ABSTRACT Chemoresistance remains a major barrier to effective treatment of gastric cancer (GC), particularly in advanced disease, where cytotoxic chemotherapy often yields limited and transient responses. The present study provides integrated computational and experimental evidence that targeting TLR2 using repurposed small‐molecule inhibitors can overcome autophagy‐dependent chemoresistance in gastric adenocarcinoma cells. A library comprising 1555 FDA‐approved drugs was sourced from the DrugBank database, virtual screening was executed, and two compounds, Nilotinib (DB04868) and Lomitapide (DB08827), achieved affinities ≤ −10 kcal/mol. Chemoresistant GC cells were developed, and experimental assessment was performed using cell proliferation assay, apoptosis assay, real‐time PCR, and western blot analysis. Nilotinib and Lomitapide significantly reduced the proliferation but increased the apoptosis of chemoresistant GC cells. Additionally, Nilotinib and lomitapide reduced the mRNA and protein levels of autophagy‐related factors, LC3B , Beclin‐1 , and p62/SQSTM1 , and activated transcription factors in chemoresistant GC cells. In conclusion, our results suggest that combining TLR2‐targeted agents with standard chemotherapy could be a promising strategy to overcome refractory disease in GC.
ABSTRACT Psoriasis is a chronic immune‐mediated inflammatory skin disease driven by abnormal interactions among keratinocytes, immune cells and cytokine networks. Dysregulated inflammatory signalling has been shown to exacerbate psoriatic inflammation. Loganin (LOG), a natural iridoid glycoside, exhibits anti‐inflammatory effects in experimental models, yet its relevance to psoriasis remains poorly characterised. This study investigated the effects of LOG during the development of IMQ‐induced psoriasis‐like inflammation, evaluating its influence on inflammatory signalling and associated tissue responses using PASI scoring, histopathology and stereology. Molecular and cellular alterations were assessed using qPCR, immunohistochemistry, immunofluorescence, and ELISA to determine changes in pro‐inflammatory cytokine profiles, NOD‐like receptor protein 3 (NLRP3) inflammasome components, markers of epidermal proliferation and keratinocyte remodelling, and vascular responses. Topical IMQ induced characteristic psoriatic alterations, including epidermal hyperplasia, immune cell infiltration, microvascular activation, and elevated pro‐inflammatory cytokines. LOG significantly attenuated IMQ‐associated body weight loss, reduced psoriatic clinical severity scores and epidermal thickening, and decreased proliferating cell nuclear antigen (PCNA) and cytokeratin‐17 (CK‐17) immunoreactivity. Furthermore, LOG attenuated vascular endothelial growth factor receptor‐2 (VEGFR2) immunoreactivity and decreased interleukin‐17A (IL‐17A) and interleukin‐1β (IL‐1β) levels, suggesting modulation of inflammatory and vascular responses. LOG also downregulated the expression of NLRP3, apoptosis‐associated speck‐like protein (ASC), and caspase‐1. Collectively, these findings indicate that LOG attenuates IMQ‐induced inflammatory responses and is associated with reduced expression of NLRP3 inflammasome‐related components. These findings support the anti‐inflammatory effects of LOG in the IMQ‐induced psoriasis model while indicating that further functional studies are required to determine whether LOG directly affects NLRP3 inflammasome activation.
ABSTRACT Doxorubicin (DOX)–induced cardiotoxicity remains a major therapeutic limitation, emerging at the intersection of oxidative stress, mitochondrial impairment, and disruption of survival signaling pathways. The Wnt/β‑catenin–GSK‑3β pathway is an essential regulator of cardiomyocyte survival. To assess the cardioprotective potential of nanocurcumin (N‐Cur) in this condition, twenty‐four Wistar rats were divided into four groups (N‐Cur; 80 mg/kg, oral) was given for 2 weeks, while DOX was administered on day seven as a single dose. N‐Cur treatment significantly standardized DOX‑induced elevations in cTnI and CK‑MB, restored cardiac antioxidants (GSH, SOD), decreased MDA levels with p ≤ 0.01, significantly restored Nrf2, and reduced pro‑inflammatory mediators (TNF‑α, IL‑6, NF‑κB‑p65) ( p < 0.001), thereby augmenting its twin roles as a potent anti‐inflammatory and antioxidant agent. The histopathological changes and inflammatory infiltration caused by DOX were significantly diminished following N‐Cur treatment. Further, DOX inhibited Wnt/β‑catenin signaling and increased GSK‑3β expression, whereas N‐Cur reversed these changes in immunohistochemistry studies. Collectively, these findings indicate that N‐Cur provides significant cardiomyocyte protection and efficiently modifies the Wnt/β‑catenin–GSK‑3β axis.
ABSTRACT Lung cancer, the deadliest malignant tumor worldwide, consists predominantly of non‐small cell lung cancer (NSCLC) and accounts for most cancer‐related deaths; its aggressive metastatic nature severely compromises treatment outcomes and overall survival. Abelson tyrosine kinase (ABL), a key regulator of metastasis across multiple tumor types, has emerged as a promising therapeutic target. Gramicidin's effects on NSCLC cell proliferation, migration, and invasion were assessed using CCK‐8, colony formation, Transwell, and wound healing assays. ABL protein levels were analyzed using Western blot (WB). The effects of ABL expression on MMP9 levels and cellular migration and invasion were examined in ABL‐knockdown cells using gelatin zymography, WB, Transwell, and wound healing assays. ABL‐overexpressing cells were treated with gramicidin to examine gramicidin's suppression of the ABL‐MMP9 axis using WB, Transwell, and wound healing assays. In a BALB/c nude mouse model of lung metastasis established via tail vein injection of tumor cells, we evaluated the inhibitory effects of gramicidin on metastatic nodule formation in vivo and its influence on ABL and MMP9 expressions. Gramicidin significantly suppressed lung cancer cell proliferation, migration, and invasion. ABL was upregulated in human lung cancer cells and could be effectively suppressed by gramicidin treatment. Gramicidin downregulated MMP9 expression by suppressing ABL protein expression, thereby attenuating lung cancer metastasis. In vivo , gramicidin treatment reduced the number of lung metastatic nodules and simultaneously downregulated ABL and MMP9 proteins in lung tissue, effects that were partially reversed by ABL overexpression. This study revealed the molecular mechanism by which gramicidin inhibits lung cancer metastasis through suppression of the ABL‐MMP9 axis, providing a theoretical foundation for developing gramicidin‐based anti‐metastatic strategies.
ABSTRACT PEGylated chrysin, a natural flavonoid conjugated with methoxypolyethylene glycol, exhibits in vitro cytotoxic properties, likely through apoptosis induction. In this study, we investigated its biological effects on HepG2 hepatocellular carcinoma cells, comparing its activity with the chemotherapeutic agent paclitaxel. We evaluated reactive oxygen species (ROS) production, membrane integrity, DNA damage, and wound closure using the scratch assay. At equivalent concentrations, PEGylated chrysin induced higher cell membrane damage but generated lower ROS levels compared to paclitaxel. Both compounds exhibited similar efficacy to reduce wound closure under the evaluated experimental conditions. Additionally, PEGylated chrysin significantly increased the frequency of micronuclei in binucleated cells, indicating genotoxic potential. To assess cellular uptake, a novel fluorescein−tagged conjugate (fluorescein−PEG−chrysin) was synthesized which demonstrated that the PEGylated drug is accumulated in the cytoplasm of HepG2 cells. These results highlight PEGylated chrysin as a promising candidate with antiproliferative potential, capable of inducing diverse cellular damage pathways in liver cancer cells while showing a distinct cytotoxic profile compared with Paclitaxel.
