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Whether vitamin A (VA) has a role in the development of metabolic abnormalities associated with intake of a high-fat diet (HFD) is unclear. Sprague--Dawley rats after weaning were fed an isocaloric VA sufficient HFD (VAS-HFD) or a VA deficient HFD (VAD-HFD) for 8 weeks. Body mass, food intake, liver and adipose tissue mass, and the hepatic expression levels of key proteins for metabolism were determined. VAD-HFD rats had lower body, liver, and epididymal fat mass than VAS-HFD rats. VAD-HFD rats had lower hepatic protein expression levels of cytochrome P450 26A1, glucokinase, and phosphoenolpyruvate carboxykinase than VAS-HFD rats. VAD-HFD rats had higher protein levels of glycogen synthase kinase (GSK)-3[alpha] and lower levels of GSK-3[beta], but not glycogen synthase, than VAS-HFD rats. VAD-HFD rats had higher hepatic levels of insulin receptor substrate-1 (IRS-1), insulin receptor [beta]-subunit, mitogen-activated protein kinase proteins, and peroxisome proliferator-activated receptor-gamma coactivator 1[alpha] mRNA, and lower level of IRS-2 protein than VAS-HFD rats. These results indicate that in a HFD setting, VA deficiency attenuated HFD-induced obesity, and VA status altered the expression levels of proteins required for glucose metabolism and insulin signaling. We conclude that VA status contributes to the regulation of hepatic glucose and lipid metabolism in a HFD setting, and may regulate hepatic carbohydrate metabolism. Key words: vitamin A, high-fat diet, Sprague-Dawley rats, hepatic glucose metabolism, body mass. Le rôle de la vitamine A (VA) dans le développement d'anomalies métaboliques associées à régime alimentaire riche en gras (RARG) n'est pas clair. Des rats Sprague--Dawley ont été nourris après sevrage avec un RARG comportant un apport suffisant en VA (RARG-VAS) ou un RARG isocalorique déficient en VA (RARG-VAD) pendant huit semaines. La masse corporelle, la prise alimentaire, la masse hépatique et du tissu adipeux et les niveaux d'expression hépatique de protéines clés du métabolisme ont été déterminés. La masse corporelle et la masse hépatique et du tissu adipeux épididymaire étaient plus faibles chez les rats soumis au RARG-VAD, comparativement aux rats soumis au RARG-VAS. Les niveaux d'expression protéique du cytochrome P450 26A1, de la glucokinase et de la phosphoénolpyruvate carboxykinase dans le foie étaient plus faibles chez les rats soumis à un RARG-VAD, comparativement aux rats soumis à une RARG-VAS. Chez les rats soumis à un RARG-VAD, les niveaux protéiques de laglycogène synthase kinase (GSK)-3[alpha] étaient plus élevés et les niveaux de GSK-3[beta] étaient plus faibles, contrairement à la glycogène synthase, comparativement aux rats soumis à un RARG-VAS. Les niveaux hépatiques du substrat du récepteur d'insuline-1 [IRS-1], de la sous-unité [beta] du récepteur d'insuline et de la protéine kinase activée par des agents mitogènes étaient plus élevés chez les rats soumis à un RARG-VAD, tout comme les niveaux d'ARNm du coactivateur 1[alpha] du récepteur gamma activé par les proliférateurs des peroxysomes, alors que les niveaux d'IRS-2 étaient plus faibles, comparativement aux rats soumis à un RARG-VAS. Ces résultats indiquent que dans le cadre d'un RARG, le déficit en VA atténuait l'obésité induite par le RARG, et que le statut en VA modifiait les niveaux d'expression des protéines requises au métabolisme du glucose et à la signalisation de l'insuline. Les auteurs concluent que le statut en VA contribue à la régulation du métabolisme hépatique du glucose et des lipides dans le cadre d'un RARG, et qu'il pourrait réguler le métabolisme hépatique des glucides. [Traduit par la Rédaction] Mots-clés : vitamine A, régime alimentaire riche en gras, rats Sprague-Dawley, métabolisme hépatique du glucose, masse corporelle., Introduction For humans and animals, dietary macronutrients provide energy while micronutrients play numerous regulatory roles in the nutrimental processes. Vitamin A (VA, retinol) is an essential micronutrient to all vertebrates [...]

ABSTRACT Vitis amurensis (Vitaceae) has been reported to have anti-oxidant and anti-inflammatory activities. The present study investigated a methanol extract from the leaf and stem of V. amurensis for neuroprotective [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.09.039 Byline: Cheolho Cheong (1), Ines Matos (1), Jae-Hoon Choi (1), Durga Bhavani Dandamudi (1), Elina Shrestha (1), M. Paula Longhi (1), Kate L. Jeffrey (2), Robert M. Anthony (3), Courtney Kluger (1), Godwin Nchinda (1), Hyein Koh (1), Anthony Rodriguez (1), Juliana Idoyaga (1), Maggi Pack (1), Klara Velinzon (4), Chae Gyu Park (1), Ralph M. Steinman (1) Keywords: CELLIMMUNO; CELLBIO; HUMDISEASE Abstract: Dendritic cells (DCs), critical antigen-presenting cells for immune control, normally derive from bone marrow precursors distinct from monocytes. It is not yet established if the large reservoir of monocytes can develop into cells with critical features of DCs in vivo. We now show that fully differentiated monocyte-derived DCs (Mo-DCs) develop in mice and DC-SIGN/CD209a marks the cells. Mo-DCs are recruited from blood monocytes into lymph nodes by lipopolysaccharide and live or dead gram-negative bacteria. Mobilization requires TLR4 and its CD14 coreceptor and Trif. When tested for antigen-presenting function, Mo-DCs are as active as classical DCs, including cross-presentation of proteins and live gram-negative bacteria on MHC I in vivo. Fully differentiated Mo-DCs acquire DC morphology and localize to T cell areas via L-selectin and CCR7. Thus the blood monocyte reservoir becomes the dominant presenting cell in response to select microbes, yielding DC-SIGN.sup.+ cells with critical functions of DCs. Author Affiliation: (1) Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA (2) Laboratory of Lymphocyte Signaling, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA (3) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA (4) Laboratory of Molecular Immunology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA Article History: Received 11 May 2010; Revised 10 August 2010; Accepted 23 September 2010 Article Note: (miscellaneous) Published: October 28, 2010

Phase-variable expression of Legionella pneumophila lipopolysaccharide (LPS) has not been described in detail for strains possessing the virulence-associated epitope recognized by the monoclonal antibody (mAb) 3/1 of the Dresden Panel. About 75% of cases of community-acquired legionellosis are caused by mAb 3/1-positive strains. In this study, the LPS architecture of the mAb 3/1-positive Corby strain was investigated during its life cycle in broth culture and inside monocytic host cells. During the exponential growth phase in broth, the highly acetylated and therefore strongly hydrophobic mAb 3/1 epitope is expressed continuously, but only 3 % of the bacteria can be detected using mAb 59/1, which recognizes a short-chain variant of the Legionella LPS that is less hydrophobic due to missing acetylations of the O-chain. The percentage of mAb 59/1 -positive legionellae increases up to 34 % in the post-exponential growth phase. LPS shed in broth during the exponential phase is mAb 59/1-negative, and mAb 3/1positive components do not possess short-chain molecules. The LPS pattern expressed and shed inside U937 cells and A/J mouse macrophages points to the same regulatory mechanisms. During the so-called 'pregnant pause', the period for establishment of the replicative phagosomes, the mAb 3/1-positive LPS is shed into the phagosome and seems to pass through the phagosomal membrane, while mAb 59/1 -positive LPS is detectable only on the bacterial surface. After egress of the legionellae into the cytoplasm followed by host cell lysis, individual bacteria are mAb 3/1positive and mAb 59/1-negative. Intracellularly formed Legionella clusters consist of surface-located mAb 3/1-positive bacteria, which are predominantly mAb 59/1-negative. They surround less hydrophobic and therefore closely packed mAb 59/1-positive bacteria. Based on the different degrees of hydrophobicity, bacteria are able to support the expression of two functionally different LPS architectures, namely more hydrophobic LPS for surviving in aerosols and more hydrophilic LPS for close-packing of legionellae inside clusters. DOI 10.1099/mic.0.039933-0

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.05.503 Byline: Meei-Hua Lin (a), Kuo-Wei Chang (c), Shu-Chun Lin (c), Jeffrey H. Miner (a)(b) Keywords: Epiregulin; Amphiregulin; Epithelial mitogen; PPAR; Skin barrier; Epidermal hyperplasia Abstract: Fatty acid transport protein (FATP) 4 is one of a family of six FATPs that facilitate long- and very long-chain fatty acid uptake. Mice lacking FATP4 are born with tight, thick skin and a defective epidermal barrier; they die neonatally due to dehydration and restricted movements. Both the skin phenotype and the lethality are rescued by transgene-driven expression of FATP4 solely in suprabasal keratinocytes. Here we show that Fatp4 mutants exhibit epidermal hyperplasia resulting from an increased number of proliferating suprabasal cells. In addition, barrier formation initiates precociously but never progresses to completion. To investigate possible mechanisms whereby Fatp4 influences skin development, we identified misregulated genes in Fatp4 mutants. Remarkably, three members of the epidermal growth factor (EGF) family (Ereg, Areg, and Epgn) showed increased expression that was associated with elevated epidermal activation of the EGF receptor (EGFR) and STAT3, a downstream effector of EGFR signaling. Both Tyrphostin AG1478, an EGFR tyrosine kinase inhibitor, and curcumin, an inhibitor of both STAT3 and EGFR, attenuated STAT3 activation/nuclear translocation, reduced skin thickening, and partially suppressed the barrier abnormalities. These data identify FATP4 activity as negatively influencing EGFR activation and the resulting STAT3 signaling during normal skin development. These findings have important implications for understanding the pathogenesis of ichthyosis prematurity syndrome, a disease recently shown to be caused by FATP4 mutations. Author Affiliation: (a) Renal Division, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA (b) Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA (c) Institute of Oral Biology, School of Dentistry, National Yang-Ming University, No. 155, Li-Nong Street, Section 2, Peitou, Taipei, Taiwan 112 Article History: Received 30 April 2010; Revised 21 May 2010; Accepted 21 May 2010

Oxidative stress is a primary trigger of cachectic muscle wasting, but the signaling pathway(s) that links it to the muscle wasting processes remains to be defined. Here, we report that activation of p38 mitogen-activated protein kinase (MAPK) (phosphorylation) and increased oxidative stress Urans-4-hydroxy-2-nonenal protein modification) in skeletal muscle occur as early as 8 h after lipopolysaccharide (1 mg/kg) and 24 h after dexamethasone (25 mg/kg) injection (intraperitoneal) in mice, concurrent with upregulation of autophagy-related genes, Atg6, Atg7, and Atg12. Treating cultured C2C12 myotubes with oxidant hydrogen peroxide (4 h) resulted in increased p38 phosphorylation and reduced FoxO3 phosphorylation along with induced Atg7 mRNA expression without activation of NF-[kappa]B or FoxO3a transcriptional activities. Furthermore, inhibition of p38[alpha]/[beta] by SB202190 blocked hydrogen peroxide-induced atrophy with diminished upregulation of Atg7 and atrogenes [muscle atrophy F-box protein (MAFbx/Atrogin-1), muscle ring finger protein 1 (MuRF-1), and Nedd4]. These findings provide direct evidence for p38[alpha]/[beta] MAPK in mediating oxidative stress-induced autophagy-related genes, suggesting that p38[alpha]/[beta] MAPK regulates both the ubiquitin-proteasome and the autophagylysosome systems in muscle wasting. skeletal muscle; atrophy; cachexia doi:10.1152/ajpcell.00192.2009

Purpose Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor of hypoxia-induced gene expression. Anesthetics and perioperative drugs have been reported to affect HIF-1 activity. However, the effect of propofol on HIF-1 activity is not well documented. In this study, we investigated the effect of propofol on HIF-1 activation using macrophage-differentiated THP-1 cells. Methods Cells were exposed to lipopolysaccharide (LPS) under 20 or 1% [O.sub.2] conditions with or without propofol treatment. The cell lysate was subjected to Western blot analysis using anti-HIF-1α and HIF-1β antibodies. HIF-1-dependent gene expression was investigated by quantitative real-time reverse-transcriptase PCR analysis and luciferase assay. The amount of cellular lactate and ATP was assayed. Results Propofol suppressed HIF-1α protein accumulation induced by LPS, but not by hypoxia in the THP-1 cells in a dose-dependent manner by inhibiting the neo-synthesis of HIF-1α protein. Induction of the HIF-1 downstream gene expression including glucose transporter 1, enolase 1, lactate dehydrogenase A, pyruvate dehydrogenase kinase-1 and vascular endothelial growth factor was inhibited by propofol. Propofol suppressed LPS-induced lactate accumulation and ATP content in THP-1 cells., Conclusion Our experimental results indicate that propofol inhibits HIF-1 activation and downstream gene expression induced by LPS and suppressed HIF-1-dependent glucose metabolic reprogramming. HIF-1 suppression by propofol in macrophages may [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tibs.2009.02.007 Byline: Linda Vermeulen, Wim Vanden Berghe, Ilse M.E. Beck, Karolien De Bosscher, Guy Haegeman Abstract: Among the mitogen-activated protein kinase (MAPK) targets, MSKs (mitogen- and stress-activated protein kinases) comprise a particularly interesting protein family. Because MSKs can be activated by both extracellular-signal-regulated kinase and p38 MAPKs, they are activated by many physiological and pathological stimuli. About ten years after their original discovery, they have been recognized as versatile kinases regulating gene transcription at multiple levels. MSKs directly target transcription factors, such as cAMP-response-element-binding protein and nuclear factor-[kappa]B, thereby enhancing their transcriptional activity. They also induce histone phosphorylation, which is accompanied by chromatin relaxation and facilitated binding of additional regulatory proteins. Here, we review the current knowledge on MSK activation and its molecular targets, focusing on recent insights into the role of MSKs at multiple levels of transcriptional regulation. Author Affiliation: Laboratory of Eukaryotic Gene Expression & Signal Transduction (LEGEST), Department of Physiology, Ghent University, K.L. Ledeganckstraat 35, 9000 Gent, Belgium

The signaling mechanisms in vasculogenesis and/or angiogenesis remain poorly understood, limiting the ability to regulate growth of new blood vessels in vitro and in vivo. Cultured human lung microvascular endothelial cells align into tubular networks in the three-dimensional matrix, Matrigel. Overexpression of MAPK phosphatase-1 (MKP-1), an enzyme that inactivates the ERK, JNK, and p38 pathways, inhibited network formation of these cells. Adenoviral-mediated overexpression of recombinant MKP-3 (a dual specificity phosphatase that specifically inactivates the ERK pathway) and dominant negative or constitutively active MEK did not attenuate network formation in Matrigel compared with negative controls. This result suggested that the ERK pathway may not be essential for tube assembly, a conclusion which was supported by the action of specific MEK inhibitor PD 184352, which also did not alter network formation. Inhibition of the JNK pathway using SP-600125 or L-stereoisomer (L-JNKI-1) blocked network formation, whereas the p38 MAPK blocker SB-203580 slightly enhanced it. Inhibition of JNK also attenuated the number of small vessel branches in the developing chick chorioallantoic membrane. Our results demonstrate a specific role for the JNK pathway in network formation of human lung endothelial cells in vitro while confirming that it is essential for the formation of new vessels in vivo. mitogen-activated protein kinase; extracellular signal-regulated kinase; mitogen-activated protein kinase phosphatase; dominant negative mitogen-activated protein kinase-extracellular signal-regulated kinase kinase; PD 184352

Mitogenactivated protein kinase kinase kinase 3 (MEKK3) plays an essential role in embryonic angiogenesis, but its role in tumor growth and angiogenesis is unknown. In this study, we further investigated the role of MEKK3 in embryonic angiogenesis, tumor angiogenesis, and angiogenic factor production. We found that endothelial cells from Mekk3-deficient embryos showed defects in cell proliferation, apoptosis, and interactions with myocardium in the heart. We also found that MEKK3 is required for angiopoietin-1 (Angl)-induced p38 and ERK5 activation. To study the role of MEKK3 in tumor growth and angiogenesis, we established both wild-type and Mekk3-deficient tumor-like embryonic stem cell lines and transplanted them subcutaneously into nude mice to assess their ability to grow and induce tumor angiogenesis. Mekk3-deficient tumors developed and grew similarly as control Mekk3 wild-type tumors and were also capable of inducing tumor angiogenesis. In addition, we found no differences in the production of VEGF in Mekk3-deficient tumors or embryos. Taken together, our results suggest that MEKK3 plays a critical role in Angl/Tie2 signaling to control endothelial cell proliferation and survival and is required for endothelial cells to interact with the myocardium during early embryonic development. However, MEKK3 is not essential for tumor growth and angiogenesis. cardiovascular: mitogen-activated protein kinase: embryonic development

p38 mitogen-activated protein kinase (MAPK) activates a number of heat shock proteins (HSPs), including HSP27 and [[alpha].sub.B]-crystallin, in response to stress. Activation of HSP27 or [[alpha].sub.B]-crystallin is known to protect organs/cells by increasing the stability of actin microfilaments. Although our previous studies showed that 17[beta]-estradiol (E2) improves cardiovascular function after trauma-hemorrhage, whether the salutary effects of E2 under those conditions are mediated via p38 MAPK remains unknown. Male rats (275-325 g body wt) were subjected to soft tissue trauma and hemorrhage (35-40 mmHg mean blood pressure for ~90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were injected intravenously with vehicle, [E.sub.2] (1 mg/kg body wt), [E.sub.2] + the p38 MAPK inhibitor SB-203580 (2 mg/kg body wt), or SB-203580 alone, and various parameters were measured 2 h thereafter. Cardiac functions that were depressed after trauma-hemorrhage were returned to normal levels by [E.sub.2] administration, and phosphorylation of cardiac p38 MAPK, HSP27, and [[alpha].sub.B]-crystallin was increased. The E2-mediated improvement of cardiac function and increase in p38 MAPK, HSP27, and [[alpha].sub.B]-crystallin phosphorylation were abolished with coadministration of SB-203580. These results suggest that the salutary effect of [E.sub.2] on cardiac function after trauma-hemorrhage is in part mediated via upregulation of p38 MAPK and subsequent phosphorylation of HSP27 and [[alpha].sub.B]-crystallin. heat shock proteins; [[alpha].sub.B]-crystallin; p38 mitogen-activated protein kinase inhibitor doi: 10.1152/ajpheart.01303.2006.