Aristolochic acid I aggravates oxidative stress-mediated apoptosis by inhibiting APE1/Nrf2/HO-1 signaling.

Nephrotoxicity induced by aristolochic acid I (AAI) is related to redox stress and apoptosis. Apurinic/apyrimidine endonuclease 1 (APE1) has antioxidant and anti-apoptotic effects. This study investigated the potential role of APE1 in AAI-induced nephrotoxicity. Renal injury was successfully induced in C57BL/6J mice by intraperitoneal injection of AAI every other day for 28 days. Expressions of APE1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) in renal tissues of the model mice was inhibited, accompanied by oxidative damage and apoptosis. Similar results were obtained in vitro in human proximal tubular (HK-2) cells damaged by AAI. In the presence of a low concentration of the APE1 inhibitor E3330, expression of Nrf2 and HO-1 proteins in HK-2 cells was decreased and AAI-induced apoptosis was aggravated. Overexpression of APE1 in HK-2 cells promoted the expression of Nrf2 and HO-1, and alleviated apoptosis and renal injury induced by AAI. The collective findings demonstrate that AAI can inhibit the induction of oxidative stress and apoptosis by the APE1/Nrf2/HO-1 axis, leading to AAI renal injury. Targeting APE1 may be an effective therapeutic strategy to treat AA nephrotoxicity.

Gender differential impact of bereavement on health outcomes: evidence from the China Health and Retirement Longitudinal Study, 2011-2015.

BACKGROUND: Bereavement is the experience of an individual following the death of a person of significance to the individual, most often referring to the spouse. Increased morbidity, health care utilization, and mortality are known to be associated with bereavement. Given China's growing population of older adults, there is a critical need to assess the health consequences of bereavement. METHOD: We use data from the China Health and Retirement Longitudinal Study to examine the impact of bereavement on mental health and quality of life among a sample of mid- and older-aged adults. We use propensity score matching to construct a matching sample and difference-in-differences method to estimate the impact of bereavement on mental health and self-assessed health. RESULTS: We find bereavement is associated with increased depression symptoms among women (1.542 point or 0.229 standard deviations of Center for Epidemiologic Studies Depression (CES-D) 10 score) but not consistently for men over time. No statistically significant effect of bereavement on self-assessed health is found. CONCLUSIONS: Our results show a harmful impact of bereavement on mental health among older women in China and point to the need for a comprehensive policy on survivor benefits in China, particularly for rural older women.

20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3.

Background: 20(S)-ginsenoside Rh2(GRh2), an effective natural histone deacetylase inhibitor, can inhibit acute myeloid leukemia (AML) cell proliferation. Lactate regulated histone lactylation, which has different temporal dynamics from acetylation. However, whether the high level of lactylation modification that we first detected in acute promyelocytic leukemia (APL) is associated with all-trans retinoic acid (ATRA) resistance has not been reported. Furthermore, Whether GRh2 can regulate lactylation modification in ATRA-resistant APL remains unknown. Methods: Lactylation and METTL3 expression levels in ATRA-sensitive and ATRA-resistant APL cells were detected by Western blot analysis, qRT-PCR and CO-IP. Flow cytometry (FCM) and APL xenograft mouse models were used to determine the effect of METTL3 and GRh2 on ATRA-resistance. Results: Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3. Conclusions: This study suggests that lactylation-modified METTL3 could provide a promising strategy for ameliorating ATRA-resistance in APL, and GRh2 could act as a potential lactylation-modified METTL3 inhibitor to ameliorate ATRA-resistance in APL.

miR-125b-5p-MAPK1-C/EBPα feedback loop regulates all-trans retinoic acid resistance in acute promyelocytic leukemia.

BACKGROUND: Various studies have highlighted the significance of miR-125b-5p in tumour chemotherapy resistance; However, whether miR-125b-5p is associated with all-trans retinoic acid (ATRA) resistance in acute promyelocytic leukemia (APL) has not been reported. METHODS: Drug-resistance-related factors in APL were predicted using the DRESIS database. The expression levels of miR-125b-5p in ATRA-sensitive and ATRA-resistant APL cells were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A nitrotetrazolium blue (NBT) reduction assay and flow cytometry (FCM) were used to detect the effect of miR-125b-5p on ATRA resistance in APL cells. An APL xenograft tumour mouse model was established to determine the effect of miR-125b-5p on ATRA resistance. A dual-luciferase gene reporter assay, qRT-PCR, and western blotting verified the regulation by miR-125b-5p of its target gene, MAPK1, and the MAPK1 downstream factor, C/EBPα. An NBT reduction assay and FCM were used to detect the effect of C/EBPα on ATRA resistance in APL cells. Western blotting and qRT-PCR were used to assess the regulation of miR-125b-5p and MAPK1 by C/EBPα. RESULTS: miR-125b-5p expression levels were dramatically increased in ATRA-resistant APL cells. Both in vitro and in vivo experiments revealed that miR-125b-5p overexpression enhanced ATRA resistance in APL. miR-125b-5p promoted ATRA resistance by sponging MAPK1. C/EBPα was negatively regulated by miR-125b-5p, which in addition, regulated ATRA resistance in APL cells. C/EBPα also regulated the miR-125b-5p-MAPK1 axis. CONCLUSION: The findings of this study indicate that the miR-125b-5p-MAPK1-C/EBPα feedback loop regulated ATRA resistance in APL. Thus, miR-125b-5p may be a promising target for treating ATRA resistance in APL.

Riemannian geometry-based transfer learning for reducing training time in c-VEP BCIs.

One of the main problems that a brain-computer interface (BCI) face is that a training stage is required for acquiring training data to calibrate its classification model just before every use. Transfer learning is a promising method for addressing the problem. In this paper, we propose a Riemannian geometry-based transfer learning algorithm for code modulated visual evoked potential (c-VEP)-based BCIs, which can effectively reduce the calibration time without sacrificing the classification accuracy. The algorithm includes the main procedures of log-Euclidean data alignment (LEDA), super-trial construction, covariance matrix estimation, training accuracy-based subject selection (TSS) and minimum distance to mean classification. Among them, the LEDA reduces the difference in data distribution between subjects, whereas the TSS promotes the similarity between a target subject and the source subjects. The resulting performance of transfer learning is improved significantly. Sixteen subjects participated in a c-VEP BCI experiment and the recorded data were used in offline analysis. Leave-one subject-out (LOSO) cross-validation was used to evaluate the proposed algorithm on the data set. The results showed that the algorithm achieved much higher classification accuracy than the subject-specific (baseline) algorithm with the same number of training trials. Equivalently, the algorithm reduces the training time of the BCI at the same performance level and thus facilitates its application in real world.