Search Results (14,979)

Background: This study addresses an important vulnerability in the treatment of high-risk neuroblastoma (NB). NB is characterized by high rates of metastasis, drug resistance, relapse, and treatment-related toxicities. Current treatments, which include intensive chemotherapy, surgical removal of tumors, and stem cell transplants, have less than 50 percent survival rates among high-risk NB patients, demonstrating the need for novel targeted treatment approaches. CXC chemokine receptor 2 (CXCR2), a G-protein-coupled receptor, has been implicated in promoting cancer cell proliferation, invasion, metastasis, angiogenesis, chemoresistance, and maintaining cancer stem cells. Methods: We analyzed transcriptomic data from 1,464 primary NB patient samples to evaluate the prognostic significance of CXCR2 expression. Pharmacological inhibition of CXCR2 using SB225002, a selective small-molecule antagonist, was evaluated to determine its effects on cell growth, colony formation, apoptosis, and cell cycle progression in different NB cell lines. Three-dimensional (3D) spheroid models were used to examine tumor growth under physiologically relevant conditions. Mechanistic studies included gene expression analyses and immunoblot validation of key signaling regulators. Results: High CXCR2 expression was found to be inversely correlated with overall survival in patient datasets, suggesting a role in NB pathogenesis. Treatment with SB225002 significantly inhibited NB proliferation and colony formation while inducing apoptosis and cell cycle arrest in a dose-dependent manner. In 3D spheroid models, SB225002 significantly impaired spheroid formation and growth, confirming its potent anti-tumor efficacy. Mechanistically, CXCR2 blockade inhibited the expression of key pathway targets, including GLIPR1, BACH2, JUN, CHEK1, AKT1, and CXCR2 itself. Immunoblot analysis confirmed significant inhibition of CXCR2 and GLIPR1 protein levels in response to SB225002 treatment. Conclusions: Taken together, our findings demonstrate that pharmacological inhibition of CXCR2 using SB225002 effectively inhibits NB tumor cell growth and tumorigenicity by modulating oncogenic signaling networks. This study provides strong evidence for elucidating CXCR2-targeted therapies as an attractive treatment option for NB. These findings support the development of CXCR2-targeted therapies for high-risk NB. Full article

The tumor microenvironment (TME) is characterized by hypoxia; acidic pH; oxidative stress; and immune suppression; all of which severely impair the efficacy of conventional cancer therapies. Recent advances in inorganic nanotechnology have led to the development of smart nanomaterials capable of modulating these abnormal features; thereby reprogramming the TME toward a more therapy-responsive state. Inorganic nanomaterials such as manganese dioxide; iron oxide; and cerium oxide can selectively alleviate hypoxia; buffer acidity; regulate redox balance; and even stimulate anti-tumor immunity through catalytic or structural mechanisms. These materials can further serve as carriers for stimuli-responsive drug delivery; enabling synergistic therapies that include chemodynamic; photothermal; and immunomodulatory treatments. This review summarizes recent developments in smart inorganic nanomaterials for TME modulation; discusses design considerations including biosafety and biodegradability; and evaluates the current translational status and future directions. Such strategies represent a promising leap toward precise and personalized cancer nanomedicine Full article

Background/Objectives: Cancer is a worldwide health concern and is the second leading cause of death, responsible for nearly one in six deaths. Discovery of new anticancer agents is still a challenge for medicinal chemists and further research will improve patients’ chances of survival. Protein kinases are among the most popular and successful biological targets for developing anticancer drugs. In this context, protein kinases were selected as targets, and a series of isatin–quinazoline hybrids were synthesized. Methods: Their antiproliferative activity was evaluated against four cancer cell lines (HepG2, MCF-7, MDA-MB-231, and HeLa) and one normal fibroblast cell line (WI38) using MTT assays. Results: The tested compounds showed variable cytotoxic effects on the four cancer cell lines. Compound 6c exhibited the most potent anticancer activity against all cancer cells. In addition, this compound was tested for the effect on the expression of anti-apoptotic Bcl-2 protein and pro-apoptotic proteins Bax, caspase-3, and caspase-9, which revealed induction of apoptosis similar to staurosporine. Furthermore, an annexin V-FITC/PI dual staining assay confirmed that compound 6c induced cell death by apoptosis. Flow cytometric analysis revealed that compound 6c induced cell cycle arrest at the sub-G1 and S phases in the HepG2 cell line. Moreover, compound 6c was found to be a multi-kinase inhibitor with potent inhibitory activity on CDK2, EGFR, VEGFR-2, and HER2, with IC₅₀ values of 0.183 ± 0.01, 0.083 ± 0.005, 0.076 ± 0.004, and 0.138 ± 0.07 μM, respectively. Finally, a molecular docking simulation was conducted to predict possible binding interactions with the active site of CDK2. Conclusions: These findings suggest that compound 6c is a promising multi-kinase inhibitor with potent anticancer activity, warranting further investigation as a potential therapeutic agent. Full article

Epithelial–mesenchymal transition (EMT) and inflammasome signalling are intercon-nected processes which underpin tumour progression, metastasis, and therapeutic re-sistance. Inflammasomes such as NLRP3 encourage pro-inflammatory states (IL-1β, IL-18, NF-κB) and the activation of signalling pathways like TGF-β that promote mes-enchymal traits crucial for EMT. EMT transcriptional programmes can then in turn modulate the inflammasome via NF-κB/TGF-β signalling, creating self-perpetuating mechanisms of cellular plasticity and dysregulated therapeutic response. We have re-viewed the mechanistic evidence for EMT–inflammasome crosstalk in cancer and discussed the potential therapeutic implications. The function of the EMT-inflammasome axis is clearly context-dependent, with the cancer type, stage, and the complexity of the tumour microenvironment heavily contributing. The crosstalk between EMT and the inflammasome is an overlooked mechanism of tumour evolution, and targeting inflammasomes like NLRP3, or their downstream signalling pathways, offers a promising therapeutic avenue, with the objective of inhibiting metastasis and overcoming drug resistance. Full article

Polypharmacology in Amyotrophic lateral sclerosis (ALS) demands models that capture irreducible higher-order drug co-action. We introduce a categorical–topological pipeline that encodes regimens as truncated multicomplexes with a hypergraph–simplicial envelope; irreducible effects are identified by Möbius inversion, and CatMixNet predicts dose-response under monotone calibration while aligning multimodal omics via sheaf constraints. Under face-disjoint evaluation, omics fusion reduced RMSE from 0.164 to 0.149 (≈9%), increased PR-AUC from 0.38 to 0.44, and lowered calibration error to 2.6–3.1% with <10 dose-monotonicity violations per ${10}^3$ surfaces. Triad-irreducible signal strengthened (95th percentile ${\mathsf{\Delta }}^{★}=0.151$; antagonism retained at 24%). A risk-sensitive selector produced triads with toxicity headroom and projected ALSFRS-R slope gains of +0.04–0.05 points/month. Ablations confirmed the necessity of Möbius consistency, sheaf regularization, and monotone heads. Distilled monotone splines yielded compact titration charts with mean error 0.023. The framework supplies reproducible artifacts and actionable shortlists for iPSC and SOD1 validation. Full article

According to the World Drug Report, there are nearly 300 million drug users globally. Drug addiction is a chronic, relapsing brain disease that leads to medical, psychological, and social complications. This neuropsychiatric disorder is characterized by a compulsive drug-seeking behavior, continued use despite harmful consequence, and long-lasting changes in the brain. The reward system, which involves dopaminergic circuits, plays a key role in addiction. Dopamine levels have been described to fluctuate throughout the day, in a circadian fashion, and the effects of drugs have been shown to depend on the time when they are used. Hence, due to its important role in the control of circadian rhythms, the orexinergic system seems to have a role in the regulation of addiction. This system is composed by the orexin receptors 1 and 2 (OX₁R and OX₂R), the ligands orexin A (OXA) and orexin B (OXB) and their respective enzymes for degradation or synthesis. Here, we explore how orexin receptors and orexin peptides are involved in addiction. For instance, OX₁R has been shown to be strongly involved in specific behaviors such as drug-seeking for stimulants, alcohol and other addiction problems, whereas OX₂R appears to be linked with arousal and stress responses. We also investigate how the orexinergic system may regulate drug-seeking behavior by interaction with other brain systems such as the dopaminergic, cannabinoid or opioid systems. Finally, the potential of receptor complexes as new therapeutic targets to treat drug addiction is explored. Full article

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf receptor binding at the BBB and penetratin (Pen), a cell-penetrating peptide, to enhance neuronal uptake. Methods: This study evaluated the efficacy of Tf-Pen-liposomes in delivering angiotensin-converting enzyme 2 (ACE2) or EGFP (control) genes across the BBB in rats. In addition, the therapeutic effect of intravenous administration of Tf-Pen-Lip carrying plasmid DNA encoding ACE2 (Tf-Pen-Lip-pACE2) was tested in a neurogenic hypertension model induced by intracerebroventricular (ICV) infusion of angiotensin II (Ang II) via osmotic pump implantation and brain cannulation. Results: Conjugation with Tf and Pen significantly enhanced liposome-mediated gene transfection in cultured cells and increased transport across an in vitro BBB model. In vivo, intravenous administration of Tf-Pen-Lip-pACE2 or Tf-Pen-Lip-pGFP successfully elevated ACE2 or EGFP expression, respectively, in the hypothalamic paraventricular nucleus (PVN). Chronic ICV infusion of Ang II produced a sustained increase in blood pressure and heart rate, accompanied by sympathetic overactivation and elevated arginine vasopressin (AVP) secretion, hallmarks of neurogenic hypertension. Notably, intravenous Tf-Pen-Lip-pACE2 treatment dramatically attenuated Ang II–induced neurogenic hypertension, whereas Tf-Pen-Lip-pGFP had no effect on pressor responses, sympathetic activity, or AVP secretion. Conclusions: This dual-functionalized liposomal delivery system effectively transported the ACE2 gene across the BBB into the brain, increased ACE2 expression, and markedly attenuated neurogenic hypertension following systemic administration. Full article

Novel coronavirus (SARS-CoV-2) is highly infectious and pathogenic. Novel coronavirus infection can not only cause respiratory diseases but also lead to multiple organ damage through direct or indirect mechanisms, in which the liver is one of the most frequently affected organs. It has been reported that 15–65% of coronavirus disease 2019 (COVID-19) patients experience liver dysfunction, mainly manifested as mild to moderate elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Severe patients may progress to liver failure, develop hepatic encephalopathy, or have poor coagulation function. The mechanisms underlying this type of liver injury are complex. Pathways—including direct viral infection (via ACE2 receptors), immune-mediated responses (e.g., cytokine storm), ischemic/hypoxic liver damage, thrombosis, oxidative stress, neutrophil extracellular trap formation (NETosis), and the gut–liver axis—remain largely speculative and lack robust clinical causal evidence. In contrast, drug-induced liver injury (DILI) has been established as a well-defined causative factor using the Roussel Uclaf Causality Assessment Method (RUCAM). Treatment should simultaneously consider antiviral therapy and liver protection therapy. This article systematically reviewed the mechanism, clinical diagnosis, treatment, and management strategies of COVID-19-related liver injury and discussed the limitations of current research and the future directions, hoping to provide help for the diagnosis and treatment of such patients. Full article

The inherent complexity and heterogeneity of tumors pose substantial challenges for the development of effective oncology therapeutics. Organoids, three-dimensional (3D) in vitro models, have become essential tools for predicting therapeutic responses and advancing precision oncology, with established correlations to clinical outcomes in patient-derived models. These systems have transformed preclinical drug screening by bridging the gap between conventional two-dimensional (2D) cultures and in vivo models, preserving tumor histopathology, cellular heterogeneity, and patient-specific molecular profiles. Despite their potential, limitations in tumor organoid biology, including inter-batch variability and microenvironmental simplification, can undermine their reliability and scalability in large-scale drug screening. To overcome these challenges, the integration of advanced technologies such as artificial intelligence (AI), automated biomanufacturing, multi-omics analytics, and vascularization strategies has been explored. This review highlights the “Organoid plus and minus” framework, which combines technological augmentation with culture system refinement to improve screening accuracy, throughput, and physiological relevance. We are convinced that the future of drug development hinges on the convergence of these multidisciplinary technologies with standardized biobanking and co-clinical validation frameworks. This integration will position organoids as a cornerstone for personalized drug discovery and therapeutic optimization, ultimately advancing the development of efficacy in oncology. Full article

Acute lymphoblastic leukemia is the most common cause of cancer-related death in children and represents a poor prognosis for patients in high-risk groups. Current treatment protocols are based on intensive polychemotherapy, which is associated with a significant toxicity profile. Due to their higher specificity and lower toxicity, immunotherapies based on monoclonal antibodies, in particular antibody–drug conjugates (ADCs), are revolutionizing cancer therapy. However, reports on the potential efficacy of ADC-targeted therapy in ALL and its subgroups are limited. Gene expression data suggest that potentially new ADC antigens are highly abundant in ALL subgroups and represent promising targets for cancer therapy. In addition, the PI3K/AKT and RAS/MAPK signaling pathways are often persistently activated in ALL and recent data showed that active feedback loops following inhibition of these pathways can lead to redundancy of cell surface receptors that can potentially serve as antigens for ADC treatment. Therefore, we provide here an overview of the most interesting receptors of the various ALL subgroups and discuss the influence that feedback loops of the PI3K/AKT and RAS/MAPK signaling pathways may have on increasing protein expression of the aforementioned receptors, which could lead to targeted combination therapy approaches in the future. Full article

Cryptococcus neoformans (C. neoformans) has emerged as a global pathogen of concern. While much is known about its pathobiology, its management is complicated by strains displaying non-fluconazole susceptibility. This contribution assessed the repurposing of artemisinin (ART) as an anti-Cryptococcus antifungal. An in vitro susceptibility assay was performed to assess the drug response of cells. To establish the ART mode of action, assays examining mitochondrial health were set up. The phagocytosis efficiency of a murine macrophage cell line towards ART-treated and non-treated cells was determined. To complement this, the immunomodulatory effects of ART were further characterised in Galleria mellonella (G. mellonella) by assessing haemocytes’ phagocytosis and expression of immune genes, i.e., insect metalloproteinase inhibitor (IMPI) and hemolin, essential for the insect antimicrobial response. In the end, the survival rate of infected larvae was calculated. We established that ART was antifungal, with cell death triggered by the uncoupling of the cytochrome c (cyt c) from the mitochondria, leading to activation of caspase-3-dependent-like apoptosis. Moreover, treatment induced ultrastructural changes with treated cells appearing more deformed than non-treated cells (p < 0.05). Treatment also increased the susceptibility of cells towards both macrophage and haemocyte phagocytosis compared to non-treated cells (p < 0.05). Importantly, treatment seemed to weaken the cells, decreasing their virulence potential based on analysis of the expression of the immune gene markers, which translated into treatment rescuing 75% of the larvae infected with 0.1 ART-treated cells. These preliminary findings support the repurposing of ART as an anti-Cryptococcus antifungal. Full article

Background and Aim: Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis of unknown etiology that symmetrically involves the synovial joints and leads to erosive arthritis. However, when inflammation remains uncontrolled, it not only affects the joints but also increases the risk of various systemic complications, particularly cardiovascular diseases, osteoporosis, and malignancies such as lymphoma. Early initiation of disease-modifying antirheumatic drugs (DMARDs) has been shown to yield superior outcomes in terms of both clinical response and the prevention of joint damage. Nevertheless, the development of hepatotoxicity during treatment may necessitate dose adjustments or even modifications of the therapeutic protocol. Our aim in this study was to retrospectively evaluate the changes in liver enzyme levels in RA patients before and during treatment, especially in MTX and combination therapies using MTX, and to evaluate how these abnormalities affect treatment strategies. Materials and Methods/Results: Among the 33 patients included in this study, 15 exhibited elevated liver enzymes prior to treatment, whereas 18 developed hepatic enzyme abnormalities during therapy. Of the 12 patients receiving methotrexate (MTX) monotherapy and the 15 patients using MTX within a combination regimen, a total of 7 patients (21%) continued to present with elevated liver enzymes during follow-up. Among these, 5 patients (19%) were managed successfully by reducing the MTX dose, while MTX therapy had to be completely discontinued in 2 patients (7%). Notably, all 7 patients who required treatment modification due to persistent enzyme elevation belonged to the group with pre-existing liver enzyme abnormalities and were receiving MTX as part of a combination therapy regimen. Conclusions: These findings indicate that hepatotoxicity risk in RA patients can be effectively managed through close laboratory monitoring and timely dose reduction, with treatment discontinuation being required only in rare cases. Full article

Background/Objectives: The advent of biologics targeting key inflammatory pathways has significantly advanced psoriasis treatment. Among them, the Interleukin-23 inhibitors Guselkumab and Risankizumab have demonstrated high efficacy and rapid clinical response in both clinical trials and real-world studies. However, up to 30% of patients fail to respond. This study aimed to identify pharmacogenetic markers associated with treatment response using a genome-wide association study (GWAS) and protein network-based approach. Methods: Fifty-three patients of Greek origin with moderate-to-severe plaque psoriasis were treated with Guselkumab or Risankizumab. Based on Psoriasis Area and Severity Index (PASI) improvement at 3 and 6 months, patients were categorized as responders or non-responders. Approximately 730,000 single-nucleotide polymorphisms (SNPs) were genotyped. After filtering, a GWAS was performed to identify variants associated with treatment response. Additionally, protein–protein interaction (PPI) network analysis was applied to the two Interleukin-23 subunits and SNPs within or near genes encoding Interleukin-23-interacting proteins to test for their association. Results: The GWAS identified two novel variants, rs73641950 and rs6627462, significantly associated with treatment response, with both surpassing the genome-wide significance threshold after Bonferroni correction. The PPI-based approach revealed rs13086445, located downstream of the Interleukin-12 subunit alpha (IL12A) gene, as another associated variant. All three SNPs lie in genomic regions with potential regulatory roles. Conclusions: This study identifies three novel genetic variants associated with response to Interleukin-23 inhibitors in psoriasis. These findings provide promising pharmacogenetic markers which, upon validation in larger, independent cohorts, will enable the translation of a patient’s genotype into a response phenotype, thereby guiding clinical decisions and improving drug effectiveness. Full article

Background/Objectives: Psoriasis is currently treated with biologics targeting the IL-17A signaling, which plays a major role in immune response and keratinocyte hyperproliferation. These include inhibitors of IL-17A and/or its heterodimer with IL-17F (Secukinumab, Ixekinumab and Bimekizumab) and the receptor IL17-RA (Brodalumab). Although these drugs are safe and highly effective, there is significant variability in response among patients. This can be partly attributed to the patients’ genetic background, thus pointing to the need to identify pharmacogenetic markers for treatment response. Methods: The study involved 88 Greek patients who were treated with inhibitors of the IL-17A signaling for at least 6 months. Patients were classified as responders and non-responders according to the change in Psoriasis Area Severity Index. A total of 730,000 variants were genotyped and analyzed for association with the 3-month and 6-month responses to treatment. Results: The analysis identified 21 variants which were associated with the response, showing statistical significance after Bonferroni correction. These include variants located in protein coding genes (TP63, NRG1, SCN8A, TAF9, TMEM9, SMIM36, SYT14, BPIFC, SEZ6L2, PCARE), as well as intergenic and long non-coding RNA intronic variants. The functional significance of the variants was assessed using in silico analysis and for several variants, a link with immune processes was proposed. Notably, rs11649499 status, which was associated with complete clinical remission at 3 months, may influence key lipid mediators involved in psoriasis. Conclusions: This GWAS identified novel variants that could be utilized upon validation in larger populations as predictive markers regarding patient response to drugs targeting the IL-17A pathway. Full article

We present a hybrid partial differential equation-agent-based model (PDE-ABM). In our framework, tumor cells secrete tumor angiogenic factor (TAF), while endothelial cells chemotactically migrate and branch in response. Reaction–diffusion PDEs for TAF, oxygen, and cytotoxic drug are coupled to discrete stochastic dynamics of tumor cells and endothelial tip cells, ensuring multiscale integration. Motivated by observed perfusion heterogeneity in tumors and its pharmacokinetic consequences, we conduct a linear stability analysis for a reduced endothelial–TAF reaction–diffusion subsystem and derive an explicit finite-domain threshold for Turing instability. We demonstrate that bidirectional coupling, where endothelial cells both chemotactically migrate along TAF gradients and secrete TAF, is necessary and sufficient to generate spatially periodic vascular clusters and inter-cluster hypoxic regions. These emergent patterns produce heterogeneous drug penetration and resistant niches. Our results identify TAF clearance, chemotactic sensitivity, and endothelial motility as effective levers to homogenize perfusion. The model is two-dimensional and employs simplified kinetics, and we outline necessary extensions to three dimensions and saturable kinetics required for quantitative calibration. The study links reaction–diffusion mechanisms with clinical principles and suggests actionable strategies to mitigate resistance by targeting endothelial–TAF feedback. Full article