Fig 1: Imatinib (Ima) enhances the sensitivity of acquired pyrotinib-resistant HER2-positive GC to pyrotinib both in vitro and in vivo. a NCI-N87-AR cells were treated with varying concentrations of imatinib for 24 h, and proteins in the SCF/c-kit signaling pathway were assessed by western blot. b–d NCI-N87-AR cells were treated with 4 μM pyrotinib, 20 μM imatinib, or both for 72 h, followed by CCK-8 and colony formation assays and detection of cell apoptosis by flow cytometry. e Western blot performed to assess changes in protein levels associated with the SCF/c-kit signaling pathway in NCI-N87-AR cells treated with 4 μM pyrotinib, 20 μM imatinib, or both for 24 h. f Schematic procedure of the in vivo experiments. Mice were subcutaneously injected with NCI-N87-AR cells, and after 7–10 days orally administered 10 mg/kg pyrotinib, 100 mg/kg imatinib, or both daily for 21 days, with saline administered as a control. g Representative image of NCI-N87-AR xenografts harvested after 21 days of treatments (n = 6). h Changes in tumor volume in mice. Data represent the mean ± SD. i Tumor weight in each group on day 21. Data represent the mean ± SD. j Body weight gain/loss profiles of mice following treatment. Data represent the mean ± SD. k Representative images showing hematoxylin and eosin and IHC staining of xenograft tumor tissues. Scale bars, 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. N.S., not significant
Fig 2: A proposed schematic of the cytotoxic effect of marizomib on cervical cancer. The illustration depicts the proposed signaling events from proteasome inhibition, leading to the upregulation of Ang-1 expression and the downregulation of Flt-3L, SCF and Tie-2 expression in cervical cancer xenografts, promoting vascular normalization and ultimately cell death.
Fig 3: A schematic model depicting the mechanism of activation of ovarian primordial follicles induced by SD. SD leads to adrenal hyperactivity, resulting in the secretion of NE and E, which act on the ADRB2 of granulosa cells in primordial follicles of the ovary. This activation of ADRB2 triggers the cAMP/PKA and cAMP/mTOR signaling pathway in granulosa cells, leading to increased expression of KITL which initiating the activating of primordial follicles. Overactivation of primordial follicles accelerates the depletion of ovarian reserves and ultimately reduces the reproductive longevity. SD, sleep deprivation; NE, norepinephrine; E, epinephrine; ADRB2, β2‐adrenergic receptor.
Fig 4: Analysis of different SCF levels between NCI-N87 and NCI-N87-AR cells and their effects. a Comparison of NCI-N87 and NCI-N87-AR cell viability by CCK-8 assay following pyrotinib treatments. Data represent the mean ± SD of triplicate experiments. b Colony formation assay of NCI-N87 and NCI-N87-AR cells treated with 1 μM pyrotinib. Data represent the mean ± SD. c RNA sequencing performed in NCI-N87 and NCI-N87-AR cells. The heat map shows the representative differentially expressed genes. d, e The top 10 enriched pathways according to Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation classification. f qRT-PCR results for the indicated genes. Experiments were performed in triplicate. g Western blot analysis of proteins in the SCF/c-kit signaling pathway in NCI-N87 and NCI-N87-AR cells. h Western blot analysis of proteins in the SCF/c-kit signaling pathway in NCI-N87-AR cells treated with varying concentrations pyrotinib for 24 h. i NCI-N87 cells were treated with varying concentrations of SCF for 72 h, followed by determination of cell viability according to absorbance at 450 nm (OD450). j NCI-N87 cells were treated with 0.1 μΜ pyrotinib combined with varying concentrations of SCF for 72 h, followed by determination of cell viability according to OD450. k NCI-N87 and NCI-N87-AR cells were treated with 0.1 μM or 4 μM pyrotinib combined with or without 100 ng/mL SCF for 72 h, followed by determination of cell viability according to OD450. Data represent the mean ± SD of triplicate experiments. l, m Colony formation assay of NCI-N87 and NCI-N87-AR cells treated with pyrotinib (0.1 μΜ and 4 μΜ) combined with or without 100 ng/mL SCF. n Western blot analysis of proteins in the SCF/c-kit signaling pathway in NCI-N87 cells treated with varying concentrations of SCF for 72 h. o Western blot analysis of proteins in the SCF/c-kit signaling pathway in NCI-N87 cells treated with 0.1 μΜ pyrotinib combined with varying concentrations of SCF for 24 h. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001
Fig 5: The immunoreactive cells (black arrow) of GDF-9 (A,B,C) and KitL (D,E,F) on immunohistochemical staining of bovine COC in the following medium: 1. control, 2. endometriosis, and 3. endometriosis + curcumin (p < 0.05). GDF9 = Growth Differentiation Factor-9; KitL = Kit Ligand; COC = cumulus oocyte complex. Magnification 400x; Olympus BX-50. Pentax optio 230 Digital Camera 2.0 megapixel.
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