Pub Date : 2025-12-09DOI: 10.1016/j.gene.2025.149949
Yang Li , Xiang Dong , Jian Guo , Ya-feng Lv
Globoid cell leukodystrophy (GLD) is an autosomal recessive lysosomal storage disorder caused by mutations in the β-galactosylceramidase (GALC) gene, resulting in enzyme deficiency and the progressive accumulation of galactosylsphingosine and galactosylceramide in the white matter of the central nervous system and in peripheral nerves, which in turn triggers demyelination. Although no curative therapy is currently available, studies in animal models in recent years have shown that gene therapy can ameliorate pathological and biochemical abnormalities and holds considerable promise for clinical translation. This article reviews advances in gene therapy in animal models of GLD and discusses key directions and challenges for future treatments.
{"title":"Gene therapy for Krabbe disease: evidence from mouse and canine models","authors":"Yang Li , Xiang Dong , Jian Guo , Ya-feng Lv","doi":"10.1016/j.gene.2025.149949","DOIUrl":"10.1016/j.gene.2025.149949","url":null,"abstract":"<div><div>Globoid cell leukodystrophy (GLD) is an autosomal recessive lysosomal storage disorder caused by mutations in the β-galactosylceramidase<!--> <!-->(<em>GALC</em>) gene, resulting in enzyme deficiency and the progressive accumulation of galactosylsphingosine and galactosylceramide in the white matter of the central nervous system and in peripheral nerves, which in turn triggers demyelination. Although no curative therapy is currently available, studies in animal models in recent years have shown that gene therapy can ameliorate pathological and biochemical abnormalities and holds considerable promise for clinical translation. This article reviews advances in gene therapy in animal models of GLD and discusses key directions and challenges for future treatments.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"980 ","pages":"Article 149949"},"PeriodicalIF":2.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As organisms age, physiological and pathological changes occur, with altered lncRNA expression playing a key role. However, their regulatory mechanisms in aging remain unclear. This study investigates the differential expression of lncRNAs between aged and young mice, and explores the lncRNA–miRNA–mRNA interplay to gain insights into the molecular basis of aging.
Methods
We performed whole-transcriptome sequencing on tibialis anterior muscles from four aged (20-month-old) and four young (3-month-old) mice. Hub genes were identified via PPI and WGCNA analyses, followed by functional enrichment. Integrative analysis revealed interactions among differentially expressed lncRNAs, miRNAs, and mRNAs, leading to the construction of cis-/trans-regulatory and ceRNA networks.
Results
Our results revealed 746 significantly differentially expressed known lncRNAs (465 upregulated, 281 downregulated) and 27 novel lncRNAs in aged mouse TA muscle, alongside 50 miRNAs and 1124 mRNAs. Based on lncRNA classification (antisense, intergenic, intronic), we constructed subtype-specific cis- and trans-regulatory networks. Hub genes were identified via PPI and WGCNA analyses to further refine these networks. Highly expressed and variable genes were also integrated into regulatory mapping. Enrichment analyses indicated involvement in extracellular matrix remodeling, epithelial cell migration, and immune response.
Conclusions
This study systematically profiled age-related changes in lncRNAs, miRNAs, and mRNAs in TA muscle, and constructed core regulatory networks based on lncRNA subtypes. This study systematically profiled age-related transcriptomic changes in mouse skeletal muscle and constructed lncRNA–miRNA–mRNA regulatory networks associated with aging. These results provide a valuable resource and generate hypotheses for future experimental validation of lncRNA-mediated regulatory mechanisms in muscle aging.
{"title":"Comprehensive transcriptomic profiling reveals lncRNA–miRNA–mRNA regulatory networks in skeletal muscle aging of mice","authors":"Jinrui Jia, Qingyan Wang, Xuanye Jiang, Hao Chen, Minwei Huang, Bing Ni, Huiying Zhang, Xin’e Shi, Jianjun Jin","doi":"10.1016/j.gene.2025.149946","DOIUrl":"10.1016/j.gene.2025.149946","url":null,"abstract":"<div><h3>Purpose</h3><div>As organisms age, physiological and pathological changes occur, with altered lncRNA expression playing a key role. However, their regulatory mechanisms in aging remain unclear. This study investigates the differential expression of lncRNAs between aged and young mice, and explores the lncRNA–miRNA–mRNA interplay to gain insights into the molecular basis of aging.</div></div><div><h3>Methods</h3><div>We performed whole-transcriptome sequencing on tibialis anterior muscles from four aged (20-month-old) and four young (3-month-old) mice. Hub genes were identified via PPI and WGCNA analyses, followed by functional enrichment. Integrative analysis revealed interactions among differentially expressed lncRNAs, miRNAs, and mRNAs, leading to the construction of cis-/<em>trans</em>-regulatory and ceRNA networks.</div></div><div><h3>Results</h3><div>Our results revealed 746 significantly differentially expressed known lncRNAs (465 upregulated, 281 downregulated) and 27 novel lncRNAs in aged mouse TA muscle, alongside 50 miRNAs and 1124 mRNAs. Based on lncRNA classification (antisense, intergenic, intronic), we constructed subtype-specific cis- and <em>trans</em>-regulatory networks. Hub genes were identified via PPI and WGCNA analyses to further refine these networks. Highly expressed and variable genes were also integrated into regulatory mapping. Enrichment analyses indicated involvement in extracellular matrix remodeling, epithelial cell migration, and immune response.</div></div><div><h3>Conclusions</h3><div>This study systematically profiled age-related changes in lncRNAs, miRNAs, and mRNAs in TA muscle, and constructed core regulatory networks based on lncRNA subtypes. This study systematically profiled age-related transcriptomic changes in mouse skeletal muscle and constructed lncRNA–miRNA–mRNA regulatory networks associated with aging. These results provide a valuable resource and generate hypotheses for future experimental validation of lncRNA-mediated regulatory mechanisms in muscle aging.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149946"},"PeriodicalIF":2.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145722080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-07DOI: 10.1016/j.gene.2025.149933
Soumi Chowdhury , Harsh Pawar
The Target of Rapamycin (TOR) kinase family is a central regulator of eukaryotic cell growth and metabolism. Unlike most eukaryotes that possess one or two TOR genes, Leishmania species encode four distinct paralogs, suggesting lineage-specific expansion and functional diversification. In this study, we performed a comprehensive phylogenetic and domain analysis of TOR paralogs across multiple Leishmania species, with Trypanosoma brucei serving as a comparative reference. TOR1 and TOR2 were found to be highly conserved, possessing canonical FAT, FRB, and PI3Kc domains, consistent with their roles in the essential TORC1 and TORC2 complexes. TOR3 and TOR4 displayed significant sequence divergence and altered domain structures, particularly in visceral and mucocutaneous species. TOR3 lacks the FRB domain but retains kinase activity and is implicated in arginine sensing and acidocalcisome biogenesis. TOR4 shows the highest divergence, including truncated domains and species-specific clustering, suggesting a role in parasite adaptation or stage differentiation. Functional annotations further support this, as TOR1 and TOR2 are enriched in kinase functions, while TOR3 and TOR4 are associated with hypothetical or uncharacterized proteins. The conserved PI3Kc domain across all paralogs offers a target for drug development. These findings enhance our understanding of TOR evolution and its therapeutic potential in leishmaniasis.
{"title":"Target of rapamycin (TOR) kinases in Leishmania: Insights from comparative analyses with Trypanosomatids","authors":"Soumi Chowdhury , Harsh Pawar","doi":"10.1016/j.gene.2025.149933","DOIUrl":"10.1016/j.gene.2025.149933","url":null,"abstract":"<div><div>The Target of Rapamycin (TOR) kinase family is a central regulator of eukaryotic cell growth and metabolism. Unlike most eukaryotes that possess one or two TOR genes, <em>Leishmania</em> species encode four distinct paralogs, suggesting lineage-specific expansion and functional diversification. In this study, we performed a comprehensive phylogenetic and domain analysis of TOR paralogs across multiple <em>Leishmania</em> species, with <em>Trypanosoma brucei</em> serving as a comparative reference. TOR1 and TOR2 were found to be highly conserved, possessing canonical FAT, FRB, and PI3Kc domains, consistent with their roles in the essential TORC1 and TORC2 complexes. TOR3 and TOR4 displayed significant sequence divergence and altered domain structures, particularly in visceral and mucocutaneous species. TOR3 lacks the FRB domain but retains kinase activity and is implicated in arginine sensing and acidocalcisome biogenesis. TOR4 shows the highest divergence, including truncated domains and species-specific clustering, suggesting a role in parasite adaptation or stage differentiation. Functional annotations further support this, as TOR1 and TOR2 are enriched in kinase functions, while TOR3 and TOR4 are associated with hypothetical or uncharacterized proteins. The conserved PI3Kc domain across all paralogs offers a target for drug development. These findings enhance our understanding of TOR evolution and its therapeutic potential in leishmaniasis.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149933"},"PeriodicalIF":2.4,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-06DOI: 10.1016/j.gene.2025.149944
Ziling Tao , Shiyu Cai , YiMing Wang, Fengxiu li, Lu Lv, Haimeng Bai, Ludan Li, Jihong Jiang, Xiaoying Cao
Dendrobium officinale is renowned as the foremost among the “Nine Immortal Herbs of China”. Our previous research showed enhanced flavonoid accumulation following induction by the endophyte Wickerhamomyces sp. KLBMPSYLp8. Transcriptome data analysis identified multiple upregulated transcription factor (TF) genes. We conducted transient overexpression analysis of 10 significantly upregulated TF genes in D. officinale leaves. The results demonstrated that transient overexpression of the DoWRKY26 significantly enhanced flavonoid accumulation, with a 33 % increase compared to the empty vector control group. Furthermore, DoWRKY26 overexpression also upregulated the expression levels of key enzyme genes implicated in the flavonoid biosynthesis pathway. Subcellular localization confirmed its nuclear presence. DoWRKY26 expression was induced by salicylic acid (SA), abscisic acid (ABA), 1-Aminocyclopropane-1-carboxylic Acid (ACC) and methyl jasmonate (MeJA). Yeast one-hybrid (Y1H), Electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assays verified that DoWRKY26 could bind and activate the promoter of DoCCoAOMT. These findings provide a foundational basis for further exploring the biosynthesis and transcriptional regulation mechanisms of flavonoids in D. officinale.
{"title":"DoWRKY26 positively regulating flavonoid biosynthesis in Dendrobium officinale","authors":"Ziling Tao , Shiyu Cai , YiMing Wang, Fengxiu li, Lu Lv, Haimeng Bai, Ludan Li, Jihong Jiang, Xiaoying Cao","doi":"10.1016/j.gene.2025.149944","DOIUrl":"10.1016/j.gene.2025.149944","url":null,"abstract":"<div><div><em>Dendrobium officinale</em> is renowned as the foremost among the “Nine Immortal Herbs of China”. Our previous research showed enhanced flavonoid accumulation following induction by the endophyte <em>Wickerhamomyces</em> sp. KLBMPSYLp8. Transcriptome data analysis identified multiple upregulated transcription factor (TF) genes. We conducted transient overexpression analysis of 10 significantly upregulated TF genes in <em>D. officinale</em> leaves. The results demonstrated that transient overexpression of the <em>DoWRKY26</em> significantly enhanced flavonoid accumulation, with a 33 % increase compared to the empty vector control group. Furthermore, <em>DoWRKY26</em> overexpression also upregulated the expression levels of key enzyme genes implicated in the flavonoid biosynthesis pathway. Subcellular localization confirmed its nuclear presence. <em>DoWRKY26</em> expression was induced by salicylic acid (SA), abscisic acid (ABA), 1-Aminocyclopropane-1-carboxylic Acid (ACC) and methyl jasmonate (MeJA). Yeast one-hybrid (Y1H), Electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assays verified that DoWRKY26 could bind and activate the promoter of <em>DoCCoAOMT</em>. These findings provide a foundational basis for further exploring the biosynthesis and transcriptional regulation mechanisms of flavonoids in <em>D. officinale</em>.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149944"},"PeriodicalIF":2.4,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-06DOI: 10.1016/j.gene.2025.149934
Xin Lin , Zi-yan Xu , Li-jun Xie , Juan Zhu , Hong-ping Yu , Ruo-li Wang , Yi-jia Luo , Jing Zou , Jian-hui Zhang , Qian Chen , Peng-fei Wang , Dan-dan Ruan , Yan-feng Zhou , Li Chen , Fang-meng Huang , Mei-zhu Gao , Li Zhang , Yun-fei Li , Zhu-ting Fang , Jue Wang , Jie-wei Luo
Type A insulin resistance syndrome (TAIRS) is a rare autosomal dominant disorder associated with variants in the Insulin Receptor (INSR) gene. It is characterized by insulin resistance, hyperandrogenism, and acanthosis nigricans. The severity of the condition may be influenced by homozygosity or heterozygosity, with some female patients being misdiagnosed with polycystic ovary syndrome (PCOS). A 13-year-old female proband from a family was identified with hyperinsulinemia, hyperandrogenism, acanthosis nigricans, hirsutism, acne, oligomenorrhea, and masculinization. Exome sequencing and Sanger sequencing confirmed that the proband was a carrier of the INSR (NM_000208.2): c.3734 T > A(p.V1245E) variant. This variant is not listed in the Human Gene Mutation Database (HGMD) or ClinVar. The novel variant was predicted to be deleterious by the bioinformatic tools SIFT, MutationTaster, and Condel. According to the American College of Medical Genetics and Genomics (ACMG) criteria, it was evaluated as PM6, PM2_Supporting, and PP3, and classified as uncertain significance. The variant was not detected in the proband’s parents or other family members, all of whom lacked the associated clinical phenotypes. The p.V1245E variant was found to be a de novo variant. SWISS-MODEL analysis suggested that the p.V1245E variant induces structural changes in the three-dimensional configuration of the INSR protein, potentially impairing its normal function. RT-qPCR revealed a significant reduction in INSR mRNA expression in the proband. In a 293 T cell model transfected with lentivirus carrying the p.V1245E variant, both Western blotting and RT-qPCR demonstrated decreased INSR mRNA and protein expression, while immunofluorescence showed reduced INSR protein levels with altered localization. Therefore, the ACMG evaluation (PS2, PS3, PM2_Supporting, PP3) was further upgraded to pathogenic. In conclusion, this de novo variant represents the pathogenic variant responsible for TAIRS in this family, expanding the variant spectrum of the INSR gene.
A型胰岛素抵抗综合征（TAIRS）是一种罕见的常染色体显性遗传病，与胰岛素受体（INSR）基因变异有关。它的特点是胰岛素抵抗、雄激素过多和黑棘皮病。多囊卵巢综合征的严重程度可能受纯合性或杂合性的影响，一些女性患者被误诊为多囊卵巢综合征（PCOS）。来自一个家庭的13岁女性先证被鉴定为高胰岛素血症、高雄激素症、黑棘皮病、多毛症、痤疮、少月经和男性化。外显子组测序和Sanger测序证实先证者为INSR （NM_000208.2）的携带者：c.3734 T > a (p。V1245E)变异。这种变异没有在人类基因突变数据库（HGMD）或ClinVar中列出。通过生物信息学工具SIFT、MutationTaster和Condel预测该新变异是有害的。根据美国医学遗传学和基因组学学会（ACMG）的标准，评估为PM6、pm2_support和PP3，并归类为不确定意义。该变异未在先证者的父母或其他家庭成员中检测到，他们都缺乏相关的临床表型。p.V1245E改型被发现是一个全新的改型。SWISS-MODEL分析表明，p.V1245E变异诱导了INSR蛋白三维构型的结构变化，潜在地损害了其正常功能。RT-qPCR显示先证者中INSR mRNA表达显著降低。在携带p.V1245E变异体的慢病毒转染293 T细胞模型中，Western blotting和RT-qPCR均显示INSR mRNA和蛋白表达降低，而免疫荧光显示INSR蛋白水平降低，定位改变。因此，ACMG评价（PS2、PS3、pm2_support、PP3）进一步升级为致病性。总之，这一新生变异代表了该家族中导致TAIRS的致病变异，扩大了INSR基因的变异谱。
{"title":"A de novo INSR variant in Type A insulin resistance syndrome: familial investigation and genetic implications","authors":"Xin Lin , Zi-yan Xu , Li-jun Xie , Juan Zhu , Hong-ping Yu , Ruo-li Wang , Yi-jia Luo , Jing Zou , Jian-hui Zhang , Qian Chen , Peng-fei Wang , Dan-dan Ruan , Yan-feng Zhou , Li Chen , Fang-meng Huang , Mei-zhu Gao , Li Zhang , Yun-fei Li , Zhu-ting Fang , Jue Wang , Jie-wei Luo","doi":"10.1016/j.gene.2025.149934","DOIUrl":"10.1016/j.gene.2025.149934","url":null,"abstract":"<div><div>Type A insulin resistance syndrome (TAIRS) is a rare autosomal dominant disorder associated with variants in the Insulin Receptor (<em>INSR</em>) gene. It is characterized by insulin resistance, hyperandrogenism, and acanthosis nigricans. The severity of the condition may be influenced by homozygosity or heterozygosity, with some female patients being misdiagnosed with polycystic ovary syndrome (PCOS). A 13-year-old female proband from a family was identified with hyperinsulinemia, hyperandrogenism, acanthosis nigricans, hirsutism, acne, oligomenorrhea, and masculinization. Exome sequencing and Sanger sequencing confirmed that the proband was a carrier of the <em>INSR</em> (NM_000208.2): c.3734 T > A(p.V1245E) variant. This variant is not listed in the Human Gene Mutation Database (HGMD) or ClinVar. The novel variant was predicted to be deleterious by the bioinformatic tools SIFT, MutationTaster, and Condel. According to the American College of Medical Genetics and Genomics (ACMG) criteria, it was evaluated as PM6, PM2_Supporting, and PP3, and classified as uncertain significance. The variant was not detected in the proband’s parents or other family members, all of whom lacked the associated clinical phenotypes. The p.V1245E variant was found to be a <em>de novo</em> variant. SWISS-MODEL analysis suggested that the p.V1245E variant induces structural changes in the three-dimensional configuration of the <em>INSR</em> protein, potentially impairing its normal function. RT-qPCR revealed a significant reduction in <em>INSR</em> mRNA expression in the proband. In a 293 T cell model transfected with lentivirus carrying the p.V1245E variant, both Western blotting and RT-qPCR demonstrated decreased <em>INSR</em> mRNA and protein expression, while immunofluorescence showed reduced <em>INSR</em> protein levels with altered localization. Therefore, the ACMG evaluation (PS2, PS3, PM2_Supporting, PP3) was further upgraded to pathogenic. In conclusion, this de novo variant represents the pathogenic variant responsible for TAIRS in this family, expanding the variant spectrum of the <em>INSR</em> gene.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149934"},"PeriodicalIF":2.4,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pharmacogenomics investigates how genetic variation influences individual responses to drug therapy and aims to optimize treatment outcomes through personalized approaches. Bioinformatics plays a foundational role in this field, enabling the processing, annotation, and interpretation of complex genomic and multi-omics datasets. This review explores the current landscape of bioinformatics in pharmacogenomics, including key databases, variant analysis tools, and artificial intelligence-driven predictive models. It also discusses the integration of multi-omics data, real-world clinical applications, and the regulatory and ethical frameworks supporting clinical implementation. Finally, the role of pharmacogenomics in drug discovery and development is highlighted, illustrating how genetic insights contribute to target identification, trial design, and drug repurposing. Together, these components form the computational backbone of precision medicine and are essential for translating genomic knowledge into actionable, patient-centered care.
{"title":"Bioinformatics applications in pharmacogenomics: towards personalized medicine","authors":"Nabil Zaid , Lamyaa Benchikhi , Banacer Himmi , Hassan Ghazal","doi":"10.1016/j.gene.2025.149935","DOIUrl":"10.1016/j.gene.2025.149935","url":null,"abstract":"<div><div>Pharmacogenomics investigates how genetic variation influences individual responses to drug therapy and aims to optimize treatment outcomes through personalized approaches. Bioinformatics plays a foundational role in this field, enabling the processing, annotation, and interpretation of complex genomic and multi-omics datasets. This review explores the current landscape of bioinformatics in pharmacogenomics, including key databases, variant analysis tools, and artificial intelligence-driven predictive models. It also discusses the integration of multi-omics data, real-world clinical applications, and the regulatory and ethical frameworks supporting clinical implementation. Finally, the role of pharmacogenomics in drug discovery and development is highlighted, illustrating how genetic insights contribute to target identification, trial design, and drug repurposing. Together, these components form the computational backbone of precision medicine and are essential for translating genomic knowledge into actionable, patient-centered care.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149935"},"PeriodicalIF":2.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.gene.2025.149936
Sampurna Raha, Rajiv S. Desai, Shivani P. Bansal, Pankaj M. Shirsat, Pooja S. Prasad
Oral Submucous Fibrosis (OSF) is a long-standing, scarring, inflammatory, potentially malignant disorder induced by areca nut. The transient receptor potential vanilloid 4 (TRPV4), a cation channel permeable to Ca2+, in the TRPV family, is implicated in wound healing, fibrotic changes and malignancy, but its role as a mechanosensor for matrix-stiffness and stress in OSF and its malignant transformation to oral squamous cell carcinoma (OSCC) remains unexplored. The current research sought to investigate the probable involvement of TRPV4 in the onset different OSF stages and its progression to malignancy by immunohistochemistry. Primary antibodies targeting TRPV4 were applied to formalin-fixed paraffin-embedded blocks from ten cases for each category: (a) Stage-1 OSF, (b) Stage 2 OSF, (c) Stage 3 OSF, (d) Stage 4 OSF, (e) OSCC + OSF, and (vi) OSCC − OSF. Additionally, buccal mucosa tissues from ten healthy individuals (NOM) were utilized as control. Mean epithelial quick scores of TRPV4 in NOM, Stages 1–4 OSF, and OSCC with and without OSF were 1.2, 2.5, 3.9, 4.5, 4.6, 5.8, and 6.2, while connective tissue scores were 1.5, 3.5, 4.1, 4.7, 5.3, 5.9, and 6.5, respectively. TRPV4 expression was upregulated in Stages 3 OSF and 4 OSF and OSCC in the presence or absence of OSF compared to NOM and Stage 1 and 2 OSF. This study evaluates the unpaved role of TRPV4 in OSF, mediated by various canonical pathways, contributing to its development by increasing matrix-stiffness and rigidity, which further upregulates TRPV4 expression, ultimately facilitating carcinogenesis.
{"title":"TRPV4-mediated mechanotransduction of matrix stiffness in the pathogenesis, progression, and malignant transformation of oral submucous fibrosis","authors":"Sampurna Raha, Rajiv S. Desai, Shivani P. Bansal, Pankaj M. Shirsat, Pooja S. Prasad","doi":"10.1016/j.gene.2025.149936","DOIUrl":"10.1016/j.gene.2025.149936","url":null,"abstract":"<div><div>Oral Submucous Fibrosis (OSF) is a long-standing, scarring, inflammatory, potentially malignant disorder induced by areca nut. The transient receptor potential vanilloid 4 (TRPV4), a cation channel permeable to Ca<sup>2+</sup>, in the TRPV family, is implicated in wound healing, fibrotic changes and malignancy, but its role as a mechanosensor for matrix-stiffness and stress in OSF and its malignant transformation to oral squamous cell carcinoma (OSCC) remains unexplored. The current research sought to investigate the probable involvement of TRPV4 in the onset different OSF stages and its progression to malignancy by immunohistochemistry. Primary antibodies targeting TRPV4 were applied to formalin-fixed paraffin-embedded blocks from ten cases for each category: (a) Stage-1 OSF, (b) Stage 2 OSF, (c) Stage 3 OSF, (d) Stage 4 OSF, (e) OSCC + OSF, and (vi) OSCC − OSF. Additionally, buccal mucosa tissues from ten healthy individuals (NOM) were utilized as control. Mean epithelial quick scores of TRPV4 in NOM, Stages 1–4 OSF, and OSCC with and without OSF were 1.2, 2.5, 3.9, 4.5, 4.6, 5.8, and 6.2, while connective tissue scores were 1.5, 3.5, 4.1, 4.7, 5.3, 5.9, and 6.5, respectively. TRPV4 expression was upregulated in Stages 3 OSF and 4 OSF and OSCC in the presence or absence of OSF compared to NOM and Stage 1 and 2 OSF. This study evaluates the unpaved role of TRPV4 in OSF, mediated by various canonical pathways, contributing to its development by increasing matrix-stiffness and rigidity, which further upregulates TRPV4 expression, ultimately facilitating carcinogenesis.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149936"},"PeriodicalIF":2.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.gene.2025.149938
Khushboo Pradhan , Sindhu Anoop
Non-canonical CRISPR systems adaptation has led to genome editing through nucleases, and the development of transcriptional and epigenetic regulation, transcriptome editing, and molecular diagnostics has resulted in a diversified set of tools—CRISPR 2.0. In this review, the author summarizes the mechanisms and recent engineering advances of (i) dCas9-based epigenetic effectors, (ii) RNA-targeting Cas13 systems and engineered RNA editors, (iii) DNA base editors and prime editors, and (iv) CRISPR-powered diagnostic platforms and their translational readiness. There is a critical comparison of the various approaches (e.g., RNAi/ASO versus Cas13-based methods; base editing versus prime editing) along with practical translational considerations such as delivery technologies, safety (off-target/edit windows, mosaicism), and regulatory pathways which are evaluated. Three concise case studies refer to map laboratory evidence to clinical or near-clinical outcomes and the ethical and governance discussion is widened to include global access, intellectual property and equity in deployment. Finally, the authors classify technologies according to their level of readiness — diagnostics and some ex-vivo therapeutic approaches are already in or very close to clinical use, chosen in-vivo editing methods are undergoing early trials, and AI-assisted nuclease design is still mostly theoretical but is getting better fast. This comprehensive viewpoint is intended to help researchers and physicians understand which CRISPR tools are most likely to be translated soon and where more validation is required.
{"title":"CRISPR 2.0: Expanding the genome engineering Toolbox for epigenetics, RNA editing, and molecular diagnostics","authors":"Khushboo Pradhan , Sindhu Anoop","doi":"10.1016/j.gene.2025.149938","DOIUrl":"10.1016/j.gene.2025.149938","url":null,"abstract":"<div><div>Non-canonical CRISPR systems adaptation has led to genome editing through nucleases, and the development of transcriptional and epigenetic regulation, transcriptome editing, and molecular diagnostics has resulted in a diversified set of tools—CRISPR 2.0. In this review, the author summarizes the mechanisms and recent engineering advances of (i) dCas9-based epigenetic effectors, (ii) RNA-targeting Cas13 systems and engineered RNA editors, (iii) DNA base editors and prime editors, and (iv) CRISPR-powered diagnostic platforms and their translational readiness. There is a critical comparison of the various approaches (e.g., RNAi/ASO versus Cas13-based methods; base editing versus prime editing) along with practical translational considerations such as delivery technologies, safety (off-target/edit windows, mosaicism), and regulatory pathways which are evaluated. Three concise case studies refer to map laboratory evidence to clinical or near-clinical outcomes and the ethical and governance discussion is widened to include global access, intellectual property and equity in deployment. Finally, the authors classify technologies according to their level of readiness — diagnostics and some ex-vivo therapeutic approaches are already in or very close to clinical use, chosen in-vivo editing methods are undergoing early trials, and AI-assisted nuclease design is still mostly theoretical but is getting better fast. This comprehensive viewpoint is intended to help researchers and physicians understand which CRISPR tools are most likely to be translated soon and where more validation is required.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149938"},"PeriodicalIF":2.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1016/j.gene.2025.149932
Chun Feng , Teng Zhang , Yuan Li , Yuyun Long , Qian Meng , Shi-Wen Jiang
Syncytin-2 is an endogenous retroviral envelope protein constitutively expressed in human placental trophoblasts. As a membrane glycoprotein, Syncytin-2 together with Syncytin-1 mediates the fusion of mononucleated cytotrophoblasts to form multinucleated syncytiotrophoblasts. Syncytiotrophoblasts constitute the fetal-maternal interface important for fetal-maternal exchange, barrier and endocrine functions of the placenta. Besides the fusogenic function, Syncytin-2 also possesses an immunosuppressive activity. In this study, the results of quantitative PCR indicated that Syncytin-2 expression was downregulated in third-trimester preeclamptic placentas, which is consistent with the result of previous studies. Importantly, the results of Combined Bisulfite Restriction Assay (COBRA) suggested hypermethylation of the downstream CpG-rich region, but not the promoter/exon1/intron1 and exon2 CpG- rich regions of SYN-2 gene in third-trimester preeclamptic placentas. Subsequent bisulfite conversion and PCR amplification, cloning and sequencing of the downstream CpG- rich region confirmed hypermethylation of the 4 CpGs in this region in preeclamptic placentas. Moreover, treatment of human choriocarcinoma BeWo cells with DNMT inhibitor ADC (5-aza-deoxycytidine) resulted in a dose-responsive demethylation of the downstream CpG-rich region and an increased SYN-2 mRNA level. Thus, the hypermethylation of the downstream CpG-rich region closely correlated with the downregulation of Syncytin-2 expression in preeclamptic placentas. These new findings underscore the significance of epigenetic alterations in preeclamptic placentas, and facilitate a better understanding on the pathological mechanism of preeclampsia.
{"title":"Downregulation of Syncytin-2 expression in preeclamptic placentas is associated with DNA hypermethylation of the downstream CpG-rich region","authors":"Chun Feng , Teng Zhang , Yuan Li , Yuyun Long , Qian Meng , Shi-Wen Jiang","doi":"10.1016/j.gene.2025.149932","DOIUrl":"10.1016/j.gene.2025.149932","url":null,"abstract":"<div><div>Syncytin-2 is an endogenous retroviral envelope protein constitutively expressed in human placental trophoblasts. As a membrane glycoprotein, Syncytin-2 together with Syncytin-1 mediates the fusion of mononucleated cytotrophoblasts to form multinucleated syncytiotrophoblasts. Syncytiotrophoblasts constitute the fetal-maternal interface important for fetal-maternal exchange, barrier and endocrine functions of the placenta. Besides the fusogenic function, Syncytin-2 also possesses an immunosuppressive activity. In this study, the results of quantitative PCR indicated that Syncytin-2 expression was downregulated in third-trimester preeclamptic placentas, which is consistent with the result of previous studies. Importantly, the results of Combined Bisulfite Restriction Assay (COBRA) suggested hypermethylation of the downstream CpG-rich region, but not the promoter/exon1/intron1 and exon2 CpG- rich regions of <em>SYN-2</em> gene in third-trimester preeclamptic placentas. Subsequent bisulfite conversion and PCR amplification, cloning and sequencing of the downstream CpG- rich region confirmed hypermethylation of the 4 CpGs in this region in preeclamptic placentas. Moreover, treatment of human choriocarcinoma BeWo cells with DNMT inhibitor ADC (5-aza-deoxycytidine) resulted in a dose-responsive demethylation of the downstream CpG-rich region and an increased <em>SYN-2</em> mRNA level. Thus, the hypermethylation of the downstream CpG-rich region closely correlated with the downregulation of Syncytin-2 expression in preeclamptic placentas. These new findings underscore the significance of epigenetic alterations in preeclamptic placentas, and facilitate a better understanding on the pathological mechanism of preeclampsia.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149932"},"PeriodicalIF":2.4,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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