13-Oxyingenol-dodecanoate inhibits the growth of non-small cell lung cancer cells by targeting ULK1.

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.

Exploring the mechanism of daphne-type diterpenes against gastric cancer cells.

Gastric cancer is one of the common malignant tumors. It is reported that daphne-type diterpenes have inhibitory effects on gastric cancer cells, but the mechanism is still unknown. To explore the detailed mechanism of the anticancer effect of daphne-type diterpenes, we carried out an integrated network pharmacology prediction study and selected an effective component (yuanhuacine, YHC) for the following validation in silico and in vitro. The result showed that daphne-type diterpenes exerted an anti-tumor effect by targeting proto-oncogene tyrosine-protein kinase SRC as well as regulating the Ras/MAPK signaling pathway, which caused the apoptosis and mitochondrial damage in gastric cancer cells.

Central memory CD4+ T cells play a protective role against immune checkpoint inhibitor-associated myocarditis.

AIMS: The widespread use of immune checkpoint inhibitors (ICIs) has demonstrated significant survival benefits for cancer patients and also carry the risk of immune-related adverse events (irAEs). ICIs-associated myocarditis is a rare and serious adverse event with a high mortality rate. Here, we explored the mechanism underlying ICIs-associated myocarditis. METHODS AND RESULTS: Using the peripheral blood of patients with ICIs therapy and ICIs treated mice with transplanted tumors, we dissect the immune cell subsets and inflammatory factors associated with myocarditis. Compared to the control group, patients with myocarditis after ICIs therapy showed an increase in NK cells and myeloid cells in peripheral blood, while T cells significantly decreased. Among T cells, there was an imbalance of CD4/CD8 ratio in the peripheral blood of myocarditis patients, with a significant decrease in central memory CD4+ T (CD4+ TCM) cells. RNA-Seq revealed that CD4+ TCM cells in myocarditis patients were an immunosuppressive cell subset, which highly express the immunosuppressive factor IL4I1. To elucidate the potential mechanism of the decrease in CD4+ TCM cells, protein array was performed and revealed that several inflammatory factors gradually increased with the severity of myocarditis in the myocarditis group, such as IL-1B/CXCL13/CXCL9, while the myocardial protective factor IL-15 decreased. Correlation analysis indicated a positive correlation between IL-15 and CD4+ TCM cells, with high expression of IL-15 receptor IL15RA. Furthermore, in vivo studies using an anti-PDL1 antibody in a mouse tumor model indicated a reduction in CD4+ TCM cells and an increase in CD8+ TEMRA cells, alongside evidence of cardiac fibrosis. Conversely, combining anti-PDL1 antibody treatment with IL-15 led to a resurgence of CD4+ TCM cells, a reduction in CD8+ TEMRA cells, and a mitigated risk of cardiac fibrosis. CONCLUSIONS: Our data highlight CD4+ TCM cells as a crucial role in cardiac protection during ICIs therapy. IL-15, IL4I1 and CD4+ TCM cells can serve as therapeutic targets to reduce ICIs-associated myocarditis in cancer patients.

Impact of innovative immunization strategy on PCV13 vaccination coverage among children under 5 years in Weifang city, China: A retrospective study.

BACKGROUND: Pneumococcal Diseases (PDs) remains a serious public health problem around the world and in China. Pneumococcal vaccination is the most cost-effective measure to prevent PDs. In 2021, the government of Weifang City, Shandong Province, China introduced a free dose of domestic 13-valent Pneumococcal Conjugate Vaccine (PCV 13) to vaccinate registered children aged 6 months-2 years. This study aimed to evaluate the vaccination rate of PCV13 in children aged under 5 years before and after the vaccination program to provide evidences for further improving the prevention and control strategy for PDs. METHODS: We collected data from the children's vaccination information management system in Weifang City and analyzed the PCV13 vaccination coverage and characteristics in all vaccination clinics of Weifang City for children aged under 5 years. We compared the differences in vaccination rates by gender, birth year, manufacturer, and county before and after innovative immunization strategy. RESULTS: Among the included 593,784 children aged under 5 years, the PCV13 vaccination rate in Weifang was generally low before the innovative immunization strategy. Urban children had a higher PCV13 coverage than rural children (P < 0.001), and parents tended to vaccinate their children with imported PCV13.The full vaccination rate for domestic and imported PCV13 was 0.67 % and 1.70 %, respectively. After the vaccination program, the PCV13 coverage of children increased significantly in all counties within Weifang City (P < 0.001), especially for children above 12 months of age. Most parents preferred to vaccinate their children with domestic PCV13, and the full vaccination rate of domestic and imported PCV13 was 6.59 % and 0.16 %, respectively. CONCLUSIONS: The vaccination rate of PCV13 in children is still much lower than the global average, posting a severe health challenge that needs to be addressed thoroughly. To improve the prevention and control strategy for PDs, it is recommended to continue to explore other relevant incentives based on the innovative immunization strategy. Furthermore, it is also recommended that China should incorporate PCV13 into the National Immunization Programs (NIP) as soon as possible.

Fulminant type 1 diabetes mellitus in pregnancy

Fulminant type 1 diabetes mellitus (FT1DM) has received clinical attention for its low incidence and poor prognosis. Currently, few cases of FT1DM are associated with pregnancy in clinical practice, but it poses a great threat to the life of mothers and infants. Here, we present two cases of FT1DM in pregnancy. In Case 1, the patient was a 26-year-old woman who was admitted to the hospital with reduced fetal movement. She was diagnosed with FT1DM and delivered a dead female fetus. Lispro and lantus were administered to control blood glucose, and lipoic acid for antioxidant therapy. In Case 2, the patient was a 28-year-old woman who developed nausea, vomiting, diarrhea, and polydipsia, which later proved to be FT1DM. An abortion was induced and blood glucose levels were controlled using an insulin pump. All physicians should be aware of this disease in order to provide prompt diagnosis and emergency treatment, thus improving maternal prognosis. We suggest that plasma glucose/hemoglobin A1C ratio be adopted as a new clinical parameter in predicting FT1DM.