다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity

Vitamin A metabolite retinoic acid (RA) plays important roles in cell growth, differentiation, organogenesis, and reproduction and a key role in mucosal immune responses. RA promotes dendritic cells to express CD103 and to produce RA, enhances the differentiation of Foxp3+ inducible regulatory T cells, and induces gut-homing specificity in T cells. Although vitamin A is crucial for maintaining homeostasis at the intestinal barrier and equilibrating immunity and tolerance, including gut dysbiosis, retinoids perform a wide variety of functions in many settings, such as the central nervous system, skin aging, allergic airway diseases, cancer prevention and therapy, and metabolic diseases. The mechanism of RA is interesting to explore as both a mucosal adjuvant and a combination therapy with other effective agents. Here, we review the effect of RA on innate and adaptive immunity with a special emphasis on inflammatory status.

/pdf/impact-of-retinoic-acid-on-immune-cells-and-inflammatory-3h6avh7iv0.pdf

Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases.

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (ie, bioenergetics, biogenesis and dynamics) However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D

Insulin Resistance and Mitochondrial Dysfunction

Th17 cells, γδ T cells and their interplay in EAE and multiple sclerosis.

Retinoic acid (RA) in the steady state enhances induction of Foxp3(+) regulatory T (Treg) cells and inhibits differentiation of Th1 and Th17 cells, thereby maintaining tolerance, but can in inflammatory conditions promote effector Th1 and Th17 cells that mediate inflammation. IL-17-producing γδ T cells have recently been shown to have a major pathogenic role in autoimmune diseases. Here, we examined the immunomodulatory effects of RA on γδ T cells. We found that RA had a dramatic suppressive effect on IL-17A and IL-17F production by γδ T cells stimulated with IL-1β and IL-23. RA suppressed RORγt, IL-1R and IL-23R expression in γδ T cells. Treatment of mice with RA suppressed IL-17 production by γδ T cells in vivo. Furthermore, treatment of T cells with RA attenuated their ability to induce disease in experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis. This was associated with a reduction in the number of central nervous system-infiltrating γδ T cells, but also CD4(+) T cells that produced IL-17A, IL-17F or GM-CSF. Interestingly, treatment of γδ T cells with RA or removal of γδ T cells from a bulk population of T cells significantly reduced their capacity to induce EAE, demonstrating a critical role for γδ T cells in promoting pathogenic Th17 cells. Our findings demonstrate that the anti-inflammatory properties of RA are mediated in part by suppressing STAT3-mediated activation of cytokine production and cytokine receptor expression in γδ T cells, which suppresses their ability to activate Th17 cells.

/pdf/retinoic-acid-suppresses-il-17-production-and-pathogenic-2a3kqivwuk.pdf

Retinoic acid suppresses IL-17 production and pathogenic activity of γδ T cells in CNS autoimmunity.

Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase

Metformin is the main drug of choice for treating type 2 diabetes, yet the therapeutic regimens and side effects of the compound are all undesirable and can lead to reduced compliance. The aim of this study was to elucidate the mechanism of action of two novel compounds which improved glucose handling and weight gain in mice on a high-fat diet. Wildtype C57Bl/6 male mice were fed on a high-fat diet and treated with novel, anti-diabetic compounds. Both compounds restored the glucose handling ability of these mice. At a cellular level, these compounds achieve this by inhibiting complex I activity in mitochondria, leading to AMP-activated protein kinase activation and subsequent increased glucose uptake by the cells, as measured in the mouse C2C12 muscle cell line. Based on the inhibition of NADH dehydrogenase (IC50 27µmolL(-1)), one of these compounds is close to a thousand fold more potent than metformin. There are no indications of off target effects. The compounds have the potential to have a greater anti-diabetic effect at a lower dose than metformin and may represent a new anti-diabetic compound class. The mechanism of action appears not to be as an insulin sensitizer but rather as an insulin substitute.

/pdf/novel-mitochondrial-complex-i-inhibitors-restore-glucose-h8mcbowqq2.pdf

Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice

STRA6 is a plasma membrane protein that mediates the transport of vitamin A, or retinol, from plasma retinol binding protein (RBP) into the cell. Mutations in human STRA6 are associated with Matthew-Wood syndrome, which is characterized by severe developmental defects. Despite the obvious importance of this protein to human health, little is known about its structure and mechanism of action. To overcome the difficulties frequently encountered with the production of membrane proteins for structural determination, STRA6 has been expressed in Pichia pastoris as a fusion to green fluorescent protein (GFP), a strategy which has been a critical first step in solving the crystal structures of several membrane proteins. STRA6-GFP was correctly targeted to the cell surface where it bound RBP. Here we report the large-scale expression, purification and characterisation of STRA6-GFP. One litre of culture, corresponding to 175 g cells, yielded about 1.5 mg of pure protein. The interaction between purified STRA6 and its ligand RBP was studied by surface plasmon resonance-based binding analysis. The interaction between STRA6 and RBP was not retinol-dependent and the binding data were consistent with a transient interaction of 1 mole RBP/mole STRA6.

/pdf/production-of-functional-human-vitamin-a-transporter-rbp-2f8idnmop4.pdf

Conor J Breen

Papers

Retinoic acid suppresses IL-17 production and pathogenic activity of γδ T cells in CNS autoimmunity.

Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase

Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice

Production of functional human vitamin A transporter/RBP receptor (STRA6) for structure determination.