{"title":"Underlining the Molecular Mechanism of Nonalcoholic Fatty Liver Disease and Coronary Artery Disease in Lipid Metabolism by Combining Multiple Sets of Data Sets","authors":"Wei Zheng, Shouhao Wang, Huafang Wang, Chengan Xu, Qiaoqiao Yin, Hua Di","doi":"10.1002/iub.70040","DOIUrl":"10.1002/iub.70040","url":null,"abstract":"<p>Nonalcoholic fatty liver disease (NAFLD) is closely associated with coronary artery disease (CAD); however, their shared genetic traits and molecular mechanisms in lipid metabolism remain unclear. In this study, we identified that the differentially expressed genes in NAFLD and CAD intersected with lipid metabolism genes to obtain three key genes—GPD1, MVK, and PIK3R2. Data from the GeneCards database indicated a significant correlation between NAFLD-related regulatory genes and the expression levels of these key genes. Notably, GPD1 showed a significant positive correlation with PNPLA3 (<i>r</i> = 0.715), while PIK3R2 exhibited a significant negative correlation with MIR21 (<i>r</i> = −0.691). Similarly, CAD regulatory genes were significantly correlated with the expression levels of these key genes; GPD1 showed a significant positive correlation with APOA1 (<i>r</i> = 0.751), and PIK3R2 had a significant negative correlation with LPA (<i>r</i> = −0.362). Additionally, single-cell sequencing analysis of NAFLD showed that GPD1, MVK, and PIK3R2 had higher activity in cells with a high expression of bile acid metabolism genes in the immune pathway. In CAD, GPD1 showed higher activity in cells with high oxidative phosphorylation in the immune pathway. Finally, we found that one drug interacted with MVK, while 38 drugs interacted with PIK3R2. This study highlights GPD1, MVK, and PIK3R2 as key genes involved in NAFLD, CAD, and lipid metabolism, suggesting potential targets for further mechanistic studies and novel therapeutic approaches for patients with NAFLD and CAD.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144581979","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":"SPP1 Regulates SASP via the p53 Signaling Pathway to Affect ALI Progression","authors":"Congcong Yuan, Shilong Zhao, Wentao Ma, Hongjun Na, Qiuyue Tan, Jing Gao","doi":"10.1002/iub.70038","DOIUrl":"10.1002/iub.70038","url":null,"abstract":"<div>\u0000 \u0000 <p>Acute lung injury (ALI) is a condition with acute respiratory failure caused by various factors, characterized by severe hypoxemia and diffuse alveolar damage, involving multiple cytokines and signaling pathways. This study investigates the role of secreted phosphoprotein 1 (SPP1) in ALI and explores its underlying mechanisms through a series of in vitro and in vivo experiments. Our results demonstrate that SPP1 expression is significantly upregulated in ALI animal models, correlating with increased oxidative stress and inflammatory responses. In LPS-induced lung injury models, elevated levels of malondialdehyde (MDA) and IL1β, along with decreased superoxide dismutase (SOD) levels, were observed, further confirming the active state of SPP1 in ALI. In vitro experiments using BEAS-2B cells revealed that LPS treatment increased IL1β and reactive oxygen species (ROS) levels while decreasing SOD levels, with concomitant upregulation of SPP1. SPP1 knockdown significantly inhibited these changes, directly confirming its regulatory role in ALI progression. We further explored the regulatory mechanisms of SPP1 on the senescence-associated secretory phenotype (SASP), a key pathological process in ALI. SA-β-GAL staining and γ-H2AX results indicated elevated cellular senescence in LPS-treated cells and ALI models. SPP1 knockdown reduced senescence markers, enhanced cell viability, decreased apoptosis, and improved cell proliferation capacity, suggesting that SPP1 promotes ALI via the SASP phenotype. Mechanistically, we found that SPP1 regulates ALI via the p53 signaling pathway. LPS treatment increased p-p53 levels, whereas SPP1 knockdown reduced p53 activation. The use of a p53 inhibitor further suppressed SASP and improved ALI-related indicators. Animal model validation corroborated these findings, showing that SPP1 knockdown and p53 inhibitor treatment reduced lung tissue damage and improved ALI-related indicators. Collectively, our study reveals a novel mechanism by which SPP1 regulates ALI progression via the p53 signaling pathway and SASP. This discovery not only enriches our understanding of ALI pathogenesis but also provides a new therapeutic target and potential intervention strategies for ALI treatment.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515013","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}
IUBMB LifePub Date : 2025-06-20DOI: 10.1002/iub.70034
Julio Mena-Portales, Yordanis Pérez-Llano, Marco Antonio Vásquez-Dávila, Taimy Cantillo, Gladys Isabel Manzanero-Medina, María del Rayo Sánchez-Carbente, Ramón Alberto Batista-García
{"title":"Fungi and Myxomycetes of the Tehuacán-Cuicatlán Biosphere Reserve, Mexico: A Comprehensive Review and Future Perspectives","authors":"Julio Mena-Portales, Yordanis Pérez-Llano, Marco Antonio Vásquez-Dávila, Taimy Cantillo, Gladys Isabel Manzanero-Medina, María del Rayo Sánchez-Carbente, Ramón Alberto Batista-García","doi":"10.1002/iub.70034","DOIUrl":"10.1002/iub.70034","url":null,"abstract":"<p>The Tehuacán-Cuicatlán Biosphere Reserve in Mexico, spanning approximately 10,000 km<sup>2</sup>, is crucial for conserving arid and semi-arid ecosystems, as it hosts unique endemic species and complex ecological interactions. Despite their environmental significance, fungi and myxomycetes in this region have been understudied, particularly those adapted to extreme conditions. These organisms are vital for nutrient cycling, soil stability, and plant health, making them excellent bioindicators for monitoring ecosystem health and detecting environmental changes. However, challenges such as limited historical data, remote fieldwork, and advanced identification techniques complicate their study. Based on a review of mycological literature and various biodiversity databases, the first inventory of fungi and myxomycetes of the Tehuacán-Cuicatlán Biosphere Reserve (Tehuacán Desert) was prepared in this work. This inventory lists 436 taxa of organisms traditionally identified as fungi, belonging to 254 different genera. Of these, 266 taxa belong to 214 genera of fungi <i>sensu stricto</i>, and 170 taxa from 40 genera of myxomycetes. Fungal and myxomycete communities must be documented, and their inherent variability understood through baseline research. Research on fungal adaptation to shifting environments in the Tehuacán Valley may reveal resilience mechanisms in desert ecosystems. Fungi and myxomycetes are useful bioindicators for assessing ecosystem health and ecological alterations under global climate stress, due to their rapid environmental response. Understanding these adaptive strategies helps preserve the environment, produce new drugs, and foster agricultural resilience. Polyextremotolerant and extremophilic fungi are studied in the reserve to understand the boundaries of life and survival processes. To use fungi to protect sensitive ecosystems and mitigate climate change in the Tehuacán-Cuicatlán Biosphere Reserve, interdisciplinary collaboration and innovative methods are needed. The Tehuacán Desert can be considered a natural laboratory for studying polyextremotolerant and extremophilic fungi.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323448","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}
IUBMB LifePub Date : 2025-06-19DOI: 10.1002/iub.70029
Yuxuan Xu, Jinsheng Ding, Zhenyu Shi, Li Bao
{"title":"Single-Cell Profiling of the Microenvironment in High-Risk Neuroblastoma","authors":"Yuxuan Xu, Jinsheng Ding, Zhenyu Shi, Li Bao","doi":"10.1002/iub.70029","DOIUrl":"10.1002/iub.70029","url":null,"abstract":"<div>\u0000 \u0000 <p>Although tumor biology and treatment of neuroblastoma (NB) have substantially advanced, the clinical outcomes of patients with high-risk NB (HR-NB) still remain unsatisfactory. Increasing evidence suggests that targeting the tumor microenvironment (TME) is an effective strategy for the treatment of patients with HR-NB, highlighting the necessity to deepen the understanding of the complex TME in HR-NB. We analyzed the single-cell RNA sequencing data of 16 NB samples from 11 patients with HR-NB and 5 patients with intermediate-/low-risk NB. We found that proliferating CD8+ <i>TUBA1B</i>+ T cells, <i>H2AFZ</i>+ macrophages, and proliferating <i>HMGB2</i>+ B cells were particularly enriched in HR-NB samples and played an immunosuppressive role. <i>LAG3</i> and <i>HAVCR2</i> could serve as potential immunotherapeutic targets for HR-NB. SCENIC analysis innovatively revealed that proliferating <i>HMGB2</i>+ B cells had a special differentiation process compared with that of plasma cells. <i>H2AFZ</i>+ macrophages evolved from monocytes and M1-like macrophages and exhibited an M2-like phenotype. HR-NB-enriched cancer-associated fibroblasts and endothelial cells were related to tumor migration and progression. An immune-related risk model based on five genes (<i>BIRC5</i>, <i>UBE2C</i>, <i>CDKN3</i>, <i>TK1</i>, and <i>PTTG1</i>) was constructed in the training set and applied to the validation set. Both sets showed a promising clinical prediction value. In sum, this study preliminarily revealed the landscape of the TME in HR-NB at a single-cell level; several TME cell clusters that could inhibit immune activities or promote tumor progression in HR-NB were determined, thereby providing novel immunotherapeutic targets and an immune-related prognostic signature for HR-NB and promoting the development of immunotherapy of HR-NB.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315048","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}
IUBMB LifePub Date : 2025-06-19DOI: 10.1002/iub.70035
Qinkao Xuan, Jin Li, Zexiong Feng, Li Zhu, Tingbo Jiang, Hongxia Li, Ming Liu, Xiaodong Qian, Xiao Ma
{"title":"Modulation of PPAR-α and PPAR-γ Influences Cardiomyocyte Growth and Cardiac Remodeling","authors":"Qinkao Xuan, Jin Li, Zexiong Feng, Li Zhu, Tingbo Jiang, Hongxia Li, Ming Liu, Xiaodong Qian, Xiao Ma","doi":"10.1002/iub.70035","DOIUrl":"10.1002/iub.70035","url":null,"abstract":"<div>\u0000 \u0000 <p>Peroxisome proliferator–activated receptors (PPARs), particularly PPAR-α and PPAR-γ, are key regulators of cardiac energy metabolism and have been implicated in cardiac remodeling. However, their roles in cardiomyocyte proliferation and hypertrophy remain incompletely understood. In this study, we investigated the effects of PPAR-α and PPAR-γ modulation on neonatal rat cardiomyocytes (NRCMs) using pharmacological agonists (WY-14643 for PPAR-α and pioglitazone for PPAR-γ) and inhibitors (MK-886 for PPAR-α and GW9662 for PPAR-γ), as well as siRNA-mediated knockdown approaches. Cardiomyocyte proliferation and hypertrophy were assessed by immunofluorescence, cell size measurements, and proliferation assays. Our findings demonstrate that PPAR-α activation significantly promotes cardiomyocyte proliferation and reduces hypertrophy, whereas PPAR-α inhibition induces hypertrophic changes and suppresses proliferation. Similarly, PPAR-γ activation enhances both proliferation and hypertrophy of cardiomyocytes, suggesting its involvement in physiological hypertrophy and a potential protective role in pathological remodeling. In contrast, pharmacological activation or genetic inhibition of PPAR-δ showed no significant effects on cardiomyocyte proliferation or hypertrophy, highlighting its distinct role in metabolic homeostasis rather than structural remodeling. PPAR-α and PPAR-γ play distinct but complementary roles in regulating cardiomyocyte proliferation and hypertrophy. These results suggest that targeting PPAR-α and PPAR-γ may represent promising therapeutic strategies for cardiac hypertrophy and heart failure. Further in vivo studies are warranted to clarify their molecular mechanisms and potential clinical applications.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315047","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}
IUBMB LifePub Date : 2025-06-18DOI: 10.1002/iub.70026
Rashmi Fotedar, Polona Zalar, Amina Al Malaki, Aisha Al Zeyara, Ridhima Kaul, Anna Kolecka, Jack W. Fell, Teun Boekhout, Nina Gunde-Cimerman
{"title":"Euryhaline Black Yeasts From the Arabian Gulf: Descriptions of Salinomyces qatarensis sp. nov. and Hortaea werneckii Genotypic Variations","authors":"Rashmi Fotedar, Polona Zalar, Amina Al Malaki, Aisha Al Zeyara, Ridhima Kaul, Anna Kolecka, Jack W. Fell, Teun Boekhout, Nina Gunde-Cimerman","doi":"10.1002/iub.70026","DOIUrl":"10.1002/iub.70026","url":null,"abstract":"<div>\u0000 \u0000 <p>The Arabian Gulf surrounding Qatar is an oligotrophic marine environment characterized by extreme conditions, such as increased water temperatures and high salinity compared to other semi-enclosed seas, such as the Mediterranean Sea. Thirty-six black yeast-like isolates were obtained from marine waters surrounding Qatar, representing 4% of all isolated yeasts. DNA sequence analysis of the internal transcribed spacers (ITS1, ITS2), the 5.8S rRNA gene, and the D1/D2 domains of the LSU rDNA identified 20 isolates as <i>Hortaea werneckii</i>, and 15 (75%) of them represent previously unknown genotypes with a wide NaCl tolerance at 37°C. In addition, 16 meristematic black yeast-like cultures were isolated that grew as multi-cellular bodies and reproduced by endoconidiation. Phylogenetic analysis based on the D1/D2 domains of LSU rDNA, partial sequences of the second largest subunit of RNA polymerase II (RPB2) and translation elongation factor 1-alpha (TEF) of selected representative strains of Dothideomycetes and of morphologically similar taxa, <i>Pseudotaeniolina globosa</i> and <i>Trimmatostroma salinum</i>, supported the proposal of meristematic black yeast-like cultures as a new species, <i>Salinomyces qatarensis</i> sp. nov., within Teratosphaeriaceae, Mycosphaerellales. The holotype is designated as CBS 150510, with ex-type strains EXF-15246 and QCC/Y38/18, and the species is registered in Mycobank as MB#848869. In addition, based on the above molecular analysis, a new combination was proposed for an euryhaline fungus from Mediterranean salterns, <i>Trimmatostroma salinum</i>, into the genus <i>Verrucocladosporium</i> as <i>V. salinum</i>, MB#856063. This study increases our knowledge of the distribution and genetic diversity of <i>Hortaea werneckii</i>, the etiological agent of tinea nigra. In addition, the description of <i>S. qatarensis</i> and the combination of euryhaline <i>T. salinum</i> to <i>Verrucocladosporium</i> provides support for halotolerance as one of the traits in Dothideomycetes.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308995","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}
{"title":"Squalene: A High-Value Compound for COVID-19 Vaccine Adjuvants and Beyond Pathways, Production Strategies, and Market Potential","authors":"Dileep Dasari, Reeta Rani Singhania, Shashi Kant Bhatia, Cheng-Di Dong, Anil Kumar Patel","doi":"10.1002/iub.70032","DOIUrl":"10.1002/iub.70032","url":null,"abstract":"<div>\u0000 \u0000 <p>Squalene, a naturally occurring triterpene, has gained significant attention due to its critical role as an adjuvant in COVID-19 vaccines and its broad applications in pharmaceuticals, cosmetics, and nutraceuticals. This review explores the potential of squalene production, prompting a shift toward sustainable and innovative approaches. Key biosynthetic pathways across various organisms, including plants, fungi, and microalgae, are analyzed to identify efficient production systems as compared to fast-growing heterotrophic thraustochytrids. Advanced strategies to enhance squalene yields are explored, including the use of chemical enhancers (methyl jasmonate), antioxidants (alpha-tocopherol), cofactor recycling, and squalene epoxidase inhibitors (terbinafine). Additionally, the global market potential of squalene is assessed, highlighting its economic importance and growing demand in the healthcare and cosmetic industries. The challenges of large-scale squalene production are addressed with a focus on sustainable alternatives to shark-derived sources as a high ethical concern. By aligning with Sustainable Development Goals (SDG-3: Good Health and Well-Being), squalene production supports advancements in vaccine development and biotechnological innovations. Future opportunities are highlighted, including novel applications in cancer therapy, functional foods, and anti-aging products, offering pathways to harness its full potential while contributing to a sustainable bioeconomy.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308996","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}
IUBMB LifePub Date : 2025-06-06DOI: 10.1002/iub.70031
Emanuele Vitale, Davide Ricci, Federica Corrao, Ignazio Fiduccia, Ilenia Cruciata, Pietro Salvatore Carollo, Alessio Branchini, Laura Lentini, Ivana Pibiri
{"title":"Nonsense Mutations in Rare and Ultra-Rare Human Disorders: An Overview","authors":"Emanuele Vitale, Davide Ricci, Federica Corrao, Ignazio Fiduccia, Ilenia Cruciata, Pietro Salvatore Carollo, Alessio Branchini, Laura Lentini, Ivana Pibiri","doi":"10.1002/iub.70031","DOIUrl":"10.1002/iub.70031","url":null,"abstract":"<p>Over 7000 rare diseases have been described, collectively affecting 350 million people worldwide. Most of these conditions result from nonsense mutations, representing approximately 10% of all genetic mutations associated with human inherited diseases. Nonsense mutations convert a sense codon into a premature termination codon (PTC), leading to premature translation termination and the production of truncated, nonfunctional proteins. This results in a loss-of-function phenotype in many genetic disorders, contributing to the disease's severity and progression. The molecular mechanisms of PTC formation involve various genetic alterations, including single-nucleotide changes, frameshifts, and splicing mutations. The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons (PTCs). In contrast, 25% of PTC mRNAs, depending on the PTC position and cellular context, can evade NMD, resulting in the synthesis of truncated proteins. A termination codon during translation is essential for proper protein synthesis, and translational readthrough—a process in which the ribosome bypasses the PTC and reaches the natural stop codon—may restore some level of protein function. The effectiveness of readthrough depends on the surrounding genetic context and the type of amino acid incorporated at the PTC position. This review aims to explore the molecular characteristics of nonsense-related diseases (NRDs), including cystic fibrosis, hemophilia, Fabry disease, choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and certain hereditary neuropathies and cancers.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219913","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}
IUBMB LifePub Date : 2025-06-06DOI: 10.1002/iub.70030
Megha Jhanji, Ashita Bhan, Colin Arrowood, Dina W. Yakout, Ankit Shroff, Danielle McManus, Henrietta Gifford, Janay Vacharasin, Sofia B. Lizarraga, Taras Y. Nazarko, Angela M. Mabb, Mathew Sajish
{"title":"Tyrosine and Phenylalanine Activate Neuronal DNA Repair but Exhibit Opposing Effects on Global Transcription and Adult Female Mice Are Resilient to TyrRS/YARS1 Depletion","authors":"Megha Jhanji, Ashita Bhan, Colin Arrowood, Dina W. Yakout, Ankit Shroff, Danielle McManus, Henrietta Gifford, Janay Vacharasin, Sofia B. Lizarraga, Taras Y. Nazarko, Angela M. Mabb, Mathew Sajish","doi":"10.1002/iub.70030","DOIUrl":"10.1002/iub.70030","url":null,"abstract":"<p>Serum tyrosine and phenylalanine levels increase during aging and age-associated disorders. We previously showed that tyrosyl-tRNA synthetase (TyrRS/YARS1) is reduced in Alzheimer's Disease (AD) brains, and tyrosine and phenylalanine decrease TyrRS in neurons. Here, we found that tau is a negative regulator, whereas estrogen and leucine act as positive regulators of TyrRS. Young female mice exhibit increased TyrRS in the cortex compared to male mice. Notably, young <i>Tau</i> knockout male, but not female mice showed increased cortical TyrRS. Tau accumulation in middle-aged female mice did not decrease cortical TyrRS compared to males, suggesting that middle-aged females are resilient to tau-mediated TyrRS depletion. Tyrosine and phenylalanine treatment decreased tubulin tyrosination, activated DNA repair pathways, and protected against etoposide (ETO) and camptothecin (CPT)-induced toxicity, respectively, in neurons. While tyrosine facilitated topoisomerase 1 (TOP1) recruitment to chromatin and inhibited global transcription, in contrast, phenylalanine recruited topoisomerase 2 beta (TOP2β) to chromatin and stimulated global transcription. Furthermore, tyrosine decreased the presence of DNA fragments in a comet assay whereas phenylalanine increased them. Addition of <i>cis</i>-resveratrol (<i>cis</i>-RSV) protected against tyrosine-induced transcription inhibition by facilitating the recruitment of both TOP1 and TOP2β to chromatin and increasing tubulin tyrosination. Moreover, <i>cis</i>-RSV decreased both total and phosphorylated tau and protected neurons against amyloid beta (Aβ)-induced neurite degeneration and DNA damage. Gene expression profiling using human embryonic stem cell (hESC)-derived neurons demonstrated that <i>cis</i>-RSV is a broad-spectrum neuroprotective and anti-viral agent. In contrast, <i>trans</i>-RSV mimics phenylalanine-induced gene expression, including downregulation of long genes and induction of an AD-like gene expression signature. This work suggests that age and disease-associated increases in serum tyrosine and phenylalanine levels would activate neuronal DNA repair while inhibiting transcription and tubulin tyrosination. <i>cis</i>-RSV protects against their toxicity by restoring tubulin tyrosination, TOP1 and TOP2β-mediated transcription, and decreasing tau in primary neurons.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144220010","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}
IUBMB LifePub Date : 2025-05-27DOI: 10.1002/iub.70027
Davide Ricci, Ilenia Cruciata, Ignazio Fiduccia, Emanuele Vitale, Federica Corrao, Alessio Branchini, Pietro Salvatore Carollo, Ivana Pibiri, Laura Lentini
{"title":"Advancing Therapeutic Strategies for Nonsense-Related Diseases: From Small Molecules to Nucleic Acid-Based Innovations","authors":"Davide Ricci, Ilenia Cruciata, Ignazio Fiduccia, Emanuele Vitale, Federica Corrao, Alessio Branchini, Pietro Salvatore Carollo, Ivana Pibiri, Laura Lentini","doi":"10.1002/iub.70027","DOIUrl":"10.1002/iub.70027","url":null,"abstract":"<p>Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman–Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140486","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}