Cardioprotective potentials of myricetin on doxorubicin-induced cardiotoxicity based on biochemical and transcriptomic analysis.

Doxorubicin (DOX) is a commonly used anthracycline in cancer chemotherapy. The clinical application of DOX is constrained by its cardiotoxicity. Myricetin (MYR) is a natural flavonoid widely present in many plants with antioxidant and anti-inflammatory properties. However, MYR's beneficial effects and mechanisms in alleviating DOX-induced cardiotoxicity (DIC) remain unknown. C57BL/6 mice were injected with 15 mg/kg of DOX to establish the DIC, and MYR solutions were administrated by gavage to investigate its cardioprotective potentials. Histopathological analysis, physiological indicators assessment, transcriptomics analysis, and RT-qPCR were used to elucidate the potential mechanism of MYR in DIC treatment. MYR reduced cardiac injury produced by DOX, decreased levels of cTnI, AST, LDH, and BNP, and improved myocardial injury and fibrosis. MYR effectively prevented DOX-induced oxidative stress, such as lowered MDA levels and elevated SOD, CAT, and GSH activities. MYR effectively suppressed NLRP3 and ASC gene expression levels to inhibit pyroptosis while regulating Caspase1 and Bax levels to reduce cardiac cell apoptosis. According to the transcriptomic analysis, glucose and fatty acid metabolism were associated with differential gene expression. KEGG pathway analysis revealed differential gene enrichment in PPAR and AMPK pathways, among others. Following validation, MYR was found to alleviate DIC by regulating glycolipid metabolism and AMPK pathway-related genes. Our findings demonstrated that MYR could mitigate DIC by regulating the processes of oxidative stress, apoptosis, and pyroptosis. MYR is critical in improving DOX-induced myocardial energy metabolism abnormalities mediated by the AMPK signaling pathway. In conclusion, MYR holds promise as a therapeutic strategy for DIC.

Safety Study of Targeted and Localized Intra-Arterial Delivery of Gemcitabine in Patients with Locally Advanced Pancreatic Adenocarcinoma.

Purpose: This is a first-in-man safety study in locally advanced pancreatic cancer (LAPC) using a targeted intra-arterial delivery catheter (RenovoCath™). Methods: Twenty patients were enrolled in a four-stage dose escalation of intra-arterial, locally delivered gemcitabine, at doses up to 1000 mg/m2. Patients' symptoms and laboratory values were monitored for safety and tolerability. Secondary endpoints included the effect on tumor size, tumor markers, and survival. Results: One hundred one treatments were administered to 20 patients. Five patients dropped out early due to adverse events or withdrawing consent. Serious adverse events and complications were as follows: sepsis (n = 3), grade 3 neutropenia (n = 3), guide-mediated vascular dissection (n = 3), and pulmonary toxicity (n = 1). There were no cases of elevated liver or pancreatic enzymes. All sepsis cases occurred in patients with biliary stent/drains, prompting the addition of periprocedural treatment with antibiotics, which effectively prevented further sepsis in the study. Efficacy analysis was limited to 15 patients who received more than two treatments. Fifty-eight percent of these patients had a reduction in CA 19-9 tumor markers, 3 patients had tumor progression, 1 had partial response, and 11 showed disease stability. The survival rate at 12 months was 60%. Conclusions: The results demonstrate feasibility of localized and selective intra-arterial chemotherapy delivery to the pancreas utilizing the RenovoCath. With gemcitabine, this approach is safe, with the sole prerequisite of perioperative antibiotics for patients with prior biliary drainage/stent. Efficacy results suggest a survival benefit when compared to historical control, especially in patients with prior radiation therapy.

Generation of human interferon gamma and tumor Necrosis factor alpha chimeric TNT-3 fusion proteins.

Studies have shown that cytokines can effectively treat solid tumors by a direct cytotoxic effect as well as by immunomodulation. Both human interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) have been used to treat a variety of colon carcinoma cell lines and tumors in patients. These cytokines, however, are dose limited by their toxicity and fast clearance rates when given intravenously. To improve their therapeutic value, we now report on the generation of two new fusion proteins consisting of human IFNgamma and TNFalpha genetically linked to the C-terminal portion of chTNT-3, a monoclonal antibody (MAb), which targets human solid tumors by binding to intracellular antigens exposed in degenerating cells associated with tumor necrosis. In vitro characterization studies demonstrate that both the IFNgamma and TNFalpha fusion proteins are able to maintain their binding affinity to antigen as well as their direct cytotoxic effect and immunomodulatory functions. When both fusion proteins are combined at optimal doses, they demonstrate a 30% direct cellular cytotoxicity of human colon carcinoma cells of which approximately 14% can be attributed to apoptosis. In vivo, these agents were studied for their pharmakocinetic clearance rates and their ability to target human colon carcinomas heterotransplanted in nude mice. The results of these studies show that, compared with chTNT-3 parental antibody, both fusion proteins have a substantially shorter whole body half-life, yet are able to target tumor in a similar manner. As each of these fusion proteins are cleared from the circulation and normal tissues, tumor-to-normal-tissues ratios rise demonstrating the retention of these reagents in tumor. The generation of long-acting and targeted human IFNgamma and TNFalpha antibody fusion proteins will enable investigators to study the role of these potent immunostimulatory cytokines in the treatment of human solid tumors.