Xiao-Hua Yu

Foam cells in atherosclerosis.

Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of these cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol esterification. ATP-binding cassette transporters A1(ABCA1), ABCG1 and scavenger receptor BI (SR-BI) play crucial roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow decrease, the macrophages are ultimately transformed into lipid-laden foam cells, the prototypical cells in the atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol uptake, esterification and release in macrophages. An increased understanding of the process of macrophage foam cell formation will help to develop novel therapeutic interventions for atherosclerosis.

PI3K/Akt signaling in osteosarcoma.

Osteosarcoma (OS) is the most common nonhematologic bone malignancy in children and adolescents. Despite the advances of adjuvant chemotherapy and significant improvement of survival, the prognosis remains generally poor. As such, the search for more effective anti-OS agents is urgent. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is thought to be one of the most important oncogenic pathways in human cancer. An increasing body of evidence has shown that this pathway is frequently hyperactivated in OS and contributes to disease initiation and development, including tumorigenesis, proliferation, invasion, cell cycle progression, inhibition of apoptosis, angiogenesis, metastasis and chemoresistance. Inhibition of this pathway through small molecule compounds represents an attractive potential therapeutic approach for OS. The aim of this review is to summarize the roles of the PI3K/Akt pathway in the development and progression of OS, and to highlight the therapeutic potential of targeting this signaling pathway. Knowledge obtained from the application of these compounds will help in further understanding the pathogenesis of OS and designing subsequent treatment strategies.

Apelin and its receptor APJ in cardiovascular diseases.

Apelin is an adipokine that has been identified as an endogenous ligand for the orphan receptor APJ. Apelin and APJ are expressed in a diverse range of tissues with particular preponderance for the heart and vasculature. Apelin has powerful positive inotropic actions and causes endothelium- and nitric oxide-dependent vasodilatation. Growing evidence shows that apelin/APJ system functions as a critical mediator of cardiovascular homeostasis and is involved in the pathophysiology of cardiovascular diseases. Targeting apelin/APJ axis produces protection against cardiovascular diseases. In the current review we have summarized recent data concerning the role and therapeutic potential of apelin/APJ in several major cardiovascular diseases. An increased understanding of the cardiovascular actions of apelin/APJ system will help to develop novel therapeutic interventions for cardiovascular diseases.

ABCG5/ABCG8 in cholesterol excretion and atherosclerosis.

Cholesterol is essential for the growth and function of all mammalian cells, but abnormally increased blood cholesterol is a major risk factor for atherosclerotic cardiovascular disease. ATP-binding cassette (ABC) transporters G5 (ABCG5) and G8 (ABCG8) form an obligate heterodimer that limits intestinal absorption and facilitates biliary secretion of cholesterol and phytosterols. Consistent with their function, ABCG5 and ABCG8 are located on the apical membrane of enterocytes and hepatocytes. Liver X receptor is the major positive regulator of ABCG5 and ABCG8 expression. Mutations in either of the two genes cause sitosterolemia, a condition in which cholesterol and plant sterols accumulate in the circulation leading to premature cardiovascular disease. Overexpression of ABCG5 and ABCG8 in mice retards diet-induced atherosclerosis because of reduced circulating and hepatic cholesterol. In the current review, we summarize recent developments and propose a future framework that provides new perspectives on the regulation of cholesterol metabolism and treatment of atherosclerotic cardiovascular disease.

MicroRNAs in osteosarcoma

Osteosarcoma (OS) is a primary malignant bone tumor with high morbidity that principally emerges in children and adolescents. Presently, the prognosis of OS patients remains poor due to resistance to chemotherapy, highlighting the need for new therapeutic approaches. MicroRNAs (miRNAs), a class of small noncoding RNA molecules, can negatively modulate protein expression at the post-transcriptional level. miRNAs regulate a variety of normal physiologic processes and are involved in tumorigenesis and development of multiple malignancies, including OS. Some miRNAs are differentially expressed in OS tissues, cell lines and serum, and have been shown to correlate with the malignant phenotype and prognosis. These altered miRNAs function as oncogenes or tumor suppressor genes in this process. Moreover, restoration of miRNA expression has shown promise for the treatment of OS. Here, we describe miRNA biochemistry with a focus on expression profile, role and therapeutic potential in OS. A better understanding will facilitate the identification and characterization of novel biomarkers and development of miRNA-targeted therapies.

NPC1, intracellular cholesterol trafficking and atherosclerosis

Post-lysosomal cholesterol trafficking is an important, but poorly understood process that is essential to maintain lipid homeostasis. Niemann-Pick type C1 (NPC1), an integral membrane protein on the limiting membrane of late endosome/lysosome (LE/LY), is known to accept cholesterol from NPC2 and then mediate cholesterol transport from LE/LY to endoplasmic reticulum (ER) and plasma membrane in a vesicle- or oxysterol-binding protein (OSBP)-related protein 5 (ORP5)-dependent manner. Mutations in the NPC1 gene can be found in the majority of NPC patients, who accumulate massive amounts of cholesterol and other lipids in the LE/LY due to a defect in intracellular lipid trafficking. Liver X receptor (LXR) is the major positive regulator of NPC1 expression. Atherosclerosis is the pathological basis of coronary heart disease, one of the major causes of death worldwide. NPC1 has been shown to play a critical role in the atherosclerotic progression. In this review, we have summarized the role of NPC1 in regulating intracellular cholesterol trafficking and atherosclerosis.

MMPs and ADAMTSs in intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is the most common diagnosis in patients with low back pain, a leading cause of musculoskeletal disability worldwide. The major components of extracellular matrix (ECM) within the discs are type II collagen (Col II) and aggrecan. Excessive destruction of ECM, especially loss of Col II and aggrecan, plays a critical role in promoting the occurrence and development of IDD. Matrix metalloproteinases (MMPs) and a disintegrin and metalloprotease with thrombospondin motifs (ADAMTSs) are primary enzymes that degrade collagens and aggrecan. There is a large and growing body of evidence that many members of MMPs and ADAMTSs are highly expressed in degenerative IVD tissue and cells, and are closely involved in ECM breakdown and the process of disc degeneration. In contrast, targeting these enzymes has shown promise for promoting ECM repair and mitigating disc regeneration. In the current review, after a brief description regarding the biology of MMPs and ADAMTSs, we mainly focus on their expression profiles, roles and therapeutic potential in IDD. A greater understanding of the catabolic pathways involved in IDD will help to develop potential prophylactic or regenerative biological treatment for degenerative disc disease in the future.

Hydrogen sulfide as a potent cardiovascular protective agent

Hydrogen sulfide (H2S) is a well-known toxic gas with the characteristic smell of rotten eggs. It is synthesized endogenously in mammals from the sulfur-containing amino acid l-cysteine by the action of several distinct enzymes: cystathionine-γ-lyase (CSE), cystathionine-ß-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) along with cysteine aminotransferase (CAT). In particular, CSE is considered to be the major H2S-producing enzyme in the cardiovascular system. As the third gasotransmitter next to nitric oxide (NO) and carbon monoxide (CO), H2S plays an important role in the regulation of vasodilation, angiogenesis, inflammation, oxidative stress and apoptosis. Growing evidence has demonstrated that this gas exerts a significant protective effect against the progression of cardiovascular diseases by a number of mechanisms such as vasorelaxation, inhibition of cardiovascular remodeling and resistance to form foam cells. The aim of this review is to provide an overview of the physiological functions of H2S and its protection against several major cardiovascular diseases, and to explore its potential health and therapeutic benefits. A better understanding will help develop novel H2S-based therapeutic interventions for these diseases.

Interleukin-1β in intervertebral disk degeneration.

Intervertebral disk degeneration (IDD) is the most common diagnosis in patients with low back pain, a main cause of musculoskeletal disability in the world. Interleukin-1 (IL-1) β is the most important member of the IL-1 family, and has a strong pro-inflammatory activity by stimulating the secretion of multiple pro-inflammatory mediators. IL-1β is highly expressed in degenerative intervertebral disk (IVD) tissues and cells, and it has been shown to be involved in multiple pathological processes during disk degeneration, including inflammatory responses, matrix destruction, angiogenesis and innervation, cellular apoptosis, oxidative stress and cellular senescence. However, inhibition of IL-1β is found to promote extracellular matrix (ECM) repair and protect against disk regeneration. In this review, after a brief description of IL-1β signaling, we mainly focus on the expression profiles, roles and therapeutic potential of IL-1β in IDD. A better understanding will help develop novel IL-1β-based therapeutic interventions for degenerative disk disease.

Interleukin-17A in lipid metabolism and atherosclerosis.

Interleukin-17 (IL-17) A, the most important cytokine of the IL-17 family predominantly secreted by T helper 17 (Th17) cells, plays a critical role in the development of inflammatory diseases. Its receptor is an obligate heterodimer composed of IL-17 receptor (IL-17R) A and C, the main members of the IL-17R family. Binding of IL-17A to the IL-17RA/C complex can activate a variety of downstream signaling pathways such as nuclear factor kappa-B (NF-κB), activator protein 1 (AP1) and CCAAT/enhancer-binding protein (C/EBP) to induce the expression of proinflammatory cytokines and chemokines. IL-17A also promotes mRNA stability. Growing evidence shows that IL-17A is involved in lipid metabolism and the pathogenesis of atherosclerosis, a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins. In the current review, we describe recent progress on regulation and signaling of IL-17A, and highlight its impacts on lipid metabolism and atherosclerosis.