Search Results (813)

Osteosarcoma, the most prevalent primary malignant bone tumor in children and adolescents, is characterized by high rates of metastasis, recurrence, and chemotherapy resistance, leading to suboptimal patient survival. The MDM2-p53 pathway plays a pivotal role in its tumorigenesis and progression, where dysregulation leads to loss of p53 function. This review systematically elucidates the molecular mechanisms of this pathway and summarizes diverse targeted therapeutic strategies, including small-molecule MDM2 inhibitors, mutant p53 reactivators, and innovative modalities such as gene therapy and Proteolysis Targeting Chimeras (PROTACs). Despite demonstrating potent preclinical activity with low IC₅₀ values, the clinical translation of these agents has faced significant challenges. Early-generation MDM2 inhibitors (e.g., RG7112, Idasanutlin) showed limited monotherapy efficacy and dose-limiting toxicities like thrombocytopenia, halting their development at early-phase clinical trials. In contrast, novel MDM2 inhibitors like APG-115 have advanced to Phase II trials, marking a significant breakthrough. Although not yet tested in dedicated osteosarcoma cohorts, their safety and efficacy in MDM2-amplified solid tumors provide a critical foundation for the development of precision medicine and combination regimens for osteosarcoma. Future efforts to accelerate drug development may leverage single-cell sequencing and AI-aided drug design to decipher osteosarcoma heterogeneity and optimize drug profiles for reduced toxicity. Full article

Osteosarcoma, the most common malignant bone tumor in young individuals, often exhibits poor outcomes due to MDM2-mediated suppression of the p53 pathway. Whereas conventional MDM2 inhibitors block the p53–MDM2 interaction but frequently induce compensatory MDM2 upregulation, proteolysis-targeting chimeras (PROTACs) directly degrade MDM2 and bypass this limitation. Here, we investigated the anticancer efficacy of two MDM2-targeting PROTAC compounds, CL0144 and CL0174, in osteosarcoma models. In Saos-2 and U2OS cells, both PROTACs efficiently induced MDM2 degradation, leading to activation of p53 or p73 signaling, increased reactive oxygen species production, apoptotic cell death, and marked reductions in viability. PROTAC treatment also significantly suppressed proliferation, colony formation, sphere formation, migration, and invasion. In vivo, xenograft assays demonstrated robust tumor growth inhibition following PROTAC administration. Collectively, these findings demonstrate that MDM2-targeting PROTACs exert strong antitumor effects by degrading MDM2 and disrupting downstream oncogenic pathways, supporting their potential as a promising therapeutic strategy for osteosarcoma. Full article

Pulmonary tuberculosis (TB) remains a major global health challenge. The molecular and metabolic responses of monocyte-derived macrophages (MDMs), which are critical for host defense against Mycobacterium tuberculosis (Mtb), are not fully characterized. A murine pulmonary TB model was established by intravenous injection of BALB/c mice with the attenuated Mtb strain H37Ra; controls received saline. After 8 weeks, lung MDMs were isolated for integrated transcriptomic and untargeted metabolomic profiling. Transcriptomic analysis identified 3970 differentially expressed genes (DEGs) in infected MDMs, including upregulated Ptpn1, Dgat2, and Alox5ap and downregulated Cyld, Zfp61, and Mapk11. Metabolomic profiling revealed 113 differentially accumulated metabolites (DAMs). Taurocholic acid and linoleic acid were identified as potential diagnostic biomarkers, both achieving an area under the curve (AUC) of 1.0 in ROC analysis. Integrated omics analysis showed a positive correlation between linoleic acid levels and the expression of Tbxas1, Acaa1b, and Acox1, implicating lipid metabolic pathways in the host response to TB. This multi-omics study delineates key molecular and metabolic alterations in lung MDMs during TB infection. The identified metabolites, taurocholic acid and linoleic acid, show promise as biomarkers, while dysregulated linoleic acid metabolism represents a potential target for novel diagnostic and therapeutic strategies against TB. Full article

The hepatitis C virus (HCV) Core activates the ATM-Chk2 pathway, leading to phosphorylation of p53 at Ser-15, which inhibits mouse double minute 2 (MDM2)-mediated proteasomal degradation. This study reveals that HCV Core also promotes E6-associated protein (E6AP)-mediated degradation of p53 during HCV replication. In the presence of HCV Core, E6AP expression induced p53 ubiquitination, reduced its stability, and decreased p53 levels, whereas E6AP knockdown increased p53 levels. The E3 ubiquitin ligase activity of E6AP was critical for this process, as demonstrated using the E6AP C833A mutant and the E3 ligase inhibitor Heclin. Proteasomal inhibition with MG132 confirmed that HCV Core and E6AP act together to regulate p53 levels via the proteasome. Importantly, HCV Core-induced p53 phosphorylation was essential for E6AP-mediated degradation, as shown by the impairment of degradation in the presence of the ATM inhibitor KU-55933. E6AP also targeted p53 phosphorylated at Ser-15 by etoposide, as well as phosphomimetic mutants such as p53 S15D, but not non-phosphorylatable mutants such as p53 S15A. These findings suggest that HCV Core-induced p53 phosphorylation enhances E6AP-mediated degradation while preventing MDM2 from targeting p53, thereby maintaining p53 levels that support cell survival, viral replication, and potentially oncogenesis in human hepatocytes. Full article

Background: The turnaround of the tumor suppressor p53 protein, the guardian of the genome, is closely regulated to ensure avoidance of its untimely activation, which could lead to the demise of normal cells. Cancer cells often display mutations in the gene TP53 encoding for p53, which interferes with its normal function. Methods: The genomic series of colorectal cancer from the Cancer Genome Atlas (TCGA) was interrogated to discover genomic alterations and determine the mRNA expression of enzymes affecting p53 ubiquitination in colorectal cancers with wild-type and mutant TP53. Results: Genomic alterations of p53-regulating E3 ubiquitin ligases were uncommon in colorectal cancers, the most frequent being mutations in RCHY1. Several p53-regulating E3 ligases were well expressed in subsets of colorectal cancers, two of which, MDM2 and TRIM24, displayed higher mRNA expressions than the normal colorectal epithelia. The former was particularly upregulated in TP53 wild-type colorectal cancers, and the latter was upregulated in both wild-type and mutant TP53 cancers. Upregulation of TRIM24 in TP53 mutant cancers was observed independently of the type of mutations (gain-of-function or other). Among E3 ligases used in proteolysis-targeting chimeras (PROTACs), VHL was upregulated together with its E2-conjugating enzyme UBE2S in colorectal cancers. Conclusions: This survey of p53-targeting ubiquitin ligases provides a roadmap for potential therapeutic strategies working by promoting the destruction of the mutant protein or reactivating its normal function in TP53-mutated colorectal cancers and promoting p53 function by preventing degradation in TP53 wild-type cancers. Full article

The success of titanium dental implants rely on osseointegration, influenced by surface properties and early immune responses. While sandblasted and acid-etched (SLA) titanium surfaces have shown clinical success, macrophage-mediated immune responses at these interfaces remain poorly understood. Anatase nanostructures have been shown to influence macrophage polarization on smooth titanium, but their effects on micro-rough SLA surfaces are not fully explored. This study investigates the immunomodulatory effects of micro-nanostructured anatase coatings on SLA titanium using human monocyte-derived macrophages (MDMs). M0-MDMs, were cultured and polarized to M1 and M2- macrophages on Ti-machined, Ti-SLA, Ti-SLA-anatase, and coverslip control surfaces for 48 h. Macrophage behavior was assessed using CCK-8 assay, confocal microscopy, SEM, ELISA, and qRT-PCR. All surfaces demonstrated excellent cytocompatibility, with similar macrophage viability across all investigated groups. M1 macrophages showed upregulation of CCR7 and TNF-α, while M2 macrophages expressed CD209 and CCL13 across all surfaces. Importantly, Ti-SLA-anatase did not significantly alter M1 or M2 markers, cytokine secretion, or gene expression, and did not exacerbate inflammatory responses. Micro-nanostructured anatase coatings on SLA titanium are immunologically well-tolerated and do not increase inflammation. These findings, combined with previously reported enhanced osteogenic properties, suggest the clinical potential of anatase-coated SLA surfaces. Full article

This study presents the Moisture Dynamic Model (MDM), a new semi-physical formulation designed to estimate Fuel Moisture Content (FMC) using only air temperature and relative humidity. The core innovation of this work lies in the introduction of an Arrhenius-type kinetic term into a fuel moisture prediction framework, allowing temperature-driven desorption processes to be explicitly represented within a lightweight operational model. Its predictive capability was assessed through experimental campaigns on Cistus monspeliensis shrublands in Corsica and validated using FireStar3D simulations. A second major contribution is the coupling of the MDM with the physical wildfire simulator FireStar3D to quantify how FMC prediction errors propagate into fire spread predictions. The MDM accurately reproduced the seasonal variability of FMC, achieving strong correlation with experimental data during dry summer periods. When coupled with FireStar3D, discrepancies in the predicted rate of spread remained below 4% under high-risk meteorological conditions. While the model performed robustly during summer, its accuracy decreased during spring, when rainfall events and microclimatic variability introduced greater uncertainty. This work represents a proof of concept demonstrating the potential of a simple physically interpretable FMC model for operational fire behaviour prediction. Full article

Receptive endometrium (RE) is essential for mammalian embryo implantation. The establishment of RE is a complex and precise dynamic process regulated by various cytokines, including non-coding RNAs (miRNAs, lncRNAs, and circRNAs). We identified candidate miR-26b-3p and circRNA3890 from our previous endometrial non-coding RNA sequencing data. CircRNA3890 adsorbs miR-26b-3p and inhibits its activity. Mouse double minute 4 (MDM4) is a target gene of miR-26b-3p, and circRNA3890 up-regulates the expression level of MDM4 by inhibiting the activity of miR-26b-3p in dairy goat endometrial epithelial cells (gEECs) in vitro. circRNA3890/miR-26b-3p/MDM4 could promote the proliferation of gEECs through the p53 signaling pathway. MiR-26b-3p could regulate the expression levels of vascular endothelial growth factor A (VEGFA) and leukemia inhibitory factor (LIF) through MDM4 in gEECs, which contributes to the development of endometrial receptivity. Furthermore, the results showed that miR-26b-3p significantly promoted the development of RE and embryo implantation. These findings demonstrate that circRNA3890 targets and adsorbs miR-26b-3p to relieve MDM4 inhibition and promotes EEC proliferation through the p53 signaling pathway. They reveal the regulatory effect of miR-26b-3p on receptive endometrial development and embryo implantation in vitro and in vivo. Full article

(1) Background: This study evaluates the anticancer potential of a newly synthesized azomethine-based compound, 6,6′,5,8-Dioxa-2,11-diazadodeca-1,11-diene-1,12-diyl)bis(4-bromo-2-methoxyphenol) (B-134-0), against osteosarcoma (SAOS-2) cells, focusing on its effects on apoptosis and DNA-damage-related gene expression. (2) Methods: B-134-0 was synthesized via condensation and tested at eight concentrations (0.5–100 μg/mL) for 24, 48, and 72 h. Cytotoxicity was assessed through MTT assay, and gene expression levels of TP53, RAD51, BRCA2, CASP2, MYC, MDM2, CDKN1A, ERCC1, ATR, and PRKDC were quantified through qPCR using the ΔΔ_Ct method. Molecular docking and DFT analyses were performed to explore structural stability and protein interactions. (3) Results: B-134-0 exhibited strong time-dependent cytotoxicity (IC₅₀: 71.58, 54.36, and 12.59 μg/mL at 24, 48, and 72 h, respectively) and significantly modulated the expression of cell cycle and DNA-repair-associated genes. The compound notably downregulated TP53, RAD51, CASP2, MYC, and MDM2, while CDKN1A and BRCA2 showed relative upregulation, indicating activation of the DNA damage response. Docking results revealed strong binding affinity with BRCA2 and CDKN1A, consistent with experimental findings. (4) Conclusions: These results indicate that B-134-0 exhibits potent anticancer activity by modulating DDR and apoptosis pathways, with strong molecular stability, suggesting its promise as a therapeutic candidate for osteosarcoma. Full article

Formation damage near the wellbore reduces permeability and limits well productivity, with its effect commonly quantified by the skin factor. This parameter can strongly influence both the technical performance and the economic feasibility of oil recovery projects. In Brazilian pre-salt carbonate reservoirs, acidizing is widely applied, often conducted immediately after well completion. However, the long-term production and economic implications of these treatments remain insufficiently quantified. In this study, synthetic carbonate reservoir models were constructed using porosity and permeability profiles derived from well data representative of pre-salt conditions. Ten models with flow capacities ranging from 3000 to 130,000 mD·m were simulated over 30 years of water injection, considering skin factors from −3 to +20. The results show that wells with flow capacities below 10,000 mD·m exhibited the strongest response to stimulation, achieving up to 35% higher cumulative oil recovery and more than a 100% increase in net present value (NPV) compared with unstimulated cases. For flow capacity values between 10,000 and 40,000 mD·m, production and economic improvements were marginal, with NPV differences typically within 10%. At higher flow capacity (>60,000 mD·m), the stimulation response became negligible, with NPV variations below 0.1%. These findings demonstrate that stimulation effectiveness is primarily governed by reservoir flow capacity. The integrated reservoir–economic evaluation framework developed in this study provides quantitative guidance for optimizing acidizing strategies in carbonate systems representative of deepwater pre-salt environments. Full article

Fault detection is an important topic in control theory and engineering. This article analyzes the active fault detection of switched multi-valued logical control networks with state constraints based on the semi-tensor product of matrices. Firstly, by using the block selection matrix, the faulty system with state constraints is converted into an equivalent faulty system without constraints. Secondly, an auxiliary system is constructed, and a pair of distinguishable set and indistinguishable set is defined. Thirdly, the strong active fault detection and active fault detection are analyzed through checking the reachability from indistinguishable set to distinguishable set, and two criteria are established with the help of set controllable matrix. Finally, the effectiveness of the proposed results is demonstrated by the p53-MDM2 network. Full article

Background/Objectives: Plant-derived bioactives offer pharmacological potential but are often limited by poor delivery and selectivity. The Pulicaria crispa dichloromethane fraction (DCMF) shows potent but non-selective antiproliferative activity. This study aimed to engineer a functional nanoformulation using a MIL-53(Fe) metal–organic framework (MOF) to achieve sustained release and improve in vitro potency and selectivity against colorectal cancer cells. Methods: DCMF was phytochemically profiled by GC-MS. A DCMF@MIL-53(Fe) nanocomposite was synthesized and characterized for particle size, zeta potential, and entrapment efficiency. In vitro release kinetics were evaluated. Anticancer activity and selectivity were assessed in HCT-116 cells. Mechanistic studies included cell-cycle analysis, cell-death assays, and molecular docking. Results: Tomentosin was identified as the predominant constituent (28.82%). The nanocomposite displayed suitable physicochemical properties (mean size: 218 nm; entrapment efficiency: 83.6%) and a clear transition from burst to sustained drug release over 48 h. Nanoencapsulation resulted in a 53-fold increase in cytotoxic potency, calculated on a DCMF-equivalent basis (IC₅₀ = 0.40 µg/mL), compared with free DCMF (IC₅₀ = 21.51 µg/mL), along with a modest improvement in selectivity. Enhanced activity was associated with G0/G1 cell cycle arrest and a shift toward necrotic, non-apoptotic cell death. Docking of the predominant constituent, tomentosin, supported plausible interactions with CDK4/Cyclin D3 and the MDM2–p53 axis, providing structural context for G1/S checkpoint disruption. Conclusions: MIL-53(Fe) nanoencapsulation converted a non-selective plant extract into a sustained-release formulation with improved in vitro efficacy and selectivity. These findings provide proof-of-concept that rational nano-delivery strategies can mitigate key pharmaceutical limitations of plant-derived fractions and enhance the anticancer potential of traditional medicinal resources. Full article

The p53 tumor suppressor protein plays a central role in maintaining genomic stability by regulating cell cycle arrest, apoptosis, and DNA repair under cellular stress. Mouse double minute 2 (MDM2), an E3 ubiquitin ligase, negatively regulates p53 via direct binding and proteasomal degradation. Overexpression or amplification of MDM2 can disrupt this pathway and promote tumorigenesis, even in cancers with wild-type p53. This review outlines the structural features of MDM2, particularly its N-terminal hydrophobic pocket and C-terminal RING domain, and their roles in p53 regulation. We further examine the pathological effects of MDM2 dysregulation and SNPs linked to increased cancer risk. Recent progress in small molecule MDM2 inhibitors is discussed, with a focus on non-covalent agents such as rhein-derived anthraquinone analogs, including AQ-101, which demonstrate promising anti-cancer activity with reduced toxicity. These findings support the continued development of non-covalent MDM2 inhibitors as a novel therapeutic approach for cancers involving both wild-type and mutant p53. Full article

Background: Smart healthcare is increasingly promoted to strengthen primary care services; however, adoption challenges are amplified on remote islands due to geographic isolation and resource constraints. Objectives: This study aimed to identify and prioritize key success factors (KSFs) for smart healthcare adoption in remote-island primary care clinics and to examine whether priorities differ across physician subgroups. Methods: A hybrid framework combining the Modified Delphi Method (MDM) and the Analytic Hierarchy Process (AHP) was applied. MDM (two rounds) refined a literature-based indicator pool to five dimensions and 20 criteria. AHP pairwise comparisons were collected from 21 physicians in Kinmen to derive weights and rankings. Results: System Quality (0.308) was the most critical dimension, followed by Organization (0.221), System Functionality (0.212), Environment (0.165), and Resource Investment (0.094). At the criterion level, Competitive Advantage and Security and Privacy were the two highest-ranked factors, followed by Accuracy and Data Integrity. Subgroup profiles varied across medical specialties and age groups. Conclusions: For remote-island primary care, adoption strategies should prioritize system quality and information assurance, while implementation support and resource considerations should be tailored to specialty- and cohort-specific needs. Full article

Genomic instability not only drives tumor initiation and progression but also cooperates with apoptosis resistance to promote therapeutic evasion in hepatocellular carcinoma (HCC). Activation of MDM2, a negative regulator of p53, together with XIAP overexpression, represents a critical axis underlying this resistance. Simultaneous targeting of MDM2 and XIAP by MX69, a small molecule inhibitor, may therefore offer a potent interventional strategy to suppress cell proliferation and enhance pro-apoptotic signaling in HCC in vitro models. To evaluate the effects of MX69, cell viability was assessed via CVDK-8, colony formation, and real-time cell analysis. Oxidative stress levels and DNA damage were examined using fluorescence imaging and comet assays, respectively, while mitochondrial membrane potential was monitored through JC-1 staining. Furthermore, flow cytometry was employed to quantify apoptotic cell death and cell cycle distribution, while Western blot analysis was used to characterize the expression of apoptosis-related proteins. In vitro cytotoxicity assays revealed that MX69 reduced the viability of HUH7 and Hep3B cells in a dose-dependent manner, suppressed colony formation, and exerted anti-proliferative effects in real-time proliferation assays. Cell viability and IC50 values were evaluated using CVDK-8 and RTCA assays. Furthermore, MX69 induced oxidative stress and mitochondrial dysfunction, as evidenced by elevated ROS levels and loss of mitochondrial membrane potential. This was accompanied by significant DNA damage, detected by comet assay and γ-H2AX immunofluorescence, and G0–G1 cell cycle arrest. Moreover, MX69 triggered apoptotic cell death, demonstrating potent anticancer activity. Collectively, our findings identify MDM2/XIAP dual inhibition by MX69 as a promising therapeutic approach in HCC, with potential to overcome apoptosis resistance linked to genomic instability. Full article