SEC62-dependent ER-phagy contributes to apelin-13/APJ-induced monocyte-vascular endothelial cell adhesion in atherosclerosis pathogenesis
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Insufficient expression of COL6A1 promotes the development of early-onset severe preeclampsia by inhibiting the APJ/AKT signaling pathway
Early-onset severe preeclampsia (eosPE) is one of the most severe complications of pregnancy. To identify the genes related to the development of eosPE. We downloaded and integrated analyzed microarray data from GSE44711, GSE66273, and GSE74341, which contains the expression profile of placental tissues from patients with eosPE and healthy controls. Our analysis revealed that collagen type VI alpha 1 (COL6A1) was downregulated in the eosPE placenta compared to normal pregnancy. COL6A1 promoted the migration, invasion and tube formation ability of HTR8/SVneo cells, HUVECs and primary extravillous trophoblasts (EVTs). To explore the underlying mechanisms, we conducted transcriptome sequencing, which indicated that the Apelin/APJ signaling pathway was affected by COL6A1 knockdown. In addition, we found that APJ expression was lower in the placental tissue of patients with eosPE compared to healthy pregnancies. Inhibition of APJ suppressed the invasion, migration, and tube formation abilities of trophoblasts. We also observed that COL6A1 increased the levels of p-AKT and p-mTOR, while the APJ inhibitor ML221 impaired this effect. Furthermore, transwell and tube formation assays demonstrated that ML221 attenuated the capabilities enhanced by COL6A1, an effect that could be rescued by the AKT activator SC79. Overall, these findings indicate that insufficient expression of COL6A1 attenuates the migration, invasion, and endothelial-like tube formation of HTR8/SVneo cells and primary EVTs via the APJ/AKT/mTOR pathway, thereby promoting the development of eosPE.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Packaged release and targeted delivery of cytokines by migrasomes in circulation
In dynamic systems like the circulatory system, establishing localized cytokine gradients is challenging. Upon lipopolysaccharide (LPS) stimulation, we observed that monocytes release numerous migrasomes enriched with inflammatory cytokines, such as TNF-α and IL-6. These cytokines are transported into migrasomes via secretory carriers, leading to their immediate exocytosis or eventual release from detached migrasomes. We successfully isolated TNF-α and IL-6-enriched, monocyte-derived migrasomes from the blood of LPS-treated mice. Total secretion analysis revealed a substantial amount of TNF-α and IL-6 released in a migrasome-packaged form. Thus, detached, monocyte-derived migrasomes represent a type of extracellular vesicle highly enriched with cytokines. Physiologically, these cytokine-laden migrasomes rapidly accumulate at local sites of inflammation, effectively creating a concentrated source of cytokines. Our research uncovers novel mechanisms for cytokine release and delivery, providing new insights into immune response modulation.
Oral microbiome diversity associates with carotid intima media thickness in middle-aged male subjects
Although there have been significant advancements in reducing the burden of cardiovascular disease (CVD) by modifying traditional CVD risk factors, substantial risks persist, particularly among male subjects who exhibit heightened susceptibility to atherosclerosis. In this context, we aim to study the link between oral microbiome and carotid intima media thickness (cIMT).
Immune pathogenic response landscape of acute posterior multifocal placoid pigment epitheliopathy revealed by scRNA sequencing
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an exceptionally rare inflammatory disorder affecting choroid and retinal pigment epithelial (RPE) cells. Although recent studies suggest an immune-driven nature, the underlying etiology of APMPPE remains elusive. In this study, we conducted a comprehensive investigation on the peripheral blood mononuclear cells (PBMCs) profile of an APMPPE patient using single-cell RNA sequencing. Our analysis revealed striking transcriptional alterations in monocytes within the PBMCs, identifying five distinct subpopulations: S100A12, CD16, pro-inflammatory, megakaryocyte-like, and NK-like monocyte subsets. Employing pseudotime inference, we observed a shift in APMPPE monocytes towards differentiation into inflammation-associated pro-inflammatory monocytes and a CD16 monocyte trajectory. Furthermore, we identified IFITM3 as a key player in the immune response driving the pathogenesis of APMPPE. Notably, two disease-relevant subgroups of monocytes, pro-inflammatory and CD16 monocytes, were implicated in APMPPE. CD16 monocytes, in particular, were involved in melanogenesis, suggesting that the abnormal expression of melanin in monocytes might result from autoimmune responses against pigment-enriched RPE cells. This study provided a comprehensive view of immune landscape in APMPPE, shedding light on the previously unrecognized contributions of pro-inflammatory and CD16 monocytes to this autoimmune condition.
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