miR-29b-triggered epigenetic regulation of cardiotoxicity following exposure to deltamethrin in zebrafish.

Deltamethrin is a classical pyrethroid insecticide that is frequently detected in aquatic environments and organisms. Furthermore, deltamethrin has been detected in samples related to human health and is a potential risk to public health. This study aimed to investigate the mechanism of cardiotoxicity induced by deltamethrin. Zebrafish were exposed to 0.005, 0.05, or 0.5 µg/L deltamethrin for 28 days. The results showed a significant reduction in male reproduction compared to female reproduction. Additionally, the heart rate decreased by 15.75 % in F1 after parental exposure to 0.5 µg/L deltamethrin. To evaluate cardiotoxicity, deltamethrin was administered to the zebrafish embryos. By using miRNA-Seq and bioinformatics analysis, it was discovered that miR-29b functions as a toxic regulator by targeting dnmts. The overexpression of miR-29b and inhibition of dnmts resulted in cardiac abnormalities, such as pericardial edema, bradycardia, and abnormal expression of genes related to the heart. Similar changes in the levels of miR-29b and dnmts were also detected in the gonads of F0 males and F1 embryos, confirming their effects. Overall, the results suggest that deltamethrin may have adverse effects on heart development in early-stage zebrafish and on reproduction in adult zebrafish. Furthermore, epigenetic modifications may threaten the cardiac function of offspring.

Site 1 protease aggravates acute kidney injury by promoting tubular epithelial cell ferroptosis through SIRT3-SOD2-mtROS signaling.

Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) is a common clinical syndrome with high morbidity and mortality. Ferroptosis, a newly discovered form of oxidative cell death, is involved in the pathogenesis of renal I/R injury; however, the underlying mechanism remains to be explored. Here, we reported that site 1 protease (S1P) promotes ischemic kidney injury by regulating ferroptotic cell death of tubular epithelial cells. S1P abundance was measured in hypoxia/reoxygenation (H/R)-treated Boston University mouse proximal tubular (BUMPT) cells and I/R-induced murine kidney tissue. S1P expression in BUMPT cells and kidneys was initially activated by hypoxic stimulation, accompanied by the ferroptotic response. Blocking S1P blunted H/R-induced ferroptotic cell death, which also restored sirtuin 3 (SIRT3) expression and superoxide dismutase 2 (SOD2) activity in BUMPT cells. Next, inhibition of S1P expression restored I/R-suppressed SIRT3 abundance, SOD2 activity and reduced the elevated level of mitochondria reactive oxygen species (mtROS), which attenuated tubular cell ferroptosis and renal I/R injury. In conclusion, S1P promoted renal tubular epithelial cell ferroptosis under I/R status by activating SIRT3-SOD2-mtROS signaling, thereby accelerating kidney injury. Thus, targeting S1P signaling may serve as a promising strategy for I/R kidney injury.

Overview of tumor immunotherapy based on approved drugs.

Tumor immunotherapy has become a new hotspot for cancer treatment. Various immunotherapies, such as immune checkpoint inhibitors, oncolytic viruses (OVs), cytokines, and cancer vaccines, have been used to treat tumors. They operate through different mechanisms, along with certain toxicities and side effects. Understanding the mechanisms by which immunotherapy modulates the immune system is essential for improving the efficacy and managing these adverse effects. This article discusses various currently approved cancer immunotherapy mechanisms and related agents approved by the Food and Drug Administration, the European Medicines Agency, and the Medicines and Medical Devices Agency. We also review the latest progress in immune drugs approved by the National Medical Products Administration, including monoclonal antibodies, cytokines, OVs, and chimeric antigen receptor-T cell therapy, to help understand the clinical application of tumor immunotherapy.

ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy.

Diabetes nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, and podocyte injury is the central contributor to the progression of DN. Despite the emerging evidence that has established the importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of DN, abnormal protein O-GlcNAcylation is also augmented. Currently, the mechanism associating these two hyperglycemia-induced disorders remains poorly understood. This study intended to elucidate whether ER stress drives hyper-protein O-GlcNAcylation to cause podocyte injury in DN. We used both type 1 and type 2 DN models to confirm the occurrence of ER stress and excessive protein O-GlcNAcylation, and then podocyte purification was also conducted for further investigation. Nephroseq V5 data were mined and in vitro studies were applied to reveal the involvement of ER stress and hyper-O-GlcNAcylation in podocyte injury. Our results indicated that ER stress was induced in both type 1 and type 2 DN, and the human RNA-seq data from Nephroseq V5 showed that O-GlcNAcylation-related genes were significantly upregulated in the DN patients. We further demonstrated that ER stress occurred prior to hyper-O-GlcNAc modification and that pharmacologically inhibited protein O-GlcNAcylation can help decrease the podocyte apoptosis induced by hyperglycemia. Together, these discoveries will aid in uncovering the activation of the ER stress-O-GlcNAcylation axis in podocyte injury under DN, which will help open up new therapeutic approaches for preventing DN progression.

The effect of city size on the disability rate of the older adults: empirical evidence from CHARLS data.

Background: Exploring the value orientation of city development from the perspective of people's well-being is key to clarifying the current debate on city size strategies. Methods: Based on the survey data of the China Health and Retirement Longitudinal Study in two phases, and by using the unbalanced panel-ordered logit model, stepwise analysis method, and KHB method, among others, we discuss the impact of city size on the disability rate of older adults. Results: The study finds that city size significantly and positively affects the activities of daily living (ADL) of older adults, with odd ratios of 1.3286 (95% CI = [1.082243, 1.631089]), and exhibits significant group heterogeneity in terms of age, registered residence, income, and education level. City size has indeed played an mediation role through the health improvement effect, disease mitigation effect, emotional effect, and employment structure optimization effect, with a cumulative contribution rate of the mediation effect of 35.17%. In addition, the urban sprawl index has a significant moderation role. Discussion: Robust urban sprawl is conducive to promoting the improvement of the regional health environment, the improvement of the medical security policy, the optimization of the family support policy, and the employment structure, thus helping to reduce the disability rate of older adults.

Tetramethylpyrazine potentiates arsenic trioxide activity against HL-60 cell lines

The objective of this study was to evaluate the effects of tetramethylpyrazine (TMP) in combination with arsenic trioxide (As2O3) on the proliferation and differentiation of HL-60 cells. The HL-60 cells were treated with 300 µg/mL TMP, 0.5 µM As2O3, and 300 µg/mL TMP combined with 0.5 µM As2O3, respectively. The proliferative inhibition rates were determined with MTT. Differentiation was detected by the nitroblue tetrazolium (NBT) reduction test, Wright’s staining and the distribution of CD11b and CD14. Flow cytometry was used to analyze cell cycle distribution. RT-PCR and Western blot assays were employed to detect the expressions of c-myc, p27, CDK2, and cyclin E1. Combination treatment had synergistic effects on the proliferative inhibition rates. The rates were increased gradually after the combination treatment, much higher than those treated with the corresponding concentration of As2O3 alone. The cells exhibited characteristics of mature granulocytes and a higher NBT-reducing ability, being a 2.6-fold increase in the rate of NBT-positive ratio of HL-60 cells within the As2O3 treatment versus almost a 13-fold increase in the TMP + As2O3 group. Cells treated with both TMP and As2O3 expressed far more CD11b antigens, almost 2-fold compared with the control group. Small doses of TMP potentiate As2O3-induced differentiation of HL-60 cells, possibly by regulating the expression and activity of G0/G1 phase-arresting molecules. Combination treatment of TMP with As2O3 has significant synergistic effects on the proliferative inhibition of HL-60 cells.