Search Results (3,545)

Reactive oxygen species (ROS) are highly reactive molecules that, when produced in excess, contribute to oxidative stress, promoting cellular damage and the progression of various diseases, including cancer. Polydatin (PD) is known for its antioxidant, anti-inflammatory, and pro-apoptotic properties, proving effective in several in vitro studies as an antitumor agent. However, its clinical application is limited by low bioavailability, poor water solubility, and chemical instability. To overcome these limitations, nanocarrier systems based on biopolymers, such as chitosan (CS), represent promising strategies for drug delivery. In this study, we developed and optimized CS nanocapsules loaded with Polydatin using the ionotropic gelation method. The final formulation was characterized by UV-Vis spectrophotometry, scanning electron microscopy (SEM), and dynamic and dielectrophoretic light scattering (DLS, DELS). Encapsulation efficiency (EE) and the biological effects of the nanocapsules on cancer cells were also evaluated. To assess their antitumor potential, PD-CS nanoparticles were tested on the human breast cancer SKBR3 cells, analyzing their effects on cell viability. The results demonstrate that CS nanocapsules loaded with PD are able to reduce SKBR3 cell proliferation, highlighting their potential for developing new therapeutic tools for cancer treatment. Full article

Bovine viral diarrhea virus (BVDV) is a major pathogen responsible for significant economic losses in the global cattle industry. The diverse transmission routes and the characteristics of asymptomatic infections make it difficult to contain the spread; there is an urgent need to develop new effective antiviral strategies. Nanobodies (Nbs) have become a promising new type of antiviral agent due to their advantages, including small molecular size, stable structure, high specificity, and ease of production. This study successfully screened a specific nanobody, Nb7, targeting the key functional protein NS5A of BVDV using phage display technology. Furthermore, the nanobody was effectively delivered into Madin–Darby bovine kidney (MDBK) cells by fusing it with the cell-penetrating peptide TAT. The results demonstrate that TAT-Nb7, specifically targeting the non-structural protein NS5A of BVDV, significantly inhibits viral replication in MDBK cells. In conclusion, this study indicates that TAT-Nb7 holds promise as a therapeutic candidate for the prevention and control of BVDV infection. Full article

Tyrosine kinase inhibitors (TKIs), such as sunitinib and sorafenib, are standard treatments for renal cell carcinoma (RCC). However, most patients treated with these drugs eventually develop drug resistance and relapse; therefore, new treatment options for RCC are urgently required. Recent studies have focused on combination therapies targeting distinct molecular pathways that may produce synergistic effects and help overcome drug resistance in RCC. Niclosamide, an anthelmintic agent, is effective against various cancers; however, its potential in combination with sunitinib for treating RCC has not been evaluated. In this study, we assessed the therapeutic efficacy of niclosamide in combination with sunitinib against RCC and explored the underlying molecular mechanisms. Niclosamide alone inhibited RCC cell proliferation, whereas its combination with sunitinib produced a synergistic anticancer effect, both in vitro and in vivo. RNA sequencing (RNA-seq) and bioinformatic analyses showed that niclosamide modulated critical pathways, including BRIP1- and FANCA-mediated DNA repair and E2F2-regulated cell cycle progression. These findings provide proof-of-concept that niclosamide enhances TKI efficacy through modulation of DNA repair and cell cycle pathways, supporting the rationale for DNA damage response (DDR)-targeted combination strategies in RCC. Full article

This study aimed to investigate the role and underlying mechanism of apolipoprotein C2 (APOC2) in the progression of clear cell renal cell carcinoma (ccRCC). Analysis of The Cancer Genome Atlas (TCGA) datasets, combined with validation in ccRCC cell lines, revealed that APOC2 was markedly upregulated in ccRCC tissues and cells and was associated with poor patient prognosis. Functional assays demonstrated that APOC2 knockdown significantly suppressed cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Mechanistic studies showed that silencing APOC2 reduced the phosphorylation levels of key components of the JAK-STAT signaling pathway, including Jak1/2 and STAT3, without affecting their total protein expression. Gene enrichment analysis further indicated the involvement of JAK-STAT signaling, and functional rescue experiments using the STAT3 agonist Colivelin partially reversed the decreased cell viability and increased apoptosis caused by APOC2 knockdown, confirming the pathway’s mediating role. Collectively, these findings suggest that APOC2 promotes ccRCC cell proliferation and inhibits apoptosis, at least in part, through activation of the JAK-STAT signaling pathway, highlighting APOC2 as a novel oncogenic regulator and potential therapeutic target, and providing new insight into the metabolic–inflammatory axis in ccRCC progression. Clinically, APOC2 may serve as a biomarker to identify ccRCC patients with hyperactivated JAK-STAT signaling and could potentially guide combination therapies involving JAK/STAT inhibitors or metabolic-targeted agents. Full article

Ischemic stroke remains a major cause of mortality and long-term disability, yet current therapeutic strategies are largely limited to reperfusion approaches such as intravenous thrombolysis and thrombectomy, which are constrained by narrow treatment windows and the risk of complications. Moreover, the blood–brain barrier (BBB) severely restricts drug penetration into the injured brain, limiting the translation of promising neuroprotective agents into clinical success. Intranasal (IN) delivery has emerged as a compelling alternative route that bypasses the BBB and enables rapid access to the central nervous system through olfactory, trigeminal, and perivascular pathways. This narrative review highlights recent advances in preclinical research on IN therapeutics for ischemic stroke, ranging from small molecules and biologics to nucleic acids and cell-based therapies. Particular emphasis is placed on the application of nanotechnology, including extracellular vesicles, liposomes, and inorganic nanoparticles, which enhance drug stability, targeting, and bioavailability. Studies demonstrate that IN delivery of growth factors, cytokines, and engineered stem cells can promote neurogenesis, angiogenesis, white matter repair, and functional recovery, while nanocarriers further expand the therapeutic potential. Overall, intranasal delivery represents a promising and non-invasive strategy to overcome the limitations of conventional stroke therapies, offering new avenues for neuroprotection and regeneration that warrant further investigation toward clinical translation. Full article

Background: Medicinal plants continue to offer a promising source of novel bioactive compounds for cancer therapy due to their affordability, biocompatibility, and low toxicity. Rhus punjabensis Stewart, an ethnomedicinal species from the family Anacardiaceae, has long been used in the traditional medicine of northern Pakistan to treat inflammatory, hepatic, and infectious diseases. However, its phytochemical composition and anticancer potential remain largely unexplored. Methods: This study employed a bioactivity-guided isolation strategy to identify and characterize anticancer constituents from R. punjabensis leaves. The plant material was sequentially fractionated using solvents of increasing polarity, followed by purification via column chromatography. Each fraction and purified compound was evaluated using antioxidant (DPPH, total antioxidant capacity, and total reducing power) and cytotoxic assays, including brine shrimp lethality, Sulfo-rhodamine B (SRB) against five human cancer cell lines, protein kinase inhibition, and NF-κB chemo-preventive assays. Results: Comparative analysis of spectral data (UV, 1D/2D NMR, and ESI-MS) led to the identification of three triterpenoid compounds—Lupeol, Cycloartenol, and β-sitosterol—reported for the first time from R. punjabensis. Among them, Lupeol displayed the most potent cytotoxicity against DU-145 prostate (IC₅₀ = 11.2 ± 1.2 μg/mL) and HL-60 leukemia (IC₅₀ = 15.2 ± 1.1 μg/mL) cell lines and showed significant NF-κB inhibitory activity (IC₅₀ = 19.4 ± 1.1 μg/mL), indicating its chemo-preventive potential. Cycloartenoland β-sitosterol exhibited moderate antioxidant and antimicrobial activities. Conclusion: The findings validate the ethnopharmacological use of R. punjabensis and confirm it as a new source of triterpenoids with notable anticancer activity. This study provides the first comprehensive account of its bioactive metabolites, reinforcing the significance of bioactivity-directed isolation as a powerful approach for discovering natural anticancer agents. Further in vivo and mechanistic evaluations are warranted to establish their therapeutic efficacy and safety profiles. Full article

Marine ecosystems represent an exceptional reservoir of structurally diverse metabolites with remarkable pharmacological potential. Over the past decades, the exploration of marine organisms has led to the discovery of an ever-expanding number of bioactive compounds. Many of these metabolites display highly original chemical scaffolds that are not typically found in terrestrial organisms, offering new opportunities for drug discovery. Among the most promising applications is their development as anticancer agents, given their ability to interfere with key cellular processes. This review highlights marine natural products currently under investigation in preclinical studies as potential anticancer lead compounds. The molecules are classified into major structural families: aromatic and heterocyclic alkaloids, terpenes and their derivatives, macrolide frameworks, and diverse peptide-based scaffolds, alongside other complex classes (polyketides, thiazole lipids, alkylamino alcohols, and pyrrolocarbazole derivatives). A particular emphasis has been placed on the role of total synthesis over the last decade. Advances in synthetic methodology have not only enabled the production of these complex metabolites in sufficient quantities but have also facilitated the development of novel chemotherapeutic agents. To overcome the challenges of limited natural availability, the advanced synthetic approaches are crucial for harnessing the full therapeutic potential of marine-derived compounds. Full article

Drug repurposing, that is, the identification of new therapeutic indications for existing medications, has been shown to be a cost-effective and time-efficient alternative to de novo drug development. This review provides a comprehensive overview of repurposed drugs in veterinary oncology, describing their mechanisms of action, current evidence of clinical benefit, and translational relevance. The therapeutic agents discussed include non-steroidal anti-inflammatory drugs (e.g., piroxicam), metabolic modulators (e.g., metformin), anti-parasitic drugs (e.g., fenbendazole), immunomodulators (e.g., thalidomide, oclacitinib), cardiovascular agents (e.g., propranolol, statins, losartan), and other compounds such as auranofin and disulfiram. A critical evaluation of the extant evidence-based data from preclinical research, naturally occurring tumor models, and clinical studies is provided, with particular emphasis on both the therapeutic potential and the current limitations. The present review also focused on combination strategies and multimodal protocols, where repurposed drugs may enhance the efficacy of chemotherapy, targeted therapies, or immunotherapy. Challenges to clinical implementation, including limited funding, regulatory and ethical considerations, and the need for well-designed, multi-institutional clinical trials, are discussed. Ultimately, drug repurposing represents a practical and translationally valuable approach to broaden therapeutic options, improve quality of life in companion animals, and advance comparative oncology by promoting progress that benefits both veterinary and human patients. Full article

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumour with limited treatment options and a poor prognosis. Hypoxia, a hallmark of solid tumours, contributes to therapeutic resistance and tumour progression. Gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in SCLC; however, its regulation under hypoxic conditions is not well described. In this study, we demonstrate that hypoxia significantly enhances GRPR expression in SCLC cell lines, COR-L24 and DMS79, as confirmed by Western blot, immunofluorescence, and flow cytometric analysis of binding with fluorescein isothiocyanate–labelled bombesin (BBN-FITC), a known GRPR ligand. To exploit this upregulation, we synthesised a previously discovered butylated neuropeptide antagonist (BU peptide) using a new method of solid-phase peptide synthesis (SPPS) by Boc chemistry and evaluated its therapeutic potential. BU peptide exhibited potent, dose-dependent cytotoxicity in both cell lines, with significantly greater efficacy under hypoxic conditions compared to normoxia. Mechanistic studies revealed that BU peptide inhibits GRP–GRPR-mediated activation of the PI3K/Akt and MAPK/ERK signalling pathways, known to be key regulators of tumour cell survival and proliferation. Moreover, BU peptide induced robust caspase 3/7-mediated apoptosis, especially under hypoxic conditions. These findings suggest that GRPR is a hypoxia-inducible target in SCLC and demonstrate that a synthetically optimised BU peptide antagonist exerts selective efficacy against hypoxic tumour cells, outperforming conventional chemotherapy agents. These findings provide new mechanistic insights into SCLC and suggest translational potential to inform the development of future treatment strategies for this and other hypoxia-driven malignancies. Full article

Background: The Warburg effect, historically regarded as a hallmark of cancer metabolism, is often interpreted as a universal metabolic feature of tumor cells. However, accumulating experimental evidence challenges this paradigm, revealing a more nuanced and context-dependent metabolic landscape. Methods: In this study, we present a hybrid multiscale model of tumor metabolism that integrates cellular and environmental dynamics to explore the emergence of metabolic phenotypes under varying conditions of stress. Our model combines a reduced yet mechanistically informed description of intracellular metabolism with an agent-based framework that captures spatial and temporal heterogeneity across tumor tissue. Each cell is represented as an autonomous agent whose behavior is shaped by local concentrations of key diffusive species—oxygen, glucose, lactate, and protons—and governed by internal metabolic states, gene expression levels, and environmental feedback. Building on our previous work, we extend existing metabolic models to include the reversible transport of lactate and the regulatory role of acidity in glycolytic flux. Results: Simulations under different environmental perturbations—such as oxygen oscillations, acidic shocks, and glucose deprivation—demonstrate that the Warburg effect is neither universal nor static. Instead, metabolic phenotypes emerge dynamically from the interplay between a cell’s history and its local microenvironment, without requiring genetic alterations. Conclusions: Our findings suggest that tumor metabolic behavior is better understood as a continuum of adaptive states shaped by thermodynamic and enzymatic constraints. This systems-level perspective offers new insights into metabolic plasticity and may inform therapeutic strategies targeting the tumor microenvironment rather than intrinsic cellular properties alone. Full article

Scorpion venom is a rich source of diverse bioactive molecules with medicinal importance. While the venoms of many Buthidae scorpions have been extensively studied for their toxicity and therapeutic potential, Hottentotta judaicus scorpion venom (HjSV) remains poorly explored. In this study, using LC-ESI-MS, we show that HjSV has a complex composition. We find that HjSV has no significant cytotoxic effects on three human cancer cell lines, even at concentrations of up to 1000 µg/mL. However, it exerts a dose-dependent insecticidal effect against Drosophila melanogaster, a well-established genetic model organism, and two medically relevant mosquito species, Aedes albopictus and Culex pipiens. These findings highlight the venom’s selective activity and reveal a species-dependent susceptibility in insects, with mosquitoes being more sensitive than Drosophila. Furthermore, we show that at sub-lethal doses, HjSV alters D. melanogaster behavioral patterns, significantly reducing locomotor activity and increasing sleep duration. Altogether, our results provide new insights into the dual role of HjSV as both an insecticidal agent and behavioral modulator, shedding light on its ecological function in prey subduing and its potential application in pest control strategies. Full article

Oral squamous cell carcinoma (OSCC) is marked by profound differences in survival between the localized and disseminated disease, estimated to result in a 70% and less than a 40% five-year survival rate with surgical and/or radiation approaches (in localized cases) and chemotherapy (in metastatic cases), respectively. Given the suboptimal efficacy of current management options, new therapeutic approaches are needed to supplement existing chemotherapies and improve outcomes. One emerging therapeutic option is naltrexone (NTX), an opioid antagonist that has shown promising outcomes at low doses in other forms of cancer. This study sought to determine the effectiveness of intermittent dosing of naltrexone on oral cancer cell survival, either as a single agent or in combination with traditional chemotherapy. Two human OSCC lines (locally invasive SCC-25 and metastatic Detroit 562) were cultured. Cells were exposed to 1 µM and 10 µM NTX alone, using intermittent (5 h once, 5 h daily, 5 h every other day) or constant 72 h exposure. Cells were exposed to combination therapy with cisplatin or docetaxel under three NTX regimens (5 h, 24 h, and continuous). Cell viability was determined using Sulphorhodamine B (SRB) assay and Cell Counting Kit-8 (CCK-8). Differences across treatments were assessed using ANOVA (p < 0.05). The effect of low-dose NTX alone, across varying treatment regimens, did not yield significant, consistent changes in OSCC cell survival. Combination with cytotoxic drugs reduced cell viability more efficiently than chemotherapy alone at select doses, particularly through intermittent short-term pretreatment schedules, but the full dose response demonstrated antagonism between NTX and chemotherapy, independent of the dosing schedule. These results contrast with previous findings in other cancers, and, thus, further study and optimization will be needed to determine the clinical benefit and reproducibility of these findings. Full article

Pattern recognition and machine learning algorithms have become integral to modern drug discovery, offering powerful tools to uncover complex patterns in biomedical data. This article provides a comprehensive review of state-of-the-art pattern recognition techniques—including traditional machine learning (e.g., support vector machines), deep learning approaches, genome-wide association studies (GWAS), and biomarker discovery methods—as applied in pharmacogenomics and computational drug repurposing. We discuss how these methods facilitate the identification of genetic factors that influence drug response, as well as the in silico screening of existing drugs for new therapeutic uses. Two antiviral agents, ribavirin and lopinavir, are examined as extended case studies in the context of COVID-19, illustrating practical applications of pattern recognition algorithms in analyzing pharmacogenomic data and guiding drug repurposing efforts during a pandemic. We highlight successful approaches such as the machine learning-driven prediction of responders and the AI-assisted identification of repurposed drugs (exemplified by the case of baricitinib for COVID-19), alongside current limitations, including data scarcity, model interpretability, and translational gaps. Finally, we outline future directions for integrating multi-omics data, improving algorithmic interpretability, and enhancing the synergy between computational predictions and experimental validation. The insights presented highlight the promising role of pattern recognition algorithms in advancing precision medicine and accelerating drug discovery, while recognizing the challenges that must be addressed to fully realize their potential. Full article

Targeted therapies, including treatment with inhibitors of BRAF^V600 and MEK kinases, have improved outcomes in advanced melanoma. However, most patients relapse due to acquired resistance, underscoring the need for new drug targets. This study evaluated PRI-724, a CBP/β-catenin inhibitor, in patient-derived drug-naïve melanoma cells and their trametinib- or vemurafenib-resistant counterparts. While PRI-724 has demonstrated efficacy in preclinical models and clinical trials in different cancer types, its potential in melanoma has not been previously assessed. We found that treatment with PRI-724 downregulated survivin and other CBP/β-catenin target proteins, reduced invasiveness, and induced apoptosis in drug-naïve and trametinib- and vemurafenib-resistant cells. Trametinib-resistant melanoma cells showed the greatest sensitivity to PRI-724, indicating that CBP/β-catenin transcriptional activity may represent a new therapeutic vulnerability. Transcriptomic and immunoblotting analyses revealed the highest survivin levels in vemurafenib-resistant cells, which may underlie their reduced responsiveness to PRI-724. Bioinformatic analyses (TCGA and GSE50509) confirmed that a high survivin level predicts poor prognosis and reduced response to treatment. The results of the study point to the potential of PRI-724 as a chemotherapeutic agent for the treatment of melanoma. Its efficacy might depend on CBP/β-catenin transcriptional activity in melanoma cells, and further evaluation of this signaling with survivin as a biomarker is therefore warranted. Full article

To date, breast cancer remains one of the leading causes of death among women worldwide. Although various treatments are used in clinical settings, the efficacy and safety of such treatments are limited by tumor biology factors and patient preferences. Previous studies have shown that triple-negative BRCA1-deficient breast cancer is susceptible to DNA-damaging agents, including platinum-based drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, alone or in combination. To address whether the combinative treatment of these DNA-damaging agents can be extended to the triple-negative BRCA1-proficient breast cancer population, we investigated the anticancer activity of the well-known FDA-approved PARP inhibitor olaparib in combination with the antimetastatic ruthenium(II)–arene PTA compound RAPTA-T for triple-negative BRCA1-competent breast cancer cells (MDA-MB-468 and MDA-MB-231), with consideration of sporadic breast cancer MCF-7 cells. RAPTA-T, olaparib, and the combined agents exhibited a dose-dependent inhibition of breast cancer cell growth in selected breast cancer cells. The combination compound inhibited colony formation most effectively in MDA-MB-468 cells. Additionally, the scratch-wound assay showed that MDA-MB-468 cells migrated more slowly than MCF-7 and MDA-MB-231 cells. The results indicated that the olaparib and RAPTA-T combination can reduce or inhibit the survival, invasion, and metastasis of breast cancer cells. Moreover, the combined agents promoted apoptotic cell death, with a higher percentage of apoptosis observed in MDA-MB-468 cells than in MDA-MB-231 and MCF-7 cells. Olaparib and RAPTA-T also interfered with cell cycle progression, with the greatest inhibition observed in the S and G2/M phases of MCF-7 cells (1.6- and 3.4-fold), followed by MDA-MB-468 cells (1.6- and 1.8-fold) and MDA-MB-231 cells (1.5- and 1.4-fold). Interestingly, MDA-MB-468 cells presented the highest degree of inhibition for BRCA1 replication and BRCA1 expression. The p53, PARP, and Chk1 proteins were more strongly upregulated in MDA-MB-231 cells than in Ru-untreated control cells. Moreover, the expression levels of protein biomarkers associated with the epithelial-to-mesenchymal transition (EMT), including E-cadherin and SLUG, were remarkably reduced in all tested breast cancer cells. Together, our results show the feasibility of extending the application of PARP inhibitors beyond breast cancer with BRCA1 mutations and optimizing the combinative treatment of PARP inhibitors with antimetastasis ruthenium-based chemotherapy as new therapeutic approaches for TNBC harboring wild-type BRCA1. Full article