No abstract

Viruses are the intracellular pathogens that reproduce only in the living cell and manipulate the cellular machinery to produce more viruses. Viral replications can affect cellular genes of the host in multiple cancerous ways. Approximately, 20% of all human oncogenesis is caused by cancer-causing viruses known as oncoviruses. Viral infection causes chronic inflammation leading to cell death, uncontrollable proliferation, and modulated expression of some of the regulatory proteins. Oncogenesis is a multistep phenomenon in which normal host cells are transformed into cancerous cells on the basis of host genetic variability. Oncogenic viruses encode genes that cause viral replication and transformation of the host cells to produce viral proteins and protein complexes. The phenomenon from basic viral infection to tumorigenesis is lengthy due to the involvement of factors like immunity complications, cellular mutations, and exposure to other cancerous agents. The viruses that are involved in human cancer development are Hepatitis B virus (HBV), Hepatitis C virus (HCV), Epstein-Barr virus (EBV), Human papilloma virus (HPV), Kaposi's sarcoma herpes virus (KSHV), and Human T lymphotrophic virus 1 (HTLV-1). This review article summarizes advanced knowledge related to human oncogenic viruses and the molecular mechanisms that lead to tumorigenesis in humans.

Objective Apolipoprotein A-II (apo A-II) is the second major apolipoprotein of HDLs, yet its pathophysiological roles in the development of atherosclerosis remain unknown. We aimed to examine whether apo A-II plays any role in atherogenesis and if so, to elucidate the mechanism involved. Methods and Results We compared the susceptibility of human apo A-II transgenic (Tg) rabbits to cholesterol diet-induced atherosclerosis with non-Tg littermate rabbits. Tg rabbits developed significantly less aortic and coronary atherosclerosis than their non-Tg littermates while total plasma cholesterol levels were similar. Atherosclerotic lesions of Tg rabbits were characterized by reduced macrophages and smooth muscle cells and apo A-II immunoreactive proteins were frequently detected in the lesions. Tg rabbits exhibited low levels of plasma CRP and blood leukocytes compared to non-Tg rabbits and HDLs of Tg rabbit plasma exerted stronger cholesterol efflux activity and inhibitory effects on the inflammatory cytokine expression by macrophages in vitro than HDLs isolated from non-Tg rabbits. In addition, β-VLDLs of Tg rabbits were less sensitive to copper-induced oxidation than β-VLDLs of non-Tg rabbits. Conclusions These results suggest that enrichment of apo A-II in HDL particles has atheroprotective effects and apo A-II may become a target for the treatment of atherosclerosis.

Bisphenol A (BPA) is an environmental endocrine disrupter. Excess exposure to BPA may increase susceptibility to many metabolic disorders, but it is unclear whether BPA exposure has any adverse effects on the development of atherosclerosis. To determine whether there are such effects, we investigated the response of Watanabe heritable hyperlipidemic (WHHL) rabbits to 400-µg/kg BPA per day, administered orally by gavage, over the course of 12 weeks and compared aortic and coronary atherosclerosis in these rabbits to the vehicle group using histological and morphometric methods. In addition, serum BPA, cytokines levels and plasma lipids as well as pathologic changes in liver, adipose and heart were analyzed. Moreover, we treated human umbilical cord vein endothelial cells (HUVECs) and rabbit aortic smooth muscle cells (SMCs) with different doses of BPA to investigate the underlying molecular mechanisms involved in BPA action(s). BPA treatment did not change the plasma lipids and body weights of the WHHL rabbits; however, the gross atherosclerotic lesion area in the aortic arch was increased by 57% compared to the vehicle group. Histological and immunohistochemical analyses revealed marked increases in advanced lesions (37%) accompanied by smooth muscle cells (60%) but no significant changes in the numbers of macrophages. With regard to coronary atherosclerosis, incidents of coronary stenosis increased by 11% and smooth muscle cells increased by 73% compared to the vehicle group. Furthermore, BPA-treated WHHL rabbits showed increased adipose accumulation and hepatic and myocardial injuries accompanied by up-regulation of endoplasmic reticulum (ER) stress and inflammatory and lipid metabolism markers in livers. Treatment with BPA also induced the expression of ER stress and inflammation related genes in cultured HUVECs. These results demonstrate for the first time that BPA exposure may increase susceptibility to atherosclerosis in WHHL rabbits.

BackgroundIndividuals with insulin resistance and resulting impaired glucose tolerance along with type 2 diabetes showed an increased prevalence of atherosclerosis. Our aim in this study was to address whether diet-induced insulin resistance plays any roles in the development of aortic and coronary atherosclerosis in hyperlipidemic rabbits.MethodsWe fed Watanabe heritable hyperlipidemic (WHHL) rabbits with a high-fructose and high-fat diet (HFFD) with restricted normal calories and compared the lesions of both aortic and coronary atherosclerosis with those of control WHHL rabbits fed a normal chow diet.ResultsHFFD-fed WHHL rabbits showed insulin resistance and impaired glucose tolerance accompanied by elevated plasma lipid levels and accumulation of adipose tissue even though their body weight was unchanged compared to the control rabbits. At 8 weeks, the aortic gross lesion area of HFFD-fed WHHL rabbits was increased by 40 % over the controls and their lesions were characterized by increased number of macrophages and smooth muscle cells. At 16 weeks, the lesions of HFFD-fed WHHL rabbits showed more advanced lesions such as lipid core formation and calcification. In addition, coronary atherosclerosis was significantly increased in HFFD-fed WHHL rabbits.ConclusionsThese results suggest that insulin resistance accelerates lesion formation of atherosclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-015-0024-3) contains supplementary material, which is available to authorized users.

Objective-Apolipoprotein AII (apoAII) is the second major apolipoprotein in high-density lipoprotein (HDL). However, the physiological functions of apoAII in lipoprotein metabolism have not been fully elucidated. Methods and Results-We generated human apoAII transgenic (Tg) rabbits, a species that normally does not have an endogenous apoAII gene. Plasma levels of human apoAII in Tg rabbits were Ϸ30 mg/dL, similar to the plasma levels in healthy humans. The expression of human apoAII in Tg rabbits resulted in increased levels of plasma triglycerides, total cholesterol, and phospholipids accompanied by a marked reduction in HDL-cholesterol levels compared with non-Tg littermates. Analysis of lipoprotein fractions showed that hyperlipidemia exhibited by Tg rabbits was caused by elevated levels of very-low-density lipoproteins ( Key Words: apolipoprotein Ⅲ lipase Ⅲ transgenic rabbits Ⅲ hyperlipidemia Ⅲ HDL H igh levels of plasma high-density lipoproteins (HDL) are associated with a low incidence of cardiovascular disease. 1 HDL contains 2 major apolipoproteins (apo): apoAI and apoAII. It is generally accepted that apoAI plays a central role in reverse cholesterol transport and protects against atherosclerosis 2,3 ; however, apoAII functions have not been clearly characterized. 4 -6 See accompanying article on page 1984Clinical and epidemiological studies have yielded conflicting results regarding the relationship between plasma apoAII levels and coronary heart disease: apoAII is either proatherogenic 7 or atheroprotective. 8 The Ϫ265C polymorphism in the apoAII promoter region was shown to be associated with decreased plasma apoAII concentration and enhance postprandial metabolism of large very-low-density lipoproteins (VLDL). 9 Nevertheless, apoAII has long been considered to be of physiologically minor importance in lipoprotein metabolism because apoAII deficiency is not associated with a high susceptibility to coronary heart disease. 10 ApoAII transgenic (Tg) mice along with knock-out (KO) mice have revealed multiple functions of apoAII. 4,5 Both human and mouse apoAII in Tg mice are involved in VLDL metabolism, but mouse apoAII is also associated with obesity and insulin resistance. [11][12][13] In addition, mouse apoAII is proatherogenic in chow-fed Tg mice, whereas human apoAII is either atheroprotective or proatherogenic in Tg mice dependent on an atherogenic diet. 14 -17 Although the cause of these discrepancies in different mice expressing different transgenes is unclear, it seems that there is a species difference in apoAII functions between human and mouse, and that the precise physiological functions of apoAII in vivo remain to be elucidated. Studies using Tg mice are often complicated by additional factors such as the effect of human homodimer apoAII versus murine monomer apoAII, transgenic apoAII (either human or murine) versus endogenous murine apoAII,

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Bisphenol A (BPA) is an artificial environmental endocrine disrupter. Excess exposure to BPA may induce many disorders in the metabolism and cardiovascular system. However, the underlying toxicological mechanisms remain largely unknown. In this study, we administered genetically hyperlipidemic Watanabe heritable hyperlipidemic (WHHL-MI) rabbits (male, 14 week old), which have more common features with humans than the mouse and rat especially in the metabolism and cardiovascular system, with BPA at 40 mg kg(-1)  day(-1) for 8 weeks by gavage and compared their plasma lipids, glucose and insulin response with those of the vehicle group. All of the rabbits were sacrificed, and their pancreas, liver, adipose tissue, heart and aorta were analyzed using histological and morphometric methods. Furthermore, we treated human hepatoma HepG2 cells and human umbilical cord vein endothelial cells (HUVECs), with different doses of BPA based on the serum BPA levels in the WHHL rabbits for 6 h to investigate the possible molecular mechanisms. Our results showed that BPA-treated rabbits showed insulin resistance, prominent adipose accumulation and hepatic steatosis. Additionally, BPA exposure also caused myocardial injury and enhanced the development of atherosclerosis in the aortic arch with increased macrophage number (86%) and advanced lesion areas (69%). Increased expression of inflammatory genes found in the liver of BPA-treated rabbits along with the up-regulation of ER stress, lipid and glucose homeostasis and inflammatory genes in the cultured HepG2 cells and HUVECs suggest that BPA may induce metabolic disorders and enhance atherosclerosis through regulating above molecular pathways in the liver and endothelium.