Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2 α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2 α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2 α , increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2 α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.
Purpose Aberrant activation of STAT3 signal pathway promotes tumor progression in many solid tumor types, including cervical cancer and endometrial cancer. BBI608, the STAT3 inhibitor had been reported in previous studies for restraining cancer stem cells. However, whether BBI608 is available for inhibiting the proliferation of cervical cancer or endometrial cancer remains poorly understood. This study investigated the anti-tumor effect and molecular mechanism of BBI608 on the patient-specific primary cells (PSPC) generated from cervical and endometrial cancer in vitro. Methods PSPCs were obtained from four patients via biopsy. The cell viability was analyzed by the CCK8 assay. The PSPCs were treated with various concentrations of BBI608 or/and paclitaxel; and then, western blot was applied to investigate the expression of phosphorylated STAT3 (pSTAT3). Results The PSPCs cell viability was reduced after treated with BBI608 at a lower concentration. Western blot results showed a reduction trend of pSTAT3 after PSPCs treated with BBI608. Our results demonstrated that BBI608 at the certain concentrations worked well in reducing the cell viability of PSPC from the patients who suffered from cervical cancer and endometrial cancer. Conclusions In this study, the patient-specific primary cell (PSPC) was used as the pre-clinical model for investigating the efficiency of BBI608 in reducing cancer cells viability. BBI608, at a clinical-relevant concentration, had valid efficiency in PSPCs from the patients. The dose of drugs treatment and the measured results were more valuable for further guiding clinical trials.
Cerebral ischemia-reperfusion (I/R) injury involves brain tissue damage caused by a temporary interruption of blood flow followed by reperfusion, leading to inflammation, oxidative stress, and neuronal death. Diosmetin, a flavonoid with known anti-inflammatory and antioxidant properties, has been shown to mitigate I/R injury, but its impact on systemic inflammation is not fully understood. In this study, we investigated its protective effects on I/R injury and the mechanisms mediated through the microbiota-gut-brain axis. Using MCAO-induced rats and OGD/R-induced PC12 cells, we employed multiomics sequencing and molecular biology techniques. The results showed that the IL-6/pJAK1/pSTAT3 signaling pathway was the key mechanism influenced by tryptophan metabolites. Diosmetin alleviated intestinal and systemic inflammation by modulating tryptophan metabolism and gut microbiota dysbiosis. Microbiota transplantation from diosmetin-treated rats produced similar protective effects. In conclusion, diosmetin mitigated I/R injury by influencing tryptophan metabolism through the microbiota-gut-brain axis, offering potential therapeutic strategies for I/R injury.
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