Search Results (890)

With global cancer cases projected to reach 35 million by 2050 and drug resistance to existing chemotherapeutic drugs remaining a significant threat in cancer therapy, accounting for up to 90% of chemotherapy failures, the search for novel anticancer compounds continues to be increasingly important. This systematic review (2021–2025) examined the role of thiazoles and 4-thiazolidinones/thiazolidinediones as popular scaffolds in existing anticancer drug design. While researchers continue to focus on well-established molecular targets, such as EGFR, VEGFR-2, and tubulin, there is a notable difference regarding other preferred choices for thiazoles and 4-thiazolidinones/thiazolidinediones. Among analyzed mechanisms of anticancer activity notably favored for thiazoles was the inhibition of serine/threonine protein kinases (CDK-2, BRAF^V600E), while for 4-thiazolidinones/thiazolidinediones more studied were ROS generation and PPARγ activation. Furthermore, less-researched mechanisms of anticancer activity with no FDA-approved drugs such as PTP1B, SIRT2, PKM2, eIF4E, CA XI and XII inhibition for thiazole derivatives and pan-PIM kinase and BAG3 protein inhibition for 4-thiazolidinones/thiazolidinediones were evaluated as well. Notable was the popularity of the multi-targeting approach for modern drug design, with ~30% reporting two or more targets for their compounds. Despite these advancements, the review identified critical gaps in ADMET evaluations, safety analyzing against normal human cells and the lack of mechanistic studies connecting the targeted protein and the compounds anticancer effects. Full article

Objective: This study aims to analyze the dynamic changes in lymphatic endothelial cell (LEC) markers during the progression of intervertebral disk degeneration (IDD) and to investigate their association with the progression of IDD. Method: In this study, intervertebral disk (IVD) specimens were first collected from patients who underwent open lumbar fusion surgery for spinal fractures (control group, n = 10) and lumbar disk herniation (IDD group, n = 10). Concurrently, a mouse IDD model was established, and IVD specimens were collected from mouse in the Sham group and the IDD group 1, 3, and 6 weeks after modeling (n = 5 per group at each time point). Pathological morphological changes in human and mouse IVD specimens were observed using Hematoxylin and Eosin (H&E) and Masson’s Trichrome staining. The degree of degeneration in the mouse IVD specimens was quantified using a histopathological scoring system. Subsequently, real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry (IHC), and immunofluorescence (IF) staining were employed to examine LEC markers in IVD tissue, including lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), podoplanin (PDPN), prospero homeobox protein 1 (PROX-1), and vascular endothelial growth factor receptor 3 (VEGFR-3), as well as matrix metabolism-related markers such as matrix metalloproteinase 13 (MMP-13) and collagen II (Col II). Finally, we performed Spearman’s rank correlation analysis between the histopathological scores of all mouse IVD specimens and the corresponding expression levels of LEC markers. Results: In human IVD tissue, expression levels of LYVE-1, PDPN, PROX-1, and VEGFR-3 were extremely low in the normal group. In contrast, expression of these markers was significantly upregulated in the IDD group. In the mouse IDD model, compared with the Sham group at the same time point, the IDD group exhibited higher histopathological scores in IVD tissue, accompanied by upregulation of LYVE-1, PDPN, PROX-1, and MMP-13, as well as downregulation of Col II. In-depth analysis revealed that these differences between the Sham and IDD groups were not static but exhibited a dynamic pattern of increasing magnitude over time. Concurrently, as the modeling period progressed, the histopathological scores of mouse IVD in the IDD group, as well as the expression levels of LYVE-1, PDPN, PROX-1, and MMP-13, showed a progressive upward trend, while Col II expression progressively decreased. In addition, Spearman’s rank correlation analysis revealed that the expression levels of LYVE-1, PDPN, and PROX-1 in mouse IVD tissue were all significantly positively correlated with histopathological scores. Conclusions: In the process of IDD, the dynamic upregulation of LEC markers is highly consistent with its severity in the time dimension. At the same time, there was also a significant positive correlation between the expression level of LEC markers and the severity of IDD. Taken together, these findings suggest that the dynamic upregulation of LEC markers may be potentially associated with the pathological progression of IDD. Full article

The Hippo pathway effector Yes-associated protein (YAP), acting through TEA domain (TEAD) transcription factors, regulates transcriptional programs in ovarian tissues; however, its role in interferon tau (IFNT) signaling within bovine luteal cells has not been investigated. This study aimed to determine whether YAP-TEAD interaction is required for IFNT-induced interferon-stimulated gene (ISG) expression in primary bovine luteal cells and to perform an exploratory assessment of selected receptor genes (ITGB1, GRP78, VEGFR2). Primary luteal cells were treated with recombinant ovine IFNT (roIFNT; 1 ng/mL) in the presence or absence of verteporfin (VP; 0.1, 0.5, or 1.0 µM), a pharmacological YAP-TEAD inhibitor, and mRNA expression was quantified by RT-qPCR. VP dose-dependently suppressed YAP target genes (YAP1, CTGF, ANKRD1) and reduced roIFNT-induced expression of MX1, MX2, and OAS1, whereas ISG15 was unaffected. Steroidogenic gene expression (3β-HSD, P450scc, StAR) remained unchanged across treatments, indicating preserved cell viability. Among the exploratory receptor endpoints, VP decreased ITGB1 and increased GRP78 at the highest concentration, while VEGFR2 was unaffected. These findings indicate that YAP-TEAD activity contributes to IFNT-induced ISG responsiveness in bovine luteal cells, with preliminary evidence of effects on integrin-mediated signaling pathways. Full article

Ischemic stroke (IS) remains a major cause of global disability and mortality. While exogenous H₂S has demonstrated neuroprotective potential, the role of endogenous H₂S generated by cystathionine β-synthase (CBS) in cerebral ischemia–reperfusion injury (CIRI) remains incompletely elucidated. L-Cysteine (L-Cys), as a substrate for CBS, serves as a key precursor for endogenous H₂S. Using the established pre-clinical model of CIRI—middle cerebral artery occlusion/reperfusion (MCAO/R) in rats—we investigated the neuroprotective effects of brain-derived CBS-generated H₂S through neurological function scoring, 2,3,5-triphenylchlorotetrazole (TTC) staining, enzyme-linked immunosorbent assay (ELISA), and histopathological examination. Immunofluorescence, Western blot, and laser speckle contrast imaging were utilized to analyze the protein expression of ZO-1, claudin-5, CBS, vascular endothelial growth factor receptor-2 (VEGFR₂) and CD31, as well as cerebral blood flux changes. L-Cys treatment ameliorated neurological deficits, reduced cerebral infarct volume, decreased serum lactate dehydrogenase (LDH) and neuron-specific enolase (NSE) levels, attenuated histopathological damage, alleviated cerebral edema, and restored blood–brain barrier integrity via upregulation of tight junction proteins ZO-1 and claudin-5. Additionally, L-Cys improved MCAO/R-induced cognitive impairment and behavioral deficits. Furthermore, L-Cys upregulated CBS and VEGFR₂ expression, enhanced endogenous H₂S production, promoted post-ischemic cerebral angiogenesis, and improved cerebral blood flux recovery. CBS-derived H₂S promoted post-ischemic angiogenesis mediated by VEGFR₂, enhances cerebral reperfusion flux, and consequently ameliorated MCAO/R-induced CIRI in rats, providing experimental evidence for clinical translation. Full article

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and an established therapeutic target in diseases such as cancer and ocular disorders. However, long-term use of most current anti-VEGF agents is often limited by their associated side effects, including hypertension, bleeding, and gastrointestinal complications. These limitations have stimulated interest in naturally occurring VEGF inhibitors derived from dietary sources, which may offer safer alternatives due to their favorable safety profiles. In this study, we investigated shared structural features of potent VEGFR2 inhibitors, focusing on naturally derived polyphenols. Polyphenols representing multiple structural subclasses were evaluated for their ability to inhibit VEGFR2 kinase activity using an in vitro kinase assay, to suppress VEGF-induced phosphorylation of VEGFR2 and downstream MAPK signaling in endothelial cells by Western blot, and to reduce VEGF-stimulated endothelial cell proliferation. Across all assays, flavonoids with strong VEGFR2 inhibitory activity displayed consistent structural characteristics, including the number and specific positioning of hydroxyl groups on the A- and B-rings, as well as specific structural elements of the C-ring. Our findings provide a strong foundation for further structure–activity relationship (SAR) studies and facilitate identification of key molecular determinants required for VEGFR2 inhibition. Elucidation of these structural patterns may contribute to the development of more effective and safer angiogenesis inhibitors with reduced adverse effects. Full article

Background/Objectives: Biodegradable magnesium (Mg)-based biomaterials release Mg²⁺ ions during degradation and may promote vascular-related regeneration. However, their effects on lymphatic endothelial cells (LECs) and lymphangiogenesis remain unclear. This study investigated whether magnesium powder-derived ionic extracts could enhance lymphangiogenesis-related behaviors of LECs in vitro. Methods: Mg powder extracts were prepared and diluted for in vitro treatment. After viability screening, Mg (1:10), Mg (1:100), and Mg (1:1000) were selected for further analysis. LEC proliferation, migration, and tube formation were assessed, together with intracellular reactive oxygen species (ROS) levels and the expression of VEGFA, VEGFC, and VEGFR3. Results: Mg (1:10) and Mg (1:100) showed good cytocompatibility and significantly promoted LEC proliferation, migration, and tube formation compared with the control and Mg (1:1000) groups. These effects were accompanied by reduced intracellular ROS levels and increased expression of VEGFA, VEGFC, and VEGFR3. Conclusions: Magnesium powder-derived ionic extracts enhance lymphangiogenesis-related responses of LECs in vitro, particularly at the 1:10 and 1:100 dilutions. These findings support the potential of Mg-based biodegradable biomaterials for lymphatic tissue regeneration. Full article

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Advances in molecular characterization and tumor biology have driven the development of antibody-based therapies targeting immune checkpoints, angiogenesis, and oncogenic signaling pathways critical for tumor growth and progression. Among these agents, Ramucirumab, Atezolizumab, and Amivantamab have demonstrated significant clinical efficacy in selected NSCLC populations. This review summarizes the mechanisms of action, pivotal clinical trials, and current clinical evidence supporting the use of ramucirumab, atezolizumab, and amivantamab in the management of advanced NSCLC. Relevant literature was identified through searches of PubMed, clinical trial registries, and recent international conference proceedings, with an emphasis on therapeutic efficacy, safety profiles, and rational combination strategies. Ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2), has shown a survival benefit when combined with docetaxel in patients with previously treated advanced NSCLC. Atezolizumab, a programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI), has become a cornerstone of NSCLC treatment across multiple disease stages, both as monotherapy and in combination with chemotherapy. Amivantamab, a bispecific antibody targeting both epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET), has demonstrated robust and durable clinical activity in patients with EGFR exon 20 insertion–mutated NSCLC. Collectively, these agents highlight the expanding role of antibody-based therapies in NSCLC and underscore the importance of biomarker-driven patient selection and treatment personalization. Ongoing research into resistance mechanisms, predictive biomarkers, and combination approaches is expected to further refine the integration of antibody-based strategies in precision oncology for NSCLC. Full article

Clear-cell renal cell carcinoma (ccRCC) is characterised by constitutive activation of hypoxia-inducible factors (HIFs) following VHL loss, which contributes to tumour progression and therapeutic resistance. Given the limitations of VEGFR-targeted therapies, we investigated the biological and potential therapeutic relevance of the HIF axis in ccRCC. Nuclear and cytoplasmic HIF1A and EPAS1/HIF2A expression were assessed by immunohistochemistry in tumours from 40 patients and correlated with clinicopathological parameters and cancer-specific survival. The functional effects of HIF pathway inhibitors (GN44028, KC7F2, and FM19G11) and sunitinib were analysed in VHL-mutant 786-O and VHL-wild-type Caki-1 cell lines using SRB viability assay, cell cycle analysis, wound closure assay, and RT-qPCR of HIF-related genes, with comparison to non-malignant HK-2 cells. TCGA-ccRCC data from advanced-stage patients (III–IV, n = 185) were analysed as a complementary transcriptomic context. Nuclear, but not cytoplasmic, HIF1A and EPAS1/HIF2A expression was associated with advanced stage and shorter survival in univariable analyses. GN44028 showed the most pronounced antiproliferative effect under tested conditions and was associated with broad suppression of HIF-related transcription, whereas sunitinib was associated with increased expression of selected HIF-related genes. GN44028 did not demonstrate clear selectivity over non-malignant HK-2 cells. Overall, nuclear HIF activation is associated with aggressive ccRCC biology, and broader HIF pathway modulation warrants further experimental investigation; however, the clinical findings remain exploratory, and therapeutic selectivity and translational relevance are not yet established. Full article

Marine-derived natural products are increasingly recognized for their therapeutic potential in cancer and other chronic diseases. Despite significant advances, current cancer treatments remain challenged by toxicity, drug resistance, and limited survival benefits. Natural compounds offer promising alternatives due to their multi-target mechanisms and favorable safety profiles. Among them, Spirulina, a filamentous cyanobacterium, stands out for its rich composition and diverse biological activities. Its anticancer effects involve apoptosis induction via intrinsic and extrinsic pathways, cell cycle arrest at G1/S or G2/M phases, inhibition of angiogenesis through the VEGF/VEGFR2 axis, and suppression of epithelial–mesenchymal transition. These activities are mainly attributed to C-phycocyanin, allophycocyanin, phenolic compounds, and immunomodulatory polysaccharides. Spirulina also exhibits potent immunomodulatory effects by enhancing natural killer cell activity, promoting M1 macrophage polarization, and regulating Th1 and Th17 cytokine responses, highlighting its potential as both an immunotherapeutic and chemoprotective agent. Moreover, preclinical findings suggest it may reduce chemotherapy-associated side effects. However, translation into clinical therapy remains limited by low bioavailability, lack of standardized extracts, and scarce clinical evidence. This review summarizes current mechanistic and immunological insights and highlights the need for optimized formulations, defined dosing strategies, and well-designed clinical trials to validate Spirulina’s potential in cancer treatment. Full article

Background: The prevalence of severe aortic stenosis (AS) is increasing, in accordance with a longer life expectancy. Aortic valve calcification is a multifactorial pathological process involving a complex interplay between different types of regenerative cellular and genetic factors. Among these cells, endothelial progenitor cells (EPCs) and their osteoblastic phenotype subpopulation (EPC-OCNs) have been implicated in vascular remodeling and disease progression. Objectives: To assess longitudinal changes in EPC and EPC-OCN levels in patients with severe symptomatic AS undergoing transcatheter aortic valve implantation (TAVI). Methods: In this prospective observational study, 65 patients with severe AS undergoing TAVI were enrolled. Circulating EPC and EPC-OCN levels were quantified by flow cytometry before the procedure, at 4 ± 1 days, and at 90 ± 29 days after TAVI. EPCs were defined by expression of CD133, CD34, and VEGFR-2. Results: Circulating EPC levels remained unchanged throughout the follow-up. In contrast, circulating EPC-OCNs increased significantly over time. Specifically, CD133+/VEGFR-2+/OCN+ cells rose from 2.50% to 6.25%, CD34+/VEGFR-2+/OCN+ from 2.04% to 4.05%, and VEGFR-2+/OCN+ from 1.46% to 3.01% (all p < 0.01). This suggests an osteogenic response to TAVI, while classical endothelial repair mechanisms were not systemically activated. Conclusions: EPC-OCNs increased significantly following TAVI, possibly reflecting ongoing tissue remodeling or calcification processes. In contrast, the stability of classical EPCs levels suggests limited systemic endothelial regeneration. These observations underscore the potential role of EPC-OCNs as markers or modulators of pre- and post-TAVI vascular remodeling. Full article

Melanoma remains a highly aggressive malignancy, particularly in advanced metastatic stages where therapeutic options are limited. Natural compounds provide a structural basis for discovering novel anticancer agents. In this study, we employed an integrated in silico approach to evaluate the pharmacokinetic properties, toxicity profiles, and molecular targets of key alkaloids from Chelidonium majus, including berberine, sanguinarine, chelerythrine, chelidonine, protopine, umbelliferone and coptisine. ADME/T predictions (SwissADME and DeepPK) revealed favorable drug-likeness and oral bioavailability for most compounds, with berberine exhibiting the most balanced safety and absorption profile. All compounds demonstrated high intestinal absorption (>99%) and implicated key melanoma targets, including APE1/Ref-1, CXCR4, CCR2, TLR8, galectin-3, and VEGFR2. These molecules represent valuable templates for the development of melanoma therapies. Among the tested compounds, chelidonine emerged as a potential APE1 inhibitor, exhibiting the highest binding affinity and forming specific interactions within the enzyme’s catalytic site, suggesting its potential as a DNA repair-targeted agent in melanoma. These findings support the further exploration of natural alkaloids, including structural optimization or advanced formulation strategies, to enhance safety, bioavailability, and therapeutic efficacy in melanoma. Full article

In response to recent advances in computer-aided drug discovery (CADD) enabled by high-performance computing, computational approaches were employed to support and rationalize the investigation of a VEGFR-2-targeted anticancer candidate, combining molecular-level modeling with experimental validation. Initial in silico ADMET profiling and molecular docking were conducted to support the evaluation of drug-like properties and target engagement within a series of para-toluidine-based derivatives (1–14). The most biologically active compound was further evaluated through 100 ns molecular dynamics simulations and comprehensive DFT calculations to investigate binding stability and electronic characteristics. Based on a rational design strategy and supported by computational analyses, the compounds were synthesized and fully characterized using IR, MS, ¹H/¹³C NMR, and elemental analysis. Biological evaluation was performed against HepG-2, MCF-7, HCT-116, and normal WI-38 cells. Mechanistic studies included VEGFR-2 inhibition, wound-healing migration assays, cell-cycle distribution analysis, apoptosis assessment, and caspase-3 activation. Several derivatives exhibited micromolar cytotoxic activity, with compound 14 emerging as the most active against HepG-2 cells (IC₅₀ = 7.84 ± 0.5 µM), showing cytotoxic activity comparable to that of sorafenib (IC₅₀ = 9.18 ± 0.6 µM) and demonstrating favorable selectivity toward normal WI-38 cells (IC₅₀ = 67.75 ± 3.6 µM). Compound 14 showed moderate VEGFR-2 inhibitory activity (IC₅₀ = 0.55 µM), significant suppression of cell migration, pronounced G₀/G₁ cell-cycle arrest, and robust apoptosis induction supported by caspase-3 activation. Molecular docking and MD simulations supported a stable binding mode within the VEGFR-2 active site. This integrated framework highlights compound 14 as a selectively active VEGFR-2-oriented anticancer candidate scaffold with a favorable selectivity profile, supported by experimental and computational analyses, warranting further lead optimization. Full article

Mycobacterium tuberculosis (Mtb) remains a significant public health threat, responsible for 1.6 million deaths in 2021. The development of new treatments is particularly urgent for immunocompromised individuals, including those with Mtb/HIV coinfection, who experience severe disease outcomes. Previous studies demonstrated that blockade of VEGFR1, a receptor expressed on monocytes that mediates their recruitment to infection sites, limits Mtb-induced pathology in immunocompetent mice of both Mtb-resistant (C57BL/6J) and Mtb-susceptible (B6.C3H-sst1) strains. The present study extends these findings by evaluating the VEGFR1/2 blockade strategy in immunocompromised hosts. Treatment with the VEGFR1/2 blocker SU5416 (semaxanib) reduced monocyte infiltration into the lungs of Mtb-infected immunocompromised RAG1KO mice without affecting bacterial protection. Reduced monocyte recruitment improved lung pathology. VEGFR1/2 blockade also decreased the number of NK cells in the lungs of RAG1KO mice. Notably, an elevated ratio and increased absolute number of neutrophil granulocytes were observed in the Mtb-infected lungs of both immunocompetent and immunocompromised mice following SU5416 administration. However, this increase in neutrophils did not exacerbate lung pathology, as most recruited granulocytes remained within the lung vasculature. The beneficial effect of VEGFR1/2 blockade in RAG1KO animals suggests that further investigation of VEGFR blockers, such as SU5416, as adjunctive therapy to anti-tuberculosis drug regimens for immunocompromised populations with tuberculosis is warranted. Full article

Dysregulated angiogenesis is involved in cancer and numerous ischemic, autoimmune and inflammatory diseases, prompting extensive research that has yielded a growing array of angiogenesis-modulating molecules used in clinical practice. The dietary phytocomplex of Cruciferous vegetables exhibits multiple biological activities in both in vitro and in vivo models. However, the impact of a myrosinase-activated broccoli extract (MaBE) on angiogenesis, as well as on stromal–endothelial interactions governing endothelial cell behavior, has not yet been explored. We investigated the effects of MaBE on endothelial–stromal crosstalk using endothelial cells (HUVECs) and fibroblasts (HFF1) both individually and in a fibroblast-conditioned medium model. MaBE dose-dependently inhibited endothelial viability, migration and tube formation, key steps of angiogenesis, through interference with the VEGF–VEGFR2 axis. Notably, MaBE also markedly suppressed HFF1-driven HUVEC migration and capillary-like structure formation, likely through the inhibition of fibroblast motility and the downregulation of VEGF and angiogenin signaling in HFF1 cells. Overall, these findings provide new insight into MaBE regulation of pro-angiogenic behaviors in both endothelial cells and fibroblasts while disrupting their functional interplay. By targeting multiple cellular compartments and key mediators involved in angiogenesis, MaBE emerges as a promising bioactive extract with potential relevance for the management of pathological angiogenesis-related disorders. Full article

Ganglioside GM3, a fundamental glycosphingolipid on the mammalian cell surface, is a key regulator of transmembrane signaling and cellular recognition. In oncology, GM3 acts as a tumor suppressor by modulating the activity of various receptor tyrosine kinases (RTKs) and their downstream pathways. Recent studies highlight its function in the tumor microenvironment (TME), specifically its ability to impede pathological angiogenesis. This review summarizes the molecular mechanisms by which GM3 interferes with pro-angiogenic signaling, such as the VEGF/VEGFR axis, and discusses how this inhibition can be used for therapy. We explore the clinical potential of GM3-based strategies, including monoclonal antibodies and cancer vaccines, discussing the potential of targeting GM3 to reshape the TME and suppress tumor-associated vascularization. Full article