Enterovirus 71 (EV71), a major pathogen that is responsible for causing hand-foot-and-mouth disease (HFMD) worldwide, is a member of the Human Enterovirus species A, family Picornaviridae. HFMD that is caused by EV71 is usually characterized by vesicular lesions on the skin and oral mucosa and high morbidity rates in children; additionally, occasional fatal cases have been reported involving brainstem encephalitis and myelitis associated with cardiopulmonary collapse. Although viral pathogenesis in humans is unclear, previous animal studies have indicated that EV71, inoculated via various routes, is capable of targeting and injuring the central nervous system (CNS). We report here the pathogenic process of systemic EV71 infection in rhesus monkeys after inoculation via intracerebral, intravenous, respiratory and digestive routes. Infection with EV71 via these routes resulted in different rates of targeting to and injury of the CNS. Intracerebral inoculation resulted in pulmonary edema and hemorrhage, along with impairment of neurons. However, intravenous and respiratory inoculations resulted in a direct infection of the CNS, accompanied by obvious inflammation of lung tissue, as shown by impairment of the alveoli structure and massive cellular infiltration around the terminal bronchioles and small vessels. These pathological changes were associated with a peak of viremia and dynamic viral distribution in organs over time in the infected monkeys. Our results suggest that the rhesus monkey model may be used to study not only the basic pathogenesis of EV71 viral infections, but also to examine clinical features, such as neurological lesions, in the CNS and pathological changes in associated organs.
Obesity and insulin resistance are independent risk factors for metabolic syndrome, diabetes, and cardiovascular disease. Adipose tissue samples from nonobese (NO), insulin-sensitive obese (ISO), and insulin-resistant obese (IRO) subjects from subcutaneous (SC) and omental (OM) adipose tissue (n 5 28) were analyzed by microarray and confirmed by real-time PCR. Insulin signaling gene expression changes were greater in OM than in SC tissue and were related to insulin resistance rather than to obesity; few genes correlated with body mass index. Insulin receptor and insulin receptor substrate 1 (IRS-1) increased in the IRO versus pooled insulin-sensitive (NO1ISO) subjects. In glucose transport, PI3Ka and PDK2 decreased in IRO subjects, whereas PI3Kg, Akt2, GLUT4, and GLUT1 increased. IRS-1 regulators Jnk and IKK increased in IRO (P , 0.01 and P , 0.001 respectively). In protein synthesis, most genes examined were downregulated in IRO subjects, including mTor, Rheb, and 4EBP and eIF members (all P , 0.05). In proliferation, SHC, SOS, and Raf1 (P , 0.05) were increased, whereas Ras and MEK1/2 kinase 1 (P , 0.05) were decreased, in IRO subjects. Finally, in differentiation, PPARg, CEBPa, and CEBPb decreased, whereas PPARd, CEBPg, and CEBP: increased, in IRO subjects (P , 0.05). Together, microarray and real-time PCR data demonstrate that insulin resistance rather than obesity is associated with altered gene expression of insulin signaling genes, especially in OM adipose tissue.-MacLaren, R., W. Cui, S. Simard, and K. Cianflone. Influence of obesity and insulin sensitivity on insulin signaling genes in human omental and subcutaneous adipose tissue. J. Lipid Res. Obesity and insulin resistance have both been identified as independent risk factors for metabolic syndrome, diabetes, and cardiovascular disease (1, 2). Many studies have focused on the physiologic parameters and genetic predisposition of subjects presenting with both obesity and insulin resistance (3). It was recently brought to attention, however, that subsets of obese individuals remain relatively insulin-sensitive (4-6). In the literature, they are referred to as insulin-sensitive obese (ISO) (7), metabolically healthy but obese (8), and metabolically normal but obese (9) subjects. For consistency, we use the term ISO throughout the present discussion. A number of studies have been conducted to identify physiologically different characteristics of the ISO population (10). In addition to insulin sensitivity, ISO subjects have lower plasma triglycerides and higher HDL cholesterol (9, 11). Shin et al. (12) determined that circulating C-reactive protein, interleukin 6, oxidized LDL, and visceral fat were lower in ISO compared with insulin-resistant obese (IRO) subjects. However, there are few data describing gene regulation that might account for this overall healthier status of ISO individuals.Adipose tissue is one of the key peripheral targets of insulin; acting as both an endocrine organ and an energy storage depot (13), it can affect whole-body ins...
Reg proteins constitute a conserved family in human and rodents; their production in the pancreas (including the islets of Langerhans) is induced upon beta-cell damage. While some members of the family (Reg1 and islet neogenesis-associated protein, i.e. INGAP) have been implicated in beta-cell replication and/or neogenesis, including from in vivo studies using transgenic and knockout mice; the roles of the other five members have yet to be characterized. Among them, Reg2 was recently proposed to serve as an autoantigen on beta-cells that elicits T-cell attack in type 1 diabetes mellitus. Elucidation of their actions and identification of their molecular targets should provide insight into the biology of these proteins and lead to the design and development of novel strategies aimed at promoting the survival and function of the pancreatic islets. As the current terminology used for mammalian Reg genes/proteins is very confusing, we also proposed a uniformed classification in human and rodents through sequence alignments.
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