High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines.

OBJECTIVE: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. METHODS: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. RESULTS: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. CONCLUSIONS: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

Photoacoustic mediated multifunctional tumor antigen trapping nanoparticles inhibit the recurrence and metastasis of ovarian cancer by enhancing tumor immunogenicity.

The hypoimmunogenicity of tumors is one of the main bottlenecks of cancer immunotherapy. Enhancing tumor immunogenicity can improve the efficacy of tumor immunotherapy by increasing antigen exposure and presentation, and establishing an inflammatory microenvironment. Here, a multifunctional antigen trapping nanoparticle with indocyanine green (ICG), aluminum hydroxide (Al(OH)3) and oxaliplatin (OXA) (PPIAO) has been developed for tumor photoacoustic/ultrasound dual-modality imaging and therapy. The combination of photothermal/photodynamic therapy and chemotherapy induced tumor antigen exposure and release through immunogenic death of tumor cells. A timely capture and storage of antigens by aluminum hydroxide enabled dendritic cells to recognize and present those antigens spatiotemporally. In an ovarian tumor model, the photoacoustic-mediated PPIAO NPs combination therapy achieved a transition from "cold tumor" to "hot tumor" that promoted more CD8+ T lymphocytes activation in vivo and intratumoral infiltration, and successfully inhibited the growth of primary and metastatic tumors. An in situ tumor vaccine effect was produced from the treated tumor tissue, assisting mice against the recurrence of tumor cells. This study provided a simple and effective personalized tumor vaccine strategy for better treatment of metastatic and recurrent tumors. The developed multifunctional tumor antigen trapping nanoparticles may be a promising nanoplatform for integrating multimodal imaging monitoring, tumor treatment, and tumor vaccine immunotherapy.

Factors Underlying the Prevalence of Pythium Infection of Corn Seeds Following Seed Treatment Application of Tebuconazole.

Microbial communities are essential for soil health, but fungicide application may have significant effects on their structure. It is difficult to predict whether nontarget pathogens of applied fungicides in the soil will cause crop damage. Tebuconazole is a triazole fungicide that can be used as a seed treatment and, thereby, introduced to the soil. However, seed-applied tebuconazole has a potential risk of causing poor emergence of corn (Zea mays) seedlings. Using soil with a history of poor corn seedling emergence, we demonstrate through TA cloning and isolation that the poor emergence of corn seedlings from tebuconazole-coated corn seeds was primarily because of infection by surviving soil pathogens, specifically Pythium species that are not targeted by tebuconazole, rather than the phytotoxic effects of tebuconazole. Bioassay tests on tebuconazole-amended media showed that tebuconazole can suppress soil fungi while allowing Pythium to grow. Pythium species primarily contributing to the corn seed rot were more pathogenic at cooler temperatures. Furthermore, the nontarget biocontrol agent of Trichoderma spp. was strongly inhibited by tebuconazole. Taken together, the nontarget effects of tebuconazole are likely not significant under favorable plant growing conditions but are considerable because of low-temperature stress.

Folate-Targeted and Oxygen/Indocyanine Green-Loaded Lipid Nanoparticles for Dual-Mode Imaging and Photo-sonodynamic/Photothermal Therapy of Ovarian Cancer in Vitro and in Vivo.

We have successfully fabricated versatile folate-targeted and oxygen/indocyanine green-loaded lipid nanoparticles (FA-OINPs) for dual-mode imaging-guided therapy in ovarian cancer cells and subcutaneous xenograft models. FA-OINPs were demonstrated to have great potential as superb contrast agents to enhance ultrasound and photoacoustic (US/PA) imaging We have successfully fabricated versatile folate-targeted and oxygen/indocyanine green-loaded lipid nanoparticles (FA-OINPs) for dual-mode imaging-guided therapy in ovarian cancer cells and subcutaneous xenograft models. FA-OINPs were demonstrated to have great potential as superb contrast agents to enhance ultrasound and photoacoustic (US/PA) imaging in vitro and in vivo. Confocal laser scanning microscopy and flow cytometry analysis verified that FA-OINPs could specifically target SKOV3 ovarian cancer cells and be endocytosed with a remarkable efficiency. Compared with other therapeutic options, FA-OINPs exhibited an excellent therapeutic outcome after exposure to laser and ultrasound. The MTT assay and flow cytometry analysis confirmed that cytotoxicity effects and apoptosis/necrosis rates were significantly increased. The fluorescence microscopy and fluorescence microplate reader detection validated that the generation of intracellular reactive oxygen species (ROS) was dramatically improved. Immunohistochemical analyses of tumor tissues demonstrated the enhanced tumor apoptosis, the decreased vascular endothelial growth factor (VEGF) and microvascular density (MVD) expression, and the decreased expression of CD68 after treatment. The presented results suggest that photo-sonodynamic/photothermal mediated FA-OINPs could provide a promising strategy for synergistic therapy in ovarian cancer with the guidance of US/PA dual-mode imaging.

A multifunctional-targeted nanoagent for dual-mode image-guided therapeutic effects on ovarian cancer cells.

PURPOSE: Nanomedicine has emerged as a novel therapeutic modality for cancer treatment and diagnosis. Lipid-polymer hybrid nanoparticles (LPHNPs) are core-shell nanoparticle (NP) structures comprising polymer cores and lipid shells, which exhibit complementary characteristics of both polymeric NPs and liposomes. However, it is difficult to wrap perfluoropentane (PFP) into core-shell NPs in the existing preparation process, which limits its application in the integration of diagnosis and treatment. METHODS: The folate-targeted LPHNPs-loaded indocyanine green/PFP-carrying oxygen (TOI_HNPs) using a combination of two-step method and solution evaporation technique for the first time. The essential properties and dual-mode imaging characteristics of developed NPs were determined. The cellular uptake of TOI_HNPs was detected by confocal microscopy and flow cytometry. The SKOV3 cell viability and apoptosis rate were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry. The ROS was demonstrated by fluorescence microplate reader and the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and IL-6 was detected by Western blot. RESULTS: TOI_HNPs showed spherical morphology with particle size about (166.83±5.54) nm and zeta potential at -(30.57±1.36) mV. It exhibited better stability than lipid NPs and higher encapsulation efficiency as well as active targeting ability than poly (lactic-co-glycolic acid) (PLGA) NPs. In addition, the novel NPs could also act as the contrast agents for ultrasound and photoacoustic imaging, providing precision guidance and monitoring. Furthermore, TOI_HNPs-mediated photo-sonodynamic therapy (PSDT) caused more serious cell damage and more obvious cell apoptosis, compared with other groups. The PSDT mediated by TOI_HNPs induced generation of intracellular ROS and downregulated the expression of HIF-1α and IL-6 in SKOV3 cells. CONCLUSION: This kind of multifunctional-targeted nanoagent may provide an ideal strategy for combination of high therapeutic efficacy and dual-mode imaging guidance.

Fabrication of porous starch microspheres by electrostatic spray and supercritical CO2 and its hemostatic performance.

Effective control of bleeding is critical to saving lives whether on the battle field or in civilian life. Microporous starch (MS) is a promising hemostat for its extensive sources, huge surface area and good biocompatibility. However, the hemostatic performance of MS is limited because of its complex preparation process and lack of effective component to activate coagulation factors. Herein, porous starch microspheres modified by calcium (Ca-PSM) with dense shell and honeycomb micro-porous core were prepared by electrostatic spray and supercritical CO2 for the first time. The topological morphology of Ca-PSM changed with the increase of Tween-80 content within 0.5%. Ca-PSM possessed excellent water absorbability due to high specific surface area, and what's more, it showed good hemostatic performance because of the synergistic effects of physical adsorption and chemical activation mechanisms. The results of thrombelastograph (TEG) showed that the initial clotting time (R) and coagulation time (R + K) of Ca-PSM-1 were shortened by 47.1%, 53.3% than that of control group. The maximum blood clot strength (MA) of Ca-PSM-1 was also significantly raised. Furthermore, it was noteworthy that Ca-PSM could activate clotting cascade and induce erythrocyte adsorption. In summary, Ca-PSM as a hemostat will be a promising and alternative candidate for clinical application.