Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders

PLoS Computational Biology, Год журнала: 2025, Номер 21(5), С. e1012382 - e1012382

Опубликована: Май 2, 2025

The link between p53 tumor suppressive functions and organismal lifespan is multifaceted. Its DNA-repair mechanism longevity-enhancing while its role in cellular senescence pathways induces pro-aging phenotypes. To understand how may regulate lifespan, cross-species genotype-phenotype (GP) studies of the DNA-binding domain (DBD) have been used to assess correlation amino acid changes lifespan. Amino non-DNA-binding regions such as transactivation (TAD), proline-rich (PRD), regulatory (REG), tetramerization (TET) are largely unexplored. In addition, existing GP tools SigniSite do not account for phylogenetic relationships aligned sequences correlating genotypic differences phenotypes identify phylogenetically significant, longevity-correlated residues full-length alignments, we developed a Python- R-based workflow, Relative Evolutionary Scoring (RES). While RES-predicted longevity-associated (RPLARs) concentrated primarily DBD, PRD, TET, REG domains also house RPLARs. yeast functional assay enrichment reveals that RPLARs be dispensable p53-mediated transactivation, PEPPI Rosetta-based protein-protein interaction prediction suggests stability interfaces complexes. With experimental validation RPLARs’ roles stability, transactivity, involvement senescence-regulatory pathways, can gain crucial insights into mechanisms underlying dysregulated suppression accelerated aging.

Язык: Английский

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Overcoming Chemoresistance in Cancer: The Promise of Crizotinib

Cancers, Год журнала: 2024, Номер 16(13), С. 2479 - 2479

Опубликована: Июль 7, 2024

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, changes the tumor microenvironment. These processes allow cells survive despite chemotherapy, underscoring need for new strategies overcome resistance improve treatment efficacy. Crizotinib, first-generation multi-target kinase inhibitor, approved by FDA of ALK-positive or ROS1-positive non-small cell lung (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) relapsed/refractory anaplastic large lymphoma (ALCL). Crizotinib exists two enantiomeric forms: (R)-crizotinib its mirror image, (S)-crizotinib. assumed that R-isomer responsible carrying out reviewed here The S-isomer, on other hand, shows strong inhibition MTH1, an enzyme important repair mechanisms. Studies have shown crizotinib effective multi-kinase inhibitor targeting kinases c-Met, native/T315I Bcr/Abl, JAK2. Its mechanism action involves competitive ATP binding allosteric inhibition, particularly at Bcr/Abl. showed synergistic effects when combined with poly ADP ribose polymerase (PARP), especially ovarian harboring BRCA gene mutations. In addition, targets critical vulnerability many p53-mutated cancers. Unlike wild-type counterpart, p53 mutant promotes survival. can cause degradation mutant, sensitizing these DNA-damaging substances triggering apoptosis. Interestingly, reports demonstrated exhibits anti-bacterial activity, Gram-positive bacteria. Also, it active against drug-resistant strains. summary, exerts anti-tumor several mechanisms, including restoration sensitivity. potential combination therapies emphasized, cancers high prevalence triple-negative breast (TNBC) high-grade serous (HGSOC).

Язык: Английский

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Epigenetic patterns, accelerated biological aging, and enhanced epigenetic drift detected 6 months following COVID-19 infection: insights from a genome-wide DNA methylation study

Clinical Epigenetics, Год журнала: 2024, Номер 16(1)

Опубликована: Авг. 20, 2024

The epigenetic status of patients 6-month post-COVID-19 infection remains largely unexplored. existence long-COVID, or post-acute sequelae SARS-CoV-2 (PASC), suggests potential long-term changes. Long-COVID includes symptoms like fatigue, neurological issues, and organ-related problems, regardless initial severity. mechanisms behind long-COVID are unclear, but virus-induced changes could play a role. Our study explores the lasting impacts infection. We analyzed genome-wide DNA methylation patterns in an Italian cohort 96 6 months after COVID-19 exposure, comparing them to 191 healthy controls. identified 42 CpG sites with significant differences (FDR < 0.05), primarily within islands gene promoters. Dysregulated genes highlighted links glutamate/glutamine metabolism, which may be relevant PASC symptoms. Key significance effects include GLUD1, ATP1A3, ARRB2. Furthermore, Horvath's clock showed slight age acceleration patients. also observed substantial increase stochastic mutations (SEMs) group, implying drift. SEM analysis 790 affected genes, indicating dysregulation pathways related insulin resistance, VEGF signaling, apoptosis, hypoxia response, T-cell activation, endothelin signaling. provides valuable insights into consequences COVID-19. Results suggest possible associations accelerated aging, drift, disruption critical biological linked immune vascular health. Understanding these crucial for elucidating complex developing targeted therapeutic interventions.

Язык: Английский

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Fruquintinib inhibits the migration and invasion of colorectal cancer cells by modulating epithelial-mesenchymal transition via TGF-β/Smad signaling pathway

Frontiers in Oncology, Год журнала: 2025, Номер 15

Опубликована: Март 11, 2025

Background Fruquintinib, a selective vascular endothelial growth factor receptor (VEGFR) inhibitor, has shown considerable efficacy in colorectal cancer (CRC) treatment. Despite its promising therapeutic effects, the precise molecular mechanisms underlying effects remain incompletely understood. In this study, we explored functional roles and of fruquintinib CRC therapy. Material methods Human cells (HCT-116 LOVO) were cultured treated with fruquintinib. Cell counting kit-8 assay kit (CCK-8) colony formation assays performed to investigate on cell proliferation. Wound healing transwell conducted explore role migration invasion. RNA sequencing bioinformatics analysis was used potential mechanism development CRC. Western blot measure protein level. Results Fruquintinib significantly inhibited proliferation, migration, invasion cells. Bioinformatics indicated that modulated epithelial-mesenchymal transition (EMT) pathway, experimental validation confirmed regulatory core EMT-associated biomarkers. Notably, treatment resulted upregulation E-cadherin downregulation N-cadherin, vimentin, MMP9. revealed dose-dependently suppressed SMAD2/3 expression. TGF-β agonist KRFK TFA attenuated fruquintinib’s effect, reversing as well downregulatin N-cadherin SMAD2/3. Additionally, partially restored assays, counteracting inhibitory impact. Conclusion These findings indicate effectively hampers by disrupting EMT process via TGF-β/Smad signaling pathway. This study sheds light which inhibits progression underscores for further clinical investigation.

Язык: Английский

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In-silico analysis unveiling the role of cancer stem cells in immunotherapy resistance of immune checkpoint-high pancreatic adenocarcinoma

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 26, 2025

Although immune checkpoint (IC) inhibition is a major treatment modality in cancer-immunotherapy, multiple cancers show low response. Our in-silico exploration by mining cancer datasets using R2, available clinical trial data, and Kaplan–Meier analysis from GEPIA depicted that unlike low-responder (LR) cancers, high-responder (HR) furnish higher IC expression, upon lowering may provide better prognosis. Contrastingly, pancreatic adenocarcinoma (PAAD) demonstrated high expression but immunotherapy-response. Infiltration scores TIMER2.0 revealed pro-tumor subsets cancer-associated fibroblasts (CAFs) while depicting lower anti-tumor PAAD as compared to HR lung (LUAD). Additionally, bioinformatic tool cBioportal showed lesser tumor mutational burden, mismatch repair deficiency greater percent of driver mutations TP53, KRAS CDKN2A PAAD, supporting its immunotherapy-resistance than LUAD. search for the 'key' immunotherapy response-deciding factor(s) stem cells (CSCs), known contributors therapy-resistance immuno-evasion, be positively correlated with above-mentioned mutations, CAF subsets; furnished CSC genes UMAP/tSNE analyses signature pro-cancer cells, negatively cytotoxic-T PAAD. study explains immunotherapy-response IC-expressing wherein plays pivotal role. Further portrayed correlation CSCs other LR too, substantiating need personalized evaluation targeting successful outcomes.

Язык: Английский

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M2 macrophage-derived exosomes reverse TGF-β1-induced epithelial mesenchymal transformation in BEAS-2B cells via the TGF-βRI/Smad2/3 signaling pathway

European journal of medical research, Год журнала: 2025, Номер 30(1)

Опубликована: Апрель 11, 2025

Airway remodeling in bronchial asthma can be inhibited by disrupting the epithelial mesenchymal transition (EMT) of activated airway cells. Exosomes, as key mediators intercellular communication, have been implicated pathophysiology asthma-related inflammation, remodeling, and hyperresponsiveness. This study aimed to investigate role M2 macrophage-derived exosomes (M2φ-exos) modulating TGF-β1-induced EMT (BEAS-2B) cells elucidate underlying molecular mechanism, if any. THP-1 were induced differentiate into macrophages via phorbol 12-myristate 13-acetate (PMA) IL-4. Exosomes subsequently isolated purified ultracentrifugation. M2φ-exos expression was characterized protein marker levels, transmission electron microscopy imaging, nanoparticle tracking analysis. BEAS-2B exposed determine latter's effects. successfully differentiated macrophages, confirmed vitro flow cytometry. The presented typical cup-shaped structures expressed CD81 TSG101. TGF-β1 induction altered morphological characteristics TGF-βRI/Smad2/3 signaling pathway, leading increased Snail, Vimentin Collagen 1 decreased E-cadherin. After exosome or SB431542 induction, reversed. GW4869, an release inhibitor, exhibited ability block beneficial effects exosomes. M2Φ-exos through pathway. novel insight may important implications for asthma, particularly addressing remodeling.

Язык: Английский

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Hovenia dulcis Honey Suppresses Androgen‐Induced Epithelial–Mesenchymal Transition in Benign Prostatic Hyperplasia

Food Frontiers, Год журнала: 2025, Номер unknown

Опубликована: Апрель 28, 2025

ABSTRACT Benign prostate hyperplasia (BPH) is characterized by abnormal epithelial and stromal cell growth, which leads to bladder outlet obstruction (BOO) lower urinary tract symptoms (LUTS). BPH pathogenesis involves key signaling pathways, including androgen/androgen receptor (AR) transforming growth factor‐beta (TGF‐β)/Smad, contribute proliferation, transformation, epithelial–mesenchymal transition (EMT). To date, the effect of Hovenia dulcis honey (HH) on has not been reported. Herein, in vivo vitro models were used determine whether HH therapeutic effects its underlying mechanisms, if present. evaluate anti‐BPH vivo, mice treated with testosterone propionate (TP; 10 mg/kg, s.c.), finasteride (Fi; i.p.), or (600 p.o.) for 4 weeks. Additionally, efficacy was evaluated using a dihydrotestosterone (DHT)‐stimulated RWPE‐1 model. significantly reduced size, thickness, markers AR (prostate‐specific antigen [PSA], proliferating nuclear [PCNA], DHT) as well exhibited anti‐inflammatory lowering expression inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α) inhibited EMT process decreasing α‐smooth muscle actin (α‐SMA), neural cadherin (N‐cadherin), vimentin levels while restoring (E‐cadherin) expression. These findings suggest that inhibits androgen/AR TGF‐β/Smad pathways may offer novel approach treatment.

Язык: Английский

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IBSP Promotes Breast Cancer Bone Metastasis and Proliferation via BMP‐SMAD Signaling Pathway

Cancer Reports, Год журнала: 2024, Номер 7(8)

Опубликована: Авг. 1, 2024

Integrin-Binding Sialoprotein (IBSP) has been implicated in tumor progression across various cancers. However, the specific role of IBSP breast cancer remains underexplored. There is a need to investigate mechanisms by which influences and its potential as therapeutic target.

Язык: Английский

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TGFβ family signaling in human stem cell self-renewal and differentiation

Cell Regeneration, Год журнала: 2024, Номер 13(1)

Опубликована: Ноя. 28, 2024

Abstract Human stem cells are undifferentiated with the capacity for self-renewal and differentiation into distinct cell lineages, playing important role in development maintenance of diverse tissues organs. The microenvironment provides crucial factors components that exert significant influence over determination fate. Among these factors, cytokines from transforming growth factor β (TGFβ) superfamily, including TGFβ, bone morphogenic protein (BMP), Activin Nodal, have been identified as regulators governing differentiation. In this review, we present a comprehensive overview pivotal roles played by TGFβ superfamily signaling human embryonic cells, somatic induced pluripotent cancer cells. Furthermore, summarize latest research advancements family various cell-based therapy, discussing their potential clinical applications therapy regeneration medicine.

Язык: Английский

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Prognostic Relevance of Copy Number Losses in Ovarian Cancer

Genes, Год журнала: 2024, Номер 15(11), С. 1487 - 1487

Опубликована: Ноя. 19, 2024

Aneuploidy is a prevalent cancer feature that occurs in many solid tumors. For example, high-grade serous ovarian shows high level of copy number alterations and genomic rearrangements. This makes variants appealing as diagnostic or prognostic biomarkers, well for their easy detection. In this study, we focused on (CN) losses shared by stem cells (CSCs) to identify chromosomal regions may be important CSC features and, turn, patients' prognosis.

Язык: Английский

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