Search Results (2,332)

APR-246 (Eprenetapopt) is a small-molecule drug that restores the activity of dysfunctional p53 proteins caused by missense mutations that affect the DNA-binding domain. However, recent studies suggest that APR-246 can also induce cell death in cancer cells that carry wild-type (WT) TP53. Here, we aimed to determine the impact of APR-246 on the survival of acute myeloid leukemia (AML) cells using isogenic Molm13 cells that harbor WT TP53, a missense mutation of TP53^R175H, or a biallelic deletion of TP53 (TP53^−/−). Our results showed that Molm13 TP53^−/− cells were significantly more resistant to APR-246-induced cell death compared with their Molm13 TP53^R175H/− mutant and Molm13 TP53^+/+ counterparts. In addition, knockdown of TP53 significantly reduced cytotoxicity induced by APR-246 in two TP53 WT AML cell lines (MV4-11 and OCI-AML2). Moreover, APR-246 markedly decreased the clonogenicity of TP53 WT hematopoietic stem/progenitor cells (HSPCs) isolated from humans and mice. In contrast, biallelic loss of TP53, but not TP53 missense mutation, significantly increased the resistance of mouse HSPCs to APR-246. Mechanistically, the loss of functional p53 proteins in Molm13 and MV4-11 cells decreased intrinsic apoptosis and impaired the production of cellular reactive oxygen species (ROS) induced by APR-246. Together, our results indicate that, in at least a subset of AML cell lines and normal HSPCs, APR-246-induced ROS production and cytotoxicity are enhanced in the presence of WT p53 proteins. Full article

Therapeutic resistance in cancer arises not only from intrinsic metabolic plasticity within the tumor, but also from the systemic metabolic state of the host organism. This review advances an integrated framework centered on the metabolic network between the host and tumor to examine how host-related factors—particularly aging, nutrition, and psychological stress—remodel systemic metabolism and thereby influence the efficacy of diverse cancer therapies. We highlight a bidirectional metabolic interplay: host physiology establishes a permissive context for tumor metabolic adaptation, whereas anticancer therapies, in turn, perturb host metabolic homeostasis, accelerating aging and compromising neurocognitive health. Ultimately, we propose that overcoming therapeutic resistance will require strategies that simultaneously target tumor metabolic dependencies and reprogram the host metabolic milieu—a systemic approach poised to redefine precision oncology. Full article

Background: The translocation of diet-derived antigens from the maternal intestine to breast milk represents a primary gateway for neonatal immune priming, yet the structural basis for why certain proteins survive this transit while others do not remains poorly understood. This review introduces the “Survivor Peptide” hypothesis, proposing that specific food allergens possess intrinsic “stability architectures” that enable them to resist maternal digestion and navigate the gut–mammary axis to reach the infant in an immunologically active form. Methods: We analyzed the current literature regarding the detection and structural characteristics of food allergens in human milk. Integrating evidence from 26 major sources, we performed an in silico structural analysis of five representative “survivor” proteins: Gal d 1 (egg white), Bos d 5 (cow’s milk), Gal d 6 (egg yolk), Tri a 19 (wheat), and tropomyosin (Der p 10-mite/shellfish). High-resolution 3D models were retrieved from the Protein Data Bank and AlphaFold2, and then visualized in UCSF ChimeraX to map stability anchors, including disulfide bonds and hydrophobic clusters, against solvent-accessible IgE-binding epitopes. Results: We identified and categorized allergens into distinct Molecular Resilience Architectures: the “Covalent Cage” (Gal d 1), defined by dense disulfide stapling, the “Glycoprotein Shield” (Gal d 6), utilizing yolk-matrix structural anchors, the “Topological Shield” (Bos d 5), characterized by a stable β-barrel, and “Coiled-Coil Rigidity” (Der p 10). These frameworks protect large, immunogenic fragments that maintain the spatial arrangement required for IgE cross-linking. Conclusions: Allergen persistence in the gut–mammary axis is dictated by a protein’s intrinsic structural architecture. Identifying these stability fingerprints provides a unified theory for allergen persistence and offers a path for refining component-resolved diagnostics and neonatal oral tolerance strategies. Full article

Refractory status epilepticus refers to persistent and recurrent seizures unresponsive to medication, often leading to neuronal injury and neurobehavioral deficits. Studies have demonstrated that intraperitoneal bolus administration of pyruvate attenuates neuronal damage in rodent models of chemically induced status epilepticus (SE), while the precise neuroprotective mechanism remains to be further explored. This study investigated the neuroprotective effects of long-term supplementation with exogenous pyruvate against SE. When male C57BL/6 mice received 3% sodium pyruvate (SP) in the drinking water ad libitum for 20 weeks, they exhibited elevated levels of essential neurochemicals and energy metabolites in the brain compared to the control mice that received the equimolar saline solution. Following the intraperitoneal administration of kainate (KA) to induce severe SE, the SP-fed mice showed enhanced resistance to seizure activity, reduced neuronal injury, and improved neurobehavioral performance compared to the saline-fed mice. Regarding the molecular mechanisms underlying their neuroprotective properties, the levels of pyruvate metabolism-mediating proteins, neuronal and synaptic proteins, and neuroprotective proteins remained upregulated in the brains of the SP-fed mice following KA-induced SE. Conversely, the levels of pro-apoptotic and oxidative stress markers were suppressed. Collectively, this study indicates that long-term pyruvate supplementation may sustainably augment neurochemical and energy metabolism in the normal brain, thereby eliciting intrinsic neuroprotective properties. These effects contribute to preventing or ameliorating seizure activity, neuronal damage, and neurobehavioral deficits in mice following KA-induced SE, suggesting its prophylactic or therapeutic potential against epileptic seizures and SE through metabolic preconditioning. Full article

EML4-ALK-positive lung cancer represents an important molecular subtype of non-small-cell lung cancer (NSCLC) that initially responds to ALK inhibitors but invariably develops resistance, highlighting the need for novel targeted therapeutic strategies. Death receptors DR4 and DR5 are frequently upregulated in malignancies and can selectively induce tumor cell apoptosis upon binding TRAIL. ISZ-sTRAIL, a trimer-stabilized soluble TRAIL fusion protein, exhibits potent antitumor effects via DR4/DR5 signaling activation. However, the expression status of DR4/DR5 in EML4-ALK-positive NSCLC cells and the therapeutic potential of targeting this pathway remain poorly defined. In this study, we evaluated DR4/DR5 protein expression in EML4-ALK-positive NSCLC cells and investigated the antitumor effect of ISZ-sTRAIL produced in an Escherichia coli expression system. Our results showed that DR4 and DR5 were abundantly expressed in EML4-ALK-positive NCI-H2228 and NCI-H3122 cells compared with normal human bronchial epithelial 16HBE cells. Furthermore, ISZ-sTRAIL significantly suppressed the proliferation of NCI-H2228 and NCI-H3122 cells, with IC₅₀ values of 4.51 ± 0.22 nM and 14.98 ± 3.34 nM, respectively, while showing low cytotoxicity toward normal 16HBE cells (IC₅₀ > 1 μM). Moreover, ISZ-sTRAIL induced caspase-dependent apoptosis in both cell lines via activation of extrinsic and intrinsic pathway, and these effects were markedly abrogated by the pan-caspase inhibitor Z-VAD. These findings identify DR4/DR5 as a potential therapeutic target and provide preclinical evidence for the development of TRAIL-based strategies in the treatment of EML4-ALK-positive NSCLC. Full article

Natural gas hydrates are regarded as a vital strategic energy resource for the future owing to their high energy density and clean combustion characteristics. To facilitate research into the physical and mechanical properties of pressure-maintained hydrate samples, this paper presents an integrated multi-parameter online analysis system capable of rapidly measuring the P-wave velocity, electrical resistivity, thermal conductivity, and shear strength of core samples under pressure-maintaining conditions. The system comprises hardware acquisition boards based on ZYNQ and ARM platforms, specialized measurement probes, and comprehensive data acquisition and analysis software. To mitigate the susceptibility of P-wave signals to noise interference, an improved denoising algorithm combining Empirical Mode Decomposition (EMD) and wavelet thresholding is proposed. By employing autocorrelation function analysis, the algorithm identifies the transition boundary between noise-dominated and signal-dominated Intrinsic Mode Functions (IMFs), subsequently applying wavelet soft-thresholding to the noise-dominant components. Experimental results demonstrate that the proposed algorithm achieves a superior signal-to-noise ratio (SNR) compared to traditional EMD methods, particularly under low SNR conditions. System validation indicates measurement accuracies of 3.2% for P-wave velocity at 20 °C, 1.76% for electrical resistivity at 25 °C, and within 7% for both thermal conductivity and shear strength. Furthermore, sea trials conducted aboard the “HAIYANG SHIYOU 708” drilling vessel confirm that the system operates stably and effectively fulfills the requirements for deep-sea core parameter characterization. Full article

In recent years, diseases caused by species of the genus Campylobacter have increased, due to improvements in identification methods, but also because, as part of global travel and trade, these species have spread to countries where no cases had previously been reported. The methodologies for their identification, whether classic through culture media and morphological characteristics, or using molecular biology or even proteomics techniques, play a fundamental role in establishing their diagnosis and providing timely treatment. Likewise, epidemiology will help guide this diagnosis when dealing with poorly defined diarrhoea, as well as the control and prevention of these infections. Similarly, expanding information on the relationship between these species and Guillain-Barré syndrome will lead to a better understanding and timely identification. We must not forget that both intrinsic and acquired antimicrobial resistance are key factors to consider for the successful treatment of infections caused by Campylobacter species. Full article

Renal cancer remains a major global health burden, and current targeted and immunotherapeutic strategies are frequently limited by toxicity, therapeutic resistance, and suboptimal response rates. Natural bioactive compounds such as epigallocatechin gallate (EGCG) and cafestol exhibit anticancer activity; however, their therapeutic utility is constrained by limited potency and dose-dependent adverse effects. In this study, the antiproliferative and synergistic effects of cafestol and a hyaluronic acid (HA)–EGCG conjugate were investigated in renal cancer cells. HA conjugation significantly enhanced the antiproliferative efficacy of EGCG in both ACHN and A498 human renal cancer cells, whereas unmodified HA exhibited no intrinsic anticancer activity. Importantly, the HA–EGCG conjugate enabled a pronounced synergistic interaction with cafestol, particularly in ACHN cells, as confirmed by combination index analysis, while free EGCG and cafestol failed to achieve synergistic inhibition. In addition, the HA–EGCG conjugate and its combination with cafestol exhibited favorable selectivity toward renal cancer cells compared with normal renal proximal tubule epithelial cells (RPTECs). This combination robustly enhanced apoptosis and was associated with significant downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL at the transcriptional level, together with suppression of the epithelial–mesenchymal transition-associated transcription factor SNAIL at both transcriptional and protein levels. Notably, the enhanced antiproliferative effects were achieved at reduced concentrations, highlighting the potential to mitigate dose-related toxicity. Collectively, these findings support HA-based conjugation as an effective strategy to potentiate the anticancer activity of natural bioactive compounds and to enable synergistic, multi-targeted therapeutic effects against renal cancer. Full article

Electrochemical water splitting stands as a feasible approach for sustainable hydrogen production, but its industrial implementation is restricted by sluggish oxygen evolution reaction (OER) kinetics and excessive dependence on freshwater resources. As a widely existing alternative, seawater contains a high concentration of chloride ions (Cl⁻), which give rise to serious electrode corrosion and catalyst deactivation, bringing great challenges to actual electrolysis applications. Herein, we report a facile room-temperature two-step soaking strategy to fabricate sulfur-modified NiFe layered double hydroxide (S-NiFe-LDH) catalysts for efficient OER in both alkaline freshwater and seawater electrolytes. The introduction of sulfur not only optimizes the electronic structure of NiFe-LDH to strengthen intrinsic catalytic activity and speed up charge transfer, but also promotes the formation of a Cl⁻-resistant layer, thus significantly improving corrosion resistance. In addition, DFT calculations show sulfur modification in NiFe layered double hydroxide upshifts the O 2p-band center to activate lattice oxygen, switches the oxygen evolution reaction pathway to the lattice oxygen mechanism with reduced thermodynamic barriers, and realizes the selective adsorption of OH⁻ over Cl⁻. As a result, the as-prepared S-NiFe-LDH catalyst exhibits exceptional OER performance, requiring overpotentials (η) of 250, 270, and 290 mV to reach current densities of 50, 100, and 200 mA·cm⁻² in 1 M KOH, respectively, with a Tafel slope of 22.3 mV·dec⁻¹. Moreover, it maintains remarkable stability for more than 200 h in alkaline seawater electrolytes and achieves nearly 100% Faradaic efficiency for water splitting, effectively avoiding the parasitic chlorine evolution reaction (CER). This work provides a scalable and energy-efficient synthetic route for designing advanced non-noble metal catalysts, paving the way for industrial-scale hydrogen production from seawater. Full article

Cancer stem cells (CSCs) are a highly influential population of tumor cells involved in tumor initiation, progression, metastasis, recurrence, and resistance to therapy. Although CSCs have been widely investigated, their behavior cannot be understood solely through intrinsic cellular features, as these cells strongly depend on a specialized supportive microenvironment known as the CSC niche. In this review, we discuss the CSC niche as a dynamic and therapeutically relevant ecosystem that is distinct from, but closely connected with, the broader tumor microenvironment. Particular attention is given to stromal cells, immune cells, endothelial cells, extracellular matrix components, hypoxia, cytokines, chemokines, and metabolic stress as regulators of CSC self-renewal, plasticity, dormancy, immune escape, epithelial–mesenchymal transition, metastatic dissemination, and survival under therapeutic pressure. We further consider how CSC–niche interactions contribute to pre-metastatic niche formation and tumor relapse. Finally, we outline emerging therapeutic strategies aimed at disrupting CSC-supportive signals, including approaches targeting developmental pathways, angiogenesis, hypoxia, extracellular matrix remodeling, immunosuppressive networks, and cytokine-mediated communication. Overall, this review emphasizes that targeting the CSC-supportive microenvironment is essential for limiting metastasis, recurrence, and long-term treatment failure. Full article

In the surface protection of stone and brick cultural heritage, a primary challenge is that traditional polymeric coatings are prone to photooxidative degradation under ultraviolet (UV) irradiation, and the resulting aged fragments readily block the substrate micropores, leading to a loss of “breathability”. To address the performance conflict among waterproofing, breathability, and weather resistance, this study prepared few-layer Ti₃C₂T_X MXene using a minimally intensive layer delamination (MILD) method. The poor compatibility between MXene and the fluorosilicone (FPS) resin matrix was effectively resolved through covalent modification with a silane coupling agent (KH-550). Results demonstrate that at an ultralow loading (0.5 wt%), the functionalized f-MXene is uniformly dispersed within the resin. This structure not only spontaneously constructs a hierarchical rough architecture on the surface that imparts high hydrophobicity (water contact angle of 131.6°), but its internal “labyrinth effect” also effectively blocks corrosive media. Simultaneously, the intrinsic water vapor transmission rate of the substrate is effectively maintained (with a reduction of less than 3%), and no visually perceptible color difference is generated (∆E = 1.2). Mechanically, f-MXene relies on interfacial interactions to act as a “nano-skeleton” for stress transfer, thereby increasing the uniaxial compressive strength of fragile limestone by 32.4%. Optical and spectroscopic characterizations further elucidate its anti-aging mechanism: f-MXene not only provides broadband UV shielding but also exhibits highly efficient radical scavenging activity during long-term UV aging. After 400 h of aging, the concentrations of hydroxyl and superoxide anion radicals within the system are significantly reduced, blocking the photooxidative chain reaction from the source. This work develops a composite protective material system for stone cultural heritage that simultaneously integrates high moisture permeability, minimal visual intervention, and long-term antioxidant performance. Full article

Zinc germanium phosphide (ZnGeP₂) is an important nonlinear crystal for mid-infrared conversion, but its performance is limited by residual absorption and intrinsic impurity phases. In this study, polycrystalline ZnGeP₂ was synthesized by a modified two-temperature method, purified by inclined directional recrystallization for up to three cycles, and then grown into single crystals by the vertical Bridgman method. The resulting material was examined by shadow-projection imaging, transmission spectroscopy in the 650–2500 nm range, absorption measurements at 2.097 µm, laser-induced damage threshold (LIDT) testing, and powder X-ray diffraction. Repeated purification improved optical homogeneity and near-infrared transparency, while the absorption coefficient at 2.097 µm decreased from 0.45 to 0.30 cm⁻¹ after three purification cycles. Semi-quantitative PXRD analysis showed progressive suppression of intrinsic impurity phosphides, with phase purity increasing from 86.31% after the first cycle to 95.995% after the second and reaching 100% after the third within the detection limit of the method. However, the LIDT decreased with increasing purification number, indicating a trade-off between lower optical losses and damage resistance. These results demonstrate that inclined directional recrystallization is an effective pre-growth purification route for ZnGeP₂ and that the optimal number of purification cycles should be selected according to the intended application. Full article

The increasing frequency and intensity of hotter droughts are driving widespread forest dieback, yet the role of tree nutritional status in drought-induced growth dieback remains poorly understood. We investigated how nutrient composition across tissues (leaves, wood) relates to water use patterns and growth resilience in rear-edge populations of Scots pine (Pinus sylvestris L.) in Northeastern Spain. Using a multi-proxy approach, we combined analyses of foliar and sapwood nutrient concentrations, stable isotopes (δ¹³C, δ¹⁸O), and dendrochronological indicators across contrasting tree vigor classes. Defoliated trees exhibited pronounced shifts in elemental composition, including depletion of foliar K and increased concentrations of Ca, S, and Fe, alongside higher intrinsic water use efficiency and reduced growth resistance to drought. In contrast, the sapwood elemental composition was less responsive to defoliation but showed stronger associations with isotopic signals and drought resilience, suggesting its integrative role in tree functioning. Coordination of nutrient concentrations between tissues was limited, suggesting organ-specific regulation of nutrient allocation under drought stress. Our results reveal that nutrient imbalances are linked to water–carbon dynamics and drought responses and emphasize the importance of considering multi-organ nutrient dynamics to improve our understanding of long-term nutritional imbalances during drought-induced forest dieback. Full article

Locally advanced rectal cancer is commonly treated using total neoadjuvant therapy (TNT), which integrates radiotherapy with systemic chemotherapy to improve tumor downstaging, local control, and long-term oncologic outcomes. Despite its central role in treatment, responses to radiotherapy remain highly heterogeneous. While some tumors undergo complete regression, others exhibit intrinsic or acquired treatment resistance, resulting in incomplete tumor control while experiencing treatment-related toxicity. Understanding the biological determinants that govern radiation sensitivity in rectal cancer, therefore, represents a major clinical challenge. Ionizing radiation induces tumor cell death primarily through the generation of reactive oxygen species (ROS) and DNA damage, particularly DNA double-strand breaks. In addition to nuclear DNA injury, radiation-induced oxidative stress can initiate lipid peroxidation within cellular membranes. When lipid peroxide accumulation exceeds the capacity of cellular antioxidant systems, this process can trigger ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid oxidation. Ferroptotic susceptibility is regulated by interconnected metabolic pathways, including cystine transport through system Xc⁻ (SLC7A11/SLC3A2), glutathione synthesis, glutathione peroxidase-4 (GPX4) activity, iron metabolism, and membrane lipid remodeling. Recent evidence further indicates that ferroptosis intersects with antitumor immunity. Ferroptotic tumor cells release oxidized lipid mediators and damage-associated molecular signals that can influence immune activation, while interferon-γ produced by activated CD8⁺ T cells during immune checkpoint blockade suppresses SLC7A11 expression, limiting cystine uptake and promoting ferroptotic tumor cell death. These findings suggest that ferroptosis represents a mechanistic interface between tumor metabolic vulnerability and immune-mediated cytotoxicity. This interaction is particularly relevant in colorectal cancer biology, where immune checkpoint inhibitors demonstrate clinical benefit primarily in tumors with deficient mismatch repair or microsatellite instability-high (MSI-H) status. The vast majority of rectal cancers are microsatellite stable (MSS) and exhibit limited responsiveness to immunotherapy due to reduced immunogenicity and immune exclusion within the tumor microenvironment. Strategies capable of increasing tumor immunogenicity in this setting are therefore of considerable interest. In this review, we examine the molecular mechanisms linking radiation-induced oxidative stress to ferroptosis and tumor immunity in colorectal cancer, while focusing on the clinical context of radiotherapy in rectal cancer. We discuss how lipid metabolism, iron homeostasis, cysteine-dependent antioxidant systems, and immune signaling pathways converge to regulate ferroptotic vulnerability and radiation response. We further explore the therapeutic potential of integrating radiotherapy, ferroptosis-targeting strategies, and immunotherapy to overcome radioresistance and improve treatment outcomes in colorectal cancer. Full article

The p53 biomolecule is critical for facile antitumor response in cancer therapy. Once fully activated, p53 will kill tumor cells by activating programmed cell death (PCD), such as apoptosis and ferroptosis, and inducing immunogenic cell death. It is not surprising, therefore, that in about 50% of cancers p53 is mutated and non-functional, which induces drug resistance. Paradoxically, many cancers harboring the wild-type p53 genotype also become resistant via loss of drug-induced activation of p53. Efforts to convert loss-of-function or gain-of-function mutant p53 to the wild-type phenotype or to activate wild-type p53 through drug design have been disappointing. There is also a failure to recognize the existence of a sizeable number of mutant p53s that are phenotypically normal but cannot be functionally activated. Since such mutants and wild-type p53 retain intrinsic PCD pathways, focus on activating p53 could be more rewarding if the efforts implemented recognize and incorporate mechanistic factors that are vital for activating p53 function. This would realize a seminal goal of harnessing the true potential of p53 through more rational and effective therapeutic strategies and finally fulfill a critical unmet clinical need, particularly in the context of precision medicine. For such a vision, functional evaluation of normal (wild-type) or mutant p53 (or FENOMP) is vital and, thus, proposed herein as a conceptual assay to predict the phenotype of p53. Full article