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Galaxamide improve cisplatin-induced uterine damage via attenuating inflammation and apoptosis in in mice

ABSTRACT: Objective: To evaluate the protective effects of marine cyclopeptide galaxamide against cisplatin-induced uterine toxicity in cervical cancer models, focusing on macrophage polarization and NF-κB signaling modulation Methods: In vivo tumor-bearing mouse models and in vitro cervical cancer cell lines were treated with cisplatin (CIS, 5 mg/kg) ± galaxamide (20 mg/kg). Uterine histopathology (hematoxylin-eosin staining), apoptosis (TUNEL assay), macrophage subsets (flow cytometry for M1/M2 markers), NF-κB activation (western blot for p65 phosphorylation), and serum cytokines (ELISA for TNF-α/IL-6) were analyzed. Embryo implantation rates were assessed to quantify endometrial receptivity Results: Cisplatin caused significant endometrial atrophy (↓45% thickness vs. control, P<0.01), NF-κB hyperactivation (2.8-fold p65 increase), and M1-macrophage dominance (M1/M2 ratio ↑40%). These changes correlated with elevated pro-inflammatory cytokines (TNF-α↑300%, IL-6↑180%) and reduced embryo implantation (↓67%, P<0.001). Galaxamide co-treatment: Suppressed NF-κB activation (p65↓65%, P<0.01) and apoptosis (TUNEL+ cells↓50%) Restored M2-macrophages (↑25%, P<0.05) and cytokine balance (TNF-α↓55%, IL-6↓48%) Preserved endometrial integrity and increased implantation rates (1.9-fold vs. CIS alone, P<0.01) Conclusion: Galaxamide mitigates cisplatin-induced uterine damage by reprogramming macrophages toward M2 phenotype and inhibiting NF-κB-mediated inflammation, offering a promising adjuvant strategy to preserve fertility in young cervical cancer patients Keywords: cisplatin toxicity, uterine protection, galaxamide, macrophage polarization, NF-κB pathway

ORGANISM(S): Mus musculus

PROVIDER: GSE302127 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAb) and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift towards an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T-cell proliferation and IFNγ secretion. Indeed, M1-like and M2-like macrophage differentiation involves complex signaling pathways leading to specific gene expression profiles. Typically, stimuli from the TME induce pathways including JAK/STATs, MAPK, PI3K/AKT, NOTCH and NF-κB influencing TAMs polarization. We investigated the signaling pathways activated in monocytes and M-CSF-induced M2-like macrophages upon BTN2A1 engagement using anti-BTN2A mAb5. After 30 min of treatment, we observed phosphorylation of MAPKs (i.e. ERK1/2, P38 and JNK) in CD14+ monocytes and in M2-like macrophages, unlike isotype control-treated cells. In contrast, the PI3K/AKT, JAK/STAT, and NF-kB pathways were not consistently activated after 30 min of anti-BTN2A mAb5 treatment. Since BTN2A1 lacks intrinsic kinase activity, we explored whether BTN2A1 could form complexes with molecular partners in M2-like macrophages that provide kinase activity. We prepared lysates from M2-like macrophages treated with mAb5 or with its isotype control for 30 min and performed immunoprecipitation (IP) using another anti-BTN2A mAb followed by western blotting with anti-phosphoTyrosine (pTyr). A 70 kDa was co-immunoprecipitated with BTN2A1 and revealed by the anti-pTyr in lysates from anti-BTN2A mAb5-treated M2-like macrophages. To identify which Tyrosine kinase is enriched in anti-BTN2A mAb5-treated M2-like macrophages, we performed LC-MS/MS on anti-pTyr immunoprecipitates from treated cells. Several tyrosine kinases, including P38α/δ and JNK, were enriched. Notably, SYK was also identified and matched the 72kDa molecular weight of the pTyr band co-immunoprecipitated with BTN2A1.

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Galaxamide improve cisplatin-induced uterine damage via attenuating inflammation and apoptosis in in mice

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