RESUMEN
BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.
Asunto(s)
Ferroptosis , Necroptosis , Humanos , Acrilamidas , Apoptosis , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Proteínas de Complejo Poro Nuclear , Piperazinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Unión al ARN , Sulfonamidas , Células THP-1RESUMEN
BACKGROUND: Personalized risk assessments can help medical providers determine targeted populations for counseling and risk reduction interventions. OBJECTIVE: The objective of this study was to develop a social media platform-based HIV risk prediction tool for men who have sex with men (MSM) in China based on an independent MSM cohort to help medical providers determine target populations for counseling and risk reduction treatments. METHODS: A prospective cohort of MSM from Shenyang, China, followed from 2009 to 2016, was used to develop and validate the prediction model. The eligible MSM were randomly assigned to the training and validation dataset, and Cox proportional hazards regression modeling was conducted using predictors for HIV seroconversion selected by the training dataset. Discrimination and calibration were performed, and the related nomogram and social media platform-based HIV risk assessment tool were constructed. RESULTS: The characteristics of the sample between the training dataset and the validation dataset were similar. The risk prediction model identified the following predictors for HIV seroconversion: the main venue used to find male sexual partners, had condomless receptive or insertive anal intercourse, and used rush poppers. The model was well calibrated. The bootstrap C-index was 0.75 (95% CI 0.65-0.85) in the training dataset, and 0.60 (95% CI 0.45-0.74) in the validation dataset. The calibration plots showed good agreement between predicted risk and the actual proportion of no HIV infection in both the training and validation datasets. Nomogram and WeChat-based HIV incidence risk assessment tools for MSM were developed. CONCLUSIONS: This social media platform-based HIV infection risk prediction tool can be distributed easily, improve awareness of personal HIV infection risk, and stratify the MSM population based on HIV risk, thus informing targeted interventions for MSM at greatest risk for HIV infection.