. Understanding the impact of nsSNPs in IL-18 protein structure, function, and disease association can be crucial in understanding its biological roles and clinical implications. The study aims to predict the functional consequence of nsSNPs in the human IL18 gene and explore the correlation between IL-18 dysregulation and cancer patient survival rates. The study involves an in-silico approach to identify, characterize, and validate harmful nsSNPs. The tools include SIFT, PROVEAN, and PolyPhen-2 to identify deleterious SNP. I-Mutant 2.0 was used to assess protein stability, MutPred2 was used to identify disease-associated SNPs, and Clustal Omega and ConSurf were used for conservation analysis. Furthermore, the tertiary structure of the mutant protein was modelled and compared to the wild type using I-Tasser, ChimeraX, and ClusPro. Finally, the Kaplan Meier plot explores the correlation between gene deregulation and cancer patient survival rates. Analysis of 7802 SNPs identified 31 high-confidence nsSNPs in coding regions, with stability analysis revealing 23 destabilizing and 5 stabilizing nsSNPs. MutPred2 suggested potential functional changes. Conservation analysis identified critical residues, including D71G, E67D, E34A, and S111F (highly conserved and exposed) and Y24H, A162T, F137S, F137L, and V98G (conserved and buried). The mutant-modelled protein showed minor deviations from wild-type IL-18 proteins. The docking result revealed altered binding affinities with the IL-18 receptor. The Kaplan-Meier analysis revealed that high IL18 expression is associated with poor survival in gastric and lung cancers, while low expression is linked to poor outcomes in breast and ovarian cancers.
{"title":"Predicting the functional consequences of non-synonymous single nucleotide polymorphism (nsSNPs) in human IL-18 gene: an in-silico approach","authors":"Praveen Kumar Sahni , Bunty Sharma , Sanjay Kumar Singh , Damandeep Kaur , Shafiul Haque , Hardeep Singh Tuli , Ujjawal Sharma","doi":"10.1016/j.humgen.2025.201451","DOIUrl":"10.1016/j.humgen.2025.201451","url":null,"abstract":"<div><div>Single nucleotide polymorphisms (SNPs) are prevalent genetic variations that can alter protein structure and function, contributing to disease susceptibility and progression. Among SNPs, non-synonymous SNPs (nsSNPs) occurring in coding regions lead to amino acid substitutions, potentially altering protein properties. Interleukin 18 (IL-18), a pro-inflammatory cytokine, plays a significant role in maintaining immune responses, inflammation, and cell signaling and has been associated with various inflammatory diseases and cancer. Understanding the impact of nsSNPs in IL-18 protein structure, function, and disease association can be crucial in understanding its biological roles and clinical implications. The study aims to predict the functional consequence of nsSNPs in the human <em>IL18</em> gene and explore the correlation between IL-18 dysregulation and cancer patient survival rates. The study involves an in-silico approach to identify, characterize, and validate harmful nsSNPs. The tools include SIFT, PROVEAN, and PolyPhen-2 to identify deleterious SNP. I-Mutant 2.0 was used to assess protein stability, MutPred2 was used to identify disease-associated SNPs, and Clustal Omega and ConSurf were used for conservation analysis. Furthermore, the tertiary structure of the mutant protein was modelled and compared to the wild type using I-Tasser, ChimeraX, and ClusPro. Finally, the Kaplan Meier plot explores the correlation between gene deregulation and cancer patient survival rates. Analysis of 7802 SNPs identified 31 high-confidence nsSNPs in coding regions, with stability analysis revealing 23 destabilizing and 5 stabilizing nsSNPs. MutPred2 suggested potential functional changes. Conservation analysis identified critical residues, including D71G, E67D, E34A, and S111F (highly conserved and exposed) and Y24H, A162T, F137S, F137L, and V98G (conserved and buried). The mutant-modelled protein showed minor deviations from wild-type IL-18 proteins. The docking result revealed altered binding affinities with the IL-18 receptor. The Kaplan-Meier analysis revealed that high IL18 expression is associated with poor survival in gastric and lung cancers, while low expression is linked to poor outcomes in breast and ovarian cancers.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201451"},"PeriodicalIF":0.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Long non-coding RNAs (lncRNAs), once deemed to be non-coding sequences, but recent discoveries in genomic profiling prove that they code for small peptides with functional properties. These lncRNA-encoded peptides, known as lncPeptide (lncPEPs), have found to be involved various biological pathways with critical implications in various diseases. This review explores the expanding role of lncPEPs by examining their structural domains and their functions across various cellular pathways. It also elaborates its applications as novel biomarkers and therapeutical targets, with major focus on their involvement in disease progression. We have presented both the experimental and computational approaches used to discover and validate lncPEPs and key methodologies including ribosome profiling, targeted proteomics, CRISPR-based loss-of-function screens, and specialized bioinformatic pipelines for coding-potential prediction. Based on recent experimental findings and computational analysis, we highlight the growing functional significance of lncRNAs which underscore the potential of lncPEPs in future research on disease diagnosis and therapeutic development.
{"title":"Unveiling the functional implications of long noncoding RNA (lncRNA) encoded peptides in various diseases","authors":"Anto Antony Selvaraj , Rajshri Singh , Sagar Barage","doi":"10.1016/j.humgen.2025.201452","DOIUrl":"10.1016/j.humgen.2025.201452","url":null,"abstract":"<div><div>Long non-coding RNAs (lncRNAs), once deemed to be non-coding sequences, but recent discoveries in genomic profiling prove that they code for small peptides with functional properties. These lncRNA-encoded peptides, known as lncPeptide (lncPEPs), have found to be involved various biological pathways with critical implications in various diseases. This review explores the expanding role of lncPEPs by examining their structural domains and their functions across various cellular pathways. It also elaborates its applications as novel biomarkers and therapeutical targets, with major focus on their involvement in disease progression. We have presented both the experimental and computational approaches used to discover and validate lncPEPs and key methodologies including ribosome profiling, targeted proteomics, CRISPR-based loss-of-function screens, and specialized bioinformatic pipelines for coding-potential prediction. Based on recent experimental findings and computational analysis, we highlight the growing functional significance of lncRNAs which underscore the potential of lncPEPs in future research on disease diagnosis and therapeutic development.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201452"},"PeriodicalIF":0.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-11DOI: 10.1016/j.humgen.2025.201450
Eman Mohamed Abdellatif , Emad Hamdy Hamouda Mohammed , Sally Wassfi Zaki Hammad
Background
Early diagnosis of sepsis is a crucial component in improving disease prognosis and reducing mortality. The interindividual variations in susceptibility to sepsis, and in disease outcome, can be affected by several interacting elements including genetic factors. We aimed to investigate the relation of the angiotensin converting enzyme 1 (ACE1) gene polymorphism rs1799752 with the risk of sepsis in adult patients, and its relation with disease severity and prognosis.
Methods
In this case-control prospective study, we included 65 adult sepsis patients and 65 control subjects. For all study subjects, blood samples were collected for DNA extraction, followed by polymerase chain reaction for ACE1 rs1799752 genotyping. Clinical, laboratory data, and severity scores were recorded. Patients were followed up, and were divided into survivors (n = 40) and non-survivors (n = 25).
Results
DD genotype and D allele were significantly more frequent in sepsis patients than in control group, (p = 0.011, p = 0.022, respectively). Although DD genotype was associated with an increased risk of sepsis in univariate analysis, it was an insignificant risk factor in multivariate analysis (OR 1.455, 95 %CI 0.609–3.476, p = 0.399). SOFA scores and APACHEII scores were significantly higher in patients with DD genotype than other genotypes (p < 0.001). Multivariate regression analysis showed that DD genotype was a significant independent predictor of mortality in the included patients.
Conclusion
The current observations revealed a potential prognostic role of the ACE1 insertion/deletion polymorphism in sepsis, where the DD genotype was significantly associated with greater disease severity and higher mortality rates, in comparison with other genotypes.
背景败血症的早期诊断是改善疾病预后和降低死亡率的重要组成部分。对败血症的易感性和疾病结局的个体间差异可能受到包括遗传因素在内的几个相互作用因素的影响。我们旨在探讨血管紧张素转换酶1 （ACE1）基因多态性rs1799752与成人患者脓毒症风险的关系，以及与疾病严重程度和预后的关系。方法在本病例-对照前瞻性研究中，我们纳入65例成人脓毒症患者和65例对照组。对所有研究对象采集血样进行DNA提取，然后进行聚合酶链反应进行ACE1 rs1799752基因分型。记录临床、实验室数据和严重程度评分。对患者进行随访，将患者分为幸存者（n = 40）和非幸存者（n = 25）。结果脓毒症患者中dd基因型和D等位基因的发生率明显高于对照组（p = 0.011, p = 0.022）。虽然DD基因型在单因素分析中与脓毒症风险增加相关，但在多因素分析中，它是一个不显著的危险因素（OR 1.4555, 95% CI 0.609-3.476, p = 0.399）。DD基因型患者的SOFA评分和APACHEII评分均显著高于其他基因型患者(p <；0.001)。多因素回归分析显示，DD基因型是入选患者死亡率的重要独立预测因子。目前的观察结果揭示了ACE1插入/缺失多态性在脓毒症中的潜在预后作用，与其他基因型相比，DD基因型与更大的疾病严重程度和更高的死亡率显著相关。
{"title":"Relationship between the rs1799752 polymorphism of angiotensin-converting enzyme gene and susceptibility to sepsis in Egyptian patients: A single-center prospective study","authors":"Eman Mohamed Abdellatif , Emad Hamdy Hamouda Mohammed , Sally Wassfi Zaki Hammad","doi":"10.1016/j.humgen.2025.201450","DOIUrl":"10.1016/j.humgen.2025.201450","url":null,"abstract":"<div><h3>Background</h3><div>Early diagnosis of sepsis is a crucial component in improving disease prognosis and reducing mortality. The interindividual variations in susceptibility to sepsis, and in disease outcome, can be affected by several interacting elements including genetic factors. We aimed to investigate the relation of the angiotensin converting enzyme 1 (ACE1) gene polymorphism rs1799752 with the risk of sepsis in adult patients, and its relation with disease severity and prognosis.</div></div><div><h3>Methods</h3><div>In this case-control prospective study, we included 65 adult sepsis patients and 65 control subjects. For all study subjects, blood samples were collected for DNA extraction, followed by polymerase chain reaction for ACE1 rs1799752 genotyping. Clinical, laboratory data, and severity scores were recorded. Patients were followed up, and were divided into survivors (<em>n</em> = 40) and non-survivors (<em>n</em> = 25).</div></div><div><h3>Results</h3><div>DD genotype and D allele were significantly more frequent in sepsis patients than in control group, (<em>p</em> = 0.011, <em>p</em> = 0.022, respectively). Although DD genotype was associated with an increased risk of sepsis in univariate analysis, it was an insignificant risk factor in multivariate analysis (OR 1.455, 95 %CI 0.609–3.476, <em>p</em> = 0.399). SOFA scores and APACHEII scores were significantly higher in patients with DD genotype than other genotypes (<em>p</em> < 0.001). Multivariate regression analysis showed that DD genotype was a significant independent predictor of mortality in the included patients.</div></div><div><h3>Conclusion</h3><div>The current observations revealed a potential prognostic role of the ACE1 insertion/deletion polymorphism in sepsis, where the DD genotype was significantly associated with greater disease severity and higher mortality rates, in comparison with other genotypes.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201450"},"PeriodicalIF":0.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144632122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1016/j.humgen.2025.201448
Zahraa isam jameel , Hanan Ali Kareem , Zahraa Mohammed Yahya , Ahmed Ali Hussein , zahraa abdel Kareem
Non-coding RNAs known as microRNAs (miRNAs) play a role as oncogenes or tumor suppressors. One form of genetic variation in the human genome is single nucleotide polymorphism (SNP) in miRNA regions. The relationships between miRNA SNPs and different types of cancer have been the subject of numerous investigations. This article looks into the link between colorectal cancer (CRC) and specific variations known as mir-196a2 and mir-146a. It does this by reviewing related research studies. To find all the papers that were relevant, we searched the literature in PubMed, Web of Science, and Science Direct. We evaluated the associations using three genetic models, which included a pooled ratio and a 95 % confidence range. In the groups from China, Italy, and Greece, we found a strong connection between the mir-196a2 genetic variation and colorectal cancer (CRC). The odds ratios (OR) for the different models were: for the additive model, it was 1.99, which means there was a significant link; for the dominant model, it was 1.24, which also meant there was a significant link; and for the recessive model, it was 1.09, which also meant there was a significant link. We found that the mir-146a variant greatly lowered the risk of cancer in allele (OR 0.32, 95 % CI 0.30–0.34, p = 0.0001, G vs. C), dominant (OR 0.72, 95 % CI 0.68–0.77), and heterozygous codominant (OR 0.51, 95 % CI 0.49–0.54, p = 0.000, GC vs. CC) genetic models. Stratified studies found that the mir-146a variation significantly reduced the risk of colon cancer. This meta-analysis adds to the growing body of evidence linking the mir-196a2 gene variant to colorectal cancer, particularly in the populations of Greece, Italy, and China. Our results indicate that the C/G polymorphism of miR-146a does not seem to be associated with CRC susceptibility. We need additional case-control studies to back up our findings in the future.
被称为microRNAs （miRNAs）的非编码rna扮演癌基因或肿瘤抑制因子的角色。人类基因组遗传变异的一种形式是miRNA区域的单核苷酸多态性（SNP）。miRNA snp与不同类型癌症之间的关系已经成为许多研究的主题。本文探讨了结直肠癌（CRC）与mir-196a2和mir-146a特异性变异之间的联系。它通过回顾相关研究来做到这一点。为了找到所有相关的论文，我们搜索了PubMed、Web of Science和Science Direct的文献。我们使用三种遗传模型来评估相关性，其中包括合并比率和95%的置信范围。在来自中国、意大利和希腊的人群中，我们发现mir-196a2遗传变异与结直肠癌（CRC）之间存在很强的联系。不同模型的比值比（OR）为：加性模型的比值比为1.99，表明存在显著关联；对于主导模型，它是1.24，这也意味着有显著的联系；对于隐性模型，它是1.09，这也意味着有显著的联系。我们发现mir-146a变体大大降低了等位基因（OR 0.32, 95% CI 0.30-0.34, p = 0.0001, G vs C）、显性（OR 0.72, 95% CI 0.68-0.77）和杂合共显性（OR 0.51, 95% CI 0.49-0.54, p = 0.000, GC vs CC）遗传模型的癌症风险。分层研究发现，mir-146a变异显著降低结肠癌的风险。这项荟萃分析增加了越来越多的证据将mir-196a2基因变异与结直肠癌联系起来，特别是在希腊、意大利和中国的人群中。我们的研究结果表明，miR-146a的C/G多态性似乎与CRC易感性无关。我们需要更多的病例对照研究来支持我们未来的发现。
{"title":"Association of mir196a2 and mir146a polymorphisms and colorectal cancer risk: A meta-analysis","authors":"Zahraa isam jameel , Hanan Ali Kareem , Zahraa Mohammed Yahya , Ahmed Ali Hussein , zahraa abdel Kareem","doi":"10.1016/j.humgen.2025.201448","DOIUrl":"10.1016/j.humgen.2025.201448","url":null,"abstract":"<div><div>Non-coding RNAs known as microRNAs (miRNAs) play a role as oncogenes or tumor suppressors. One form of genetic variation in the human genome is single nucleotide polymorphism (SNP) in miRNA regions. The relationships between miRNA SNPs and different types of cancer have been the subject of numerous investigations. This article looks into the link between colorectal cancer (CRC) and specific variations known as mir-196a2 and mir-146a. It does this by reviewing related research studies. To find all the papers that were relevant, we searched the literature in PubMed, Web of Science, and Science Direct. We evaluated the associations using three genetic models, which included a pooled ratio and a 95 % confidence range. In the groups from China, Italy, and Greece, we found a strong connection between the mir-196a2 genetic variation and colorectal cancer (CRC). The odds ratios (OR) for the different models were: for the additive model, it was 1.99, which means there was a significant link; for the dominant model, it was 1.24, which also meant there was a significant link; and for the recessive model, it was 1.09, which also meant there was a significant link. We found that the mir-146a variant greatly lowered the risk of cancer in allele (OR 0.32, 95 % CI 0.30–0.34, <em>p</em> = 0.0001, G vs. C), dominant (OR 0.72, 95 % CI 0.68–0.77), and heterozygous codominant (OR 0.51, 95 % CI 0.49–0.54, p = 0.000, GC vs. CC) genetic models. Stratified studies found that the mir-146a variation significantly reduced the risk of colon cancer. This meta-analysis adds to the growing body of evidence linking the mir-196a2 gene variant to colorectal cancer, particularly in the populations of Greece, Italy, and China. Our results indicate that the C/G polymorphism of miR-146a does not seem to be associated with CRC susceptibility. We need additional case-control studies to back up our findings in the future.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201448"},"PeriodicalIF":0.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144632123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1016/j.humgen.2025.201449
Kolawole Yusuf Suleiman , Hamidu Ahmed , Kigir Esther Solomon , Gbadebo Hakeem Ibraheem , Abdulbaki Adio Alfa-Ibrahim , Okediran Babatunde Samuel , Alhaji Zubair Jaji
Osteoporosis is a pervasive skeletal disorder characterized by diminished bone mass and structural deterioration, resulting in heightened fracture risk. While genetic predispositions and hormonal factors have been extensively studied, a significant portion of osteoporosis pathogenesis remains unexplained, necessitating a deeper exploration of the role of epigenetic modifications. This review elucidates the intricate interplay between epigenetic mechanisms, specifically DNA methylation, histone modifications, and non-coding RNAs, and bone metabolism. We discuss how these reversible modifications serve as critical regulators influenced by environmental factors, lifestyle, and age, thus representing a nexus between genetic susceptibility and external risk factors.
Emerging evidence highlights the epigenetic alterations in key genes involved in osteogenesis and osteoclastogenesis, underscoring their contributions to the development of osteoporosis. Furthermore, we explore innovative therapeutic strategies targeting these epigenetic changes, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, which offer promising routes for restoring normal bone function and providing personalized therapeutic options. The insights garnered from this review position epigenetics as a transformative frontier in osteoporosis research, with the potential to unveil novel biomarkers for early diagnosis and targeted treatment strategies. This comprehensive examination of epigenetic influences on bone health underlines the urgency for continued research in this domain, aiming to improve therapeutic outcomes and enhance overall disease management.
{"title":"Epigenetic modifications in Bone metabolism: Exploring the link with osteoporosis","authors":"Kolawole Yusuf Suleiman , Hamidu Ahmed , Kigir Esther Solomon , Gbadebo Hakeem Ibraheem , Abdulbaki Adio Alfa-Ibrahim , Okediran Babatunde Samuel , Alhaji Zubair Jaji","doi":"10.1016/j.humgen.2025.201449","DOIUrl":"10.1016/j.humgen.2025.201449","url":null,"abstract":"<div><div>Osteoporosis is a pervasive skeletal disorder characterized by diminished bone mass and structural deterioration, resulting in heightened fracture risk. While genetic predispositions and hormonal factors have been extensively studied, a significant portion of osteoporosis pathogenesis remains unexplained, necessitating a deeper exploration of the role of epigenetic modifications. This review elucidates the intricate interplay between epigenetic mechanisms, specifically DNA methylation, histone modifications, and non-coding RNAs, and bone metabolism. We discuss how these reversible modifications serve as critical regulators influenced by environmental factors, lifestyle, and age, thus representing a nexus between genetic susceptibility and external risk factors.</div><div>Emerging evidence highlights the epigenetic alterations in key genes involved in osteogenesis and osteoclastogenesis, underscoring their contributions to the development of osteoporosis. Furthermore, we explore innovative therapeutic strategies targeting these epigenetic changes, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, which offer promising routes for restoring normal bone function and providing personalized therapeutic options. The insights garnered from this review position epigenetics as a transformative frontier in osteoporosis research, with the potential to unveil novel biomarkers for early diagnosis and targeted treatment strategies. This comprehensive examination of epigenetic influences on bone health underlines the urgency for continued research in this domain, aiming to improve therapeutic outcomes and enhance overall disease management.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201449"},"PeriodicalIF":0.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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