Search Results (1,127)

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

Legumain, an asparaginyl endopeptidase, has emerged as a critical cysteine protease with diverse and complex roles in human health and disease. While traditionally known for its function in endolysosomal protein degradation, a growing body of evidence has revealed its presence in multiple cellular compartments and its involvement in a vast array of pathological processes. This review provides a comprehensive synthesis of the current literature, bridging the often-siloed research in oncology and cardiovascular medicine to present a unified view of legumain’s function. We first detail the multifaceted role of legumain in cancer, where it acts as a driver of tumour proliferation, invasion, and metastasis. We explore its function as a modulator of the tumour microenvironment, particularly its ability to polarise macrophages towards an immunosuppressive phenotype, and discuss its emerging value as a candidate prognostic biomarker and a versatile therapeutic target. Notably, however, therapeutic targeting of legumain remains predominantly at the preclinical stage. Subsequently, we examine its significant contribution to cardiovascular diseases, detailing its mechanistic involvement in promoting atherosclerosis, hypertension, and adverse cardiac remodelling through pathways involving inflammation, extracellular matrix turnover, and immune cell modulation. By synthesising these findings, we highlight the convergent pathological mechanisms, discuss current controversies and methodological limitations—such as the lack of standardised assays—and propose key future directions. This review frames legumain as a biological rheostat and a potentially important node in chronic disease, underscoring its potential as a powerful biomarker and a sophisticated therapeutic target across a broad spectrum of human pathologies. Full article

Magnetoelectric materials couple magnetic and electrical order parameters and can convert remotely applied magnetic fields into localized electrical responses. At the nanoscale, this functionality is commonly pursued through core–shell architectures in which a magnetostrictive or magnetic core is mechanically coupled to a piezoelectric or ferroelectric shell. The resulting strain-mediated transduction is attractive for biomedical and bioelectronic applications because magnetic fields penetrate biological tissue with comparatively low attenuation, whereas the generated electrical signals can interact directly with charged biomolecules, cell membranes, ion channels, and electroactive tissues. This review critically evaluates magnetoelectric core–shell nanoparticles from a broad biomedical and bioelectronic perspective. The physical basis of direct and converse magnetoelectric coupling is first discussed, with emphasis on nanoscale boundary conditions, magnetic-domain state, ferroelectric polarization, interfacial strain transfer, ionic screening, and nonlinear field dependence. Representative magnetic-core/piezoelectric-shell material families, including ferrite-based, multiferroic-oxide, lead-free piezoelectric, PZT-containing, and polymer-integrated architectures, are compared in terms of magnetic response, piezoelectric activity, chemical stability, biocompatibility, toxicity, and processability. Particular attention is given to CoFe₂O₄–BaTiO₃ (CFO-BTO) as a benchmark magnetoelectric core–shell system, while alternative material combinations are comparatively discussed to reflect the broader diversity of the field. Synthesis and processing strategies, structural and physicochemical characterization, surface engineering, and local or macroscopic magnetoelectric measurement methods are examined together with the artifacts that can complicate quantitative interpretation. Particular attention is paid to particle size, shell thickness, crystallinity, aggregation, colloidal stability, surface chemistry, biomolecular functionalization, and their influence on magnetoelectric performance and biological interactions. The available literature demonstrates substantial progress in magnetically triggered drug delivery and cancer therapy, wireless neural and cardiac stimulation, tissue engineering, immunomodulation, wound healing, multimodal imaging, and related bioelectronic applications. Biosensing is also considered an important emerging direction; however, direct quantitative detection of proteins, nucleic acids, pathogens, and cancer biomarkers using isolated core–shell magnetoelectric nanoparticles remains comparatively underdeveloped. The review therefore distinguishes experimentally established biomedical and bioelectronic functionalities from less mature biosensing concepts and identifies the measurement, safety, clinically relevant magnetic-field exposure, scalable manufacturing, device-integration, and regulatory challenges that must be addressed for translation. A practical roadmap is proposed for developing reproducible, lead-free, biologically stable, and quantitatively characterized magnetoelectric nanoparticle platforms for next-generation wireless biomedical and bioelectronic technologies. Full article

Following the first approval for prostate cancer (PCa) treatment of competitive antagonists of the androgen receptor (AR) function that bind to the androgen-binding pocket, much progress has been achieved regarding compound efficacy and specificity. Second-generation compounds and androgen synthesis blockers are now standard-of-care AR pathway inhibitors given to PCa patients. More recently, approaches targeting AR regions other than the ligand-binding domain (LBD), stimulating proteasome-mediated AR degradation, or bringing together the AR with an effector protein (EP) in prostate tumor cells, have been explored and, in several cases, clinically tested. Compounds blocking AR mRNA splicing or directly addressing AR splice variants, especially the constitutively active AR-V7 form, are also being evaluated. In addition, there are ongoing efforts aiming at impairing the function of essential AR cofactors, mainly those involved in downstream gene transcription and chromatin modulation. Alternative techniques to impair AR activity, such as nanoparticle formulations and targeting biomolecular condensates are furthermore being explored. Here we present the most recent developments in these different strategies to target the AR, directly or indirectly, for a more potent and long-lasting blockade. This will hopefully soon lead to treatments that improve progression-free and overall survival in PCa patients, while maintaining a good safety profile. Full article

Cytoplasmic stress granules (SGs) form in response to diverse insults; they are dismantled when the stress subsides. SG clearance is facilitated by molecular chaperones, nuclear transport factors, and other components. The anti-parasitic drug ivermectin inhibits nuclear trafficking and has potential anti-cancer activities. However, the molecular pathways that promote ivermectin’s therapeutic actions are poorly understood. Our study defined the effects of ivermectin on stress recovery in human neuroblastoma and cervical carcinoma cells. We demonstrate that ivermectin interferes with SG disassembly in neuroblastoma cells. The delay of SG dissolution is accompanied by significant changes in the proteostasis network. Notably, ivermectin diminishes de novo protein synthesis in unstressed and stressed cells. During recovery, ivermectin reduces the abundance of hsp70 in neuroblastoma, but not in cervical carcinoma cells. Surprisingly, ivermectin has no effect on Hsf1 abundance and localization. Moreover, ivermectin does not diminish the levels of transcripts encoding hsp70. Bioorthogonal Non-Canonical Amino Acid Tagging revealed that ivermectin markedly reduces the stress-induced de novo synthesis of hsp70 in neuroblastoma cells. Taken together, ivermectin can derail stress responses by a unique mechanism that alters the translation of hsp70 mRNA and is determined by the cellular context. This information is directly relevant to ivermectin-based anti-cancer therapies. Full article

Although expression-based omics has greatly contributed to biological research, the biochemical state of cells or tissues cannot be fully explained by transcript or gene expression data alone. This systematic review investigated when matrix-assisted laser desorption/ionisation (MALDI)-based approaches can support the integration of multiple molecular layers and when they remain limited to single-class molecular mapping. PubMed was searched between 1 February and 8 June 2026. English-language peer-reviewed publications relevant to the principles, methods, molecular classes, or biomedical applications of matrix-assisted laser desorption/ionisation-based multiomics were eligible. Publications outside this scope were excluded. Records were independently screened by two reviewers, and disagreements were resolved through discussion. The findings were narratively synthesised based on the analytical platform, molecular layer, integrated spatial multiomics, spatial application, and biomedical use. The methodological quality and risk of bias were not formally assessed, which limits the certainty and strength of the conclusions drawn from this narrative synthesis. Following the reapplication of the relevance criteria, 111 publications from 1633 identified records were included in the final review. The evidence was reclassified and presented separately as true multilayer MALDI studies, MALDI integrated with orthogonal modalities, and background uniomics or spatial molecular profiling studies. These publications included human, animal, cellular, tissue-based, and methodological studies. These publications cover many molecular classes and biomedical applications. As many publications did not involve human participants, a single pooled participant total was not applicable to this study. Matrix-assisted laser desorption/ionisation-based techniques were used to analyse metabolites, lipids, glycans, peptides, and intact proteins in the reviewed literature. The literature also shows that spatial information can be retained using matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS). Its ability to map molecular signals back to specific tissue regions or areas associated with disease supports its potential clinical utility. Specific areas of application, such as cancer, neurological, and infectious disease research, are also reviewed. The use of matrix-assisted laser desorption/ionisation-based techniques for biomarker discovery has been evaluated. Small sample sizes, proof-of-concept designs, inconsistent outcome reporting, and limited external validation have limited the evidence. Technical limitations include ion suppression, limited quantification, sample preparation variability, and differing analyte sensitivity. Emerging developments, such as single-cell imaging and AI analysis, have also been explored. Matrix-assisted laser desorption/ionisation enables multiomics when two or more complementary molecular layers are analysed and integrated within the same biological system. When only a single molecular class is analysed, the approach remains spatial molecular mapping rather than multiomic analysis. However, before matrix-assisted laser desorption/ionisation-based approaches can be applied in routine clinical practice, standardised workflows and better quantitative methods are needed. This review received no external funding and was not registered. Full article

Protein-based nanoparticles (NPs) are attracting increasing attention as sustainable platforms for advanced biomedical applications. However, achieving high encapsulation efficiencies without compromising nanoparticle stability and biocompatibility remains a key challenge for these bio-based delivery systems. In this context, bovine serum albumin (BSA) NPs crosslinked with genipin were developed as green and biocompatible nanocarriers with tunable physicochemical properties. The synthesis conditions were systematically optimized by varying reaction time, temperature, and the BSA:genipin ratio, with 24 h at room temperature and a 10:1 ratio yielding the most suitable NPs in terms of formation and colloidal stability. The optimized BSA NPs were then used to encapsulate sertraline and 5-fluorouracil, achieving encapsulation efficiencies of 82% and 40%, respectively. These results highlight the ability of this nanoplatform to incorporate bioactive compounds with distinct physicochemical characteristics, with the sertraline-loaded NPs showing particularly high loading efficiency for an albumin-based system. In vitro assays performed on normal prostate epithelial cells (PNT-2) and prostate cancer cells (22Rv1) showed that the BSA NPs modulated drug-induced cytotoxicity relative to free drugs, indicating a formulation-dependent biological response. These findings highlight the potential of genipin-crosslinked BSA NPs as a versatile and sustainable platform for drug delivery in cancer therapy. Full article

Disulfiram (DSF), long used as an aversive agent in alcohol dependence therapy, has recently regained attention as a promising candidate for oncological drug repurposing. After administration, DSF is rapidly reduced to diethyldithiocarbamate (DDC), which, in the presence of Cu²⁺, forms the complex Cu(DDC)₂. This compound acts as a strong inducer of oxidative stress, an inhibitor of the ubiquitin–proteasome system, and a suppressor of endogenous hydrogen sulfide (H₂S) synthesis. DSF also modifies protein and non-protein thiol groups, disrupting cancer cell metabolism and promoting apoptosis. Despite robust preclinical evidence, clinical translation remains limited. Key obstacles include DSF’s rapid metabolism, insufficient availability of free copper ions in humans, and the lack of predictive biomarkers capable of identifying responsive patients. Another challenge is DSF’s low oral bioavailability, which prevents the drug from reaching tumor tissue at therapeutically effective concentrations. Consequently, current research focuses on advanced nanocarrier systems designed to protect DSF from premature degradation and ensure its controlled release within the tumor microenvironment. This review summarizes the multifaceted anticancer mechanisms of DSF and discusses biological and pharmacological factors underlying the discrepancies between experimental findings and clinical outcomes. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the most prevalent primary liver tumor and is often diagnosed at advanced stages with very poor therapeutic response, leading to high mortality. Thus, new therapeutic strategies and biomarkers are urgently needed. We previously showed that the combination of loratadine, raloxifene, and sorafenib exerts synergistic cytotoxicity on HCC cells. Here, we explored potential molecular mechanisms underlying the anticancer effects of this combination using multiomics analyses. Methods: We performed proteomic analyses based on mass spectrometry, transcriptomic analyses using the Clariom D Plus human microarray (Affymetrix), and metabolomic analyses based on nuclear magnetic resonance to investigate the profile changes induced by the drug combination in HuH7 cells. Bioinformatic analyses were applied to associate the omics changes with biological functions, molecular interactions, and clinical relevance in terms of patient survival. Results: We identified several molecules whose expression changed in response to treatment across the three omics profiles analyzed. Some of them were found to be involved in hallmarks of cancer, including sustained proliferation, evasion of growth suppressors, and resistance to cell death. Integrated multi-omics analyses revealed that the drug combination suppresses critical oncogenic drivers (C7orf50, NUP188, and HS2ST1) and that the mitotic cell cycle process, DNA synthesis and cholesterol biosynthesis are the primary pathways affected. Protein–protein interaction analysis revealed five key hubs (KIF2C, PCNA, TRIP13, NDC80, and RPA3), whose expression in HCC is associated with poor clinical prognosis. Conclusions: The combined treatment rewired molecular networks involved in HCC progression. These findings identify clinically relevant molecular targets associated with poor prognosis and provide mechanistic insights into the synergistic anticancer activity of this drug combination. Full article

Chronic pain is a major global health burden and often remains difficult to treat with current therapies, which frequently provide incomplete relief and may cause systemic side effects. As essential organelles in eukaryotic cells, mitochondria facilitate ATP synthesis and serve as key regulators of calcium homeostasis and apoptosis. Evidence points to mitochondrial dysfunction not merely as a result of trauma, but as a fundamental factor in why pain becomes persistent. On the other hand, the endoplasmic reticulum (ER) is more than just a structural component of the cell; it is a multi-functional organelle responsible for protein quality control, including folding and degradation, as well as lipid production and calcium signaling. ER dysfunction is a primary driver of various pathologies, such as cardiovascular disease, cancer, and neurodegenerative disorders. The organelle’s ability to execute its vital functions is strictly dependent on sufficient levels of ATP. Because mitochondrial and ER functions are closely interconnected through calcium exchange, ATP-dependent protein homeostasis, oxidative stress, and mitochondria-associated ER membranes, their dysfunction may act together to amplify nociceptive sensitization and pain chronification. In this review, we summarize current evidence linking mitochondrial dysfunction, ER stress, and ER-mitochondrial crosstalk to the pathogenesis of chronic pain and discuss their potentials as therapeutic targets. 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

Background/Objectives: Triple negative breast cancer remains the most difficult breast cancer to treat as there are no specific targeted therapies. The tumor stroma is recognized as essential for the development of solid tumors. Cancer associated myofibroblasts are known to play a major role in the construction of a tumor microenvironment conducive to tumor progression. Therefore, we established a co-culture system to identify potential molecular targets controlling myofibroblast conversion. Methods: Co-cultures of MDA-MB-468 triple negative breast cancer cells and skin fibroblasts were either mixed prior to seeding or seeded individually on opposite sides of a culture dish and incubated in complete medium. Inhibitors were preincubated with cells for 1 h. Inflammatory cytokines were measured by ELISA. Proteins were analyzed using the Wes-Protein Simple System. Immunostaining was visualized using a Hamamatsu Photonics Nanozoomer. Statistical analysis was done by student’s t-test and one-way ANOVA. Results: The data indicate that co-culturing the cells promotes myofibroblast differentiation and cytokine release and this requires direct contact between the two cell types. Both myofibroblast conversion and cytokine release were prevented by inhibitors of TLR5, TGF-β and EDA-fibronectin. Conclusions: Data suggest that the TLR5 receptor on the MDA-MB-468 cells binds to EDA-fibronectin expressed by fibroblasts thus inducing inflammatory cytokine expression. Expression of EDA fibronectin is regulated through TGF-β whose synthesis is induced by TLR5 signaling in the tumor cells. The data are consistent with a model in which TLR5-mediated crosstalk between the cancer cells and the stromal fibroblasts creates a tissue microenvironment conducive to tumor growth and metastasis. Full article

The biosynthesis of copper and copper oxide nanoparticles (Cu/CuO-NPs) has attracted considerable interest due to its non-toxic, eco-friendly nature and wide-ranging applications, especially in nanomedicine and biomedical fields. Traditional nanoparticle production methods often involve toxic chemicals and generate harmful byproducts. In contrast, biological synthesis provides a cleaner, safer, more cost-effective, and sustainable alternative. Various biological sources, including plants, bacteria, fungi, and yeast, have been employed for the efficient and non-toxic production of Cu/CuO-NPs. These organisms contain diverse biomolecules such as enzymes, proteins, amino acids, vitamins, flavonoids, and alkaloids that function as reducing, capping, and stabilizing agents during nanoparticle formation. The biologically synthesized Cu/CuO-NPs are characterized using UV-VIS spectroscopy, Raman spectroscopy, TEM, SEM, EDX, XRD, TGA, XPS, FTIR, DLS, zeta potential analyzer, etc. Cu/CuO-NPs hold promise for applications in nanomedicine, primarily because of their strong antimicrobial and anticancer activities and potential use as disinfectants against infectious diseases. Various reports have suggested that the biologically synthesized Cu/CuO-NPs have exhibited significant antimicrobial and anticancer efficacies against pathogenic bacteria, fungi and viruses and various cancer cells. Due to their nanoscale dimensions and extensive surface area, Cu/CuO nanoparticles can readily infiltrate cell walls, disrupt membrane integrity, generate reactive oxygen species, and hinder both DNA replication and protein production, leading to cell death. The present review comprehensively describes the biological synthesis of Cu/CuO-NPs, their characterization techniques, and potential antibacterial, antifungal, antiviral, and anticancer applications. The modes of action for antibacterial, antifungal, antiviral, and anticancer properties have also been explored critically. Full article

Cancer-associated cachexia (CAC) is a multifactorial syndrome characterized by systemic inflammation, muscle wasting, and progressive functional decline, affecting up to 80% of patients with advanced cancer. The inconsistent diagnostic criteria limit comparability across studies and hinder translation into clinical practice. Inflammatory biomarkers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and serum albumin, have been studied as markers of the presence, severity, and progression of CAC. This review synthesizes evidence linking these five biomarkers to key manifestations of CAC, including weight- loss, muscle depletion, fatigue, quality of life, and survival. A structured search of PubMed, Embase, and Web of Science studies published between 2000 and 2025, yielding 20 articles for final synthesis to evaluate biomarker patterns and their potential utility for early detection and risk stratification. IL-6 and CRP show consistent associations with muscle wasting and systemic inflammatory burden. Albumin and NLR demonstrate enhanced prognostic value when incorporated into composite indices such as the Cachexia index. TNF-α remains mechanistically relevant but shows limited predictive utility when assessed independently. CRP, Albumin, and NLR are derived from routine, low-cost tests, whereas IL-6 and TNF-α require specialized cytokine assays. Future research is warranted to standardize diagnostic criteria and validate biomarker thresholds to develop an accessible, multi-biomarker panel for improved detection and monitoring of CAC. Full article

Background/Objectives: Metformin is a prominent candidate for cancer drug repurposing, backed by preclinical and epidemiological evidence showing reduced cancer incidence in diabetic patients. Its pleiotropic effects include AMPK activation, protein synthesis inhibition, and metabolic alterations. This review integrates global preclinical data via a comprehensive tabular overview alongside a cross-analysis of specific investigations of hamster fibrosarcoma. Since head-to-head comparisons of metformin-based combinations on hamster fibrosarcoma remain limited, this work performs an integrated cross-study evaluation to establish a clear comparative hierarchy of various repurposed adjuvants combined with metformin. Methods: A literature review and cross-study re-analysis of peer-reviewed preclinical studies were conducted, focusing on in vivo therapeutic outcomes within the BHK-21/C13-induced hamster fibrosarcoma model. Treatment regimens from distinct primary studies were evaluated side-by-side using tumor endpoint data expressed as a percentage of control mean (± SD). Only statistically significant pairwise differences (p < 0.05) determined the comparative hierarchy. Results: Integrated analysis identified disulfiram and diclofenac as the most promising adjuvants among compared metformin combinations, showing the highest statistical significance across all evaluated endpoints. The statistical ranking of the metformin-based combinations followed a descending order: disulfiram, diclofenac, nitroglycerin, itraconazole, and caffeine. Conclusions: By synthesizing previously fragmented primary data into a unified comparative framework, these findings provide a strong, consolidated preclinical rationale for metformin-based combination strategies. The established hierarchy of adjuvant potency resolves structural ambiguity and supports further translational and clinical investigation to evaluate their therapeutic potential in fibrosarcoma and other malignancies. Full article