Colorectal cancer is a leading cause of cancer-related mortality, and chemotherapy resistance remains a major challenge. We investigated whether inhibiting glutathione could enhance the efficacy of 5-fluorouracil (5-FU) in colorectal cancer. Three small-molecule inhibitors targeting glutathione metabolism were tested in HCT-116 cells: CB-839 (glutaminase inhibitor), IKE (xCT transporter inhibitor), and Polydatin (glucose-6-phosphate dehydrogenase inhibitor). Their effects on glutathione levels, ROS accumulation, and cell viability were first evaluated. CB-839 decreased cell viability, Polydatin had no effect, and IKE reduced cystine uptake and increased ROS, although none of the inhibitors alone induced marked cell death. We next examined whether they could enhance 5-FU activity. Although CB-839 and Polydatin did not improve 5-FU efficacy, IKE increased ROS levels and reduced viability when combined with 5-FU. In an in ovo model, the combination of IKE and 5-FU reduced tumor growth, whereas each agent alone had a limited effect. These findings suggest that targeting xCT-mediated cystine uptake may enhance chemotherapy response and could be a promising approach for treating colorectal cancer.

Despite advances in cancer therapy, conventional treatment modalities often remain insufficient in achieving optimal outcomes. To address these limitations, growing attention has been directed toward combining chemotherapeutic agents with natural compounds. The present study investigates the effects of co-treatment with mangiferin and paclitaxel on key cancer-related biological processes, including proliferation, apoptosis, autophagy, and angiogenesis. The cytotoxicity was assessed using the ATP assay on Ehrlich ascites carcinoma (EAC) and HUVECs. Protein expression in EAC cells was analyzed by western blotting. In vivo, tumor growth, cell death, and autophagic activity were examined in EAC tumors. Angiogenic responses were examined using In vitro tube formation and an In vivo chorioallantoic membrane assay. The combined treatment resulted in a synergistic cytotoxic effects. Increased LC3B and decreased p62, along with the induction of FAS and cleaved PARP, suggest involvement of both apoptosis and autophagy. In vitro results were consistent with in vivo. Mangiferin (50mg/kg) combined with paclitaxel showed the greatest tumor reduction with concurrent induction of apoptosis and autophagy. Furthermore, the co-treatment exhibited stronger anti-angiogenic effect than either compound alone. In conclusion, mangiferin enhances the anticancer efficacy of paclitaxel by simultaneously targeting proliferation, programmed cell death, and angiogenesis. This supports the use of mangiferin as a promising natural agent for novel cancer treatment strategies.

BACKGROUND/OBJECTIVES:Melatonin has circadian, antioxidant, mitochondrial, and immunomodulatory functions, but human data linking relative melatonergic status to coordinated systemic biomarker burden remain limited. We examined this association and tested its internal robustness to alternative score construction, outlier handling, and missing-data assumptions. METHODS:We performed an adult-only cross-sectional secondary analysis of a deidentified biomarker dataset. Of 322 source records, six participants younger than 18 years and two records without age were excluded, yielding 314 adults. Plasma melatonin and 24 h urinary aMT6s were converted to within-cohort rank percentiles and averaged to form a relative melatonergic-axis score. Equal-weight z-score composites represented inflammation, oxidative damage, antioxidant deficit, and biological aging/biological injury; their mean was the integrated systemic biomarker-burden score. Analyses included Kruskal-Wallis tests; Spearman correlations with bootstrap confidence intervals; standardized regression adjusted for age, sex, and BMI; robust covariance estimates; principal component analysis (PCA), winsorization, leave-one-domain/marker-out analyses, and missing-BMI sensitivity models. RESULTS:The lower, intermediate, and higher relative melatonergic tertiles included 105, 104, and 105 adults, respectively. The melatonergic-axis score correlated inversely with integrated systemic burden (Spearman ρ = -0.944; 5000-resample bootstrap 95% CI, -0.953 to -0.931; p < 0.001). In age-, sex-, and BMI-adjusted complete-case models (N = 250), each 1 SD higher axis score was associated with a 0.95 SD lower integrated burden (β = -0.949; HC3 95% CI, -0.983 to -0.915; p < 0.001). Results were similar for separate plasma melatonin and aMT6s models, winsorized composites, a PCA-derived score (PC1 explained 75.5% of marker variance; ρ = -0.947), leave-one-domain/marker-out analyses, and missing-BMI sensitivity models. CONCLUSIONS:Lower relative melatonergic status was associated with a highly coordinated adverse systemic biomarker pattern. The exceptional magnitude of the association requires audit of primary assay provenance and independent external replication. Because cancer, microbiome, and liquid biopsy endpoints were not measured, oncology implications remain untested prospective hypotheses.

Diabetes mellitus (DM) is the most common metabolism-related health problem across the world and new therapeutics are still emerging into the market. One of the treatments is the inhibition of α-glucosidase, which is a validated therapeutic strategy for mitigating postprandial hyperglycemia in Type 2 DM. However, the clinical utility of current inhibitors, such as Acarbose, is often limited by gastrointestinal side effects and suboptimal pharmacokinetics linked to their surface-binding modes. In this study, we reported the design, synthesis, and biological evaluation of a novel series of 1H-Pyrrole-2,5-dione derivatives, targeting the deep catalytic cleft of human acid α-glucosidase (rhGAA). In vitro studies revealed that all the new compounds showed higher enzyme inhibitory activity than Acarbose (IC50 = 54.14 ± 6.43 mM) except 3e, 3f, and 5d. In in ovo model, compound 3d worked best to reduce blood glucose levels (around 48 mg/mL) and maintained this effect within 3 h. Molecular docking calculations covering the whole protein surface confirmed the catalytic pocket as the primary binding site, followed by focused docking, which identified 3g as the top in silico hit (-9.35 kcal/mol). In vitro kinetic experiments revealed that 5c possessed the highest inhibitory potential (IC50 = 0.21 mM) and performed significantly better than Acarbose, while structural dynamics analysis of 5c highlighted its conformational instability. Consequently, compound 3d (IC50 = 0.64 mM) was selected as the lead candidate to effectively inhibit rhGAA. Structural fingerprinting elucidated a unique "Anchor Mechanism" for 3d, characterized by a critical hydrogen bond with ARG281.

The development of innovative cancer therapies remains a critical priority, particularly those targeting angiogenesis-a key driver of tumor growth and metastasis. This study introduces bevacizumab-loaded nanoflowers (Beva-NF) as a novel strategy to enhance the anti-VEGF activity of bevacizumab through a targeted nanostructure-based delivery system. Beva-NFs were synthesized using a modified one-pot method and characterized via SEM, EDX, XRD, FTIR, and histogram analysis confirming their morphology, composition, and successful drug integration. To evaluate their anti-angiogenic potential, we employed the chorioallantoic membrane (CAM) assay, an alternative in vivo model. Beva-NF treatment significantly reduced neovascularization compared to free Beva. At 0.125 mg/mL, Beva-NF decreased total vessel length by 52%, vessel area by 48%, and branching points by 55% relative to control (p < 0.05), whereas free Beva at the same dose reduced these parameters by 28%, 25%, and 31%, respectively (p < 0.05). These results demonstrate that embedding bevacizumab into nanoflowers (NF) enhances its anti-angiogenic activity in the CAM model. While the findings suggest that nanostructure-based presentation may improve the local biological performance of bevacizumab, the chorioallantoic membrane (CAM) assay does not permit conclusions regarding clinical efficacy. Further in vivo studies are required to assess systemic safety, pharmacokinetics, and therapeutic relevance. Overall, this work highlights the preclinical potential of NF-mediated antibody delivery for future exploration in nanomedicine.

Hepatocellular carcinoma is one of the hardest-to-treat cancer types, although some recent developments have been made. Therefore, the discovery of new treatment options is still desperately desired. In this study, some novel sulfanyl-substituted hydrazone compounds 2a-2h were synthesized and characterized using spectroscopic techniques (1H NMR, 13C NMR, IR, and HRMS). Then, hydrazone compounds were tested on four different cancer types (lung, hepatocellular, breast, and colon carcinoma) and one nonmalignant cell line. Among these hydrazone compounds and tested cancer types, compound 2c resulted in a satisfactory antigrowth effect against hepatocellular carcinoma, the HepG2 cell line. Further, in ovo antitumor and antiangiogenic assays were also performed together with the in silico calculations employed by target predictions of compound 2c by a tool called Way2Drug and then followed by binding affinity calculations to those targets by AutoDock Vina. The range of binding scores of compound 2c was calculated between -4 and -8.6 kcal/mol for those targets that were suggested to be involved in a local protein-protein interaction clustering on base excision repair and DNA topological change. It has been found that compound 2c might deserve further attention (e.g., animal studies for proof-of-concept) as a novel anticancer compound for the treatment of liver cancer.

Cancer remains a complex and formidable disease that necessitates the development of diverse therapeutic strategies, including the investigation of natural products as complementary agents. Rosmarinic acid (RA), a phenolic compound, has demonstrated promising anticancer activity across various malignancies. Combining RA with conventional chemotherapeutic agents may represent a novel therapeutic approach. In the present study, the efficacy of these combinations was evaluated in vitro through the assessment of cell viability, apoptosis, autophagy, and proliferation, and in vivo by examining their effects on tumor growth in an Ehrlich Ascites Carcinoma (EAC) model. Among the tested combinations, RA and Paclitaxel (PTX) exhibited enhanced cytotoxicity and synergistic activity compared with individual treatments, whereas other combinations demonstrated limited efficacy. Morphological and moleculer analyses indicated induction of apoptosis, evidenced by increased expression of FAS, FADD, and cleaved caspases detected by Western blotting. Moreover, the RA+PTX (Rosmarinic acid + Paclitaxel) combination was associated with impaired autophagic flux, as reflected by elevated LC3 and p62 levels. Although the combined treatment reduced tumor volume in vivo, its antitumor efficacy was comparable to that of RA monotherapy. Collectively, these findings indicate that while the RA+PTX combination enhanced cytotoxicity activity against triple-negative breast cancer in vitro, its therapeutic advantage in vivo requires further investigation.

The aim of this study is to investigate the thyroid status of offspring exposed to prenatal 2.45 GHz radiofrequency radiation (RFR). In this study, which is the second phase of our previous study, the thyroids of rats exposed to prenatal 2.45 GHz RFR were examined one year after birth. The mothers of the offspring in the experimental group (n = 8) were exposed to 2.45 GHz RFR (whole-body specific absorption rate (SAR): 12 mW/kg; maximum point SAR: 25 mW/kg) 24 hours per day throughout pregnancy. The mothers in the sham group (n = 8) were kept under the same experimental conditions except for RFR exposure. The offspring in this study were not exposed to RFR after birth and continued their daily lives for one year. When the offspring reached one year of age, they were sacrificed and their thyroids were removed and evaluated. Mann-Whitney U and t tests were used for statistical analysis. Increases in fibrosis (p = 0.038), atypical thyrocytes (p = 0.002) and degenerated follicles (p = 0.007) and colloid reduction (p = 0.002) were found to be significant in the experimental group compared to the sham group. However, the increase in the percentage of apoptosis positive cells (p = 0.006) and H2A.X antibody levels (p = 0.007) showed a statistically significant difference in the experimental group compared to the sham group. This study provides evidence that prenatal exposure to 2.45 GHz RFR can induce persistent histological changes, increase apoptosis, and cause DNA double-strand breaks in thyroid tissue observed one year after birth. These results underscore the importance of further long-term studies to assess developmental risks associated with prenatal RFR exposure.

Glioblastoma multiforme (GBM) is the most aggressive and fatal primary brain tumor, characterized by rapid proliferation, resistance to therapy, and poor prognosis. Current treatment strategies, including surgery, radiotherapy, and chemotherapy, have limited efficacy and significant side effects. Phytotherapeutic agents such as thymoquinone (TQ), the major bioactive compound of Nigella sativa, have gained attention for their potential anticancer properties. TQ has been reported to exhibit pro-apoptotic, anti-inflammatory, and anti-proliferative effects in various cancer models. This study aimed to investigate the apoptotic effects of TQ on U87 human glioblastoma cells by evaluating its impact on cell viability, migration, colony formation, and the expression of key genes and proteins involved in apoptosis and inflammation. U87 glioblastoma cells were treated with increasing concentrations of TQ (10–100 µM) for 24, 48, and 72 h. Cell viability was assessed using the Sulforhodamine B (SRB) assay. A scratch assay was performed to evaluate cell migration, and a colony formation assay was used to assess clonogenic potential. Quantitative real-time PCR (qRT-PCR) and Western blotting were conducted to analyze the expression levels of genes and proteins associated with apoptosis, inflammation, and cell cycle regulation. TQ treatment significantly reduced U87 cell viability in a time- and dose-dependent manner, with IC50 values of 75 µM at 24 h, 45 µM at 48 h, and 36 µM at 72 h. The scratch assay demonstrated that TQ had no significant effect on U87 cell migration. Colony formation was inhibited at 10 µM after 24 h. qRT-PCR analysis revealed that at 50 µM TQ, caspase-3 and Bax mRNA levels were significantly upregulated. At 75 µM, caspase-9, caspase-3, Bax, and p21 mRNA levels increased, while caspase-8, Bcl-2, and Akt1 expression decreased. Western blot analysis showed increased expression of cleaved caspase-3, p21, and ATG5 proteins, along with decreased expression of caspase-8 and TNF-α at 24 h. TQ exhibits potent pro-apoptotic effects in U87 glioblastoma cells by modulating key apoptotic and inflammatory pathways, including the PI3K/AKT signaling axis. These findings suggest that TQ may serve as a promising adjuvant therapeutic agent for GBM. Further studies are required to elucidate its full molecular mechanisms and potential clinical applications.

BACKGROUND:Hepatocellular carcinoma (HCC) remains a major health concern, with angiogenesis playing a key role in its progression. Medicinal plants offer valuable anticancer potential. Eremurus spectabilis (ES), traditionally used in folk medicine, has not been fully explored for its anticancer properties. This study investigates its cytotoxicity on Hep3B cells and its anti-angiogenic activity. METHODS:E. spectabilis fractions (hexane, chloroform, ethyl acetate, and aqueous ethanol) were obtained from the ethanolic extract. The total phenolic content (TPC) was measured, and the active fractions were analyzed using gas chromatography-mass spectrometry (GC-MS). The xCELLigence Real-Time Cell Analyzer was used to evaluate cytotoxicity against Hep3B cells. Anti-angiogenic activity was assessed using the CAM assay, and docking studies were conducted to predict the mechanism of anti-angiogenesis. RESULTS:ESEA (154.80 ± 0.10 mg/g) had the highest phenolic content, followed by ESC (84.81 ± 6.81 mg/g). Palmitic acid (26%), khusimyl acid (15.9%), glycerol (12.1%), and D-(+)-talofuranose pentakis(trimethylsilyl) ether (9.7%) were the major compounds in ESC, while D-glucopyranose (19.4%), β-D-(+)-talopyranose (15.7%), and D-(-)-tagatofuranose pentakis(trimethylsilyl) ether (13.6%) were among the major compounds in ESEA. All fractions revealed significant cytotoxicity on Hep3B cells, with ESEA (24-h IC50: 6.53 μg/mL) and ESAE (24-h IC50: 7.89 μg/mL) being more effective. ESC also exhibited strong anti-angiogenic effects by reducing vessel area, length, and branching points. These findings were supported by molecular docking. The major phytochemicals significantly interact with VEGFR-2 and FGFR1. CONCLUSIONS:E. spectabilis shows a promising dual action for cancer therapy. However, further research is necessary to predict the exact mechanism of action.

Considering the significant biological potential and the privileged status of the 1,2,4-triazole-5-thione scaffold as one of the essential building blocks in medicinal chemistry, a novel series of 30 new hybrid compounds of 1,2,4triazole and 5-benzylidenethiazolidinone ring systems, named 5-benzilidene-thiazolo[3,2-b][1,2,4]triazole-6 (5H)-one, were designed and synthesized in an attempt to obtain antiproliferative agents and EGFR inhibitors. Synthesized thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones were investigated for their potential cytotoxic properties by cell viability, cell cycle, and cell death analyses. Compounds that exhibited more selective anti-growth activity in A549 cells were further scrutinized, revealing an accumulation in the G1 phase. Notably, compound 6e demonstrated outstanding results and was found to induce apoptosis. Molecular docking studies indicated that the designed compounds could act as EGFR inhibitors. Indeed, compounds 6i and 6j inhibited cell growth prevented EGFR-specific phosphorylation, and thus downregulated EGFR signaling, and inhibited EGFR enzyme activity with IC50 values of 2.46 mu M and 4.72 mu M, respectively. Additionally, druglikeness and some pharmaceutical properties of the synthesized compounds were predicted. This study underscores the promising therapeutic potential of the novel thiazolo[3,2-b]-1,2,4-triazole derivatives as EGFR inhibitors.

Cholangiocarcinoma (CCA), a devastating malignancy originating from the bile ducts, is of significant clinical importance due to its rising incidence and poor prognosis. Quinones as being naturally occurring compounds and their frequent utility in anticancer drug development studies seem to be potential sources for the discovery of new chemotherapeutics. In this study, a synthetic naphthoquinone derivative newly synthesized and previously published by our group, named as MK13, has been tested against intrahepatic-CCA (iCCA) cell lines (CCLP1 and HUCCT1). Cell viability was measured with the MTT assay at the doses of 1.56–50 µM for 48 h treatment. Cell death was showed both morphologically with fluorescent double staining and biochemically with flow cytometry analysis of phosphatidylserine translocation. Oxidative stress and DNA damage were also measured with flow cytometry and gene expressions were interpreted via qPCR analysis. MK13 resulted in a strong reduction (about 80

Objectives understanding drug resistance in cancer is of importance in treatment. Cancer stem cells are main factor for drug resistance. Therefore, the possible gene/gene interactions/proteins were explored in our study using a cancer stem cell-enriched population (H1299/S) derived from a parental non-small cell lung cancer cell line (H1299/P).Methods response to cisplatin, which is the main drug for the treatment of lung cancer, was evaluated with the Adenosine triphosphate (ATP) viability test. As a result of the gene expression analysis, while 14 genes were not evaluated, expression profiles were obtained for 37 genes out of 51 genes. By the drug-protein interaction analyses, Topoisomerase I (TOPI), Topoisomerase 2 alpha (TOP2A), Topoisomerase 2 beta (TOP2B), Cyclin-dependent kinases 4 (CDK4), Cyclin-dependent kinases 6 (CDK6), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 1 (ABCC1), ATP binding cassette subfamily C member 3 (ABCC3), B-cell leukemia/lymphoma 2 (BCL2), Poly (ADP-ribose) polymerase 1 (PARP1), Breast cancer gene 1 (BRCA1) and Cyclin dependent kinase inhibitor 1A (CDKN1A) genes and protein products were statistically significantly found to be in association with drug resistance.Results and discussion in bioinformatics analyses, it was observed that 13 pathways were affected due to expression changes and 12 genes related to these pathways were determined to activate multidrug resistance mechanisms.Conclusions platinum-based drugs, as well as a broad range of other agents including topoisomerase and PARP1 inhibitors, and anthracyclines, have been shown to potentially possess multiple drug resistance.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with an average survival time of only six months following diagnosis, even with currently available therapies. Thus, PDAC represents a significant therapeutic challenge, necessitating a deeper understanding of its biology and tumor microenvironment (TME) to develop more effective treatments and improve patient outcomes. Here, we report that the expression of Eukaryotic Elongation Factor-2 Kinase (eEF2K) is associated with shorter patient survival and demonstrate that eEF2K signaling is critical for the PDAC tumor growth and regulated by the TME. Furthermore, in vivo targeted genetic inhibition of eEF2K suppressed tumor growth in two different PDAC mouse models, reduced tumor-associated macrophages (TAMs), and induced marked apoptosis in tumor tissues without any signs of toxicity. Our data suggest that eEF2K knockdown diminishes the activity of the AXL receptor tyrosine kinase and reduces the expression of macrophage-derived factors, such as Monocyte Chemoattractant Protein-1 (MCP1), along with the Gas6/AXL signaling pathway in PDAC cells. Additionally, analysis of the NCI-TCGA PDAC patient database further showed that eEF2K expression, in the presence of TAM markers, correlates with even shorter patient survival. TAM-released factors, such as MCP1, Gas6, and exosomes, induce eEF2K expression in PDAC cells, as well as the activity of AXL, SRC, VEGF, Snail, and MMP2, contributing to epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and angiogenesis. In conclusion, our findings reveal for the first time that eEF2K is a critical oncogenic driver of PDAC tumor growth and thus targeting eEF2K represents a promising and novel therapeutic strategy for PDAC.