Chia-Hui Chen

Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A, are widely used to treat hypercholesterolemia. In addition, statins have been suggested to reduce the risk of cardiovascular events owing to their pleiotropic effects on the vascular system, including vasodilation, anti-inflammation, anti-coagulation, anti-oxidation, and inhibition of vascular smooth muscle cell proliferation. The major beneficial effect of statins in maintaining vascular homeostasis is the induction of nitric oxide (NO) bioavailability by activating endothelial NO synthase (eNOS) in endothelial cells. The mechanisms underlying the increased NO bioavailability and eNOS activation by statins have been well-established in various fields, including transcriptional and post-transcriptional regulation, kinase-dependent phosphorylation and protein-protein interactions. However, the mechanism by which statins affect the metabolism of L-arginine, a precursor of NO biosynthesis, has rarely been discussed. Autophagy, which is crucial for energy homeostasis, regulates endothelial functions, including NO production and angiogenesis, and is a potential therapeutic target for cardiovascular diseases. In this review, in addition to summarizing the molecular mechanisms underlying increased NO bioavailability and eNOS activation by statins, we also discuss the effects of statins on the metabolism of L-arginine.

Fetuin-A, a hepatokine secreted by hepatocytes, binds to insulin receptors and consequently impairs the activation of the insulin signaling pathway, leading to insulin resistance. Apigenin, a flavonoid isolated from plants, has beneficial effects on insulin resistance; however, its regulatory mechanisms are not fully understood. In the present study, we investigated the molecular mechanisms underlying the protective effects of apigenin on insulin resistance. In Huh7 cells, treatment with apigenin decreased the mRNA expression of fetuin-A by decreasing reactive oxygen species-mediated casein kinase 2α (CK2α)-nuclear factor kappa-light-chain-enhancer of activated B activation; besides, apigenin decreased the levels of CK2α-dependent fetuin-A phosphorylation and thus promoted fetuin-A degradation through the autophagic pathway, resulting in a decrease in the protein levels of fetuin-A. Moreover, apigenin prevented the formation of the fetuin-A-insulin receptor (IR) complex and thereby rescued the PA-induced impairment of the insulin signaling pathway, as evidenced by increased phosphorylation of IR substrate-1 and Akt, and translocation of glucose transporter 2 from the cytosol to the plasma membrane. Similar results were observed in the liver of HFD-fed mice treated with apigenin. Collectively, our findings revealed that apigenin ameliorates obesity-induced insulin resistance in the liver by targeting fetuin-A.

Dialysis prevents death from uremia in patients with end-stage renal disease (ESRD). Nevertheless, during hemodialysis, circulating levels of di-(2-ethylhexyl) phthalate (DEHP) are increased due to phthalates leaching from medical tubes. Statins are an effective therapy for reducing the risks associated with cardiovascular diseases in patients with chronic kidney disease; however, the mechanism by which statins fail to reduce cardiovascular events in hemodialysis ESRD patients remains unclear. In this study, we investigated whether DEHP and its metabolites interfere with the lipid-lowering effect of statins in hepatocytes. In Huh7 cells, treatment with DEHP and its metabolites abolished the simvastatin-conferred lipid-lowering effect. Mechanistically, DEHP down-regulated the expression of low-density lipoprotein receptor (LDLR) and led to a decrease in LDL binding, which was mediated by the activation of the PPARγ-PCSK9 and LXRα-IDOL signaling pathways. Additionally, the NOX-ROS-TRPA1 pathway is involved in the DEHP-mediated inhibition of LDLR expression and LDL binding activity. Blockage of this pathway abrogated the DEHP-mediated inhibition in the LDLR expression and LDL binding of simvastatin. Collectively, DEHP induces the activation of the NOX-ROS-TRPA1 pathway, which in turn activates PPARγ-PCSK9- and LXRα-IDOL-dependent signaling, and, ultimately, diminishes the statin-mediated lipid-lowering effect in hepatocytes.

Obesity-related metabolic disorders, including non-alcoholic fatty liver disease (NAFLD) and insulin resistance, are increasingly prevalent worldwide, yet effective therapeutic strategies remain limited. Recent research has highlighted the potential of natural compounds in mitigating metabolic dysfunction. Apigenin (Api), a plant-derived flavonoid, has been recognized for its anti-inflammatory, antioxidant, and anti-cancer properties; however, its role in regulating hepatic lipid metabolism and insulin sensitivity remains incompletely understood. In this study, we explored the molecular mechanisms by which apigenin improves hepatic metabolic dysfunction. Using a high-fat diet-fed mouse model, we observed that apigenin treatment significantly alleviated hepatic lipid accumulation and insulin resistance. Proteomic analysis (LC-MS/MS) of liver tissues revealed extensive alterations in protein expression, with 1025 proteins upregulated and 1435 downregulated. Pathway enrichment analysis identified key affected signaling pathways, including cell junction signaling, clathrin-mediated endocytosis, and mTOR signaling. Notably, apigenin treatment increased Rac1 protein expression, suggesting its involvement in lipid metabolism regulation. Further in vitro studies using Rac1 inhibitors and siRNA in Huh7 cells confirmed that Rac1 plays a critical role in mediating the beneficial effects of apigenin on hepatic lipid metabolism and insulin resistance. Mechanistically, apigenin alleviated hepatic lipid accumulation by upregulating Rac1 and activating the autophagy-mitochondrial pathway. Additionally, it prevented insulin resistance by downregulating fetuin-A protein levels, a known contributor to metabolic dysregulation. These findings provide new insights into the hepatoprotective properties of apigenin and highlight its therapeutic potential in managing obesity-associated metabolic disorders. • Apigenin ameliorates obesity-induced hepatic lipid accumulation and insulin resistance by targeting Rac1. • Rac1 mediates the effect of apigenin on activating autophagy and mitochondrial function. • Rac1 mediates the effect of apigenin on decreasing fetuin-A expression by palmitate. • The Rac1 protein mediates the beneficial effect of apigenin on palmitate-impaired glucose uptake.