Search Results (340)

Developing functional foods that address both oxidative stress and physiological challenges like dysphagia is a critical frontier in personalized nutrition. This study investigates the multi-component synergy of Fu Ling Yin Zi (FLYZ), a traditional dietary therapy, and translates its functional properties into a 3D-printed dysphagia-friendly food. Using response surface methodology, the optimal FLYZ formulation was established at a 5:1:5 ratio of Poria cocos (Schw.) Wolf., Amygdalus communis Vas, and Citrus reticulata. Network pharmacology and molecular docking suggested that FLYZ’s active compounds (e.g., nobiletin, stigmasterol, tangeretin, l-SPD, glabridin, estrone) may mitigate oxidative stress via multiple targets (PTGS2, AKT1, TNF, ESR1, MMP9, and MAOA), with pathway analysis pointing to a potential role of the AKT1/GSK3β/HIF-1α axis. Subsequent in vitro cellular assays demonstrated that FLYZ enhanced antioxidant enzyme activities, reduced intracellular ROS, and modulated the expression of associated genes, supporting a potential link to this pathway. To actualize these functional benefits for patients with swallowing difficulties, a novel 3D-printing ink incorporating FLYZ and walnut oil within a hydrogel matrix (3% xanthan gum, 3% pectin, 1.5% carrageenan) was developed. The printed constructs exhibited excellent shape fidelity and, based on standardized IDDSI fork and spoon tests, were categorized as level 4 (pureed/extremely thick). Furthermore, a simulated in vitro digestion model showed that the colloidal network significantly protected FLYZ’s polyphenols and flavonoids, markedly improving their bioaccessibility and post-digestion antioxidant capacity. Collectively, this work establishes an integrated approach that combines predictive molecular profiling with advanced 3D food printing, thereby supporting the development of future foods tailored for personalized nutrition. Full article

Nervonic acid (NA, C24:1 Δ15) is a vital extra-long-chain monounsaturated fatty acid essential for neural development, myelin sheath formation, and neurological health. As the most abundant natural source of NA, Malania oleifera Chun & S.K.Lee has become a key model for studying NA biosynthesis and regulation. This review systematically summarizes the metabolic pathways of nervonic acid biosynthesis in M. oleifera, including plastidial de novo fatty acid synthesis, endoplasmic reticulum (ER)-based very-long-chain fatty acid elongation, and Δ15 desaturation. We focus on the catalytic mechanisms and rate-limiting roles of the elongase complex (KCS, KCR, HCD, ECR) and Δ15 desaturase. Additionally, we integrate recent multi-omics data to analyze key enzyme KCS gene families, their phylogenetic relationships, and syntenic distribution patterns. Furthermore, transcriptional regulatory networks (MYB, bZIP, WRI1, ABI3, FUS3) and epigenetic regulation underlying NA accumulation are also discussed. Finally, we highlight advances, challenges, and prospects in metabolic engineering and synthetic biology for sustainable NA production. This review provides a theoretical basis for the conservation, molecular breeding, and biotechnological utilization of M. oleifera. Full article

Disease comorbidity—the co-occurrence of two or more diseases in the same individual—has gained growing attention due to its association with adverse clinical outcomes and increased treatment complexity. Recent subgraph-based approaches for disease comorbidity prediction model disease modules as subgraphs induced by disease-associated genes in the protein–protein interaction (PPI) network and learn disease representations from subgraph topology. However, these approaches are constrained by incomplete disease–gene annotations, which may obscure important molecular relationships between diseases. Accordingly, disease comorbidity may also be influenced by molecular events beyond annotated disease genes, such as gene fusion events that have emerged as important contributors to disease mechanisms. Motivated by the role of gene fusions in disease development, we introduce Gene Fusion-Initiated Path Propagation for Disease Comorbidity Prediction (FuDiCo), a framework that models comorbidity through influence propagation over the PPI network. FuDiCo represents fusion-associated genes as localized perturbation sources and learns how their influence propagates along interaction paths toward disease subgraphs, thereby capturing propagation patterns that link related diseases and contribute to their comorbidity. Experiments on a benchmark disease comorbidity dataset show that FuDiCo outperforms state-of-the-art methods, achieving statistically significant improvements. These results shed light on the importance of gene fusion events in understanding disease relationships. Full article

To explore the genetic diversity and evolutionary differentiation of Mastacembelus armatus from the headwaters of the Dongjiang and Ganjiang Rivers, we performed whole-genome resequencing on three populations, including Xunyushui (XW) and Jiuqu River (DN) from the Dongjiang River source as well as Taojiang River (XF) from the Ganjiang River source. We analyzed population structure, genetic differentiation, nucleotide diversity (π), pairwise FST, linkage disequilibrium, kinship, and neutrality tests (Tajima’s D, Fu and Li’s D). A total of 209.05 Gbp of clean data were obtained, with high quality and reliable alignment. Average nucleotide diversity (π) was higher in XW (0.00490 ± 0.00248) and DN (0.00478 ± 0.00312) and lower in XF (0.00463 ± 0.00158). Pairwise FST values revealed moderate differentiation between XW and DN (FST = 0.12) and strong divergence between XF and the other two populations (FST = 0.19 and 0.17). Neutrality tests showed no significant deviation from neutrality. XW and DN exhibited positive values, indicating stable demography, while XF showed negative values, suggesting a tendency of population expansion. Phylogenetic, admixture, and PCA analyses supported that all three populations belonged to one evolutionary clade with two ancestral components. XF showed the slowest linkage disequilibrium decay and distant kinship, indicating a small effective population size. Significant genetic divergence was primarily driven by geographic isolation and limited gene flow. This study reveals the genetic diversity and differentiation pattern of M. armatus and provides a genomic basis for its conservation and management. Full article

Background: Fibrolamellar carcinoma (FLC) is a rare liver malignancy affecting adolescents. FLCs harbor a DNAJB1–PRKACA gene fusion that combines heat shock protein DNAJB1 with the catalytic subunit of protein kinase A. Surgery with systemic therapy provides 5-year survivals of 30–50%, but advanced disease remains largely incurable. Three-dimensional explants from 41 FLC patients were interrogated for drug sensitivity, resistance, and synergy against cytotoxics, targeted agents, and signal transduction inhibitors. Methods: Sterile specimens from histologically confirmed FLC patients were analyzed by Ex Vivo Analysis of Programmed Cell Death (EVA/PCD™) in a CLIA-licensed laboratory. Following mechanical and enzymatic disaggregation, explants underwent 72 h drug exposure. LC₅₀ values were derived from five-point dose–response curves and compared with a database of over 10,000 human tumor analyses. Synergy was assessed by combination index. In parallel, targeted metabolomic profiling was performed in five FLC patients using tandem MS/MS. Results: Forty-one samples were analyzed. Of 24 drugs selected, tumor-cell yields were adequate for testing in 18 (75%). Single-agent activity favored vorinostat, followed by phenformin and 6-diazo-5-oxo-L-norleucine. Combinations favored gemcitabine plus oxaliplatin (GEMOX) and 5-FU plus interferon. Metabolomic analysis identified distinct signature consistent with mitochondrial dysfunction and altered polyamine metabolism. Conclusions: The present findings are exploratory, and hypothesis-generating and should not be interpreted as evidence of clinical efficacy. Prospective clinical validation and mechanistic studies will be required to further define the therapeutic relevance of these observations in fibrolamellar carcinoma. Full article

Cancer is a complex and evolutionary disease, with the development of different types of cancers leading to various different defective gene mutations. Synthetic lethality is a genetic-level precision medical strategy. Currently, treating BRCA (BReast CAncer)-mutated breast or ovarian cancer cells with a chemical inhibitor (Poly(ADP-ribose) polymerase, PARPi) is a typical synthetic lethal application in clinical practice. However, PARPi therapy has been found to cause off-target effects and therapy-induced immune escape driven by PD-L1 upregulation, allowing for cancer cells to escape attack from the immune response. To overcome these challenges, we developed a core–shell structure comprising a hydrophobic core of quercetin (Q)-mediated PARP inhibition and iron oxide nanoparticles (IONPs), enveloped by a hydrophilic fucoidan (Fu) shell to encapsulate short hairpin RNA targeting Programmed Death Ligand 1 (shPD-L1) for efficient gene transfection (shPD-L1@QIO@Fu). Structurally, the incorporation of quercetin into the intermediate hydrophobic layer enables modulate of the PARP effect, while the inner aqueous core with shPD-L1 gene silencing can inhibit the expression of PD-L1 protein. In this study, we proved that shPD-L1@QIO@Fu demonstrated a dual therapeutic mechanism against BRCA-mutant cancer cells by inducing extensive DNA double-strand breaks and promoting apoptosis. Furthermore, the combined action of quercetin-mediated DNA damage and shPD-L1-driven PD-L1 suppression led to a significant reduction in PD-L1 mRNA to approximately 5% at 72 h and decreased surface PD-L1 below baseline by 96 h. This effectively suppresses PARPi-induced PD-L1 upregulation and enhances antitumor immunity. These findings demonstrate the therapeutic efficacy of shPD-L1@QIO@Fu nanomedicine, providing a promising foundation for advanced co-delivery strategies to synergize PARP inhibition mediated synthetic lethality with immune checkpoint blockade in next-generation precision medicine. Full article

Background/Objectives: Breast cancer (BC) is a highly prevalent neoplasm worldwide. Despite the wide range of therapeutic options currently available, it remains the leading cause of cancer-related mortality among women. Capecitabine, a prodrug of 5-fluorouracil (5-FU), is widely used in the treatment of advanced BC. However, despite its efficacy, capecitabine exhibits considerable interindividual variability in therapeutic response. This study aimed to evaluate the effect of single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine bioactivation on progression-free survival (PFS) in patients with BC. Methods: An ambispective cohort study was conducted. Four relevant SNPs in the CES1, CDA, and TYMP genes were analyzed in 85 Caucasian patients with BC using real-time polymerase chain reaction (PCR) with TaqMan^® probes. Results: A significant association was observed between shorter PFS and the GA genotype of the CES1 rs71647871 SNP (p = 0.010; HR = 7.46; 95% CI = 1.24–122.52), as well as with the TT genotype of the CDA rs602950 SNP (p = 0.009; HR = 3.50; 95% CI = 1.36–9.03). Conclusions: These findings suggest that CES1 rs71647871 and CDA rs602950 may serve as predictive biomarkers of capecitabine effectiveness in patients with BC. Further studies involving larger cohorts are needed to validate these findings and generate additional evidence to support their potential implementation in clinical practice. Full article

Leydig cells (LCs) represent a somatic testicular population responsible for testosterone synthesis, a hormone essential for spermatogenesis and male fertility. The obesity condition impairs LC steroidogenic activity, contributing to testicular oxidative stress and male reproductive dysfunctions. Using a high-fat-diet (HFD) murine model, we investigated the regulatory role of the nuclear factor of activated T cells 5 (NFAT5s) in the obesity-induced LC damage and the resulting alterations in intergenerationally inherited sperm circRNA cargo. Our findings reveal a significant upregulation of both circNFAT5 and NFAT5 protein levels in HFD testis. This molecular signature correlated with decreased antioxidant defense system, increased LC apoptosis, and impaired steroidogenesis. In vitro experiments, performed in TM3 cells, confirmed that NFAT5 nuclear shuttling drives proapoptotic gene activation, while NFAT5 silencing promotes LC survival. The analysis of HFD progeny (F1H) revealed a full recovery of testis oxidative status and LC apoptosis, linked with the recovery of NFAT5 expression. However, a steroidogenic deficiency persisted in F1H offspring. Notably, HFD and F1H epididymides exhibited NFAT5 overexpression concomitantly with impaired sperm morphology, motility, viability, and altered sperm circRNA profiles alongside a deregulated 4-hydroxy-2-nonenal (4HNE) profile, a marker of sperm oxidative stress. Lastly, an enhanced FUS-related amplification of circRNA perturbations was highlighted in F1H spermatozoa. Collectively, our findings reveal a dual functional role of NFAT5 as a testicular regulator of LC fate and an epididymal sentinel of metabolic stress, in turn linking paternal obesity to the persistent transmission of sperm epigenetic anomalies across the offspring. Full article

Endometriosis (EMT) is characterized by a chronic inflammatory disorder in the female reproductive system, posing significant challenges to global women’s health. Necrosis by Sodium Overload (NESCO) is a novel immunogenic programmed cell death (PCD) pattern that may potentially inhibit natural killer (NK) cell activation by increasing cytotoxicity and the inflammatory response in the EMT microenvironment. By integrating three bulk datasets to compare endometrium tissues between endometriosis patients and normal controls and the NESCO gene list from a public database, we identified NK- and NESCO (NN)-associated hub genes via integrative bioinformatic analyses utilizing Limma, WGCNA, CIBERSORT and machine learning frameworks. The diagnostic performance of NN-associated hub genes was evaluated across the three aforementioned datasets and two independent validation sets. Furthermore, their molecular and immune features were estimated at the bulk and single-cell transcriptomic levels. In addition, endometriosis patients were classified into two novel molecular subgroups based on consensus clustering of NN. Finally, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and molecular docking were used to identify compounds in Chinese traditional medicine (CTM) that can target NN-associated hub genes for endometriosis treatment. FABP4 and SLC2A1 can be considered NN-associated hub genes that are involved in EMT pathogenesis, and natural compounds including the CTM GuiZhiFuLingWan (GZFLW) can be considered therapeutic agents for EMT treatment as they target FABP4 and SLC2A1. Our study is the first to reveal the diagnostic and druggable roles of NESCO and NK cells, the corresponding molecular and immune features of NN-associated hub genes, and the therapeutic potential of GZFLW. Full article

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. While most cases are sporadic, around 10% are familial. Recent genetic studies show that many apparently isolated cases carry pathogenic mutations, highlighting the importance of penetrance, the probability that a causal mutation manifests clinically. This review focuses on mutation penetrance in ALS (C9orf72, SOD1, TARDBP, FUS genes), its variability across genes, age, and environmental or genetic modifiers, and its implications for genetic counseling. Identification of pathogenic mutations informs the monitoring of relatives and, in some cases, gives access to targeted therapies or clinical trials. Counseling of asymptomatic relatives must consider incomplete penetrance, which can lead to delayed or absent disease manifestation. ALS exists on a clinical and genetic continuum including related disorders, such as frontotemporal dementia, further influencing risk interpretation. Advances in panel, whole-exome and whole-genome sequencing refine our understanding of penetrance and enable precise diagnostics, and potential tailored therapies. Understanding penetrance is therefore essential to translate mutation discovery into informed clinical decisions and genetic counseling in ALS. Full article

Monacha cartusiana (O. F. Müller, 1774), native to the Mediterranean region and Europe, is a terrestrial gastropod recognized as a highly destructive agricultural pest that causes significant damage to crop plants, fruit trees, vegetables, ornamentals, and natural ecosystems. Despite its broad geographic distribution, the evolutionary history and phylogeographic relationships of M. cartusiana populations remain globally unexplored. This study reports the first molecularly confirmed record of M. cartusiana in Pakistan and investigates its genetic diversity and phylogeographic structure within a global context using mitochondrial markers. After morphological identification, genomic DNA was extracted from collected specimens using the CTAB method, followed by amplification and sequencing of the mitochondrial COI and 16S rRNA genes. The resulting sequences were subsequently analyzed using DnaSP and PopART software to estimate genetic diversity, perform neutrality tests, and construct haplotype networks. Published sequences of M. cartusiana retrieved from GenBank were incorporated to provide a global comparative framework. The COI dataset (555 bp) revealed 52 haplotypes, whereas the 16S rRNA dataset (269 bp) identified 14 haplotypes across global populations. High haplotype diversity (Hd = 0.946 for COI; Hd = 0.831 for 16S rRNA) and moderate nucleotide diversity (π = 0.010 for COI; π = 0.01253 for 16S rRNA) indicated substantial genetic variability within the species. Neutrality tests produced negative and insignificant values for Tajima’s D for COI and significant values for 16S rRNA (−1.428 for COI; −0.20586 for 16S rRNA) and Fu’s Fs (−29.776 for COI; −1.263 for 16S rRNA), suggesting historical population expansion. Phylogenetic reconstruction and haplotype network analyses identified two major clades (Clade A and Clade B), reflecting genetic relationships among populations from different geographic regions. AMOVA based on COI and 16S rRNA sequences revealed significant population structuring, with 29.98–51.30% of the total genetic variation occurring among populations and high fixation indices (FST = 0.299–0.51398, p = 0.001), indicating pronounced genetic differentiation and restricted gene flow. Pairwise FST analyses indicated that the Pakistani population is most closely related to populations from Italy and Central Europe, suggesting a closer genetic affinity with Southern or Central European populations. However, FST alone does not allow definitive inference of introduction directionality, and additional analyses would be required to robustly identify the source population. Overall, this study provides the first comprehensive molecular and phylogeographic assessment of the M. cartusiana species from Pakistan within a global context. These findings contribute important baseline data for understanding the evolutionary dynamics, dispersal history, and population connectivity of this economically important pest species. The pronounced genetic differentiation among populations and the suggested genetic affinity of the Pakistani population with European lineages have direct implications for biosecurity monitoring, invasion pathway tracing, and targeted pest management strategies. Future research integrating nuclear markers with the mitochondrial data presented here will be essential for a more complete understanding of gene flow and local adaptation in this species. Full article

Mutations in an RNA-binding protein FUS are known to cause familial amyotrophic lateral sclerosis (ALS). Since this discovery, mutations in several other RNA-binding proteins (RBPs) have also been linked to ALS. Some of these ALS-associated RBPs have been shown to colocalize with ribonucleoprotein (RNP) granules such as stress granules and processing bodies (p-bodies). Increasing evidence has emerged supporting a hypothesis that the impaired clearance, inappropriate assembly, and dysregulation of RNP granules play a role in ALS. Through the genome-scale overexpression screening of a yeast model of FUS toxicity, we found that TAF15, a human RBP with a similar protein domain structure and belonging to the same FET protein family as FUS, suppresses FUS toxicity in yeast. The suppression by TAF15 is specific to FUS and not found in other yeast models of neurodegenerative disease-associated proteins. We showed that the RNA recognition motif (RRM) of TAF15 is required for its suppression of FUS toxicity. Furthermore, FUS and TAF15 physically interact, and the C-terminus of TAF15 is required for both the physical protein–protein interaction and its protection against FUS toxicity. Finally, while FUS induces and colocalizes with both stress granules and p-bodies, TAF15 only induces and colocalizes with p-bodies. Importantly, the co-expression of FUS and TAF15 induces more p-bodies than individually expressing each gene alone, and FUS toxicity is exacerbated in yeast that is deficient in p-body formation. Overall, our findings suggest a role of increased p-body formation in the suppression of FUS toxicity by TAF15. Full article

5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent that is extensively utilized in the management of malignancies; however, its clinical utility is constrained by its narrow therapeutic index and dose-limiting toxicities. The study aimed to study the hepato-nephroprotective effects of epigallocatechin gallate (EGCG) and EGCG mediated selenium nanoparticles and their effect in mitigating the toxicity induced by 5-FU. EGCG-functionalized selenium nanoparticles (EGCG-SeNPs) were produced by mixing sodium selenite, with EGCG acting as both the reducing and stabilizing agent. Nanoparticles were characterized using UV-vis spectroscopy, FT-IR, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. 35 adult rats were randomly assigned to control, 5-FU, 5-FU + Na₂SeO₃, 5-FU + EGCG, and 5-FU + EGCG-SeNPs groups. Hepatorenal toxicity was induced by intraperitoneal 5-FU administration during the final five days of the experiment. Serum biochemical markers, tissue oxidative stress, antioxidant enzyme, inflammatory cytokine levels, and apoptosis-related gene expression were evaluated. Immunohistochemical analysis of Nrf2 and Keap1 and histopathological examination of tissues were performed. 5-FU induced severe hepatorenal toxicity, evidenced by marked elevations in liver and kidney function biomarkers, excessive oxidative stress, inflammatory cytokine overproduction, NF-κB activation, and apoptotic signaling. Treatment with EGCG-SeNPs markedly ameliorated 5-FU-induced hepatic and renal dysfunction, restoring liver enzyme and kidney biomarker levels to near-normal levels more effectively than EGCG or sodium selenite alone. EGCG-SeNPs significantly suppressed lipid peroxidation, NGAL, and inflammatory mediators while robustly enhancing antioxidant defenses and activating the Nrf2/HO-1 pathway with concomitant Keap-1 downregulation, strongly inhibited NF-κB signaling, normalized cytokine balance, reduced poly (ADP-ribose) (PAR) activation, and attenuated apoptosis. EGCG–SeNPs confer superior protection against 5-FU–induced hepatorenal toxicity compared to EGCG or inorganic selenium alone. The potent protective effects of EGCG–SeNPs are mediated through coordinated antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, primarily via activation of the Nrf2/HO-1 axis and suppression of NF-κB signaling. Full article

Lodgepole pine (Pinus contorta Dougl.) exhibits pronounced morphological variation across its range, historically attributed to allopatric differentiation during the Wisconsin glaciation. However, whether genetic divergence aligns with morphological differentiation—a fundamental prediction of allopatric speciation theory—remains untested. We conducted a comprehensive phylogeographic analysis of chloroplast DNA (trnL intron and trnL/trnF spacer) and mitochondrial DNA (nad1 b/c intron) across 31 populations representing all four recognized subspecies to test hypotheses of refugial isolation and to evaluate the genetic basis of current taxonomic classification. Contrary to predictions of allopatric divergence, both organellar genomes showed striking genetic uniformity (π = 0.000178–0.000186; intersubspecific genetic distances: 1.06 × 10⁻⁴ to 3.96 × 10⁻⁴) with no phylogenetic structure corresponding to morphological boundaries. Significant negative neutrality test values (Tajima’s D = −2.26, p < 0.02; Fu and Li’s D* = −4.52, p < 0.02) suggest recent demographic expansion rather than equilibrium divergence. A distinctive 5 bp indel in coastal populations provides molecular evidence for a northern Pacific refugium, and its occurrence in interior populations is consistent with post-glacial pollen-mediated gene flow, though this directionality remains inferential pending nuclear genomic confirmation. These findings suggest that morphological divergence reflects rapid adaptive evolution in heterogeneous environments rather than deep phylogenetic divisions. This pattern exemplifies gene flow-selection balance, in which divergent selection maintains local adaptation despite extensive gene flow—supporting an ecotypic rather than a phylogenetic interpretation of intraspecific diversity. The persistence of morphological variation despite genetic homogeneity indicates strong selection on ecologically important traits, likely driven by variation in fire regimes, differential seed predation, and climate gradients. These results have critical implications for understanding adaptive evolution rates in widespread conifers and for developing conservation strategies that emphasize adaptive processes over taxonomic categories. Full article

Atractylodes lancea (AL) has been shown to be a promising candidate for the treatment of cholangiocarcinoma (CCA). The study explored the potential of atractylodin (AT) and β-eudesmol (BE) to chemosensitize the effects of standard chemotherapeutics in CCA. The cytotoxicities of AT and BE on CL6, HuCCT1, and HuH28 when used in combination with 5-fluorouracil (5FU), gemcitabine (GEM), and cisplatin (Cis) were assessed by MTT assay. The modulatory effects of both compounds on mRNA expression of the reuptake and efflux transporters were determined by real-time PCR. The FIC (Fractional Inhibitory Concentration) indices indicated synergistic interactions (AT-5FU in all cell lines and BE-5FU in HuH28) and antagonistic interactions (BE-Cis in all cell lines and AT-Cis or AT-GEM in HuCCT1). The synergistic interactions observed with the AT-5FU and BE-5FU combinations were well correlated with the significant upregulation of the mRNA expression of the reuptake transporter genes hENT1 (2.64-fold) and hOCT3 (5.02-fold) and the significant downregulation of the mRNA expression of the efflux transporter gene ABCC2 (0.33-fold). AT and BE, when purified or present as significant components in AL, may benefit CCA treatment when used as adjunct therapy to standard chemotherapeutic drugs, particularly 5FU. The mechanism of synergistic activity may, at least in part, involve modulation of transporter gene expression and activity. Full article