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11 pages, 242 KiB  
Article
Genetic Insights into Hemiplegic Migraine: Whole Exome Sequencing Highlights Vascular Pathway Involvement via Association Analysis
by Zizi Molaee, Robert A. Smith, Neven Maksemous and Lyn R. Griffiths
Genes 2025, 16(8), 895; https://doi.org/10.3390/genes16080895 - 28 Jul 2025
Viewed by 276
Abstract
Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points [...] Read more.
Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points to an overlap between migraine and cerebral small vessel disease (SVD), implicating vascular dysfunction in HM pathophysiology. Objective: This study aimed to identify rare or novel variants in genes associated with SVD in a cohort of patients clinically diagnosed with HM who tested negative for known familial hemiplegic migraine (FHM) pathogenic variants. Methods: We conducted a case-control association analysis of whole exome sequencing (WES) data from 184 unrelated HM patients. A targeted panel of 34 SVD-related genes was assessed. Variants were prioritised based on rarity (MAF ≤ 0.05), location (exonic/splice site), and predicted pathogenicity using in silico tools. Statistical comparisons to gnomAD’s Non-Finnish European population were made using chi-square tests. Results: Significant variants were identified in several SVD-related genes, including LRP1 (p.Thr4077Arg), COL4A1 (p.Pro54Leu), COL4A2 (p.Glu1123Gly), and TGFBR2 (p.Met148Leu and p.Ala51Pro). The LRP1 variant showed the strongest association (p < 0.001). All key variants demonstrated pathogenicity predictions in multiple computational models, implicating them in vascular dysfunction relevant to migraine mechanisms. Conclusions: This study provides new insights into the genetic architecture of hemiplegic migraine, identifying rare and potentially deleterious variants in SVD-related genes. These findings support the hypothesis that vascular and cellular maintenance pathways contribute to migraine susceptibility and may offer new targets for diagnosis and therapy. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
36 pages, 3579 KiB  
Article
RNA Sequencing Reveals Inflammatory and Metabolic Changes in the Lung and Brain After Carbon Black and Naphthalene Whole Body Inhalation Exposure in a Rodent Model of Military Burn Pit Exposures
by Allison M. Haaning, Brian J. Sandri, Henry L. Wyneken, William T. Goldsmith, Joshua P. Nixon, Timothy R. Nurkiewicz, Chris H. Wendt, Paul Barach, Janeen H. Trembley and Tammy A. Butterick
Int. J. Mol. Sci. 2025, 26(15), 7238; https://doi.org/10.3390/ijms26157238 - 26 Jul 2025
Viewed by 484
Abstract
Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung–brain axis. [...] Read more.
Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung–brain axis. To investigate molecular mechanisms, adult male rats were exposed to filtered air, naphthalene (a representative volatile organic compound), or a combination of naphthalene and carbon black (surrogate for particulate matter; CBN) via whole-body inhalation (six hours/day, three consecutive days). Lung, brain, and plasma samples were collected 24 h after the final exposure. Pro-inflammatory biomarkers were assessed using multiplex electrochemiluminescence and western blot. Differentially expressed genes (DEGs) were identified by RNA sequencing, and elastic net modeling was used to define exposure-predictive gene signatures. CBN exposure altered inflammatory biomarkers across tissues, with activation of nuclear factor kappa B (NF-κB) signaling. In the lung, gene set enrichment revealed activated pathways related to proliferation and inflammation, while epithelial–mesenchymal transition (EMT) and oxidative phosphorylation were suppressed. In the brain, EMT, inflammation, and senescence pathways were activated, while ribosomal function and oxidative metabolism were downregulated. Elastic net modeling identified a lung gene signature predictive of CBN exposure, including Kcnq3, Tgfbr1, and Tm4sf19. These findings demonstrate that inhalation of a surrogate burn pit mixture induces inflammatory and metabolic gene expression changes in both lung and brain tissues, supporting the utility of this animal model for understanding systemic effects of airborne military toxicants and for identifying potential biomarkers relevant to DRRD and Veteran health. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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20 pages, 44856 KiB  
Article
Characterization and Expression of TGF-β Proteins and Receptor in Sea Cucumber (Holothuria scabra): Insights into Potential Applications via Molecular Docking Predictions
by Siriporn Nonkhwao, Jarupa Charoenrit, Chanachon Ratanamungklanon, Lanlalin Sojikul, Supawadee Duangprom, Sineenart Songkoomkrong, Jirawat Saetan, Nipawan Nuemket, Prateep Amonruttanapun, Prasert Sobhon and Napamanee Kornthong
Int. J. Mol. Sci. 2025, 26(14), 6998; https://doi.org/10.3390/ijms26146998 - 21 Jul 2025
Viewed by 494
Abstract
Holothuria scabra has long been acknowledged in traditional medicine for its therapeutic properties. The transforming growth factor-beta (TGF-β) superfamily is crucial in regulating cellular processes, including differentiation, proliferation, and immune responses. This study marks the first exploration of the gene expression localization, sequence [...] Read more.
Holothuria scabra has long been acknowledged in traditional medicine for its therapeutic properties. The transforming growth factor-beta (TGF-β) superfamily is crucial in regulating cellular processes, including differentiation, proliferation, and immune responses. This study marks the first exploration of the gene expression localization, sequence conservation, and functional roles of H. scabra TGF-β proteins, specifically activin (HolscActivin), inhibin (HolscInhibin), and the TGF-β receptor (HolscTGFBR), across various organs. In situ hybridization indicated that HolscActivin and HolscInhibin are expressed in the intestine, respiratory tree, ovary, testis, and inner body wall. This suggests their roles in nutrient absorption, gas exchange, reproduction, and extracellular matrix remodeling. Notably, HolscTGFBR demonstrated a similar tissue-specific expression pattern, except for its absence in the respiratory tree. Bioinformatics analysis reveals that HolscTGFBR shares significant sequence similarity with HomsaTGFBR, especially in regions essential for signal transduction and inhibition. Molecular docking results indicate that HolscActivin may promote receptor activation, while HolscInhibin functions as a natural antagonist, reflecting the signaling mechanisms of human TGF-β proteins. Interestingly, cross-species ternary complex docking with human TGF-β receptors further supports these findings, showing that HolscActivin moderately engages the receptors, whereas HolscInhibin exhibits strong binding, suggestive of competitive inhibition. These results indicate that H. scabra TGF-β proteins retain the structural and functional features of vertebrate TGF-β ligands, supporting their potential applications as natural modulators in therapeutic and functional food development. Full article
(This article belongs to the Section Molecular Biology)
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18 pages, 1987 KiB  
Article
AI-HOPE-TGFbeta: A Conversational AI Agent for Integrative Clinical and Genomic Analysis of TGF-β Pathway Alterations in Colorectal Cancer to Advance Precision Medicine
by Ei-Wen Yang, Brigette Waldrup and Enrique Velazquez-Villarreal
AI 2025, 6(7), 137; https://doi.org/10.3390/ai6070137 - 24 Jun 2025
Cited by 2 | Viewed by 644
Abstract
Introduction: Early-onset colorectal cancer (EOCRC) is rising rapidly, particularly among the Hispanic/Latino (H/L) populations, who face disproportionately poor outcomes. The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in colorectal cancer (CRC) progression by mediating epithelial-to-mesenchymal transition (EMT), immune evasion, and [...] Read more.
Introduction: Early-onset colorectal cancer (EOCRC) is rising rapidly, particularly among the Hispanic/Latino (H/L) populations, who face disproportionately poor outcomes. The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in colorectal cancer (CRC) progression by mediating epithelial-to-mesenchymal transition (EMT), immune evasion, and metastasis. However, integrative analyses linking TGF-β alterations to clinical features remain limited—particularly for diverse populations—hindering translational research and the development of precision therapies. To address this gap, we developed AI-HOPE-TGFbeta (Artificial Intelligence agent for High-Optimization and Precision Medicine focused on TGF-β), the first conversational artificial intelligence (AI) agent designed to explore TGF-β dysregulation in CRC by integrating harmonized clinical and genomic data via natural language queries. Methods: AI-HOPE-TGFbeta utilizes a large language model (LLM), Large Language Model Meta AI 3 (LLaMA 3), a natural language-to-code interpreter, and a bioinformatics backend to automate statistical workflows. Tailored for TGF-β pathway analysis, the platform enables real-time cohort stratification and hypothesis testing using harmonized datasets from the cBio Cancer Genomics Portal (cBioPortal). It supports mutation frequency comparisons, odds ratio testing, Kaplan–Meier survival analysis, and subgroup evaluations across race/ethnicity, microsatellite instability (MSI) status, tumor stage, treatment exposure, and age. The platform was validated by replicating findings on the SMAD4, TGFBR2, and BMPR1A mutations in EOCRC. Exploratory queries were conducted to examine novel associations with clinical outcomes in H/L populations. Results: AI-HOPE-TGFbeta successfully recapitulated established associations, including worse survival in SMAD4-mutant EOCRC patients treated with FOLFOX (fluorouracil, leucovorin and oxaliplatin) (p = 0.0001) and better outcomes in early-stage TGFBR2-mutated CRC patients (p = 0.00001). It revealed potential population-specific enrichment of BMPR1A mutations in H/L patients (OR = 2.63; p = 0.052) and uncovered MSI-specific survival benefits among SMAD4-mutated patients (p = 0.00001). Exploratory analysis showed better outcomes in SMAD2-mutant primary tumors vs. metastatic cases (p = 0.0010) and confirmed the feasibility of disaggregated ethnicity-based queries for TGFBR1 mutations, despite small sample sizes. These findings underscore the platform’s capacity to detect both known and emerging clinical–genomic patterns in CRC. Conclusions: AI-HOPE-TGFbeta introduces a new paradigm in cancer bioinformatics by enabling natural language-driven, real-time integration of genomic and clinical data specific to TGF-β pathway alterations in CRC. The platform democratizes complex analyses, supports disparity-focused investigation, and reveals clinically actionable insights in underserved populations, such as H/L EOCRC patients. As a first-of-its-kind system studying TGF-β, AI-HOPE-TGFbeta holds strong promise for advancing equitable precision oncology and accelerating translational discovery in the CRC TGF-β pathway. Full article
(This article belongs to the Section Medical & Healthcare AI)
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10 pages, 3865 KiB  
Communication
Defective Mitochondrial Respiration in Hereditary Thoracic Aneurysms
by Daniel Marcos-Ríos, Antonio Rochano-Ortiz, Nerea Méndez-Barbero and Jorge Oller
Cells 2025, 14(11), 768; https://doi.org/10.3390/cells14110768 - 23 May 2025
Cited by 1 | Viewed by 640
Abstract
Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging [...] Read more.
Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests the key role of mitochondrial dysfunction. Here, we show that the overexpression of ACTA2R179H and TGFBR2G357W in murine aortic VSMCs reduces Mitochondrial Transcription Factor A (Tfam) expression, decreases mitochondrial DNA (mtDNA) content, and impairs oxidative phosphorylation, shifting metabolism toward glycolysis. Notably, nicotinamide riboside, a NAD+ precursor, restores mitochondrial respiration, increases Tfam and mtDNA levels, and promotes a contractile phenotype by enhancing actin polymerization and reducing matrix metalloproteinase activity. These findings identify mitochondrial dysfunction as a shared feature in hereditary thoracic aortic aneurysm, not only in Marfan syndrome, but also in other genetic forms, and highlight mitochondrial boosters as a potential therapeutic strategy. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Marfan Syndrome)
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18 pages, 11090 KiB  
Article
Transcriptomic Profiling of Hypoxia-Adaptive Responses in Tibetan Goat Fibroblasts
by Lin Tang, Li Zhu, Zhuzha Basang, Yunong Zhao, Shanshan Li, Xiaoyan Kong and Xiao Gou
Animals 2025, 15(10), 1407; https://doi.org/10.3390/ani15101407 - 13 May 2025
Viewed by 514
Abstract
The Tibetan goat (Capra hircus) exhibits remarkable adaptations to high-altitude hypoxia, yet the molecular mechanisms remain unclear. This study integrates RNA-seq, WGCNA, and machine learning to explore gene-environment interactions (G × E) in hypoxia adaptation. Fibroblasts from the Tibetan goat and [...] Read more.
The Tibetan goat (Capra hircus) exhibits remarkable adaptations to high-altitude hypoxia, yet the molecular mechanisms remain unclear. This study integrates RNA-seq, WGCNA, and machine learning to explore gene-environment interactions (G × E) in hypoxia adaptation. Fibroblasts from the Tibetan goat and Yunling goat were cultured under hypoxic (1% O2) and normoxic (21% O2) conditions, respectively. This identified 68 breed-specific (G), 100 oxygen-responsive (E), and 620 interaction-driven (I) Differentially Expressed Genes (DEGs). The notably higher number of interaction-driven DEGs compared to other effects highlights transcriptional plasticity. We defined two gene sets: Environmental Stress Genes (n = 632, E ∪ I) and Genetic Adaptation Genes (n = 659, G ∪ I). The former were significantly enriched in pathways related to oxidative stress defense and metabolic adaptation, while the latter showed prominent enrichment in pathways associated with vascular remodeling and transcriptional regulation. CTNNB1 emerged as a key regulatory factor in both gene sets, interacting with CASP3 and MMP2 to form the core of the protein–protein interaction (PPI) network. Machine learning identified MAP3K5, TGFBR2, RSPO1 and ITGB5 as critical genes. WGCNA identified key modules in hypoxia adaptation, where FOXO3, HEXIM1, and PPARD promote the stabilization of HIF-1α and metabolic adaptation through the HIF-1 signaling pathway and glycolysis. These findings underscore the pivotal role of gene–environment interactions in hypoxic adaptation, offering novel perspectives for both livestock breeding programs and biomedical research initiatives. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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18 pages, 3222 KiB  
Article
Regulatory T Cell Mimicry by a Subset of Mesenchymal GBM Stem Cells Suppresses CD4 and CD8 Cells
by Amanda L. Johnson, Harmon S. Khela, Jack Korleski, Sophie Sall, Yunqing Li, Weiqiang Zhou, Karen Smith-Connor, John Laterra and Hernando Lopez-Bertoni
Cells 2025, 14(8), 592; https://doi.org/10.3390/cells14080592 - 14 Apr 2025
Cited by 1 | Viewed by 886
Abstract
Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are [...] Read more.
Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and the molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We showed that this immunosuppressive Treg-like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGFβ type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a six-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2high GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics. Full article
(This article belongs to the Special Issue The Pivotal Role of Tumor Stem Cells in Glioblastoma)
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20 pages, 673 KiB  
Article
Comparative Genomic Analysis of Key Oncogenic Pathways in Hepatocellular Carcinoma Among Diverse Populations
by Cecilia Monge, Brigette Waldrup, Francisco G. Carranza and Enrique Velazquez-Villarreal
Cancers 2025, 17(8), 1309; https://doi.org/10.3390/cancers17081309 - 13 Apr 2025
Cited by 1 | Viewed by 633
Abstract
Background/Objectives: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with significant racial and ethnic disparities in incidence, tumor biology, and clinical outcomes. Hispanic/Latino (H/L) patients tend to be diagnosed at younger ages and more advanced stages than Non-Hispanic White (NHW) patients, [...] Read more.
Background/Objectives: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with significant racial and ethnic disparities in incidence, tumor biology, and clinical outcomes. Hispanic/Latino (H/L) patients tend to be diagnosed at younger ages and more advanced stages than Non-Hispanic White (NHW) patients, yet the molecular mechanisms underlying these disparities remain poorly understood. Key oncogenic pathways, including RTK/RAS, TGF-beta, WNT, PI3K, and TP53, play pivotal roles in tumor progression, treatment resistance, and response to targeted therapies. However, ethnicity-specific alterations within these pathways remain largely unexplored. This study aims to compare pathway-specific mutations in HCC between H/L and NHW patients, assess tumor mutation burden, and identify ethnicity-associated oncogenic drivers using publicly available datasets. Findings from this analysis may inform precision medicine strategies for improving early detection and targeted therapies in underrepresented populations. Methods: We conducted a bioinformatic analysis using publicly available HCC datasets to assess mutation frequencies in RTK/RAS, TGF-beta, WNT, PI3K, and TP53 pathway genes. This study included 547 patients, consisting of 69 H/L patients and 478 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were used to compare mutation frequencies, while Kaplan–Meier survival analysis assessed overall survival differences associated with pathway-specific alterations in both populations. Results: Significant differences were observed in the RTK/RAS pathway-related genes, particularly in FGFR4 mutations, which were more prevalent in H/L patients compared to NHW patients (4.3% vs. 0.6%, p = 0.02). Additionally, IGF1R mutations exhibited borderline significance (7.2% vs. 2.9%, p = 0.07). In the PI3K pathway, INPP4B alterations were more frequent in H/L patients than in NHW patients (4.3% vs. 1%, p = 0.06), while, in the TGF-beta pathway, TGFBR2 mutations were more common in H/L patients (2.9% vs. 0.4%, p = 0.07), suggesting potential ethnicity-specific variations. Survival analysis revealed no significant differences in overall survival between H/L and NHW patients, indicating that molecular alterations alone may not fully explain survival disparities and suggesting a role for additional factors such as immune response, environmental exposures, or access to targeted therapies. Conclusions: This study provides one of the first ethnicity-focused analyses of key oncogenic pathway alterations in HCC, revealing distinct molecular differences between H/L and NHW patients. The findings suggest that RTK/RAS (FGFR4, IGF1R), PI3K (INPP4B), and TGF-beta (TGFBR2) pathway alterations may play a distinct role in HCC among H/L patients, while their prognostic significance in NHW patients remains unclear. These insights emphasize the importance of incorporating ethnicity-specific molecular profiling into precision medicine approaches to improve early detection, targeted therapies, and clinical outcomes in HCC, particularly for underrepresented populations. Full article
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22 pages, 3116 KiB  
Article
Single-Nucleus RNA Sequencing Reveals Muscle-Region-Specific Differences in Fibro-Adipogenic Progenitors Driving Intramuscular Fat Accumulation
by Shuji Ueda, Chiaki Kitamura, Yuka Tateoka, Akinori Kanai, Yutaka Suzuki, Itsuko Fukuda and Yasuhito Shirai
Metabolites 2025, 15(4), 231; https://doi.org/10.3390/metabo15040231 - 28 Mar 2025
Viewed by 1430
Abstract
Background: Ectopic fat deposition refers to lipid accumulation that affects metabolic function and tissue characteristics. Japanese Black cattle are distinguished by their high intramuscular fat content, which contributes to their distinctive character. However, the genetic mechanisms underlying these traits remain unclear. This study [...] Read more.
Background: Ectopic fat deposition refers to lipid accumulation that affects metabolic function and tissue characteristics. Japanese Black cattle are distinguished by their high intramuscular fat content, which contributes to their distinctive character. However, the genetic mechanisms underlying these traits remain unclear. This study compared gene expression patterns in different muscle regions to identify genes associated with intramuscular fat accumulation. First, we conducted RNA sequencing to analyze differences in gene expression profiles among the sternocleidomastoid, pectoralis minor, and pectoralis major muscles. In addition, single-cell nuclear RNA sequencing was conducted to investigate the cellular composition of these muscle tissues. Results: Distinct gene expression patterns were observed among the different muscles. In the pectoralis, which contains a high proportion of intramuscular fat, adipocyte-related genes such as FABP4, SCD, and ADIPOQ were highly expressed. In addition, lipases such as PNPLA2, LPL, MGLL, and LIPE were predominantly expressed in intramuscular fat, whereas PLA2G12A, PLD3, and ALOX15 were specifically expressed in myofibers. Moreover, a subclass of fibro–adipogenic progenitor cells that differentiate into intramuscular adipocytes was found to express genes related to microenvironment formation, including ICAM1, TGFBRs, and members of the COL4A family. Conclusions: This study provides novel insight into the genetic regulation of intramuscular fat accumulation. It improves our understanding of the molecular mechanisms underlying their distinctive meat characteristics. Full article
(This article belongs to the Section Food Metabolomics)
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18 pages, 1621 KiB  
Article
Analysis of FBN1, TGFβ2, TGFβR1 and TGFβR2 mRNA as Key Molecular Mechanisms in the Damage of Aortic Aneurysm and Dissection in Marfan Syndrome
by María Elena Soto, Myrlene Rodríguez-Brito, Israel Pérez-Torres, Valentín Herrera-Alarcon, Humberto Martínez-Hernández, Iván Hernández, Vicente Castrejón-Téllez, Betsy Anaid Peña-Ocaña, Edith Alvarez-Leon, Linaloe Manzano-Pech, Ricardo Gamboa, Giovanny Fuentevilla-Alvarez and Claudia Huesca-Gómez
Int. J. Mol. Sci. 2025, 26(7), 3067; https://doi.org/10.3390/ijms26073067 - 27 Mar 2025
Cited by 1 | Viewed by 741
Abstract
Marfan syndrome (MFS) is an inherited connective tissue disorder, with aortic root aneurysm and/or dissection being the most severe and life-threatening complication. These conditions have been linked to pathogenic variants in the FBN1 gene and dysregulated TGFβ signaling. Our objective was to evaluate [...] Read more.
Marfan syndrome (MFS) is an inherited connective tissue disorder, with aortic root aneurysm and/or dissection being the most severe and life-threatening complication. These conditions have been linked to pathogenic variants in the FBN1 gene and dysregulated TGFβ signaling. Our objective was to evaluate the mRNA expression of FBN1, TGFBR1, TGFBR2, and TGFB2 in aortic tissue from MFS patients undergoing surgery for aortic dilation. This prospective study (2014–2023) included 20 MFS patients diagnosed according to the 2010 Ghent criteria, who underwent surgery for aneurysm or dissection based on Heart Team recommendations, along with 20 non-MFS controls. RNA was extracted, and mRNA levels were quantified using RT-qPCR. Patients with dissection showed significantly higher FBN1 mRNA levels [79 (48.1–110.1)] compared to controls [37.2 (25.1–79)] (p = 0.03). Conversely, TGFB2 expression was significantly lower in MFS patients [12.17 (6.54–24.70)] than in controls [44.29 (25.85–85.36)] (p = 0.029). A positive correlation was observed between higher FBN1 expression and a larger sinotubular junction diameter (r = 0.42, p = 0.07), while increased FBN1 expression was particularly evident in MFS patients with dissection. Additionally, TGFB2 expression showed an inverse correlation with ascending aortic diameter (r = 0.53, p = 0.01). In aortic tissue, we found decreased TGFB2 and receptor levels alongside increased FBN1 mRNA levels. These molecular alterations may reflect compensatory mechanisms in response to tissue damage caused by mechanical stress, leading to dysregulation of physiological signaling pathways and ultimately contributing to aortic dilation in MFS. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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14 pages, 1744 KiB  
Article
Whole-Genome Selective Scans Detect Genes Associated with Cashmere Traits and Climatic Adaptation in Cashmere Goats (Capra hircus) in China
by Hongying Dan, Hai’an Zhong, Zhanerke Akhatayeva, Kejian Lin and Songsong Xu
Genes 2025, 16(3), 292; https://doi.org/10.3390/genes16030292 - 27 Feb 2025
Cited by 2 | Viewed by 922
Abstract
Background: Cashmere, valued for its exceptional softness and warmth, is a major focus in goat breeding due to its high economic importance. However, the molecular mechanisms underlying cashmere production remain largely unknown, hindering efforts to optimize yield and quality. Additionally, domestic goats exhibit [...] Read more.
Background: Cashmere, valued for its exceptional softness and warmth, is a major focus in goat breeding due to its high economic importance. However, the molecular mechanisms underlying cashmere production remain largely unknown, hindering efforts to optimize yield and quality. Additionally, domestic goats exhibit remarkable adaptability to diverse climates, ranging from arid northern regions to humid southern areas, yet the genetic basis for these adaptations is poorly understood. Exploring the genetic factors driving cashmere production and climatic adaptation could provide crucial insights into trait evolution and support the development of breeding strategies for improved productivity and resilience. Methods: We utilized whole-genome resequencing data from 157 samples representing 14 goat populations to analyze the genetic diversity between cashmere and non-cashmere breeds. Additionally, we conducted the tests of selective sweeps (i.e., pairwise FST, θπ and XP-EHH) for cashmere traits and genome–environment association analysis (i.e., XtX statistic), respectively. Results: We identified strong selective signatures in previous reports (e.g., AKT3, FOXP1, FGF5, TGFBR3) and novel genes (e.g., ZEB1, ZNRF3, MAPK8IP3, MAPK8IP2, AXIN1) associated with cashmere traits. Further gene annotation and KEGG analyses showed that these genes were identified to be the most probable genes accounting for the cashmere traits. Also, we detected some genes such as PDGFRB, PRDM8, SLC26A2, SCAMP1, EPHX1, CDC25A, and POLK that played critical roles in the adaptation of goats to local climate variation. Conclusions: Collectively, our results provide novel insights into the genetic mechanisms underlying the cashmere traits and climatic adaptation, and also identified new genetic markers for genetic improvement in goats. Full article
(This article belongs to the Special Issue Systematic Analysis and Application of Omics Data in Animal Breeding)
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17 pages, 10020 KiB  
Article
Membranous Nephropathy Target Antigens Display Podocyte-Specific and Non-Specific Expression in Healthy Kidneys
by Ying Dong, Hui Xu and Damu Tang
Genes 2025, 16(3), 241; https://doi.org/10.3390/genes16030241 - 20 Feb 2025
Viewed by 1140
Abstract
Background/Objectives: Autoimmunity towards podocyte antigens causes membranous nephropathy (MN). Numerous MN target antigens (MNTAgs) have been reported, including PLA2R1, THSD7A, NTNG1, TGFBR3, HTRA1, NDNF, SEMA3B, FAT1, EXT1, CNTN1, NELL1, PCDH7, EXT2, PCSK6, and NCAM1, but their podocyte expression has not been thoroughly studied. [...] Read more.
Background/Objectives: Autoimmunity towards podocyte antigens causes membranous nephropathy (MN). Numerous MN target antigens (MNTAgs) have been reported, including PLA2R1, THSD7A, NTNG1, TGFBR3, HTRA1, NDNF, SEMA3B, FAT1, EXT1, CNTN1, NELL1, PCDH7, EXT2, PCSK6, and NCAM1, but their podocyte expression has not been thoroughly studied. Methods: We screened CZ CELLxGene single-cell RNA (scRNA) sequence datasets for those of adult, fetal, and mouse kidneys and analyzed the above MNTAgs’ expression. Results: In adult kidneys, most MNTAgs are present in podocytes, except PCSK6 and NCAM1. PLA2R1 is expressed significantly more than other MNTAgs in podocytes and is a major podocyte marker, consistent with PLA2R1 as the dominant MNTAg. Additionally, PLA2R1 is a top-upregulated gene in the podocytes of chronic kidney disease, acute kidney injury, and diabetic nephropathy, indicating its general role in causing podocyte injury. PLA2R1, NTNG1, HTRA1, and NDNF display podocyte-enriched expression along with elevated chromatin accessibility in podocytes, suggesting transcription initiation contributing to their preference expression in podocytes. In the fetal kidney, most MNTAgs are expressed in podocytes. While PLA2R1 is weakly present in podocytes, SEMA3B is abundantly expressed in immature and mature podocytes, supporting SEMA3B as a childhood MNTAg. In mouse kidneys, Thsd7a is the only MNTAg with a prominent level and podocyte-specific expression. Conclusions: Most MNTAgs are present in podocytes in adults and during renal development. In adults, PLA2R1 expression is highly enriched in podocytes and significantly upregulated in multiple kidney diseases accompanied by proteinuria. In mouse kidneys, Thsd7a is specifically expressed in podocytes at an elevated level. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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17 pages, 3064 KiB  
Article
Characterization and Anti-Inflammatory Effects of Akkermansia muciniphila-Derived Extracellular Vesicles
by Sasa Zhao, Jie Xiang, Minhazul Abedin, Jingyi Wang, Zhiwen Zhang, Zhongwei Zhang, Hua Wu and Junsong Xiao
Microorganisms 2025, 13(2), 464; https://doi.org/10.3390/microorganisms13020464 - 19 Feb 2025
Cited by 1 | Viewed by 1628
Abstract
Bacterial extracellular vesicles (EVs) play a pivotal role in host–microbe communication. Akkermansia muciniphila, a symbiotic bacterium essential for intestinal health, is hypothesized to exert its effects via EVs. Here, we successfully isolated and characterized EVs derived from A. muciniphila (Am-EVs) using ultracentrifugation. [...] Read more.
Bacterial extracellular vesicles (EVs) play a pivotal role in host–microbe communication. Akkermansia muciniphila, a symbiotic bacterium essential for intestinal health, is hypothesized to exert its effects via EVs. Here, we successfully isolated and characterized EVs derived from A. muciniphila (Am-EVs) using ultracentrifugation. Am-EVs exhibited a double-membrane structure, with an average diameter of 92.48 ± 0.28 nm and a proteomic profile comprising 850 proteins. In an in vitro model of lipopolysaccharide (LPS)-induced inflammation in human colorectal adenocarcinoma cells (Caco-2), treatment with both 25 and 50 μg/mL Am-EVs significantly reduced oxidative stress markers, including reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA), while restoring catalase activity (CAT). Am-EVs also suppressed the expression of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Subsequent transcriptomic sequencing and Western blot experiments revealed that Am-EVs attenuate the MAPK signaling pathway by downregulating TRIF, MyD88, p38 MAPK, and FOS while upregulating TGFBR2. These findings suggest that Am-EVs mediate anti-inflammatory effects through modulation of MAPK signaling, highlighting their potential as therapeutic agents in intestinal inflammation. Full article
(This article belongs to the Section Molecular Microbiology and Immunology)
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9 pages, 1634 KiB  
Review
Genetic Overlap of Thoracic Aortic Aneurysms and Intracranial Aneurysms
by Mah I Kan Changez, Afsheen Nasir, Alexandra Sonsino, Syeda Manahil Jeoffrey, Asanish Kalyanasundaram, Mohammad A. Zafar, Bulat A. Ziganshin and John A. Elefteriades
Genes 2025, 16(2), 154; https://doi.org/10.3390/genes16020154 - 26 Jan 2025
Viewed by 2119
Abstract
Objective: Thoracic aortic aneurysms (TAAs) and intracranial aneurysms (ICAs) share overlapping genetic and pathophysiological mechanisms, yet the genetic interplay between these conditions remains insufficiently explored. This study aimed to identify common genetic factors underlying TAA and ICA. Methods: A comprehensive review of genome-wide [...] Read more.
Objective: Thoracic aortic aneurysms (TAAs) and intracranial aneurysms (ICAs) share overlapping genetic and pathophysiological mechanisms, yet the genetic interplay between these conditions remains insufficiently explored. This study aimed to identify common genetic factors underlying TAA and ICA. Methods: A comprehensive review of genome-wide association studies (GWASs) and retrospective clinical studies was conducted using PubMed, Orbis, and Web of Science. Articles addressing the genetic etiologies of TAA and ICA were analyzed. Separate lists of causative genes were compiled, and commonalities were identified. A Venn diagram was constructed to illustrate genetic overlap and shared physiological pathways. Results: We identified 24 overlapping genes associated with TAA and ICA, including LTBP2, TGFB2, TGFB3, TGFBR1, TGFBR2, SMAD2, SMAD3, COL1A2, COL3A1, COL4A1, COL5A1, COL5A2, FBN1, FBN2, ELN, LOX ACTA2, MYH11, MYLK, ABCC6, NOTCH1, MED12, PKD1, and PKD2. These genes are involved in pathways related to connective tissue biology, contractile elements, extracellular matrix components, and transforming growth factor-β signaling. While vascular endothelium and cell cycle pathways were unique to ICA, TAA pathways predominantly involved extracellular matrix remodeling. Conclusions: This study highlights the significant genetic overlap between TAA and ICA, shedding light on shared molecular mechanisms. These findings underscore the importance of interdisciplinary awareness: neurologists, neurosurgeons, and neurointerventional radiologists should monitor ICA patients for potential TAA, while cardiologists, cardiac surgeons, vascular surgeons, and vascular interventionalists should consider ICA risks in TAA patients. Further research into these genetic pathways could enhance the understanding and management of both conditions. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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19 pages, 3494 KiB  
Article
Leveraging Tumor Mutation Profiles to Forecast Immune Checkpoint Blockade Resistance in Melanoma, Lung, Head and Neck, Bladder and Renal Cancers
by Guillaume Mestrallet
Onco 2024, 4(4), 439-457; https://doi.org/10.3390/onco4040031 - 10 Dec 2024
Cited by 1 | Viewed by 1262
Abstract
Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I [...] Read more.
Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I analyzed 350 lung cancer, 320 melanoma, 215 bladder cancer, 139 head and neck cancer and 151 renal carcinoma patients treated with ICB to identify tumor mutations associated with response and resistance to treatment. I identified several tumor mutations linked with a difference in survival outcomes following ICB. In lung cancer, missense mutations in ABL1, ASXL1, EPHA3, EPHA5, ERBB4, MET, MRE11A, MSH2, NOTCH1, PAK7, PAX5, PGR, ZFHX3, PIK3C3 and REL genes were indicative of favorable responses to ICB. Conversely, mutations in TGFBR2, ARID5B, CDKN2C, HIST1H3I, RICTOR, SMAD2, SMAD4 and TP53 genes were associated with shorter overall survival post-ICB treatment. In melanoma, mutations in FBXW7, CDK12, CREBBP, CTNNB1, NOTCH1 and RB1 genes predict resistance to ICB, whereas missense mutations in FAM46C and RHOA genes are associated with extended overall survival. In bladder cancer, mutations in HRAS genes predict resistance to ICB, whereas missense mutations in ERBB2, GNAS, ATM, CDKN2A and LATS1 genes, as well as nonsense mutations in NCOR1 and TP53 genes, are associated with extended overall survival. In head and neck cancer, mutations in genes like PIK3CA and KRAS correlated with longer survival, while mutations in genes like TERT and TP53 were linked to shorter survival. In renal carcinoma, mutations such as EPHA5, MGA, PIK3R1, PMS1, TSC1 and VHL were linked to prolonged overall survival, while others, including total splice mutations and mutations in B2M, BCOR, JUN, FH, IGF1R and MYCN genes were associated with shorter overall survival following ICB. Then, I developed predictive survival models by machine learning that correctly forecasted cancer patient survival following ICB within an error between 5 and 8 months based on their distinct tumor mutational attributes. In conclusion, this study advocates for personalized immunotherapy approaches in cancer patients. Full article
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