Search Results (96)

Circadian rhythms are ~24 h cycles regulated by an internal molecular clock. Disruption of this timing system has been implicated in numerous diseases, including the advancement of cancers and declines in function associated with aging. In recent years, scientists have identified various small molecules that can modulate core circadian clock proteins and pathways, providing potential therapeutic strategies to correct circadian dysfunction. This review presents a thorough overview of circadian clock mechanisms and highlights known small-molecule modulators. We describe how these compounds were discovered (through high-throughput screening and rational design) and categorize them based on their molecular targets. This review also summarizes key findings in cancer models, where clock-modulating compounds affect tumor metabolism, cell proliferation, and responsiveness to treatments, as well as in aging models, where strengthening circadian function may enhance metabolic health and longevity. Additionally, we cover clinical and preclinical studies involving these molecules and address challenges such as off-target effects and the complex nature of clock regulation. Finally, we outline future directions, emphasizing the development of new chronotherapeutics and the incorporation of circadian modulation into interventions for cancer and aging. Full article

The milk fat globule membrane (MFGM) wraps around the surface of the milk fat globule, separating the internal lipid core from the external environment. MFGM is a complex trilayer membrane structure composed of polar lipids, sphingolipids, and functional proteins. In recent years, research on the biological characteristics of MFGM has been continuously deepening. It has triggered an exploration of the relationship between MFGM composition, structure, and functional mechanisms. This reveals the potential applications of MFGM in human health and production practices. This review systematically summarizes the composition and structure of MFGM, extraction and preparation techniques, functional mechanisms and the latest research progress in its applications in various fields. This study comprehensively compares the application scope of the MFGM extraction preparation technology. The mechanism of the biological activity of MFGM was further analyzed. Its application value in infant formula, dairy processing, functional foods, drug delivery systems, and cosmetics was evaluated. Nowadays, existing research needs to face numerous challenges, such as some components being unknown and the functional mechanisms not being clear enough. In the future, it is still essential to continuously pay attention to the research progress of MFGM. Further research is needed to accelerate the transformation of MFGM from by-products of dairy processing to multifunctional biomaterials. The purpose is to fully tap its enormous potential in nutrition, health care, and application fields. Full article

Peptide binders, serving as a critical drug modality bridging small-molecule compounds and protein macromolecules, can effectively mimic the secondary structural elements of natural proteins. Peptides exhibit unique physicochemical advantages when targeting protein protein interaction (PPI) interfaces, which are typically characterized by flat surfaces and extensive contact areas. Recently, diffusion models represented by RFdiffusion have established a new computational paradigm for protein backbone generation by defining a denoising process over the rigid-body transformation group. However, in the de novo design of binders targeting “undruggable” PPI targets, this general paradigm encounters significant adaptability bottlenecks. First, its underlying rigid-body assumption struggles to accurately describe the dynamic induced-fit process of peptides at the binding interface. Second, it lacks sufficient robustness to the experimental resolution heterogeneity inherent in training data. Furthermore, the decoupled two-stage generation of sequence and structure severs the synergy of physicochemical properties, leading to backbones with idealized, singular secondary structures that lack authentic spatial binding capacity and reasonable side-chain physicochemical features. To address these challenges, this study proposes PPI-Diff, a novel generative framework. While preserving the generative capability of diffusion models, PPI-Diff introduces three core mechanisms: (1) a resolution-aware constraint mechanism that maps the measurement precision of experimental data into explicit contextual constraints to dynamically suppress geometric noise from low-resolution samples; (2) an internal-coordinate-driven manifold diffusion model that performs conformational evolution on a Riemannian manifold constructed by dihedral angles, balancing local stereochemical validity with the precise capture of flexible peptide conformations; and (3) a geometry-semantic synergistic modeling mechanism that leverages the evolutionary embeddings of a pre-trained protein language model (ESM-2) as latent variables to align structure generation with biophysical functions. Systematic benchmarking demonstrates that, on a strictly non-homologous test set, the binders generated by PPI-Diff significantly outperform existing baseline models in terms of interface contact density, stereochemical validity, and sequence novelty. Full article

Current efforts to improve photodynamic therapy focus on nanomaterials that integrate deep tissue imaging with efficient reactive oxygen species generation. Gold nanoclusters (Au NCs) are promising alternatives to conventional photosensitizers due to their effective ROS production and enhanced biocompatibility when stabilized by a protein corona. However, both photosensitizers and Au NCs are typically activated by ultraviolet or visible light, which cannot penetrate deeper into tissues and is limited to superficial applications. Here, we report a near-infrared (NIR)-activated photodynamic nanoplatform based on core–shell upconverting nanoparticles (UCNPs; NaGdF₄:Yb³⁺,Er³⁺@NaGdF₄:Yb³⁺,Nd³⁺), functionalized with a protein corona containing bovine serum albumin-stabilized Au NCs (BSA–Au NCs) and photosensitizer chlorin e6 (Ce6). Spectroscopic data confirmed the formation of the UCNP-BSA–Au-Ce6 nanoplatform and demonstrated 32% energy transfer efficiency from UCNPs to Ce6, resulting in efficient reactive oxygen species generation under 808 nm irradiation. Cellular experiments confirmed the effective internalization and optimal biocompatibility of the nanoplatform in human breast cancer and healthy cells. Upon irradiation at 808 nm, the nanoplatform significantly reduced the viability of MDA-MB-231 cancer cells. These findings indicate that the UCNP-BSA–Au-Ce6 nanoplatform couples NIR activation with enhanced singlet oxygen production, providing a multifunctional platform for deep tissue imaging and NIR-activated photodynamic therapy. Full article

Background/Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children presents with a heterogeneous clinical spectrum, whereas multisystem inflammatory syndrome in children (MIS-C) is a distinct immunological entity characterized by a hyperinflammatory phenotype and a distinct biological architecture. Identifying routine biomarkers with early discriminatory utility is essential for rapid differentiation between MIS-C and coronavirus disease 2019 (COVID-19). Methods: We conducted a retrospective comparative study of 144 pediatric patients with COVID-19 or MIS-C admitted to a single specialized medical center. The analyses integrated classical statistical methods, Benjamini–Hochberg false discovery rate correction (FDR), penalized regression models, and machine learning algorithms to identify biomarkers with discriminative value, using only routine laboratory tests. Results: MIS-C was associated with an intense inflammatory profile, characterized by increases in C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), lymphopenia, and selective electrolyte disturbances, highlighting a coherent biological architecture. In contrast, COVID-19 showed limited associations with traditional inflammatory markers. Predictive models identified a stable core of biomarkers with excellent performance in Random Forest analysis (area under the curve, AUC = 0.95), and reproducible thresholds (CRP ~3.7 mg/dL, NLR ~3.3, PLR ~376; potassium ~4.2 mmol/L). These findings were independently confirmed using penalized Ridge regression, where the reduced model achieved superior discrimination compared to the full 13-variable model (AUC = 0.93 vs. 0.89) and maintained stable performance under internal cross-validation, reinforcing the clinical relevance of this compact biomarker panel. Conclusions: MIS-C is clearly distinguished from COVID-19 by a specific and reproducible immunological signature. The identified biomarkers may represent a potential foundation for the development of simple clinical algorithms for pediatric triage and risk stratification, opening the prospect of a simplified scoring tool applicable in emergency settings. Full article

Objective: This study aims to engineer a novel nanoparticle formulation for combined tumor therapy, designated as PDA@Mn-siSur-c-NPs, which comprises a polydopamine/manganese dioxide (PDA@MnO₂) core alongside survivin-targeting siRNA and cyclo(RGD-DPhe-K)-targeting moiety. Methods: The PDA@Mn-siSur-c-NPs were constructed and subjected to detailed characterization. Inductively coupled plasma optical emission spectroscopy (ICP-OES) was employed to quantify manganese content. To assess siRNA stability within the system, samples were incubated with 50% fetal bovine serum (FBS) before agarose gel electrophoresis analysis. Additionally, cellular internalization by 4T1 cells and in vitro photothermal conversion efficiency of the formulation were evaluated. ICP-OES was further utilized to investigate the in vivo pharmacokinetics and tissue distribution of manganese. Animal model studies were conducted to assess the anti-breast cancer efficacy of PDA@Mn-siSur-c-NPs in combination with infrared irradiation. Results: The newly developed PDA@Mn-siSur-c-NPs demonstrated superior siRNA protection, reduced toxicity, and high photothermal conversion capacity. When combined with photothermal therapy (PTT), these nanoparticles exerted enhanced synergistic anti-tumor effects. Delivery of survivin siRNA resulted in a significant downregulation of survivin protein expression in tumor tissues. Moreover, magnetic resonance imaging (MRI) confirmed that the nanoparticles possess favorable imaging properties. Conclusions: This research demonstrates that the integration of PDA@Mn-siSur-c-NPs with PTT holds considerable therapeutic promise for improved breast cancer treatment. Full article

Aspartame, a widely used artificial sweetener, has been linked to various cancers, including kidney renal papillary cell carcinoma (KIRP). However, the molecular mechanisms underlying this association remain unclear. This study employed network toxicology and molecular docking to investigate potential mechanisms of aspartame-induced KIRP. Differentially expressed genes from TCGA were intersected with aspartame targets and KIRP-related genes, yielding 61 common targets. GO and KEGG analyses revealed enrichment in extracellular matrix degradation, signaling pathways, and immune microenvironment regulation. Univariate Cox regression identified 23 prognostically significant genes, from which multifactorial Cox regression with stepwise selection determined 8 core genes (APLNR, CYP2C19, EDNRA, KLK5, F2R, RAD51, AURKA, and TLR2). A risk model was constructed and validated through VIF analysis, Schoenfeld residual testing, and internal validation using a training–validation split. SHAP analysis identified EDNRA as the primary driver gene. Survival analysis demonstrated that the model effectively stratified KIRP patients, with risk score and tumor stage serving as independent prognostic factors. Molecular docking confirmed stable binding between aspartame and core target proteins. These findings provide mechanistic insights into aspartame-induced KIRP pathogenesis and establish a foundation for future experimental validation. Full article

Encapsulins are microbial protein nanocompartments that spatially organize and sequester specific biochemical processes, including iron storage. While their protein shells have been extensively characterized, the composition and structure of their mineral cores remain less understood. Here, we use bright field transmission electron microscopy (BF TEM), high-angle annular dark-field scanning TEM (HAADF STEM), energy-dispersive X-ray (EDX), and electron energy-loss spectroscopy (EELS) in STEM to characterize the iron-containing mineral granules within the Myxococcus xanthus encapsulin system at near atomic resolution. We find that the internal nanoparticles are smaller (~2 nm) and more numerous (up to ~2200 per encapsulin) than previously reported. These nanoparticles are typically amorphous and have a composition consistent with FePO₄ (measured Fe:P ratio of ≈1:1.2). Each encapsulin contains on average ~8500 iron atoms, corresponding to a volumetric density of 2.1 atoms/nm³. Phosphorus incorporation inhibits crystallization, whereas growth in phosphorus-free media leads to the formation of nano-crystalline goethite [α-FeO(OH)]. Full article

Background: Doxorubicin (DOX) is a highly effective chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity, driving the search for protective natural products. Although the herb Viscum coloratum (Kom.) Nakai is known for its cardiovascular benefits, the cardioprotective effects and mechanisms of its isolated compound, DHDK, remain unexplored. Methods: The protective effect of DHDK was first evaluated in DOX-injured H9c2 cardiomyocytes. Subsequently, an integrated network toxicology (incorporating DOX-induced toxicity targets and relevant chronic disease pathways such as aging and lipid metabolism) and pharmacology (DHDK) approach identified core targets, which were then refined through Protein–Protein Interaction (PPI) analysis and molecular docking. The underlying mechanism was investigated using lipidomics and validated through a series of in vitro assays, including CCK-8, q-PCR, biochemical tests, and flow cytometry, as well as in an in vivo rat model. Results: DHDK significantly alleviated DOX-induced cardiomyocyte toxicity. Integrated analysis identified 56 intersecting targets, with PPARG confirmed as the primary target via PPI and molecular docking. Lipidomics revealed that DHDK potently attenuated DOX-induced accumulation of pathogenic lipids (e.g., fatty acids, ceramides). Mechanistically, DHDK activated PPARG, which in turn upregulated CPT1B, a key regulator of fatty acid β-oxidation (FAO). This enhanced cell viability, ATP production, and mitochondrial membrane potential while reducing oxidative stress. These protective effects, which were abolished by the inhibition of PPARG or CPT1B, were further validated in vivo. Conclusion: This study demonstrates that DHDK exerts its cardioprotective effect by activating the PPARG-CPT1B-FAO axis, effectively correcting lipid metabolic disorders. Given that lipid dysregulation is a hallmark of various internal metabolic diseases, DHDK may also hold therapeutic potential for other heart conditions driven by metabolic disturbances, such as diabetic cardiomyopathy, highlighting its broad relevance to the field of internal diseases. Full article

Antibody–drug conjugates (ADCs) are a rapidly advancing class of targeted cancer therapeutics that couple the antigen specificity of monoclonal antibodies (mAbs) with the potent cytotoxicity of small-molecule drugs. In their core design, a tumor-targeting antibody is covalently linked to a cytotoxic payload via a chemical linker, enabling the selective delivery of highly potent agents to malignant cells while sparing normal tissues, thereby improving the therapeutic index. Humanized and fully human immunoglobulin G1(IgG1) antibodies are the most common ADC backbones due to their stability in systemic circulation, robust Fcγ receptor engagement for immune effector functions, and reduced immunogenicity. Antibody selection requires balancing tumor specificity, internalization rate, and binding affinity to avoid barriers to tissue penetration, such as the binding-site barrier effect, while emerging designs exploit tumor-specific antigen variants or unique post-translational modifications to further enhance selectivity. Advances in antibody engineering, linker chemistry, and payload innovation have reinforced the clinical success of ADCs, with more than a dozen agents FDA approved for hematologic malignancies and solid tumors and over 200 in active clinical trials. This review critically examines established and emerging conjugation strategies, including lysine- and cysteine-based chemistries, enzymatic tagging, glycan remodeling, non-canonical amino acid incorporation, and affinity peptide-mediated methods, and discusses how conjugation site, drug-to-antibody ratio (DAR) control, and linker stability influence pharmacokinetics, efficacy, and safety. Innovations in site-specific conjugation have improved ADC homogeneity, stability, and clinical predictability, though challenges in large-scale manufacturing and regulatory harmonization remain. Furthermore, novel ADC architectures such as bispecific ADCs, conditionally active (probody) ADCs, immune-stimulating ADCs, protein-degrader ADCs, and dual-payload designs are being developed to address tumor heterogeneity, drug resistance, and off-target toxicity. By integrating mechanistic insights, preclinical and clinical data, and recent technological advances, this work highlights current progress and future directions for next-generation ADCs aimed at achieving superior efficacy, safety, and patient outcomes, especially in treating refractory cancers. Full article

Background: Chinese Red Steppe cattle (CRS) combine indigenous environmental resilience with moderate dairy performance, whereas Holstein cattle (HOL), despite their high milk yield, suffer reduced genetic diversity and compromised adaptation. A comparative analysis of their population genetic architecture and selection signatures can reveal valuable targets for CRS dairy improvement. Methods: We genotyped 61 CRS and 392 HOL individuals using the Illumina GGP Bovine 100K SNP array and performed stringent quality control. Population structure was assessed via principal component analysis, neighbor-joining trees, and sparse nonnegative matrix factorization. Historical effective population size (Ne) and divergence time were inferred with SMC++. Genome-wide selection scans combined Fixation Index (FST) and Cross-Population Composite Likelihood Ratio test (XP-CLR); overlapping high-confidence regions were annotated and subjected to GO and KEGG enrichment analyses. Results: CRS and HOL were clearly separated along PC1 (explaining 57.48% of variance), with CRS exhibiting high internal homogeneity and weak substructure, versus greater diversity and complex substructure in HOL. SMC++ indicated a split approximately 3500 years ago (700 generations) and a pronounced recent decline in Ne for both breeds. Joint selection mapping identified 767 candidate genes; notably, the ACSM1/2B/3/4 cluster on chromosome 25—key to butanoate metabolism—showed the strongest signal. Enrichment analyses highlighted roles for proteasome function, endoplasmic reticulum stress response, ion homeostasis, and RNA processing in regulating milk fat synthesis and protein secretion. Conclusion: This study delineates the genetic divergence and demographic history of CRS and HOL, and pinpoints core genes and pathways—particularly those governing butanoate metabolism and protein quality control—underlying dairy traits. These findings furnish molecular markers and theoretical guidance for precision breeding and sustainable utilization of Chinese Red Steppe cattle. Full article

Lake eutrophication, often driving harmful algal blooms (HABs) and ecosystem degradation, involves complex biogeochemical shifts within sediments. Changes in the sedimentary dissolved organic matter (DOM) composition during transitions from macrophyte to algal dominance are thought to critically regulate internal phosphorus (P) loading, yet the underlying mechanisms, especially in vulnerable plateau lakes like Qilu Lake, require further elucidation. This study investigated the coupled cycling of carbon (C) and P in response to historical ecosystem succession and anthropogenic activities using a 0–24 cm sediment core from Qilu Lake. We analyzed the total organic carbon (TOC), total phosphorus (TP), sequential P fractions, and DOM fluorescence characteristics (EEM-PARAFAC), integrated with chronological series data. The results revealed an asynchronous vertical distribution of TOC and TP, reflecting the shift from a submerged macrophyte-dominated, oligotrophic state (pre-1980s; high TOC, low TP, stable Ca-P dominance) to an algae-dominated, eutrophic state. The eutrophication period (~1980s–2010s) showed high TP accumulation (Ca-P and NaOH85 °C-P enrichment), despite a relatively low TOC (due to rapid mineralization), while recent surface sediments (post-2010s) exhibited a high TOC, but a lower TP following input controls. Concurrently, the DOM composition shifted from microbial humic-like dominance (C1) in deeper sediments to protein-like dominance (C3) near the surface. This study demonstrates that the ecosystem shift significantly regulates P speciation and mobility by altering sedimentary DOM abundance and chemical characteristics (e.g., protein-like DOM correlating negatively with Ca-P), reinforcing a positive feedback mechanism that sustains internal P loading and potentially exacerbates HABs. DOM molecular characteristics emerged as a key factor controlling the internal P cycle in Qilu Lake, providing critical insights for managing eutrophication in plateau lakes. Full article

This article presents a comprehensive overview of recent advancements in photonic crystal fiber (PCF)-based sensors, with a particular focus on the surface plasmon resonance (SPR) phenomenon for biosensing. With their ability to modify core and cladding structures, PCFs offer exceptional control over light guidance, dispersion management, and light confinement, making them highly suitable for applications in refractive index (RI) sensing, biomedical imaging, and nonlinear optical phenomena such as fiber tapering and supercontinuum generation. SPR is a highly sensitive optical phenomenon, which is widely integrated with PCFs to enhance detection performance through strong plasmonic interactions at metal–dielectric interfaces. The combination of PCF and SPR technologies has led to the development of innovative sensor geometries, including D-shaped fibers, slotted-air-hole structures, and internal external metal coatings, each optimized for specific sensing goals. These PCF-SPR-based sensors have shown promising results in detecting biomolecular targets such as excess cholesterol, glucose, cancer cells, DNA, and proteins. Furthermore, this review provides an in-depth analysis of key design parameters, plasmonic materials, and sensor models used in PCF-SPR configurations, highlighting their comparative performance metrics and application prospects in medical diagnostics, environmental monitoring, and chemical analysis. Thus, an exhaustive analysis of various sensing parameters, plasmonic materials, and sensor models used in PCF-SPR sensors is presented and explored in this article. Full article

Background/Objectives: RNA-binding motif protein 3 (RBM3) is a cold-shock protein associated with a favorable prognosis in various malignancies. However, its role in epithelial ovarian cancer (OC) remains unclear. This study aimed to evaluate the prognostic significance of RBM3 expression in OC and its association with clinicopathological features. Methods: We retrospectively analyzed 183 cases of OC. Tissue microarrays were constructed using paired 2 mm tumor cores, and RBM3 expression was assessed by immunohistochemistry. Nuclear staining was semi-quantitatively scored based on intensity and proportion, generating a nuclear score (NS). Cases were classified as high (NS > 1) or low (NS ≤ 1) expression. Associations with clinicopathological parameters and survival outcomes were analyzed using chi-square tests, Kaplan–Meier survival curves, and Cox regression models. Results: High RBM3 expression was observed in 51.4% of cases and was significantly associated with favorable histologic subtypes (mucinous, endometrioid, clear cell), early International Federation of Gynecology and Obstetrics (FIGO) stage, and the absence of distant metastasis. Subgroup survival analyses stratified by histologic subtype revealed no significant differences in survival outcomes. RBM3 expression was correlated with prolonged disease-free and overall survival, although it did not retain significance in multivariate analysis. Conclusions: RBM3 expression is strongly associated with favorable pathological features in epithelial ovarian cancer. Although not an independent prognostic marker, RBM3 may serve as a complementary biomarker for risk stratification and prognosis in clinical practice. Full article

DNA sequence from a new alloherpesvirus named acipenserid herpesvirus 3 (AciHV-3) was found in sturgeon species that are vulnerable to decline globally. A study was undertaken to develop a better understanding of the virus genome and to develop diagnostic tools to support an epidemiological investigation. A 184,426 bp genome was assembled from PacBio HiFi sequences generated with DNA from a Lake Sturgeon Acipenser fulvescens gonad cell line. The AciHV-3 genome was contiguous with host chromosomal DNA and was structured with telomere-like terminal direct repeat regions, five internal direct repeat regions and a U region that included intact open reading frames encoding alloherpesvirus core proteins. Diagnostic testing conducted with a newly developed and analytically validated qPCR assay established the ubiquitous presence and high titer of AciHV-3 DNA in somatic and germline tissues from wild Lake Sturgeon in the Hudson Bay drainage basin. Phylogenetic reconstructions confirm that the monophyletic AciHV-3 lineage shares a common ancestor with AciHV-1 and that AciHV-3 taxa cluster according to their sturgeon host. The same genotype of AciHV-3 is found in disjunctive Lake Sturgeon populations within and among drainage basins. The results support the hypotheses that AciHV-3 has established latency through germline chromosomal integration, is vertically transmitted via a Mendelian pattern of inheritance, is evolving in a manner consistent with a replication competent virus and has co-evolved with its host reaching genetic fixation in Lake Sturgeon populations in central Canada. Full article