Adipose-resident T-cells (ARTs) regulate metabolic and inflammatory responses in obesity, but ART activation signals are poorly understood. Here, we describe class II major histocompatibility complex (MHCII) as an important component of high-fat diet (HFD)-induced obesity. Microarray analysis of primary adipocytes revealed that multiple genes involved in MHCII antigen processing and presentation increased in obese women. In mice, adipocyte MHCII increased within two weeks HFD, paralleling increases in pro-inflammatory and decreases in anti-inflammatory ART markers, and preceding adipose tissue macrophage (ATM) accumulation and pro-inflammatory M1 polarization. Mouse 3T3-L1 and primary adipocytes activated T-cells in an antigen-specific, contact-dependent manner, indicating adipocyte MHCII is functional. HFD-fed MHCII−/− mice developed less adipose inflammation and insulin resistance than wild-type mice, despite developing similar adiposity. These investigations uncover a mechanism whereby a HFD-induced adipocyte/ART dialogue involving MHCII instigates adipose inflammation and, together with ATM MHCII, escalates its progression.

Utilization of molecular oxygen by aerobic organisms inevitably results in the formation of a number of oxygen-containing reactive species that are collectively known as reactive oxygen species (ROS). ROS play important roles in both physiology and pathophysiology of aerobic life. The field of ‘ROS biology and medicine’ deals with the involvement of ROS and related species in contemporary biology and medicine. The purpose of this article is to survey common terms and concepts in ROS biology and medicine. It also introduces the ‘ROS paradigm’ so as to provide a conceptual framework for understanding the rapidly evolving field of ROS biology and medicine.

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic beta-cell function are very limited. In the present study, we investigated the effect of genistein on beta-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet beta-cell proliferation after 24 h of incubation, with 5 mum genistein inducing a maximal 27% increase. The effect of genistein on beta-cell proliferation was neither dependent on estrogen receptors nor shared by 17beta-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated beta-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for beta-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet beta-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic beta-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway.

Study design: Literature review. Objectives: Spinal cord injury (SCI) remains a major public health issue in developed countries as well as worldwide. The pathophysiology of SCI is characterized by an initial primary injury followed by secondary deterioration. Although the etiology and pathogenesis of SCI remain to be fully understood, it has been suggested that reactive oxygen species (ROS) and oxidative stress have a significant role in the pathophysiology of SCI. Thus, alleviating oxidative stress may be an effective strategy for therapeutic intervention of SCI. The aim of this review was to describe (i) the sources of ROS as well as the major antioxidant defenses with particular attention being paid to lipid peroxidation; (ii) the biomarkers of oxidative stress in SCI and (iii) the neuroprotective effects of various compounds with antioxidative properties in animal models of SCI. Methods: PubMed, one of the most comprehensive biomedical databases, was searched from 1976-2011. All relevant papers were read by title, abstract and full-length article. Results: Oxidative stress is considered a hallmark of injury of SCI. Thus, alleviating oxidative stress may be an effective way of therapeutic intervention of SCI. Two of these agents, the glucocorticoid steroid methylprednisolone and the non-glucocorticoid 21-aminosteroid tirilazad, have been shown to possess significant antioxidant activities and improve recovery of SCI patients in clinical trials. Other promising botanical compounds and their molecular targets and mechanisms of action with regard to potential protection against SCI were also described. These include carotenoids and phenolic compounds. Conclusion: ROS and oxidative stress have a significant role in the pathophysiology of SCI. Alleviating oxidative stress is be an effective strategy for therapeutic intervention of SCI. Extensive research over the past several decades has identified numerous bioactive compounds that have antioxidative stress benefits in animal models of SCI. Thus, continued studies on bioactive compounds with ROS-scavenging capacity may lead to the development of effective antioxidant-based modalities for treating SCI in human subjects.

Nod-like receptors (NLRs) are intracellular sensors that respond to a variety of pathogen and intracellular danger signals to induce innate immune responses. NLRC5 has recently been identified to be an important regulator of NF-κB, type I interferon (IFN) and inflammasome signaling pathways, but the in vivo function and mechanisms of NLRC5 remain to be defined. Here, we describe the generation and characterization of NLRC5 knockout mice. We show that induction of NLRC5 expression by Toll-like receptor (TLR) ligand or cytokine stimulation requires the signal transducers and activators of transcription (Stat)1-mediated signaling pathway. NLRC5 ablation reduces MHC class I expression, and enhances IKK and IRF3 phosphorylation in response to TLR stimulation or viral infection. Consistent with these observations, we found that NLRC5 deficiency enhanced IL-6 and IFN-β production in mouse embryonic fibroblasts (MEFs), peritoneal macrophages and bone marrow-derived macrophages (BMMs), but not bone marrow-derived dendritic cells (BMDCs) after LPS stimulation or vesicular stomatitis virus (VSV) infection.Furthermore, we found that NLRC5-deficient mice produced higher amounts of IL-6 and IFN-β in the sera when they were challenged with LPS or infected with VSV. Taken together, these results provide in vivo evidence that NLRC5 plays critical roles in MHC class I expression, innate immune signaling and antiviral innate immune responses, thus serving as an important target for modulating innate immune signaling and regulation.

Epigenetic factors have been implicated in the regulation of CD4+ T cell differentiation. Jmjd3 plays a role in many biological processes, but its in vivo function in T cell differentiation remains unknown. Here, we report that Jmjd3 ablation promotes CD4+ T cell differentiation into Th2 and Th17 cells in the small intestine and colon, and inhibits T cell differentiation into Th1 cells under different cytokine-polarizing conditions and in a Th1-dependent colitis model. Jmjd3 deficiency also restrains the plasticity of the conversion of Th2, Th17 or Treg cells to Th1 cells. The skewing of T cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines. H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors. Our results identify Jmjd3 as an epigenetic factor in T cell differentiation via changes in histone methylation and target gene expression.

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Objective: To estimate the occurrence and to assess the determinants of posttraumatic stress disorder (PTSD) in flood victims. Method:We carried out a retrospective study to examine the occurrence and the determinants of PTSD in victims of flood in 1998 and 1999 in Hunan, China. We used multistage sampling to select the subjects from the flood areas, and we ascertained PTSD according to DSM-IV criteria. Data were collected in face-to-face interviews carried out by experienced research assistants using a preconstructed questionnaire. We used a multiple logistic regression model to analyze the data.Results: A total of 33 340 subjects (86.0% of the selected subjects, aged 7 years or over) in the study villages were interviewed. Among them, 2875 (8.6%) had symptoms that met the diagnostic criteria for PTSD. Conclusions: PTSD is a common mental disorder in flood victims, which implies the need for improved health services, especially mental health services, for this population. (Can J Psychiatry 2006;51:350-354) Information on funding and support and author affiliations appears at the end of the article. Clinical Implications· PTSD is common in flood-affected populations. · It is important to provide psychological support, in addition to physical support, for flood-affected populations. · Particular attention should be paid to female victims and senior victims in the flood-affected areas. Limitations· The study findings were based on observations in a Chinese population in Hunan province; they may not be applicable to other populations. · The severity and type of flood were arbitrarily defined and may not necessarily reflect the nature of the flood. · We were not able to study modifiable PTSD risk factors (for example, lack of family or social support).