Single-cell transcriptomics reveals writers of RNA modification-mediated immune microenvironment and cardiac resident Macro-MYL2 macrophages in heart failure.

BACKGROUND: Heart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown. METHODS: We comprehensively characterized the expressions of 28 WRMs using datasets GSE145154 and GSE141910 to map the cardiac immunological microenvironment in HF patients. Based on the expression of WRMs, the immunological cells in the datasets were scored. RESULTS: Single-cell transcriptomics analysis (GSE145154) revealed immunological dysregulation in HF as well as differential expression of WRMs in immunological cells from HF and non-HF (NHF) samples. WRM-scored immunological cells were positively correlated with the immunological response, and the high WRM score group exhibited elevated immunological cell infiltration. WRMs are involved in the differentiation of T cells and myeloid cells. WRM scores of T cell and myeloid cell subtypes were significantly reduced in the HF group compared to the NHF group. We identified a myogenesis-related resident macrophage population in the heart, Macro-MYL2, that was characterized by an increased expression of cardiomyocyte structural genes (MYL2, TNNI3, TNNC1, TCAP, and TNNT2) and was regulated by TRMT10C. Based on the WRM expression pattern, the transcriptomics data (GSE141910) identified two distinct clusters of HF samples, each with distinct functional enrichments and immunological characteristics. CONCLUSION: Our study demonstrated a significant relationship between the WRMs and immunological microenvironment in HF, as well as a novel resident macrophage population, Macro-MYL2, characterized by myogenesis. These results provide a novel perspective on the underlying mechanisms and therapeutic targets for HF. Further experiments are required to validate the regulation of WRMs and Macro-MYL2 macrophage subtype in the cardiac immunological milieu.

The causal relationship between diet habits and cholelithiasis: a comprehensive Mendelian randomization (MR) study.

Background: Epidemiological studies show dietary habits can have an impact on the risk of cholelithiasis, but the relationship is still unclear. We used a comprehensive Mendelian randomization (MR) study to explore the relationship between dietary habits and cholelithiasis. Methods: The 18 dietary habits were divided into six categories: meat foods, cereals, vegetables, fruits, dairy products, beverages, and condiments. Cholelithiasis data came from a GWAS meta-analysis and the FinnGen consortium. The inverse variance weighted (IVW), the weighted median (WM), and MR-Egger approaches were used as the main MR analysis methods. In addition, multiple sensitivity analysis and meta-analysis were performed to verify the robustness of the results. Results: Dried fruit intake [odds ratio (OR) = 0.568; 95% confidence interval (CI), 0.405-0.797; p = 0.001] was discovered to reduce the risk of cholelithiasis. The sensitivity analysis and meta-analysis showed reliable results for the relationship between dried fruit intake and cholelithiasis. Conclusion: Our study found that dried fruit intake is a protective factor in the development of cholelithiasis. However, the mechanisms of action need to be further explored.

Characterization of ovarian progenitor cells for their potential to generate steroidogenic theca cells in vitro.

In brief: Progenitor cells with ovulation-related tissue repair activity were identified with defined markers (LGR5, EPCR, LY6A, and PDGFRA), but their potentials to form steroidogenic cells were not known. This study shows that the cells can generate progenies with different steroidogenic activities. Abstract: Adult mammalian ovaries contain stem/progenitor cells necessary for folliculogenesis and ovulation-related tissue rupture repair. Theca cells are recruited and developed from progenitors during the folliculogenesis. Theca cell progenitors were not well defined. The aim of current study is to compare the potentials of four ovarian progenitors with defined markers (LY6A, EPCR, LGR5, and PDGFRA) to form steroidogenic theca cells in vitro. The location of the progenitors with defined makers was determined by immunohistochemistry and immunofluorescence staining of ovarian sections of adult mice. Different progenitor populations were purified by magnetic-activated cell sorting (MACS) and/or fluorescence-activated cell sorting (FACS) techniques from ovarian cell preparation and were tested for their abilities to generate steroidogenic theca cells in vitro. The cells were differentiated with a medium containing LH, ITS, and DHH agonist for 12 days. The results showed that EPCR+ and LGR5+ cells primarily distributed along the ovarian surface epithelium (OSE), while LY6A+ cells distributed in both the OSE and parenchyma. However, PDGFRA+ cells were exclusively located in interstitial compartment. When the progenitors were purified by these markers and differentiated in vitro, LY6A+ and PDGFRA+ cells formed steroidogenic cells expressing both CYP11A1 and CYP17A1 and primarily producing androgens, showing characteristics of theca-like cells, while LGR5+ cells generated steroidogenic cells devoid of CYP17A1 expression and androgen production, showing a characteristic of progesterone-producing cells (granulosa- or lutea-like cells). In conclusion, progenitors from both OSE and parenchyma of adult mice are capable of generating steroidogenic cells with different steroidogenic capacities, showing a possible lineage preference.

Chrysin Inhibits TAMs-Mediated Autophagy Activation via CDK1/ULK1 Pathway and Reverses TAMs-Mediated Growth-Promoting Effects in Non-Small Cell Lung Cancer.

The natural flavonoid compound chrysin has promising anti-tumor effects. In this study, we aimed to investigate the mechanism by which chrysin inhibits the growth of non-small cell lung cancer (NSCLC). Through in vitro cell culture and animal models, we explored the impact of chrysin on the growth of NSCLC cells and the pro-cancer effects of tumor-associated macrophages (TAMs) and their mechanisms. We observed that M2-TAMs significantly promoted the growth and migration of NSCLC cells, while also markedly activating the autophagy level of these cells. Chrysin displayed a significant inhibitory effect on the growth of NSCLC cells, and it could also suppress the pro-cancer effects of M2-TAMs and inhibit their mediated autophagy. Furthermore, combining network pharmacology, we found that chrysin inhibited TAMs-mediated autophagy activation in NSCLC cells through the regulation of the CDK1/ULK1 signaling pathway, rather than the classical mTOR/ULK1 signaling pathway. Our study reveals a novel mechanism by which chrysin inhibits TAMs-mediated autophagy activation in NSCLC cells through the regulation of the CDK1/ULK1 pathway, thereby suppressing NSCLC growth. This discovery not only provides new therapeutic strategies for NSCLC but also opens up new avenues for further research on chrysin.

PhbZIP2 regulates photosynthesis-related genes in an intertidal macroalgae, Pyropia haitanensis, under stress.

Intertidal macroalgae are important research subjects in stress biology. Basic region-leucine zipper transcription factors (bZIPs) play an important regulatory role in the expression of target genes under abiotic stress. We herein identified a bZIP2 gene PhbZIP2 to regulate abiotic stress tolerance in Pyropia haitanensis, a representative intertidal macroalgal species. Cloning and sequencing of the cDNA characterized a BRLZ structure and an α coiled-coil structure between amino acids and Expression of PhbZIP2 was detected to upregulate under both high temperature and salt stresses. A DAP-seq analysis revealed the PhbZIP2-binding motifs of (T/C)TCCA(C/G) and A (A/G)AAA (G/A), which differed from the conserved motifs in plants. Overexpression of PhbZIP2 was indicative of a high temperature and salt stress tolerances in transgenic Chlamydomonas reinhardtii. It was suggested that PhbZIP2 was probably involved in regulating expression of the photosynthetic-related genes and the response to the abiotic stresses in P. haitanensis, which provide new insights for elucidating efficient adaptation strategies of intertidal macroalgae.