Search Results (266)

Synthetic lethality has reshaped oncology, particularly in tumours with defects in DNA damage response (DDR) pathways, yet therapeutic strategies centred on canonical DDR targets, including poly(ADP-ribose) polymerase (PARP), ataxia telangiectasia and Rad3-related protein (ATR), checkpoint kinase 1 (CHK1) and Wee1 G2 checkpoint kinase (WEE1), remain constrained by resistance, toxicity and biological heterogeneity of DDR alterations. Emerging evidence indicates that DDR deficiency extends beyond impaired DNA repair to generate interconnected stress phenotypes involving replication fork instability, chromosomal instability, transcriptional and cell-cycle dysregulation, oxidative/proteotoxic stress and metabolic imbalance. These states may increase tumour-cell reliance on kinases that are not canonical DNA repair enzymes or proximal DDR sensors, here referred to as non-canonical DDR-associated kinases. In this review, we examine the mechanistic rationale and translational potential of targeting kinases that regulate mitosis, transcriptional adaptation, checkpoint signalling, stress responses and metabolic homeostasis in DDR-defective tumours. We distinguish kinase dependencies supported by direct DDR-context-specific vulnerability or PARP inhibitor sensitisation from those whose relevance remains primarily mechanistic or hypothesis-generating and propose a shift from genotype-based patient selection toward functional stress phenotyping that integrates DNA repair capacity with replication stress, chromosomal instability, transcriptional conflict and the metabolic state. Finally, we evaluate pharmacological strategies, including rational combinations, allosteric modulation, polypharmacology and targeted protein degradation, and highlight the need for biomarker-guided clinical translation. Full article

Background/Objectives: Indoles and benzimidazoles are important nitrogen-containing heterocyclic scaffolds and are a cornerstone of synthetic drugs. In this study, benzamides of 2-aminophenylindoles and 2-aminophenylbenzimidazoles were synthesized and evaluated for their potential. Further, they were also subjected to computational studies for their ADMET profiling and binding with target proteins. Methods: The synthesized compounds were characterized by ATR-FTIR, 1H NMR, 13C NMR and electrospray ionization mass spectroscopy (ESI-MS). They were screened for their in vitro antibacterial activity by the Microplate Alamar Blue Assay (MABA) and for their anticancer potential by the MTT assay against the HeLa, PC3 and 3T3 cell lines. Further, the compounds were assessed for their ADMET profiles by the Deep-PK platform, and binding with selected kinases was assessed by AutoDock Vina v1.2.7, followed by MD simulations in GROMACS. Density functional theory (DFT) calculations were also performed to investigate the electronic properties of the synthesized compounds. Results: All synthesized compounds were inactive in antibacterial assays and mildly active against cancer cells. N-[4-(1H-benzimidazol-2-yl-phenyl]benzamide (4-APB-B) exhibited good activity against the HeLa cell line (IC50: 5.48 ± 0.01 µM) while showing very low cytotoxicity against the 3T3 cell line (selectivity index: 10.7), against which doxorubicin was highly active, indicating selectivity towards specific cancer cells. Docking studies indicated favorable binding affinities towards the selected kinase targets. Further, ligands with the best binding affinities in docking studies were subjected to MD simulations of 100 ns, and DFT studies were also performed to assess the electronic properties of the synthesized compounds. Conclusion: Our study provides a pathway for the synthesis of 2-phenylbenzimidazoles and 2-phenylindoles and demonstrates that the synthetic compound 4-APB-B possesses remarkable selective cytotoxic activity and can serve as a lead molecule for further development into a successful anticancer agent. Full article

Decommissioning of research reactors leads to significant amounts of low- and intermediate-level radioactive waste that is planned to be stored under cementitious conditions in Swedish repositories. These materials contain important amounts of aluminum and its alloys which are reactive under alkaline conditions found in concrete pore water. The corrosion produces hydrogen that can lead to cracks in the concrete which can be pathways for radioactive ions. As an attempt to optimize repository conditions for aluminum-based reactor waste, parts of the ordinary Portland cement I in the concrete were replaced by fly ash. This addition may reduce pH and alkali–carbonate reactions increase the durability of the concrete. Testing of fly ash concretes is also of interest from a future availability perspective given the potential phase out of ordinary Portland cement in favor of formulations such as fly ash variants with lower CO₂ emissions. Decreased corrosion rates, more uniform corrosion accompanied by ATR-FTIR (Attenuated Total Reflectance—Fourier Transform Infrared Spectroscopy) spectra and µCT (Micro computed tomography) as well as SEM-EDX (Scanning Electron Microscopy with Energy Dispersive X-ray analysis) images suggest less aggressive corrosion of the Al alloy from the decommissioned Studsvik R2 reactor in concrete with varying amount of fly ash replacement. Full article

Biogas-to-hydrogen pathways can support sustainable hydrogen refueling stations through on-site hydrogen production from renewable biogas. This study presents a techno-economic assessment of two on-grid biogas-to-hydrogen configurations based on steam and autothermal reforming, considering three station capacities of 200, 500, and 1000 kg H₂/day. Technical models were integrated with an economic model to assess the effects of plant scale and economic conditions on overall performance. The technical results show that the overall specific energy consumption is approximately 63.7 kWh/kg H₂ for autothermal reforming, compared with 80.0 kWh/kg H₂ for steam reforming. The dispensed levelized cost of hydrogen (LCOH) decreases with increasing station capacity, from 10.61 to 8.06 €/kg H₂ for steam reforming and from 11.28 to 8.08 €/kg H₂ for autothermal reforming. At the assumed hydrogen selling price of 10.66 €/kg H₂, economic performance improves with increasing station capacity. Under baseline conditions, steam reforming is more competitive at 200 and 500 kg H₂/day, whereas the two configurations become nearly equivalent at 1000 kg H₂/day. Sensitivity analyses show that BtH_SR is more competitive below biogas prices of approximately 0.058 and 0.042 €/kWh for the 500 and 1000 kg H₂/day stations, respectively, while BtH_ATR is favored above these thresholds. Higher electricity prices favor BtH_SR, with the 1000 kg H₂/day configurations becoming nearly equivalent at approximately 0.138 €/kWh. The nominal interest rate has the strongest effect on economic feasibility, with all investigated configurations becoming unfeasible above a value of 13.3%. Full article

The Alternative Lengthening of Telomeres (ALT) pathway drives replicative immortality in aggressive malignancies, particularly sarcomas and gliomas. Clinical ALT stratification has relied on screening for structural ATRX and DAXX mutations. However, this genotypic approach fails to capture the dynamic macro-reprogramming required to sustain ALT. Here, we established and validated a 28-gene transcriptomic signature that captures the ALT-associated transcriptomic phenotype of the ALT phenotype. Using multivariate Cox proportional hazards models and time-dependent ROC analyses, we demonstrate that this signature is a robust, independent predictor of poor overall survival in Sarcoma (SARC) and Lower Grade Glioma (LGG) cohorts, outperforming the prognostic value of traditional ATRX/DAXX mutational status. Genomic mapping revealed this transcriptional synchrony is structurally facilitated by non-random focal clustering on Chromosome 8. To deconstruct the machinery driving this lethal phenotype, we employed an integromic approach, synthesizing protein–protein and metabolic flux networks. Topological algorithms prioritized five indispensable hubs: TP53, ATM, ATR, PCNA, and UBE2I. Gene–metabolite profiling identified PCNA as a bottleneck funneling extreme deoxyribonucleotide (dNTP) demand to sustain break-induced telomeric recombination. To translate these vulnerabilities into actionable treatments, we mapped these hubs to a precision pharmacological network. We propose a multi-targeted strategy combining FDA-approved PARP inhibitors to exploit ATR-mediated synthetic lethality, alongside antimetabolites to induce nucleotide starvation. This study redefines ALT risk stratification and provides a data-driven framework to target and treat resistant ALT-positive tumors. Full article

The rising demand for low-carbon hydrogen has intensified interest in biogas-reforming as a renewable, decentralized alternative to fossil-based production. However, published assessments of the competing reforming routes rely on inconsistent system boundaries and assumptions, which prevents a reliable comparison between them. This study addresses that gap by evaluating four biogas-reforming pathways, steam reforming (SR), dry reforming (DR), partial oxidation (POX), and autothermal reforming (ATR), within a single, consistent techno-economic and environmental assessment framework. Thermodynamic performance, life-cycle global warming potential, and the levelized cost of hydrogen (LCOH) are analyzed together, with cost uncertainty quantified through a 10,000-iteration Monte Carlo simulation and a six-parameter sensitivity analysis. The harmonized comparison shows that steam reforming is simultaneously the most favorable route for hydrogen yield, energy efficiency, levelized cost, and life-cycle carbon intensity, establishing it as the benchmark, whereas dry reforming, although it uniquely consumes CO₂, incurs the highest cost and the greatest catalyst-deactivation risk. Across all pathways, plant scale and capacity factor emerge as the dominant cost drivers, and biogas-derived hydrogen remains more expensive than conventional gray hydrogen, so its deployment depends on impurity-tolerant catalysts, improved heat integration, life-cycle-verified CO₂ management, and supportive low-carbon incentives. The novelty of this work lies in its unified, multi-criteria framework, which enables a like-for-like ranking of biogas-reforming routes and clarifies the conditions under which each becomes competitive. Full article

Fe^II-doped zinc ferrite nanocrystals (Fe^II_xZn_1-xFe^III₂O₄) were prepared via a sol–gel approach in the presence of polyvinyl alcohol as a stabilizer and assessed for their capability to eliminate crystal violet (CV) dye from water-based solutions. The structural and surface characteristics of the prepared materials were examined by XRD, HRTEM, FESEM, ATR–FTIR, XPS, UV–visible spectrophotometer and BET analyses. XRD patterns confirmed the formation of a cubic spinel ferrite structure (Fd-3m), indicating successful incorporation of Fe^II into the ZnFe₂O₄ lattice. ATR–FTIR spectra showed characteristic metal–oxygen vibrations at the tetrahedral and octahedral sites. XPS analysis confirmed the coexistence of Fe^II and Fe^III species, which may promote interfacial charge transfer and redox reactions. HRTEM and FESEM images showed particle agglomeration and grain growth after calcination at 700 °C. Fe^II_0.2Zn_0.8Fe^III₂O₄ exhibited the highest photocatalytic performance, achieving 97.2% degradation of CV under optimized conditions. The effects of contact time, catalyst dosage, initial dye concentration, and pH were systematically studied. The maximum removal efficiency was obtained at pH 10 using 0.075 g catalyst for 20 mg L⁻¹ CV solution within 40 min. Freundlich isotherm models exhibited the strongest correlation (R² = 0.918), pointing to multilayer adsorption occurring across a non-uniform nanoparticle surface. The Dubinin–Radushkevich analysis returned an adsorption energy of 3.01 kJ mol⁻¹, implying that physical forces predominantly control the adsorption mechanism. Kinetic investigations revealed a two-stage CV uptake pathway: fast initial binding at exterior surface sites, succeeded by a slower migration of dye molecules into the internal pores of the adsorbent. Full article

Pyridopyrimidine is an important heterocyclic scaffold widely explored in anticancer drug discovery. Its structural similarity to purine enables effective interaction with various biological targets, mainly kinases involved in cancer progression. This manuscript presents recent developments reported between 2021 and 2026, focusing on the biological evaluation, and structure–activity relationships of pyridopyrimidine derivatives. Many of these synthesized compounds act as inhibitors of key targets such as EGFR, CDK4/6, and the PI3K/mTOR pathway, which are closely associated with tumor growth, survival, and resistance mechanisms. Other targets such as ATR and PIM are also explored. Recent studies show that structural modifications, including substitution on the core ring and hybridization with pharmacologically active moieties like triazoles and thiazolidinediones, significantly improve anticancer activity. Several derivatives have demonstrated strong antiproliferative effects against different cancer cell lines and are capable of inducing apoptosis and cell cycle arrest. In addition, molecular docking and other computational studies support their binding efficiency and help explain their mechanisms of action. There is also increasing interest in the development of dual-target or multi-target inhibitors to overcome drug resistance and enhance therapeutic effectiveness. Overall, pyridopyrimidine- and pyridopyrimidinones-based compounds continue to show great promise as potential anticancer agents. Further research combining synthetic chemistry, biological studies, and computational approaches may lead to the development of more effective and safer drugs in the future. Full article

The thieno[3,2-d]pyrimidine scaffolds have emerged as an important class of heterocycles in anticancer drug discovery, with clinically advanced drugs olmutinib and pictilisib highlighting their therapeutic potential. This review presents thieno[3,2-d]pyrimidine-containing anticancer agents reported between January 2008 and August 2025, focusing on synthetic methodologies, anticancer-related biological activities, and structure–activity relationships. Thieno[3,2-d]pyrimidine derivatives have been investigated as inhibitors of numerous cancer-related targets, including EGFR, PI3K/mTOR, CDKs, JAK, VEGFR, HDAC, ATR, and other oncogenic proteins. This review also summarizes thieno[3,2-d]pyrimidine scaffolds with anticancer activity, with particular emphasis on the design and synthesis of lead compounds, molecular hybridization strategies, and recent advances in this area. Synthetic pathways for lead compounds are systematically presented and discussed, along with pharmacophoric features. In addition, detailed structure–activity relationship analyses are provided to highlight the influence of heterocyclic fusion, linker optimization, hydrogen-bonding motifs, electronic effects, hydrophobic fragments, and the introduction of hybrid scaffolds on antiproliferative potency, kinase inhibition, selectivity, and multitarget activity. In addition, this review demonstrates the significant potential of thieno[3,2-d]pyrimidine-based scaffolds as a privileged platform for the development of next-generation targeted anticancer agents and offers valuable guidance for future medicinal chemistry research. Full article

The redox state of the nucleus is emerging as a critical determinant of plant cell fate: reactive oxygen species (ROS) signals that originate in chloroplasts, peroxisomes, and the apoplast ultimately converge on nuclear proteins that determine whether a cell mounts a protective response or initiates programmed cell death (PCD). Loss-of-function mutations in ATR7, which encodes a nuclear protein specific to seed plants, confer tolerance to both paraquat- and aminotriazole-induced cell death, establishing ATR7 as a positive regulator of ROS-induced PCD. Yet how ATR7 acts at the molecular level remains unknown. In this paper, we define the ATR7 protein interactome using IP-MS of GFP-tagged ATR7 and integrate it with the atr7 loss-of-function transcriptome to distinguish it as candidate direct molecular partners from transcriptionally regulated targets. To investigate the nuclear protein association with ATR7, we performed GFP affinity purification followed by mass spectrometry (IP-MS) using Arabidopsis thaliana seedlings expressing GFP-ATR7, in comparison with seedlings expressing free GFP as the negative control. The IP-MS candidates were compared with the previously published ATR7 transcriptome data. ATR7 associates with chromatin-modifying proteins, components of the ubiquitin–proteasome system, and a broad set of stress-responsive proteins whose encoding genes are constitutively de-repressed when ATR7 is non-functional. Among the candidate proteins are those that have potential chromatin-regulatory functions, including AT1G01920 (a SET-domain protein) and HDA14, as well as components associated with ubiquitin–proteasome pathways and oxidative stress responses. Several interactors have no current functional annotation and represent candidates for novel roles in oxidative stress signalling. These findings provide the first mechanistic framework for ATR7 action and implicate nuclear chromatin-level repression as a key node in the regulation of ROS-induced PCD in plants. Full article

Ultraviolet B (UVB) radiation is a primary cause of DNA damage in the skin, which is often a precursor to skin cancer. Natural products represent a rich source of compounds with unexplored photoprotective properties. Our previous work identified 3-methoxybenzyl isothiocyanate (MBITC), a meadowfoam derivative, as a promising UVB-absorptive agent that reduces DNA damage and cell proliferation; however, its clinical use is limited by dose-dependent cytotoxicity. To address this, we synthesized a novel amide lipid conjugate of MBITC, N-(3-methoxybenzyl)eicos-5-enamide (MBA), and evaluated its photoprotective efficacy and mechanism of action. Our findings demonstrate that MBA exhibited remarkably reduced cytotoxicity compared to its parent compound, while effectively retaining its photoprotective properties. In human primary keratinocyte cultures, MBA significantly reduced UVB-induced DNA damage, as evidenced by a decrease in cyclobutane pyrimidine dimers (p < 0.05) and γ-H2A.X (p < 0.05). Furthermore, MBA increased the expression of DNA damage response (DDR) proteins and DNA damage-binding protein 1 (DDB1) (p < 0.05) and the activation of Ataxia Telangiectasia and Rad3-related protein (ATR) (p < 0.05), a master regulator of DDR and repair pathways. These findings suggest that MBA acts through direct UVB absorption and/or the engagement of DDR pathways following irradiation, highlighting its potential use as a novel photoprotective compound. Full article

Tacrolimus (TAC) nephropathy is a major complication of immunosuppressive therapy and contributes to chronic kidney disease (CKD) progression through ischemia, metabolic dysfunction, and oxidative stress; however, its protein-level basis remains unclear. This study sought to identify characteristic molecular alterations in renal cortices of TAC-treated mice, so as to clarify the link between replication stress responses and metabolic dysfunction. A previously generated proteomic dataset from a TAC-induced chronic nephrotoxicity mouse model was analyzed using a protein-centered analytical strategy, including statistical, Gene Ontology, pathway, upstream regulator, and disease-enrichment analyses. A total of 7466 proteins were quantified. Upregulated proteins included KAT6A and NCKAP1, whereas downregulated proteins included NDUFC2, HSD17B12, and TECR. Coordinated impairment of CoQ₁₀-dependent and glutathione-dependent antioxidant defenses was identified, reflected by reductions in AIFM2 (FSP1) and GSTA4/GSTT2. Enrichment analyses indicated activation of MCM- and ATR-associated replication stress responses in the upregulated group, and impaired lipid metabolism, CoA biosynthesis, mitochondrial function, and redox regulation in the downregulated group. TAC nephropathy is characterized by two major molecular signatures: central disruption of antioxidant defense systems, spanning FSP1-mediated CoQ₁₀ regeneration and GST- associated antioxidant systems, together with suppression of lipid and energy metabolism and activation of replication stress responses. These findings provide a protein-level molecular framework linking coordinated impairment of antioxidant defense systems, suppression of lipid and energy metabolism, and activation of replication stress responses in TAC-induced chronic nephrotoxicity. These findings also suggest the FSP1 pathway, GST-associated antioxidant systems, and CoA-dependent metabolism as potential therapeutic targets for CKD progression. Full article

This study presents a comprehensive and integrated characterization of solid and liquid residues generated during industrial glass-cutting operations, highlighting the novelty of treating glass-cutting sludge and process wastewater as compositionally linked outputs of the same industrial comminution process. The research examined the morphology, elemental composition, and selected physicochemical properties of sludge and wastewater-derived particulates to assess material-recovery potential and provide a basis for further evaluation of water reuse. Samples were analyzed using particle morphology assessment, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS), Fourier-transform infrared spectroscopy with attenuated total reflectance (FTIR-ATR), dynamic light scattering (DLS), and pH measurements. The results showed that the solid fraction consisted predominantly of soda–lime–silica glass constituents, with oxygen, silicon, sodium, calcium, and magnesium as the main components, while potentially problematic contaminants remained at low levels. Although isolated particles enriched in Fe, Cu, Ni, Sn, La, or Ce were detected, their occurrence was limited and did not significantly affect the average particulate composition observed within the SEM-EDS dataset. This is particularly important for coated glass, where functional coatings contribute negligibly to the bulk glass matrix. From a material-recovery perspective, the sludge should be regarded as a promising glass-derived mineral residue requiring further route-specific qualification rather than as waste intended solely for disposal. However, this study does not demonstrate suitability for any specific reuse route, and additional validation is needed regarding compositional consistency, variability, moisture and organic content, leaching behavior, and route-specific acceptance criteria. For process wastewater, contamination was governed mainly by suspended glass-derived solids, indicating that solid–liquid separation is the key treatment step. However, the present dataset is insufficient to confirm the suitability of treated water for direct industrial recirculation, and the results should therefore be interpreted as indicating potential for further evaluation after appropriate clarification. This work establishes an empirical multi-scale characterization framework that links glass-cutting sludge and process wastewater as compositionally related outputs of the same comminution process, thereby supporting circular-economy strategies by jointly informing sludge valorization and water-clarification pathways. Overall, this work establishes a multiscale characterization framework for integrated residue management, jointly supporting sludge valorization and wastewater clarification assessment within a circular-economy perspective. Full article

The therapeutic potential of pharmacologically targeting kinases involved in regulating the DNA damage response (DDR) has been investigated for over two decades. Inhibitors of ATM, ATR, CHK1, CHK2 and WEE1 have been developed with the aim of subverting cell cycle checkpoint function in cancer cells, promoting cell death. The DNA repair pathway non-homologous end-joining can also be targeted through DNA-PK inhibition. However, despite extensive preclinical and clinical studies, none of the many candidate inhibitors have yet made it through to clinical approval. Emerging evidence for tumour biomarkers associated with enhanced sensitivity to DDR kinase inhibition may provide a way through this impasse. Clinical testing in appropriately stratified cohorts is now becoming increasingly common, with some promising results. Building on results obtained with small-molecule inhibitors, targeted protein degradation (TPD) utilising proteolysis-targeting chimaeras (PROTACs) or molecular glues for degradation of DDR kinases is a rapidly developing strategy. This review discusses the current ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 inhibitors that show the most promise as monotherapies and combination treatments in solid tumours, as well as the potential benefits of using TPD technology over small-molecule inhibitors. Established and emerging biomarkers that can be applied to patient selection are also discussed. Full article

The development of sustainable food systems increasingly relies on the valorization of agri-food by-products and circular economy strategies. In this context, food-grade hydrogels represent promising matrices for incorporating biological components and bioactive compounds. This study focuses on the preparation and characterization of four hydrogels formulated with natural biopolymers, such as pectin, an extract obtained from spray-dried by-products generated during the processing of strawberry and blueberry fruit preparations, with potential applications in innovative and sustainable food formulations. A specific formulation was produced by including plant cells. UV–visible spectra, pH, and moisture content of the hydrogels were evaluated. Their morphological, chemical, and hydrodynamic properties were investigated using micro-Raman and FTIR/ATR spectroscopy along with swelling degree and dehydration behavior over time. The analysis clarified gelation mechanisms, confirming the key role of calcium chloride in matrix stabilization and the influence of plant cells on water retention. The developed food-grade hydrogels demonstrated physicochemical stability, even after 20 days of storage at 4 °C. The incorporation of plant cells modulated the hydrogel’s hygroscopic behavior, maintaining the fundamental gelation pathways. These results highlight the potential of these hydrogels as sustainable matrices for incorporating biological components and support their application in innovative food formulations based on the valorization of by-products. Full article