Search Results (9,919)

Chicken (Gallus gallus domesticus) domestication, likely associated with dry-rice farming in central Thailand, has led to substantial loss of ancestral immune-related genetic diversity in commercial chicken lineages. This study addresses allelic loss by providing the first comprehensive analysis of the highly polymorphic BG1 gene, an MHC-linked marker across the wild–domestic interface in Thailand and Vietnam, using high-depth Illumina amplicon sequencing. Genomic DNA from 47 Thai and Vietnamese chicken populations was extracted using a salting-out protocol following ethical sampling. Allelic variation was examined by targeting the BG1 intron 15–exon 16 region using triplicate PCR and Salus Pro NGS sequencing. Evolutionary dynamics and selection pressures were analyzed using AmpliSAS, MrBayes, and Datamonkey, while AlphaFold 3 was used to predict and validate 3D protein structures. We identified 98 novel alleles and 172 polymorphic sites within the BG1 intron 15–exon 16 region encoding an Ig-like domain. Extensive allele sharing between indigenous chickens and red junglefowl indicated strong balancing selection and trans-species polymorphism. Selection analyses showed that purifying selection conserved structural integrity at codons 9, 13, and 18, while variation at other sites enhanced immune recognition. AlphaFold 3 modeling confirmed conservation of the β-sandwich fold across variants, maintaining stability of the Immunoreceptor Tyrosine-based Inhibition Motif (ITIM). Thus, despite the regional gene flow, geographic isolation has shaped distinct signatures, as evidenced by the presence of 38 unique Thai and 9 unique Vietnamese alleles in addition to breed-specific private markers in the Betong (BG1*TH88), Decoy (BG1*TH91), and Tre (BG1*VN54) populations. A notable adaptive outlier under positive selection (ω = 1.357) was detected in the Dong Tao population, suggesting a recent selective sweep. These findings support the mission of the Siam Chicken Bioresource Project (SCBP) to utilize indigenous breeds as genetic reservoirs and provide a molecular basis for restoring resilience traits in domestic poultry to enhance global food security. Full article

Cells contain an unexpectedly large diversity of lipid molecules. Modern lipidomics studies have revealed that even a single cell type can harbor hundreds to thousands of distinct lipid species that differ in headgroup structure, acyl chain length, and degree of unsaturation. While this remarkable diversity is now well established, its biological significance remains incompletely understood. Why do cells maintain such complex lipidomes? In this review, we examine several conceptual frameworks that may help explain the origin and functional significance of lipid diversity. First, the physical properties of biological membranes impose constraints on lipid composition, as variations in lipid structure influence membrane fluidity, curvature, thickness, and phase behavior. Second, lipids can regulate membrane protein function through specific interactions and through the physical environment of the lipid bilayer. Third, lipid metabolism generates signaling molecules that participate in diverse regulatory pathways. Fourth, lipid metabolic networks continuously remodel membrane composition, producing dynamic lipidomes that can adapt to physiological conditions. Finally, evolutionary processes have shaped membrane lipid composition across different domains of life, suggesting that lipid diversity may reflect long-term adaptation to functional and environmental constraints. Taken together, these perspectives suggest that lipid diversity is unlikely to be a simple byproduct of metabolism. Instead, the cellular lipidome may emerge from the interplay of membrane biophysics, metabolic network architecture, protein regulation, and evolutionary pressures. Understanding why cells contain thousands of lipid species therefore represents an important challenge for modern cell biology and may reveal fundamental principles governing the organization of biological membranes. Full article

Background/Objectives: Bile acids, synthesized from cholesterol in the liver, are amphipathic molecules that play an integral role in lipid digestion and absorption, while also serving as systemic endocrine hormones. They continuously undergo enterohepatic circulation, where they interact with various transporter proteins. Dysregulated bile acid transport is associated with the pathogenesis of liver disease. This review summarizes the key findings relating to bile acid transport expression and activity in the pathogenesis of liver disease. Methods: A review of the literature was performed using PubMed and relevant terms including, but not limited to, “bile acid transporters”, “liver disease”, and “bile acid uptake and efflux”. Studies published in peer-reviewed journals relevant to this review were considered and reviewed. Results: Within the gut and liver, several key bile acid and xenobiotic transporters within the enterohepatic circulation are dysregulated. The directionality and extent of changes are cell- and disease-specific. Many of the regulatory processes are driven by changes in bile acid signaling, although further work is needed to expand on post-translational modification of bile acid transporters in liver disease. Conclusions: Bile acid transporters are dynamically regulated in liver diseases with distinct etiologies. Therefore, restoring BA transporter function represents an actionable therapeutic approach to liver disease. Full article

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A expression, leading to disrupted proteostasis and synaptic dysfunction. Adenosine is a ubiquitous neuromodulator whose G protein-coupled receptors (ARs) regulate neuronal differentiation and neurite outgrowth during development. Here, we investigated AR signaling and their influence on survival–autophagy balance and neuronal morphology in an AS cellular model. Using SH-SY5Y cells with silenced UBE3A, we found that UBE3A loss markedly decreased A1AR, A2BAR, and A3AR protein levels while significantly increasing A2AR expression. Ligand affinity was preserved across genotypes, but A1AR and A2AAR desensitization kinetics were significantly slower in UBE3A-deficient cells. These effects were associated with reduced recruitment of G protein-coupled receptor kinase 2 (GRK2) to the plasma membrane and decreased GRK2–AR association in UBE3A-deficient cells, suggesting a possible contribution of altered GRK2 dynamics to prolonged AR signaling. Functionally, A1AR and A2AR agonists preferentially promoted survival of UBE3A-deficient cells and modulated the MDM2–p53 axis and autophagy markers; A1R stimulation also increased neurite density in UBE3A-deficient cells. Together, these results identify AR-level alterations and defective desensitization machinery in AS neuronal cells and link receptor changes to downstream proteostasis and morphological phenotypes relevant to AS pathophysiology. Full article

In the present study, a series of isoxazole derivatives were severally evaluated for their antifungal activity against the yeast Candida albicans and molds such as Aspergillus niger, Aspergillus flavus, and Fusarium oxysporum. The results demonstrate that the isoxazole derivatives exhibit considerable antifungal potential, particularly isoxazole-sulfonate ester 4b (Ar= 4-(Cl)C₆H₄, Ar′= 4-(CH₃)C₆H₄), which was found to be active with significant inhibition zones; the diameters of the C. albicans and F. oxysporum samples were measured at 17.00 ± 0.00 mm and 14.00 ± 0.00 mm, respectively. Furthermore, compounds 4a (Ar= 4-(CH₃)C₆H₄, Ar′= 4-(CH₃)C₆H₄), 4c (Ar: 4-(Cl)C₆H₄, Ar′: 4-(NO₂)C₆H₄) and 4d (Ar: 4-(Cl)C₆H₄, Ar′: 3-(Cl)-2-(OCH₃)C₆H₃) demonstrated MIC and MFC values of 20 µg/mL against C. albicans. In addition, the anti-hemolytic activity of these derivatives was evaluated. Compounds 4a, 4e (Ar: 4-(Cl)C₆H₄, Ar′: 3,4-(OCH₃)₂C₆H₃) and aroylisoxazole 3a (Ar: 4-(CH₃)C₆H₄) demonstrated a high degree of anti-hemolytic activity (>99%) at all concentrations evaluated (10, 15, and 20 mg/mL). Molecular docking and molecular dynamics studies over 200 ns revealed protein–ligand complexes to have high affinity and stability, which agrees with the experimental results. The compounds 4d, 4e, and 3a have shown significant interaction with the target proteins of C. albicans, A. flavus, and F. oxysporum, respectively. The results have revealed that the major interaction sites are hydrogen bonding, hydrophobic interactions, and the presence of a water molecule, especially with key residues like TYR_84, ASP_120, SER_90, and THR_89. The crystal structure of compound 4a was also obtained. Full article

Intracellular calcium (Ca²⁺) signaling is a central regulator of corticogenesis, governing haveneural stem cell behavior, fate transitions, neuronal migration, and circuit assembly. Beyond its canonical role as a second messenger, Ca²⁺ shapes cytoskeletal organization by modulating microtubule dynamics essential for mitotic spindle function, radial glial scaffold, nucleokinesis, and neurite extension. This review synthesizes evidence from in vivo, ex vivo, and in vitro studies to delineate Ca²⁺-dependent pathways and Ca²⁺-binding proteins that couple, within restricted Ca²⁺ microdomains in space and time, to microtubule regulation during mammalian cortical development. We highlight mechanistic nodes involving calmodulin, Ca²⁺/calmodulin-dependent kinases (CaMKs), S100 proteins, cadherins/protocadherins, centrins (CENs), and Ca²⁺ sensors such as STIM1 and calneurons, which collectively coordinate spindle orientation, progenitor division modes, radial migration, and neurite outgrowth. Finally, we discuss how perturbations in Ca²⁺-controlled cytoskeletal programs may contribute to abnormal cortical cytoarchitecture and neurodevelopmental disease. By integrating Ca²⁺ microdomain transients with microtubule control modules, this review provides a unified framework for understanding how Ca²⁺ orchestrates key cellular events during mammalian corticogenesis and propose that Ca²⁺ oscillatory codes are translated into direct or indirect microtubule/cytoskeletal remodeling transitions that determine neural stem cell fate, migration, and maturation, to accurately establish cortical architecture and function. Full article

DNA methylation is a fundamental epigenetic modification that regulates gene expression, genome stability, and cell identity across vertebrate development. Disruption of DNA methylation homeostasis contributes to a wide spectrum of human diseases, including developmental disorders, neurological conditions, and cancer. Understanding how DNA methylation patterns are established, maintained, and dynamically remodeled during development is therefore essential for elucidating disease mechanisms and identifying therapeutic opportunities. The zebrafish (Danio rerio) has emerged as a powerful vertebrate model for investigating DNA methylation dynamics in vivo. Its external fertilization, optical transparency, rapid embryogenesis, and high fecundity enable direct observation and experimental manipulation of epigenetic processes at developmental stages that are difficult to access in mammalian systems. In addition, the core enzymatic machinery governing DNA methylation, including DNA methyltransferase (DNMT) and ten-eleven translocation (TET) protein families, is evolutionarily conserved between zebrafish and humans. In this review, we summarize current knowledge of the zebrafish methylome and the enzymatic regulators that control DNA methylation dynamics. We discuss how DNA methylation shapes early embryonic development, organogenesis, and cell fate decisions, and highlight insights gained from zebrafish models of human disease. Finally, we examine emerging technologies that are enabling increasingly precise interrogation of epigenetic regulation in vivo. Together, these advances position zebrafish as an important platform for bridging developmental epigenetics with human disease biology and therapeutic discovery. Full article

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer Full article

Background: Quiescent cancer cells (QCCs) evade conventional therapies and contribute to minimal residual disease (MRD) and relapse, yet the signaling pathways governing their survival remain poorly understood. Methods: Here, we performed integrative proteomic and phosphoproteomic profiling of triple-negative breast cancer (TNBC) cells transitioning between proliferation and serum removal-induced quiescence, followed by re-stimulation. Results: We identified dynamic remodeling of both proteome and phosphoproteome, with quiescent cells showing downregulation of mitotic drivers and upregulation of extracellular matrix components. Notably, phosphorylation of CK2 substrates was increased during quiescence, and CK2 inhibition using CX-4945 impaired cell survival under nutrient and genotoxic stress, disrupted autophagy, microtubule dynamics, and protein synthesis. Phospho-enrichment and functional assays identified death-associated protein kinase 3 (DAPK3) as a CK2-regulated effector mediating stress-induced apoptosis. In silico analysis confirms a link between high CK2 expression and poor chemotherapy response in basal breast cancer. Conclusions: These findings establish CK2 as a critical survival kinase in QCCs and a potential therapeutic target for MRD eradication in breast cancer. Full article

Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that directly interferes with osimertinib binding, yet effective targeted therapeutic strategies for these specific mutations remain lacking. Cudratricusxanthone A (CTXA), a natural xanthone derivative isolated from Cudrania tricuspidata Bur., has demonstrated various pharmacological activities, but its effects against EGFR triple-mutant NSCLC have not been systematically investigated. Methods: Stable Ba/F3 and NIH/3T3 cell lines expressing EGFR L858R/T790M/L792H or L858R/T790M/G796R triple mutations were generated via electroporation. The antiproliferative effects of CTXA were evaluated by MTT/MTS assays, colony formation, and wound healing assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression of EGFR signaling pathway components (p-EGFR, p-ERK, p-AKT, p-STAT3) and cell cycle regulators (Cyclin D1, CDK4) were examined by Western blotting. Molecular docking and 200 ns molecular dynamics simulations were performed to investigate the stability and binding modes of CTXA to the mutant EGFR kinase domains. Results: The successfully established triple-mutant cell lines exhibited high EGFR expression, IL-3-independent growth, and significant resistance to osimertinib. CTXA inhibited the proliferation of all triple-mutant cell lines in a time- and concentration-dependent manner, with 48 h IC₅₀ values ranging from 0.362 to 2.488 μM. Mechanistically, CTXA suppressed EGFR autophosphorylation and downregulated downstream p-ERK, p-AKT, and p-STAT3. CTXA induced G1 phase cell cycle arrest by downregulating Cyclin D1 and CDK4, significantly promoted apoptosis, and inhibited cell migration. Molecular docking revealed that while osimertinib binding was blocked by steric hindrance from His-792 or Arg-796, CTXA adapted to the mutated ATP-binding pockets through multiple hydrogen bonds and extensive hydrophobic interactions. Molecular dynamics simulations confirmed the stable binding of CTXA to both mutant EGFR proteins over the 200 ns simulations. Conclusions: This study demonstrates for the first time that the natural compound CTXA possesses antitumor efficacy against EGFR L858R/T790M/L792H and L858R/T790M/G796R mutants by regulating EGFR-ERK/AKT/STAT3 signaling. Our findings position CTXA as a promising lead compound for tackling this challenging form of acquired resistance and highlight the value of natural products in multi-target antitumor drug discovery. Full article

Background: Modern oncology views immune system dysfunction as a key factor in carcinogenesis. The induction of immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immunity, represents a promising therapeutic strategy. Damage-associated molecular patterns (DAMPs) play a central role in this process. This review aims to summarize current knowledge of DAMPs, their release mechanisms during ICD, their classification, and their prognostic and therapeutic significance in antitumor immunity. Methods: We systematically reviewed and synthesized literature published in Pubmed and Google Scholar on ICD and DAMPs, focusing on distinct forms of DAMPs which were categorized based on recognition mechanisms (five classes) and cellular origin (extracellular, mitochondrial, nuclear, and cytosolic). Key molecules, their receptors, downstream signaling pathways, and clinical associations were analyzed. Results: The spatiotemporally coordinated release of the pattern of DAMPs promotes dendritic cell maturation, antigen presentation, activation of cytotoxic T lymphocytes, and elimination of tumor cells. DAMPs can exhibit a dual role: they are able to induce sterile inflammation essential for antitumor immunity, but may also contribute to metastasis and chronic inflammation. Among all DAMPs, high-mobility group box 1 (HMGB1, a nuclear DAMP) and calreticulin (CRT, a cytosolic protein) demonstrate the greatest prognostic value. Other DAMPs (e.g., extracellular matrix components, uric acid) act as signal amplifiers during various forms of cell death. Conclusions: Understanding the spatiotemporal dynamics of DAMP release is critical for activating immune responses against malignant cells. Monitoring DAMPs may improve patient stratification, predict therapeutic responses, and enable personalized immunotherapeutic strategies. Further investigation of ICD mechanisms and DAMP release represents a fundamental basis for developing novel anticancer therapies. Full article

Background/Objectives: Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction during sepsis with high mortality. Klotho protein is notable for its identified neuroprotective effects in chronic neurodegenerative diseases. This study evaluated temporal changes in serum soluble Klotho levels and their association with clinical recovery in SAE. Methods: In this prospective observational study, 750 intensive care unit (ICU) patients were screened and 42 patients with SAE were included. Serum soluble Klotho levels, inflammatory markers, and Glasgow Coma Scale (GCS) scores were recorded on days 1 and 3. Associations between changes in Klotho levels and clinical and inflammatory parameters were analyzed. Results: The median GCS score increased from 11 (IQR: 10–13) on day 1 to 12 (IQR: 10–13) on day 3 (p < 0.001). Serum soluble Klotho levels decreased significantly from 8114.5 ± 3515.7 pg/mL on day 1 to 6452.9 ± 3390 pg/mL on day 3 (p < 0.001). Inflammatory markers, including C-reactive protein and procalcitonin, also showed significant reductions over time (p < 0.001). A moderate negative correlation was observed between changes in Klotho levels and GCS scores (r = −0.56, p < 0.001). Changes in inflammatory markers were not significantly correlated with Klotho dynamics. Conclusions: Serum soluble Klotho levels decrease in parallel with neurological improvements in sepsis-associated encephalopathy and are significantly associated with changes in GCS scores. These findings suggest that Klotho may represent a potential biomarker of disease trajectory and neurological recovery. Full article

Hypertension is a severe global public health issue. Food-derived angiotensin-converting enzyme (ACE)-inhibitory peptides have shown great potential as safe and effective alternatives to synthetic antihypertensive drugs. Camel milk is rich in bioactive peptides. This study aimed to screen for ACE-inhibitory peptides from hydrolyzed camel casein, explore their inhibitory mechanisms and endothelial protective effects in vitro, and reveal their potential antihypertensive pathways using network pharmacology. This study screened three peptides with angiotensin-converting enzyme (ACE) inhibitory activity from enzymatically hydrolyzed camel casein components: MVPFLQPK, VPFLQPKVM, and QKWKFL, with IC₅₀ values of 277.1, 396.9, and 486.9 μmol/L, respectively. Enzyme inhibition kinetics analysis indicated that MVPFLQPK exhibited a non-competitive inhibition pattern, VPFLQPKVM exhibited a mixed inhibition pattern, and QKWKFL exhibited a competitive inhibition pattern. Molecular docking revealed that all three peptides formed hydrogen bond interactions with ACE, and QKWKFL and VPFLQPKVM directly bound to the enzyme’s active site to inhibit substrate catalysis. Molecular dynamics simulation further confirmed the high stability of the three peptide–ACE complexes, with binding free energies from −34.24 to −51.19 kcal/mol. The primary contributing forces include hydrogen bonds, van der Waals interactions, electrostatic forces, and nonpolar solvation effects. Network pharmacology analysis suggested that these peptides may exert synergistic antihypertensive effects by regulating multiple blood pressure-related pathways, including the renin–angiotensin system, renin secretion, and calcium signaling pathways, by acting on key targets such as ACE, REN, SRC, and MMP9. Cell experiments demonstrated that all three peptides exhibited no cytotoxicity in the Ang II-induced HUVEC injury model, significantly promoted NO release, inhibited ET-1 secretion, and possessed endothelial protective potential. This study investigated the in vitro ACE-inhibitory mechanism of peptides derived from camel milk and their potential role in blood pressure regulation, providing experimental evidence for subsequent in vivo activity validation and the development of functional camel milk protein products. Full article

The river buffalo is an economically important livestock species supplying milk and meat. However, a multi-tissue transcriptomic atlas for the key dairy river buffalo breeds, Murrah and Nili-Ravi, has not yet been established, and the lack of stable reference genes has hindered in-depth studies of their biological functions and the molecular mechanisms underlying key economic traits such as lactation. We established a multi-tissue gene expression atlas across 20 tissues and identified 717 housekeeping genes (HKGs), and RPL37A and EEF2 were further shown to be stable candidate reference genes under the conditions tested. We found 8368 tissue-specific genes (TSGs), predominantly enriched in the reproductive system. Exploratory analysis of mammary tissue (dry-period vs. public lactating samples, confounded by batch effects) revealed mammary-enriched hub genes including LALBA; these findings are preliminary and require validation. Dynamic analysis across lactation stages (early, peak, mid-, late) identified candidate genes including SEC14L2 and ACSM3. Phenotypic data showed strong negative correlations between milk yield and protein/fat content, and a positive correlation with lactose content. However, causal or regulatory roles were not inferred due to lack of paired individual-level data. Cross-dataset comparisons are descriptive only, and are not key conclusions. In summary, this study lays the foundation for advancing research in lactation trait genetics and functional genomics in river buffalo, with novel reference genes and lactation stage-specific transcriptional dynamics as its main contributions. Full article

Cadmium (Cd) is a typical heavy metal pollutant in aquatic environments. It enters fish through the gills, digestive tract, and body surface, and accumulates mainly in the liver and kidneys, with species- and tissue-specific distribution. Cadmium triggers apoptosis by inducing oxidative stress, calcium imbalance, and DNA damage. These signals are integrated and amplified by the mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/AKT, and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, ultimately activating three downstream apoptotic execution pathways: the death receptor, mitochondrial, and endoplasmic reticulum stress pathways. These three pathways form an interactive network through molecular nodes such as BH3 interacting domain death agonist (Bid), Ca²⁺, c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP), synergistically amplifying the apoptotic effect, with the mitochondrial pathway playing a central role. Cadmium-induced apoptosis is dose-dependent: low concentrations activate protective responses, whereas high concentrations strongly promote apoptosis. Current research gaps remain regarding dynamic pathway crosstalk, chronic low-dose effects, species differences, and fish-specific apoptotic molecules (e.g., caspase-12 homologs). Future studies should focus on constructing multidimensional response maps, clarifying pathway activation thresholds and interaction contributions, and developing composite protective strategies based on Nrf2 activators, metal chelators, and antioxidants, thereby promoting translation into ecological risk assessment and aquaculture pollution control. Full article