Scoparone attenuates PD-L1 expression in human breast cancer cells by MKP-3 upregulation.

Breast cancer is a frequently occurring malignant tumor that is one of the leading causes of cancer-related deaths in women worldwide. Monoclonal antibodies that block programed cell death 1 (PD-1)/programed cell death ligand 1 (PD-L1) - a typical immune checkpoint - are currently the recommended standard therapies for many advanced and metastatic tumors such as triple-negative breast cancer. However, some patients develop drug resistance, leading to unfavorable treatment outcomes. Therefore, other approaches are required for anticancer treatments, such as downregulation of PD-L1 expression and promotion of degradation of PD-L1. Scoparone (SCO) is a bioactive compound isolated from Artemisia capillaris that exhibits antitumor activity. However, the effect of SCO on PD-L1 expression in cancer has not been confirmed yet. This study aimed to evaluate the role of SCO in PD-L1 expression in breast cancer cells in vitro. Our results show that SCO downregulated PD-L1 expression in a dose-dependent manner, via AKT inhibition. Interestingly, SCO treatment did not alter PTEN expression, but increased the expression of mitogen-activated protein kinase phosphatase-3 (MKP-3). In addition, the SCO-induced decrease in PD-L1 expression was reversed by siRNA-mediated MKP-3 knockdown. Collectively, these findings suggest that SCO inhibited the expression of PD-L1 in breast cancer cells by upregulating MKP-3 expression. Therefore, SCO may serve as an innovative combinatorial agent for cancer immunotherapy.

Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment.

The tumor microenvironment comprises both tumor and non-tumor stromal cells, including tumor-associated macrophages (TAMs), endothelial cells, and carcinoma-associated fibroblasts. TAMs, major components of non-tumor stromal cells, play a crucial role in creating an immunosuppressive environment by releasing cytokines, chemokines, growth factors, and immune checkpoint proteins that inhibit T cell activity. During tumors develop, cancer cells release various mediators, including chemokines and metabolites, that recruit monocytes to infiltrate tumor tissues and subsequently induce an M2-like phenotype and tumor-promoting properties. Metabolites are often overlooked as metabolic waste or detoxification products but may contribute to TAM polarization. Furthermore, macrophages display a high degree of plasticity among immune cells in the tumor microenvironment, enabling them to either inhibit or facilitate cancer progression. Therefore, TAM-targeting has emerged as a promising strategy in tumor immunotherapy. This review provides an overview of multiple representative metabolites involved in TAM phenotypes, focusing on their role in pro-tumoral polarization of M2.

PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. Its blockers have emerged as promising therapeutics for cardiovascular diseases. Here we show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor. PCSK9 exacerbates atherosclerosis in LDL receptor knockout mice. Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. We find spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) to be the key mediators of inflammation after PCSK9-CAP1 binding. In human peripheral blood mononuclear cells, serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. The CAP1-fragment crystallizable region (CAP1-Fc) mitigates PCSK9-mediated inflammatory signal transduction more than the PCSK9 blocking antibody evolocumab does.

Association between unpredictable work schedule and work-family conflict in Korea.

Background: As unpredictable work schedule (UWS) has increased worldwide, various studies have been conducted on the resulting health effects on workers. However, research on the effect of UWS on workers' well-being in Korea is still insufficient. This study aimed to investigate the relationship between UWS and work-family conflict (WFC) using 6th Korean Working Conditions Survey (KWCS). Methods: Both UWS and WFC were measured using self-reported questionnaires, using data from the 6th KWCS conducted between 2020 and 2021, including 31,859 participants. UWS was measured by questions regarding the frequency of changes in work schedules and limited advanced notice. WFC was measured by questions regarding work to family and family to work conflicts. Logistic regression analysis was conducted to investigate the association between UWS and WFC. Results: The prevalence of UWS was higher among men, those under 40 years old, service and sales workers and blue-collar workers, and those with higher salaries. Workplace size also influenced UWS prevalence, with smaller workplaces (less than 50 employees) showing a higher prevalence. The odds ratio (OR) for WFC was significantly higher in workers with UWS compared to workers without UWS after adjusting for gender, age, marital status, occupation, salary, education, weekly working hours, shift work, company size, and having a child under the age of 18 years, employment status (OR: 3.71; 95% confidence interval: 3.23-4.25). Conclusions: The analysis of nationwide data revealed that UWS interferes with workers' performance of family roles, which can lead to WFC. Our findings suggest that it is crucial to implement policies to address unfair work schedule management, promoting a healthier work-life balance and fostering a conducive environment for family responsibilities.