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Sample records for homeostasis regulate lymphoid

  1. Adipose Type One Innate Lymphoid Cells Regulate Macrophage Homeostasis through Targeted Cytotoxicity.

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    Boulenouar, Selma; Michelet, Xavier; Duquette, Danielle; Alvarez, David; Hogan, Andrew E; Dold, Christina; O'Connor, Donal; Stutte, Suzanne; Tavakkoli, Ali; Winters, Desmond; Exley, Mark A; O'Shea, Donal; Brenner, Michael B; von Andrian, Ulrich; Lynch, Lydia

    2017-02-21

    Adipose tissue has a dynamic immune system that adapts to changes in diet and maintains homeostatic tissue remodeling. Adipose type 1 innate lymphoid cells (AT1-ILCs) promote pro-inflammatory macrophages in obesity, but little is known about their functions at steady state. Here we found that human and murine adipose tissue harbor heterogeneous populations of AT1-ILCs. Experiments using parabiotic mice fed a high-fat diet (HFD) showed differential trafficking of AT1-ILCs, particularly in response to short- and long-term HFD and diet restriction. At steady state, AT1-ILCs displayed cytotoxic activity toward adipose tissue macrophages (ATMs). Depletion of AT1-ILCs and perforin deficiency resulted in alterations in the ratio of inflammatory to anti-inflammatory ATMs, and adoptive transfer of AT1-ILCs exacerbated metabolic disorder. Diet-induced obesity impaired AT1-ILC killing ability. Our findings reveal a role for AT1-ILCs in regulating ATM homeostasis through cytotoxicity and suggest that this function is relevant in both homeostasis and metabolic disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions

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    Yao, David; Huang, Yuanshuai; Huang, Xiaoran; Wang, Weihuan; Yan, Quanjian; Wei, Lebing; Xin, Wei; Gerson, Stanton; Stanley, Pamela; Lowe, John B.

    2011-01-01

    Notch signaling is essential for lymphocyte development and is also implicated in myelopoiesis. Notch receptors are modified by O-fucosylation catalyzed by protein O-fucosyltransferase 1 (Pofut1). Fringe enzymes add N-acetylglucosamine to O-fucose and modify Notch signaling by altering the sensitivity of Notch receptors to Notch ligands. To address physiologic functions in hematopoiesis of Notch modified by O-fucose glycans, we examined mice with inducible inactivation of Pofut1 using Mx-Cre. These mice exhibited a reduction in T lymphopoiesis and in the production of marginal-zone B cells, in addition to myeloid hyperplasia. Restoration of Notch1 signaling rescued T lymphopoiesis and the marrow myeloid hyperplasia. After marrow transfer, both cell-autonomous and environmental cues were found to contribute to lymphoid developmental defects and myeloid hyperplasia in Pofut1-deleted mice. Although Pofut1 deficiency slightly decreased cell surface expression of Notch1 and Notch2, it completely abrogated the binding of Notch receptors with Delta-like Notch ligands and suppressed downstream Notch target activation, indicating that O-fucose glycans are critical for efficient Notch-ligand binding that transduce Notch signals. The combined data support a key role for the O-fucose glycans generated by Pofut1 in Notch regulation of hematopoietic homeostasis through modulation of Notch-ligand interactions. PMID:21464368

  3. Innate lymphoid cells in tissue homeostasis and diseases.

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    Ignacio, Aline; Breda, Cristiane Naffah Souza; Camara, Niels Olsen Saraiva

    2017-08-18

    Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells. They are a part of the innate immune system, but develop from the lymphoid lineage. They lack pattern-recognition receptors and rearranged receptors, and therefore cannot directly mediate antigen specific responses. The progenitors specifically associated with the ILCs lineage have been uncovered, enabling the distinction between ILCs and natural killer cells. Based on the requirement of specific transcription factors and their patterns of cytokine production, ILCs are categorized into three subsets (ILC1, ILC2 and ILC3). First observed in mucosal surfaces, these cell populations interact with hematopoietic and non-hematopoietic cells throughout the body during homeostasis and diseases, promoting immunity, commensal microbiota tolerance, tissue repair and inflammation. Over the last 8 years, ILCs came into the spotlight as an essential cell type able to integrate diverse host immune responses. Recently, it became known that ILC subsets play a key role in immune responses at barrier surfaces, interacting with the microbiota, nutrients and metabolites. Since the liver receives the venous blood directly from the intestinal vein, the intestine and liver are essential to maintain tolerance and can rapidly respond to infections or tissue damage. Therefore, in this review, we discuss recent findings regarding ILC functions in homeostasis and disease, with a focus on the intestine and liver.

  4. Regulation of cholesterol homeostasis

    NARCIS (Netherlands)

    van der Wulp, Mariette Y. M.; Verkade, Henkjan J.; Groen, Albert K.

    2013-01-01

    Hypercholesterolemia is an important risk factor for cardiovascular disease. It is caused by a disturbed balance between cholesterol secretion into the blood versus uptake. The pathways involved are regulated via a complex interplay of enzymes, transport proteins, transcription factors and

  5. Innate lymphoid cells: models of plasticity for immune homeostasis and rapid responsiveness in protection.

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    Almeida, F F; Belz, G T

    2016-09-01

    Innate lymphoid cells (ILCs) have stormed onto the immune landscape as "newly discovered" cell types. These tissue-resident sentinels are enriched at mucosal surfaces and engage in complex cross talk with elements of the adaptive immune system and microenvironment to orchestrate immune homeostasis. Many parallels exist between innate cells and T cells leading to the initial partitioning of ILCs into rather rigid subsets that reflect their "adaptive-like" effector cytokines profiles. ILCs themselves, however, have unique attributes that are only just beginning to be elucidated. These features result in complementarity with, rather than complete duplication of, functions of the adaptive immune system. Key transcription factors determine the pathway of differentiation of progenitors towards an ILC1, ILC2, or ILC3 subset. Once formed, flexibility in the responses of these subsets to stimuli unexpectedly allows transdifferentation between the different subsets and the acquisition of altered phenotypes and function. This provides a mechanism for rapid innate immune responsiveness. Here, we discuss the models of differentiation for maintenance and activation of tissue-resident ILCs in maintaining immune homeostasis and protection.

  6. The aged lymphoid tissue environment fails to support naïve T cell homeostasis

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    Becklund, Bryan R.; Purton, Jared F.; Ramsey, Chris; Favre, Stéphanie; Vogt, Tobias K.; Martin, Christopher E.; Spasova, Darina S.; Sarkisyan, Gor; LeRoy, Eric; Tan, Joyce T.; Wahlus, Heidi; Bondi-Boyd, Brea; Luther, Sanjiv A.; Surh, Charles D.

    2016-01-01

    Aging is associated with a gradual loss of naïve T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naïve T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naïve T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naïve T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naïve T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naïve T cell pool deteriorate with age. PMID:27480406

  7. Epigenetic Regulation of Cholesterol Homeostasis

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    Steve eMeaney

    2014-09-01

    Full Text Available Although best known as a risk factor for cardiovascular disease, cholesterol is a vital component of all mammalian cells. In addition to key structural roles, cholesterol is a vital biochemical precursor for numerous biologically important compounds including oxysterols and bile acids, as well as acting as an activator of critical morphogenic systems (e.g. the Hedgehog system. A variety of sophisticated regulatory mechanisms interact to coordinate the overall level of cholesterol in cells, tissues and the entire organism. Accumulating evidence indicates that in additional to the more ‘traditional’ regulatory schemes, cholesterol homeostasis is also under the control of epigenetic mechanisms such as histone acetylation and DNA methylation. The available evidence supporting a role for these mechanisms in the control of cholesterol synthesis, elimination, transport and storage are the focus of this review.

  8. Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells.

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    Cautivo, Kelly M; Molofsky, Ari B

    2016-06-01

    Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus. In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy AT, including those associated with type 2 or "allergic" immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, AT "browning," and systemic insulin sensitivity, protecting against obesity-induced metabolic dysfunction and type 2 diabetes mellitus. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines interleukin-5 and IL-13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of group 2 innate lymphoid cell cells and type 2 immunity in AT metabolism and homeostasis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Achieving global perfect homeostasis through transporter regulation

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    Springer, Michael

    2017-01-01

    Nutrient homeostasis—the maintenance of relatively constant internal nutrient concentrations in fluctuating external environments—is essential to the survival of most organisms. Transcriptional regulation of plasma membrane transporters by internal nutrient concentrations is typically assumed to be the main mechanism by which homeostasis is achieved. While this mechanism is homeostatic we show that it does not achieve global perfect homeostasis—a condition where internal nutrient concentrations are completely independent of external nutrient concentrations for all external nutrient concentrations. We show that the criterion for global perfect homeostasis is that transporter levels must be inversely proportional to net nutrient flux into the cell and that downregulation of active transporters (activity-dependent regulation) is a simple and biologically plausible mechanism that meets this criterion. Activity-dependent transporter regulation creates a trade-off between robustness and efficiency, i.e., the system's ability to withstand perturbation in external nutrients and the transporter production rate needed to maintain homeostasis. Additionally, we show that a system that utilizes both activity-dependent transporter downregulation and regulation of transporter synthesis by internal nutrient levels can create a system that mitigates the shortcomings of each of the individual mechanisms. This analysis highlights the utility of activity-dependent regulation in achieving homeostasis and calls for a re-examination of the mechanisms of regulation of other homeostatic systems. PMID:28414718

  10. The liver in regulation of iron homeostasis.

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    Rishi, Gautam; Subramaniam, V Nathan

    2017-09-01

    The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body's metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism. Copyright © 2017 the American Physiological Society.

  11. Regulation of energy homeostasis via GPR120

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    Atsuhiko eIchimura

    2014-07-01

    Full Text Available Free fatty acids (FFAs are fundamental units of key nutrients. FFAs exert various biological functions, depending on the chain length and degree of desaturation. Recent studies have shown that several FFAs act as ligands of G-protein-coupled receptors (GPCRs, activate intracellular signaling and exert physiological functions via these GPCRs. GPR120 (also known as free fatty acid receptor 4, FFAR4 is activated by unsaturated medium- to long-chain FFAs and has a critical role in various physiological homeostasis mechanisms such as incretin hormone secretion, food preference, anti-inflammation and adipogenesis. Recent studies showed that a lipid sensor GPR120 has a key role in sensing dietary fat in white adipose tissue and regulates the whole body energy homeostasis in both humans and rodents. Genetic study in human identified the loss-of-functional mutation of GPR120 associated with obesity and insulin resistance. In addition, dysfunction of GPR120 has been linked as a novel risk factor for diet-induced obesity. This review aims to provide evidence from the recent development in physiological function of GPR120 and discusses its functional roles in regulation of energy homeostasis and its potential as drug targets.

  12. Innate Lymphoid Cells: A Promising New Regulator in Fibrotic Diseases.

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    Zhang, Yi; Tang, Jun; Tian, Zhiqiang; van Velkinburgh, Jennifer C; Song, Jianxun; Wu, Yuzhang; Ni, Bing

    2016-09-02

    Fibrosis is a consequence of chronic inflammation and the persistent accumulation of extracellular matrix, for which the cycle of tissue injury and repair becomes a predominant feature. Both the innate and adaptive immune systems play key roles in the progress of fibrosis. The recently identified subsets of innate lymphoid cells (ILCs), which are mainly localize to epithelial surfaces, have been characterized as regulators of chronic inflammation and tissue remodeling, representing a functional bridge between the innate and adaptive immunity. Moreover, recent research has implicated ILCs as potential contributing factors to several kinds of fibrosis diseases, such as hepatic fibrosis and pulmonary fibrosis. Here, we will summarize and discuss the key roles of ILCs and their related factors in fibrotic diseases and their potential for translation to the clinic.

  13. Lipid Raft, Regulator of Plasmodesmal Callose Homeostasis

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    Arya Bagus Boedi Iswanto

    2017-04-01

    Full Text Available Abstract: The specialized plasma membrane microdomains known as lipid rafts are enriched by sterols and sphingolipids. Lipid rafts facilitate cellular signal transduction by controlling the assembly of signaling molecules and membrane protein trafficking. Another specialized compartment of plant cells, the plasmodesmata (PD, which regulates the symplasmic intercellular movement of certain molecules between adjacent cells, also contains a phospholipid bilayer membrane. The dynamic permeability of plasmodesmata (PDs is highly controlled by plasmodesmata callose (PDC, which is synthesized by callose synthases (CalS and degraded by β-1,3-glucanases (BGs. In recent studies, remarkable observations regarding the correlation between lipid raft formation and symplasmic intracellular trafficking have been reported, and the PDC has been suggested to be the regulator of the size exclusion limit of PDs. It has been suggested that the alteration of lipid raft substances impairs PDC homeostasis, subsequently affecting PD functions. In this review, we discuss the substantial role of membrane lipid rafts in PDC homeostasis and provide avenues for understanding the fundamental behavior of the lipid raft–processed PDC.

  14. Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution.

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    Zeng, Ming; Paiardini, Mirko; Engram, Jessica C; Beilman, Greg J; Chipman, Jeffrey G; Schacker, Timothy W; Silvestri, Guido; Haase, Ashley T

    2012-08-30

    Loss of the fibroblastic reticular cell (FRC) network in lymphoid tissues during HIV-1 infection has been shown to impair the survival of naive T cells and limit immune reconstitution after antiretroviral therapy. What causes this FRC loss is unknown. Because FRC loss correlates with loss of both naive CD4 and CD8 T-cell subsets and decreased lymphotoxin-β, a key factor for maintenance of FRC network, we hypothesized that loss of naive T cells is responsible for loss of the FRC network. To test this hypothesis, we assessed the consequences of antibody-mediated depletion of CD4 and CD8 T cells in rhesus macaques and sooty mangabeys. We found that only CD4 T-cell depletion resulted in FRC loss in both species and that this loss was caused by decreased lymphotoxin-β mainly produced by the CD4 T cells. We further found the same dependence of the FRC network on CD4 T cells in HIV-1-infected patients before and after antiretroviral therapy and in other immunodeficiency conditions, such as CD4 depletion in cancer patients induced by chemotherapy and irradiation. CD4 T cells thus play a central role in the maintenance of lymphoid tissue structure necessary for their own homeostasis and reconstitution.

  15. Regulation of energy homeostasis by GPR41

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    Daisuke eInoue

    2014-05-01

    Full Text Available Imbalances in energy regulation lead to metabolic disorders such as obesity and diabetes. Diet plays an essential role in the maintenance of body energy homeostasis by acting not only as energy source but also as a signaling modality. Excess energy increases energy expenditure, leading to a consumption of them. In addition to glucose, mammals utilize short-chain fatty acids (SCFAs, which are produced by colonic bacterial fermentation of dietary fiber, as a metabolic fuel. The roles of SCFAs in energy regulation have remained unclear, although the roles of glucose are well studied. Recently, a G protein-coupled receptor (GPCR deorphanizing strategy successfully identified GPR41 (also called free fatty acid receptor 3 or FFAR3 as a receptor for SCFAs. GPR41 is expressed in adipose tissue, gut, and the peripheral nervous system, and it is involved in SCFA-dependent energy regulation. In this mini-review, we focus on the role of GPR41 in host energy regulation.

  16. Regulation of Innate Lymphoid Cells by Aryl Hydrocarbon Receptor

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    Shiyang Li

    2018-01-01

    Full Text Available With striking similarity to their adaptive T helper cell counterparts, innate lymphoid cells (ILCs represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer cells, T-bet+ Eomes− group 1 ILCs, GATA3+ group 2 ILCs, RORγt+ group 3 ILCs, and newly identified Id3+ regulatory ILC. ILCs are abundantly present in barrier tissues of the host (e.g., the lung, gut, and skin at the interface of host–environment interactions. Active research has been conducted to elucidate molecular mechanisms underlying the development and function of ILCs. The aryl hydrocarbon receptor (Ahr is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. Here, we review recent progresses regarding Ahr function in ILCs. We focus on the Ahr-mediated cross talk between ILCs and other immune/non-immune cells in host tissues especially in the gut. We discuss the molecular mechanisms of the action of Ahr expression and activity in regulation of ILCs in immunity and inflammation, and the interaction between Ahr and other pathways/transcription factors in ILC development and function with their implication in disease.

  17. Regulation of Innate Lymphoid Cells by Aryl Hydrocarbon Receptor

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    Li, Shiyang; Bostick, John W.; Zhou, Liang

    2018-01-01

    With striking similarity to their adaptive T helper cell counterparts, innate lymphoid cells (ILCs) represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer cells, T-bet+ Eomes− group 1 ILCs, GATA3+ group 2 ILCs, RORγt+ group 3 ILCs, and newly identified Id3+ regulatory ILC. ILCs are abundantly present in barrier tissues of the host (e.g., the lung, gut, and skin) at the interface of host–environment interactions. Active research has been conducted to elucidate molecular mechanisms underlying the development and function of ILCs. The aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. Here, we review recent progresses regarding Ahr function in ILCs. We focus on the Ahr-mediated cross talk between ILCs and other immune/non-immune cells in host tissues especially in the gut. We discuss the molecular mechanisms of the action of Ahr expression and activity in regulation of ILCs in immunity and inflammation, and the interaction between Ahr and other pathways/transcription factors in ILC development and function with their implication in disease. PMID:29354125

  18. High Endothelial Venules and Other Blood Vessels: Critical Regulators of Lymphoid Organ Development and Function.

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    Ager, Ann

    2017-01-01

    The blood vasculature regulates both the development and function of secondary lymphoid organs by providing a portal for entry of hemopoietic cells. During the development of lymphoid organs in the embryo, blood vessels deliver lymphoid tissue inducer cells that initiate and sustain the development of lymphoid tissues. In adults, the blood vessels are structurally distinct from those in other organs due to the requirement for high levels of lymphocyte recruitment under non-inflammatory conditions. In lymph nodes (LNs) and Peyer's patches, high endothelial venules (HEVs) especially adapted for lymphocyte trafficking form a spatially organized network of blood vessels, which controls both the type of lymphocyte and the site of entry into lymphoid tissues. Uniquely, HEVs express vascular addressins that regulate lymphocyte entry into lymphoid organs and are, therefore, critical to the function of lymphoid organs. Recent studies have demonstrated important roles for CD11c+ dendritic cells in the induction, as well as the maintenance, of vascular addressin expression and, therefore, the function of HEVs. Tertiary lymphoid organs (TLOs) are HEV containing LN-like structures that develop inside organized tissues undergoing chronic immune-mediated inflammation. In autoimmune lesions, the development of TLOs is thought to exacerbate disease. In cancerous tissues, the development of HEVs and TLOs is associated with improved patient outcomes in several cancers. Therefore, it is important to understand what drives the development of HEVs and TLOs and how these structures contribute to pathology. In several human diseases and experimental animal models of chronic inflammation, there are some similarities between the development and function of HEVs within LN and TLOs. This review will summarize current knowledge of how hemopoietic cells with lymphoid tissue-inducing, HEV-inducing, and HEV-maintaining properties are recruited from the bloodstream to induce the development and

  19. Innate lymphoid cells in secondary lymphoid organs.

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    Bar-Ephraïm, Yotam E; Mebius, Reina E

    2016-05-01

    The family of innate lymphoid cells (ILCs) has attracted attention in recent years as its members are important regulators of immunity, while they can also cause pathology. In both mouse and man, ILCs were initially discovered in developing lymph nodes as lymphoid tissue inducer (LTi) cells. These cells form the prototypic members of the ILC family and play a central role in the formation of secondary lymphoid organs (SLOs). In the absence of LTi cells, lymph nodes (LN) and Peyer's Patches (PP) fail to form in mice, although the splenic white pulp can develop normally. Besides LTi cells, the ILC family encompasses helper-like ILCs with functional distinctions as seen by T-helper cells, as well as cytotoxic natural killer (NK) cells. ILCs are still present in adult SLOs where they have been shown to play a role in lymphoid tissue regeneration. Furthermore, ILCs were implicated to interact with adaptive lymphocytes and influence the adaptive immune response. Here, we review the recent literature on the role of ILCs in secondary lymphoid tissue from the formation of SLOs to mature SLOs in adults, during homeostasis and pathology. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice.

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    Baerenwaldt, Anne; von Burg, Nicole; Kreuzaler, Matthias; Sitte, Selina; Horvath, Edit; Peter, Annick; Voehringer, David; Rolink, Antonius G; Finke, Daniela

    2016-03-15

    Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7(-) and α4β7(+) lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer's patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46(-) group 3 ILCs in wild-type and even in Il7(-/-) mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer's patches development by targeting lymphoid progenitor cells during fetal and adult life. Copyright © 2016 by The American Association of Immunologists, Inc.

  1. G protein-coupled receptors as regulators of energy homeostasis.

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    Tao, Ya-Xiong; Yuan, Zong-Hui; Xie, Jun

    2013-01-01

    G protein-coupled receptors (GPCRs) are versatile regulators of physiological processes. They are also important drug targets. Many of the molecules controlling energy homeostasis act through GPCRs. This article summarizes the regulators of energy homeostasis in the central nervous system: those secreted by the gastrointestinal peptides and those secreted by the endocrine pancreas. Some examples of orphan GPCRs are also given. The regulation of energy homeostasis is conserved in other mammals, including those species relevant in veterinary medicine, and fish. Finally, the genetics of human obesity is briefly summarized. Genetic susceptibility in the current obesogenic environment is likely causing the obesity pandemic. A better understanding of the regulation of energy homeostasis will lead to novel pharmacotherapy for obesity treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Ca2+ homeostasis regulates Xenopus oocyte maturation.

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    Sun, Lu; Hodeify, Rawad; Haun, Shirley; Charlesworth, Amanda; MacNicol, Angus M; Ponnappan, Subramaniam; Ponnappan, Usha; Prigent, Claude; Machaca, Khaled

    2008-04-01

    In contrast to the well-defined role of Ca2+ signals during mitosis, the contribution of Ca2+ signaling to meiosis progression is controversial, despite several decades of investigating the role of Ca2+ and its effectors in vertebrate oocyte maturation. We have previously shown that during Xenopus oocyte maturation, Ca2+ signals are dispensable for entry into meiosis and for germinal vesicle breakdown. However, normal Ca2+ homeostasis is essential for completion of meiosis I and extrusion of the first polar body. In this study, we test the contribution of several downstream effectors in mediating the Ca2+ effects during oocyte maturation. We show that calmodulin and calcium-calmodulin-dependent protein kinase II (CAMK2) are not critical downstream Ca2+ effectors during meiotic maturation. In contrast, accumulation of Aurora kinase A (AURKA) protein is disrupted in cells deprived of Ca2+ signals. Since AURKA is required for bipolar spindle formation, failure to accumulate AURKA may contribute to the defective spindle phenotype following Ca2+ deprivation. These findings argue that Ca2+ homeostasis is important in establishing the oocyte's competence to undergo maturation in preparation for fertilization and embryonic development.

  3. Breast Milk Hormones and Regulation of Glucose Homeostasis

    OpenAIRE

    Francesco Savino; Stefania Alfonsina Liguori; Miriam Sorrenti; Maria Francesca Fissore; Roberto Oggero

    2011-01-01

    Growing evidence suggests that a complex relationship exists between the central nervous system and peripheral organs involved in energy homeostasis. It consists in the balance between food intake and energy expenditure and includes the regulation of nutrient levels in storage organs, as well as in blood, in particular blood glucose. Therefore, food intake, energy expenditure, and glucose homeostasis are strictly connected to each other. Several hormones, such as leptin, adiponectin, resistin...

  4. Breast Milk Hormones and Regulation of Glucose Homeostasis

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    Francesco Savino

    2011-01-01

    Full Text Available Growing evidence suggests that a complex relationship exists between the central nervous system and peripheral organs involved in energy homeostasis. It consists in the balance between food intake and energy expenditure and includes the regulation of nutrient levels in storage organs, as well as in blood, in particular blood glucose. Therefore, food intake, energy expenditure, and glucose homeostasis are strictly connected to each other. Several hormones, such as leptin, adiponectin, resistin, and ghrelin, are involved in this complex regulation. These hormones play a role in the regulation of glucose metabolism and are involved in the development of obesity, diabetes, and metabolic syndrome. Recently, their presence in breast milk has been detected, suggesting that they may be involved in the regulation of growth in early infancy and could influence the programming of energy balance later in life. This paper focuses on hormones present in breast milk and their role in glucose homeostasis.

  5. Renal renin secretion as regulator of body fluid homeostasis

    DEFF Research Database (Denmark)

    Damkjær, Mads; Isaksson, Gustaf L; Stubbe, Jane

    2013-01-01

    The renin-angiotensin system is essential for body fluid homeostasis and blood pressure regulation. This review focuses on the homeostatic regulation of the secretion of active renin in the kidney, primarily in humans. Under physiological conditions, renin secretion is determined mainly by sodium...

  6. Innate Lymphoid Cells Control Early Colonization Resistance against Intestinal Pathogens through ID2-Dependent Regulation of the Microbiota.

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    Guo, Xiaohuan; Liang, Yong; Zhang, Yuan; Lasorella, Anna; Kee, Barbara L; Fu, Yang-Xin

    2015-04-21

    Microbiota-mediated effects on the host immune response facilitate colonization resistance against pathogens. However, it is unclear whether and how the host immune response can regulate the microbiota to mediate colonization resistance. ID2, an essential transcriptional regulator for the development of innate lymphoid cell (ILC) progenitors, remains highly expressed in differentiated ILCs with unknown function. Using conditionally deficient mice in which ID2 is deleted from differentiated ILC3s, we observed that these mutant mice exhibited greatly impaired gut colonization resistance against Citrobacter rodentium. Utilizing gnotobiotic hosts, we showed that the ID2-dependent early colonization resistance was mediated by interleukin-22 (IL-22) regulation of the microbiota. In addition to regulating development, ID2 maintained homeostasis of ILC3s and controlled IL-22 production through an aryl hydrocarbon receptor (AhR) and IL-23 receptor pathway. Thus, ILC3s can mediate immune surveillance, which constantly maintains a proper microbiota, to facilitate early colonization resistance through an ID2-dependent regulation of IL-22. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Extracellular and Intracellular Regulation of Calcium Homeostasis

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    Felix Bronner

    2001-01-01

    Full Text Available An organism with an internal skeleton must accumulate calcium while maintaining body fluids at a well-regulated, constant calcium concentration. Neither calcium absorption nor excretion plays a significant regulatory role. Instead, isoionic calcium uptake and release by bone surfaces causes plasma calcium to be well regulated. Very rapid shape changes of osteoblasts and osteoclasts, in response to hormonal signals, modulate the available bone surfaces so that plasma calcium can increase when more low-affinity bone calcium binding sites are made available and can decrease when more high-affinity binding sites are exposed. The intracellular free calcium concentration of body cells is also regulated, but because cells are bathed by fluids with vastly higher calcium concentration, their major regulatory mechanism is severe entry restriction. All cells have a calcium-sensing receptor that modulates cell function via its response to extracellular calcium. In duodenal cells, the apical calcium entry structure functions as both transporter and a vitamin D–responsive channel. The channel upregulates calcium entry, with intracellular transport mediated by the mobile, vitamin D–dependent buffer, calbindin D9K, which binds and transports more than 90% of the transcellular calcium flux. Fixed intracellular calcium binding sites can, like the body's skeleton, take up and release calcium that has entered the cell, but the principal regulatory tool of the cell is restricted entry.

  8. ICOS regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice.

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    Paclik, Daniela; Stehle, Christina; Lahmann, Annette; Hutloff, Andreas; Romagnani, Chiara

    2015-10-01

    Group 2 innate lymphoid cells (ILC2s) are innate effectors playing an important role in the defense against helminthic infections and in the pathogenesis of allergic inflammation. Cytokines have been identified as the major stimuli driving ILC2 activation and expansion. Conversely, it is unclear whether costimulatory molecules contribute to regulation of ILC2 functions. ILC2s display high expression of inducible T-cell costimulator (ICOS), which belongs to the CD28 superfamily, and which has been shown to control late effector T-cell functions, and is of utmost importance for the humoral immune response. However, the biological function of ICOS expression on ILC2s is unknown. Here, we show that ICOS signaling in mice regulates ILC2 homeostasis independently of T cells and B cells, by promoting proliferation and accumulation of mature ILC2s in lung and intestine. In a model of IL-33-induced airway inflammation, ICOS controls ILC2 activation and eosinophil infiltration in the lung. Our data identify a role of ICOS in innate immunity and indicate that not only cytokines, but also costimulatory pathways such as those involving ICOS, can contribute to regulate the ILC2 pool. Thus, ICOS costimulation blockade, which is currently under clinical evaluation for inhibiting the humoral immune response, could also target innate inflammatory circuits. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. PPARα: A Master Regulator of Bilirubin Homeostasis

    Directory of Open Access Journals (Sweden)

    Cyril Bigo

    2014-01-01

    Full Text Available Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC and coronary artery smooth muscle cells (CASMC were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO- 1 and biliverdin reductase (BVR enzymes were determined. Human hepatocytes (HH and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT 1A1 enzyme and multidrug resistance-associated protein (MRP 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARα ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARα ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed.

  10. TCR down-regulation controls T cell homeostasis

    DEFF Research Database (Denmark)

    Boding, Lasse; Bonefeld, Charlotte Menné; Nielsen, Bodil L

    2009-01-01

    was caused by the combination of reduced thymic output, decreased T cell apoptosis, and increased transition of naive T cells to memory T cells. Experiments with bone marrow chimeric mice confirmed that the CD3gammaLLAA mutation exerted a T cell intrinsic effect on T cell homeostasis that resulted...... in an increased transition of CD3gammaLLAA naive T cells to memory T cells and a survival advantage of CD3gammaLLAA T cells compared with wild-type T cells. The experimental observations were further supported by mathematical modeling of T cell homeostasis. Our study thus identifies an important role of CD3gamma......-mediated TCR down-regulation in T cell homeostasis....

  11. PAS kinase: a nutrient sensing regulator of glucose homeostasis.

    Science.gov (United States)

    DeMille, Desiree; Grose, Julianne H

    2013-11-01

    Per-Arnt-Sim (PAS) kinase (PASK, PASKIN, and PSK) is a member of the group of nutrient sensing protein kinases. These protein kinases sense the energy or nutrient status of the cell and regulate cellular metabolism appropriately. PAS kinase responds to glucose availability and regulates glucose homeostasis in yeast, mice, and man. Despite this pivotal role, the molecular mechanisms of PAS kinase regulation and function are largely unknown. This review focuses on what is known about PAS kinase, including its conservation from yeast to man, identified substrates, associated phenotypes and role in metabolic disease. © 2013 International Union of Biochemistry and Molecular Biology.

  12. Neuropeptide Y: a central regulator of energy homeostasis.

    Science.gov (United States)

    White, J D

    1993-12-10

    Neuropeptide Y (NPY) is a 36 amino acid peptide belonging to the pancreatic polypeptide family of neuroendocrine hormones. It is the most abundant peptide yet discovered in the mammalian brain and is widely expressed by neurons in the central and peripheral nervous systems as well as adrenal medullary cells. Recently, a large number of studies have focussed on the potential roles played by NPY within the hypothalamus and pituitary with respect to the control of food intake and energy homeostasis. It is now clear that NPY is a potent stimulator of food intake in models of hyperphagia, that hypothalamic NPY also regulates sympathetic neural activity and it appears that NPY may also influence the glucocorticoid, growth hormone and thyroid hormone axes. Taken together, current data suggest that hypothalamic and pituitary NPY-expressing cells represent an important and critical site of integration of peripheral hormonal signals with regulation of energy homeostasis.

  13. TYK2 is a key regulator of the surveillance of B lymphoid tumors

    Science.gov (United States)

    Stoiber, Dagmar; Kovacic, Boris; Schuster, Christian; Schellack, Carola; Karaghiosoff, Marina; Kreibich, Rita; Weisz, Eva; Artwohl, Michaela; Kleine, Olaf C.; Muller, Mathias; Baumgartner-Parzer, Sabina; Ghysdael, Jacques; Freissmuth, Michael; Sexl, Veronika

    2004-01-01

    Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice. We show here that the Janus kinase TYK2 serves an opposite function. Mice deficient in TYK2 developed Abelson-induced B lymphoid leukemia/lymphoma as well as TEL-JAK2–induced T lymphoid leukemia with a higher incidence and shortened latency compared with WT controls. The cell-autonomous properties of Abelson murine leukemia virus–transformed (A-MuLV–transformed) TYK2–/– cells were unaltered, but the high susceptibility of TYK2–/– mice resulted from an impaired tumor surveillance, and accordingly, TYK2–/– A-MuLV–induced lymphomas were easily rejected after transplantation into WT hosts. The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2–/– NK and NKT cells toward tumor-derived cells. RAG2/TYK2 double-knockout mice succumbed to A-MuLV–induced leukemia/lymphoma faster than RAG2–/–TYK2+/– mice. This defines NK cells as key players in tumor surveillance in Abelson-induced malignancies. Our observations provide compelling evidence that TYK2 is an important regulator of lymphoid tumor surveillance. PMID:15578097

  14. TAK1 regulates hepatic lipid homeostasis through SREBP.

    Science.gov (United States)

    Morioka, S; Sai, K; Omori, E; Ikeda, Y; Matsumoto, K; Ninomiya-Tsuji, J

    2016-07-21

    Sterol-regulatory element-binding proteins (SREBPs) are key transcription factors regulating cholesterol and fatty acid biosynthesis. SREBP activity is tightly regulated to maintain lipid homeostasis, and is modulated upon extracellular stimuli such as growth factors. While the homeostatic SREBP regulation is well studied, stimuli-dependent regulatory mechanisms are still elusive. Here we demonstrate that SREBPs are regulated by a previously uncharacterized mechanism through transforming growth factor-β activated kinase 1 (TAK1), a signaling molecule of inflammation. We found that TAK1 binds to and inhibits mature forms of SREBPs. In an in vivo setting, hepatocyte-specific Tak1 deletion upregulates liver lipid deposition and lipogenic enzymes in the mouse model. Furthermore, hepatic Tak1 deficiency causes steatosis pathologies including elevated blood triglyceride and cholesterol levels, which are established risk factors for the development of hepatocellular carcinoma (HCC) and are indeed correlated with Tak1-deficiency-induced HCC development. Pharmacological inhibition of SREBPs alleviated the steatosis and reduced the expression level of the HCC marker gene in the Tak1-deficient liver. Thus, TAK1 regulation of SREBP critically contributes to the maintenance of liver homeostasis to prevent steatosis, which is a potentially important mechanism to prevent HCC development.

  15. Regulation of energy homeostasis by the NPY system.

    Science.gov (United States)

    Loh, Kim; Herzog, Herbert; Shi, Yan-Chuan

    2015-03-01

    Obesity develops when energy intake exceeds energy expenditure over time. Numerous neurotransmitters, hormones, and factors have been implicated to coordinately control energy homeostasis, centrally and peripherally. However, the neuropeptide Y (NPY) system has emerged as the one with the most critical functions in this process. While NPY centrally promotes feeding and reduces energy expenditure, peptide YY (PYY) and pancreatic polypeptide (PP), the other family members, mediate satiety. Importantly, recent research has uncovered additional functions for these peptides that go beyond the simple feeding/satiety circuits and indicate a more extensive function in controlling energy homeostasis. In this review, we will discuss the actions of the NPY system in the regulation of energy balance, with a particular focus on energy expenditure. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Activation of epithelial STAT3 regulates intestinal homeostasis.

    Science.gov (United States)

    Neufert, Clemens; Pickert, Geethanjali; Zheng, Yan; Wittkopf, Nadine; Warntjen, Moritz; Nikolaev, Alexei; Ouyang, Wenjun; Neurath, Markus F; Becker, Christoph

    2010-02-15

    The intestinal epithelium that lines the mucosal surface along the GI-tract is a key player for the intestinal homeostasis of the healthy individual. In case of a mucosal damage or a barrier defect as seen in patients with inflammatory bowel disease, the balance is disturbed, and translocation of intestinal microbes to the submucosa is facilitated. We recently demonstrated a pivotal role of STAT3 activation in intestinal epithelial cells (IEC) for the restoration of the balance at the mucosal surface of the gut in an experimental colitis model. STAT3 was rapidly induced in intestinal epithelial cells upon challenge of mice in both experimental colitis and intestinal wound healing models. STAT3 activation was found to be dispensable in the steady-state conditions but was important for efficient regeneration of the epithelium in response to injury. Here, we extend our previous findings by showing epithelial STAT3 activation in human patients suffering from IBD and provide additional insights how the activation of epithelial STAT3 by IL-22 regulates intestinal homeostasis and mucosal wound healing. We also demonstrate that antibody-mediated neutralization of IL-22 has little impact on the development of experimental colitis in mice, but significantly delays recovery from colitis. Thus, our data suggest that targeting the STAT3 signaling pathway in IEC is a promising therapeutic approach in situations when the intestinal homeostasis is disturbed, e.g., as seen in Crohn's disease or Ulcerative colitis.

  17. Splicing regulator SLU7 is essential for maintaining liver homeostasis.

    Science.gov (United States)

    Elizalde, María; Urtasun, Raquel; Azkona, María; Latasa, María U; Goñi, Saioa; García-Irigoyen, Oihane; Uriarte, Iker; Segura, Victor; Collantes, María; Di Scala, Mariana; Lujambio, Amaia; Prieto, Jesús; Ávila, Matías A; Berasain, Carmen

    2014-07-01

    A precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver develops as the result of hepatocellular de-differentiation and uncontrolled proliferation. Here, we identified SLU7, which encodes a pre-mRNA splicing regulator that is inhibited in hepatocarcinoma, as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Additionally, loss of SLU7 also increased hepatocellular proliferation and induced a switch to a tumor-like glycolytic phenotype. Slu7 governed the splicing and/or expression of multiple genes essential for hepatocellular differentiation, including serine/arginine-rich splicing factor 3 (Srsf3) and hepatocyte nuclear factor 4α (Hnf4α), and was critical for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte identity and quiescence.

  18. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

    Directory of Open Access Journals (Sweden)

    Katharina Timper

    2017-06-01

    Full Text Available The ‘obesity epidemic’ represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed.

  19. NK Cells Alleviate Lung Inflammation by Negatively Regulating Group 2 Innate Lymphoid Cells.

    Science.gov (United States)

    Bi, Jiacheng; Cui, Lulu; Yu, Guang; Yang, Xiaolu; Chen, Youhai; Wan, Xiaochun

    2017-04-15

    Group 2 innate lymphoid cells (ILC2s) play an important role in orchestrating type II immune responses. However, the cellular mechanisms of group 2 innate lymphoid cell regulation remain poorly understood. In this study, we found that activated NK cells inhibited the proliferation of, as well as IL-5 and IL-13 production by, ILC2s in vitro via IFN-γ. In addition, in a murine model of ILC2 expansion in the liver, polyinosinic-polycytidylic acid, an NK cell-activating agent, inhibited ILC2 proliferation, IL-5 and IL-13 production, and eosinophil recruitment. Such effects of polyinosinic-polycytidylic acid were abrogated in NK cell-depleted mice and in IFN-γ-deficient mice. Adoptively transferring wild-type NK cells into NK cell-depleted mice resulted in fewer ILC2s induced by IL-33 compared with the transfer of IFN-γ-deficient NK cells. Importantly, during the early stage of papain- or bleomycin-induced lung inflammation, depletion of NK cells resulted in increased ILC2 numbers and enhanced cytokine production by ILC2s, as well as aggravated eosinophilia and goblet cell hyperplasia. Collectively, these data show that NK cells negatively regulate ILC2s during the early stage of lung inflammation, which represents the novel cellular interaction between two family members of ILCs. Copyright © 2017 by The American Association of Immunologists, Inc.

  20. Homeostasis

    Directory of Open Access Journals (Sweden)

    Anna Negroni

    2015-01-01

    Full Text Available Intestinal epithelial cells (IECs form a physiochemical barrier that separates the intestinal lumen from the host’s internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium.

  1. Delineating the regulation of energy homeostasis using hypothalamic cell models.

    Science.gov (United States)

    Wellhauser, Leigh; Gojska, Nicole M; Belsham, Denise D

    2015-01-01

    Attesting to its intimate peripheral connections, hypothalamic neurons integrate nutritional and hormonal cues to effectively manage energy homeostasis according to the overall status of the system. Extensive progress in the identification of essential transcriptional and post-translational mechanisms regulating the controlled expression and actions of hypothalamic neuropeptides has been identified through the use of animal and cell models. This review will introduce the basic techniques of hypothalamic investigation both in vivo and in vitro and will briefly highlight the key advantages and challenges of their use. Further emphasis will be place on the use of immortalized models of hypothalamic neurons for in vitro study of feeding regulation, with a particular focus on cell lines proving themselves most fruitful in deciphering fundamental basics of NPY/AgRP, Proglucagon, and POMC neuropeptide function. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. CART in the Regulation of Appetite and Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Jackie eLau

    2014-10-01

    Full Text Available The cocaine- and amphetamine-regulated transcript (CART has been the subject of significant interest for over a decade. Work to decipher the detailed mechanism of CART function has been hampered by the lack of specific pharmacological tools like antagonists and the absence of a specific CART receptor(s. However, extensive research has been devoted to elucidate the role of the CART peptide and it is now evident that CART is a key neurotransmitter and hormone involved in the regulation of diverse biological processes, including food intake, maintenance of body weight, reward and addiction, stress response, psychostimulant effects and endocrine functions1,2. In this review, we focus on knowledge gained on CART’s role in controlling appetite and energy homeostasis, and also address certain species differences between rodents and humans.

  3. TSLP and Immune Homeostasis

    Science.gov (United States)

    Hanabuchi, Shino; Watanabe, Norihiko; Liu, Yong-Jun

    2013-01-01

    In an immune system, dendritic cells (DCs) are professional antigen-presenting cells (APCs) as well as powerful sensors of danger signals. When DCs receive signals from infection and tissue stress, they immediately activate and instruct the initiation of appropriate immune responses to T cells. However, it has remained unclear how the tissue microenvironment in a steady state shapes the function of DCs. Recent many works on thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine that has the strong ability to activate DCs, provide evidence that TSLP mediates crosstalk between epithelial cells and DCs, involving in DC-mediated immune homeostasis. Here, we review recent progress made on how TSLP expressed within the thymus and peripheral lymphoid and non-lymphoid tissues regulates DC-mediated T-cell development in the thymus and T-cell homeostasis in the periphery. PMID:22270070

  4. MicroRNAs and the regulation of intestinal homeostasis

    Directory of Open Access Journals (Sweden)

    Marah C Runtsch

    2014-10-01

    Full Text Available The mammalian intestinal tract is a unique site in which a large portion of our immune system and the 10^14 commensal organisms that make up the microbiota reside in intimate contact with each other. Despite the potential for inflammatory immune responses, this complex interface contains host immune cells and epithelial cells interacting with the microbiota in a manner that promotes symbiosis. Due to the complexity of the cell types and microorganisms involved, this process requires elaborate regulatory mechanisms to ensure mutualism and prevent disease. While many studies have described critical roles for protein regulators of intestinal homeostasis, recent reports indicate that noncoding RNAs are also major contributors to optimal host-commensal interactions. In particular, there is emerging evidence that microRNAs (miRNAs have evolved to fine tune host gene expression networks and signaling pathways that modulate cellular physiology in the intestinal tract. Here, we review our present knowledge of the influence miRNAs have on both immune and epithelial cell biology in the mammalian intestines and the impact this has on the microbiota. We also discuss a need for further studies to decipher the functions of specific miRNAs within the gut to better understand cellular mechanisms that promote intestinal homeostasis and to identify potential molecular targets underlying diseases such as inflammatory bowel disease (IBD and colorectal cancer (CRC.

  5. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Minqian Shen

    2015-01-01

    Full Text Available The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.

  6. miRNA regulation of nutrient homeostasis in plants

    Directory of Open Access Journals (Sweden)

    Soumitra ePaul

    2015-04-01

    Full Text Available Small RNAs including micro RNAs (miRNA play an indispensable role in cell signaling mechanisms. Generally, miRNAs that are 20-24 nucleotides long bind to specific complementary transcripts, attenuating gene expression at the post-transcriptional level or via translational inhibition. In plants, miRNAs have emerged as the principal regulator of various stress responses, including low nutrient availability. It has been reported that miRNAs are vital for maintaining nutrient homeostasis in plants by regulating the expression of transporters that are involved in nutrient uptake and mobilization. The present review highlights the role of various miRNAs in several macro- or micronutrient deficiencies in plants. Understanding the regulation of different transporters by miRNAs will aid in elucidating the underlying molecular signal transduction mechanisms during nutritional stress. Recent findings regarding nutrient related-miRNAs and their gene regulation machinery may delineate a novel platform for improving the nutritional status of cereal grains or crop biofortification programs in the future.

  7. Innate lymphoid cells in the initiation, regulation and resolution of inflammation

    Science.gov (United States)

    Sonnenberg, Gregory F.; Artis, David

    2016-01-01

    A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans, and found to profoundly influence the induction, regulation and resolution of inflammation. ILCs play an important role in these processes in murine models of infection, inflammatory disease and tissue repair. Further, disease association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review, we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be employed to selectively modulate ILC responses and limit chronic inflammatory diseases in patients. PMID:26121198

  8. Regulation of glucose homeostasis by KSR1 and MARK2.

    Directory of Open Access Journals (Sweden)

    Paula J Klutho

    Full Text Available Protein scaffolds control the intensity and duration of signaling and dictate the specificity of signaling through MAP kinase pathways. KSR1 is a molecular scaffold of the Raf/MEK/ERK MAP kinase cascade that regulates the intensity and duration of ERK activation. Relative to wild-type mice, ksr1⁻/⁻ mice are modestly glucose intolerant, but show a normal response to exogenous insulin. However, ksr1⁻/⁻ mice also demonstrate a three-fold increase in serum insulin levels in response to a glucose challenge, suggesting a role for KSR1 in insulin secretion. The kinase MARK2 is closely related to C-TAK1, a known regulator of KSR1. Mice lacking MARK2 have an increased rate of glucose disposal in response to exogenous insulin, increased glucose tolerance, and are resistant to diet-induced obesity. mark2⁻/⁻ksr1⁻/⁻ (DKO mice were compared to wild type, mark2⁻/⁻, and ksr1⁻/⁻ mice for their ability to regulate glucose homeostasis. Here we show that disruption of KSR1 in mark2⁻/⁻ mice reverses the increased sensitivity to exogenous insulin resulting from MARK2 deletion. DKO mice respond to exogenous insulin similarly to wild type and ksr1⁻/⁻ mice. These data suggest a model whereby MARK2 negatively regulates insulin sensitivity in peripheral tissue through inhibition of KSR1. Consistent with this model, we found that MARK2 binds and phosphorylates KSR1 on Ser392. Phosphorylation of Ser392 is a critical regulator of KSR1 stability, subcellular location, and ERK activation. These data reveal an unexpected role for the molecular scaffold KSR1 in insulin-regulated glucose metabolism.

  9. Carbonic anhydrase 5 regulates acid-base homeostasis in zebrafish.

    Directory of Open Access Journals (Sweden)

    Ruben Postel

    Full Text Available The regulation of the acid-base balance in cells is essential for proper cellular homeostasis. Disturbed acid-base balance directly affects cellular physiology, which often results in various pathological conditions. In every living organism, the protein family of carbonic anhydrases regulate a broad variety of homeostatic processes. Here we describe the identification, mapping and cloning of a zebrafish carbonic anhydrase 5 (ca5 mutation, collapse of fins (cof, which causes initially a collapse of the medial fins followed by necrosis and rapid degeneration of the embryo. These phenotypical characteristics can be mimicked in wild-type embryos by acetazolamide treatment, suggesting that CA5 activity in zebrafish is essential for a proper development. In addition we show that CA5 regulates acid-base balance during embryonic development, since lowering the pH can compensate for the loss of CA5 activity. Identification of selective modulators of CA5 activity could have a major impact on the development of new therapeutics involved in the treatment of a variety of disorders.

  10. Serum and Glucocorticoid Regulated Kinase 1 in Sodium Homeostasis

    Directory of Open Access Journals (Sweden)

    Yiyun Lou

    2016-08-01

    Full Text Available The ubiquitously expressed serum and glucocorticoid regulated kinase 1 (SGK1 is tightly regulated by osmotic and hormonal signals, including glucocorticoids and mineralocorticoids. Recently, SGK1 has been implicated as a signal hub for the regulation of sodium transport. SGK1 modulates the activities of multiple ion channels and carriers, such as epithelial sodium channel (ENaC, voltage-gated sodium channel (Nav1.5, sodium hydrogen exchangers 1 and 3 (NHE1 and NHE3, sodium-chloride symporter (NCC, and sodium-potassium-chloride cotransporter 2 (NKCC2; as well as the sodium-potassium adenosine triphosphatase (Na+/K+-ATPase and type A natriuretic peptide receptor (NPR-A. Accordingly, SGK1 is implicated in the physiology and pathophysiology of Na+ homeostasis. Here, we focus particularly on recent findings of SGK1’s involvement in Na+ transport in renal sodium reabsorption, hormone-stimulated salt appetite and fluid balance and discuss the abnormal SGK1-mediated Na+ reabsorption in hypertension, heart disease, edema with diabetes, and embryo implantation failure.

  11. Keratins regulate β-cell mitochondrial morphology, motility, and homeostasis.

    Science.gov (United States)

    Silvander, Jonas S G; Kvarnström, Sofie M; Kumari-Ilieva, Angeli; Shrestha, Anup; Alam, Catharina M; Toivola, Diana M

    2017-10-01

    Loss of the epithelial intermediate filament protein keratin 8 (K8) in murine β cells leads to irregular insulin vesicles and decreased insulin levels. Because mitochondria are central in glucose-stimulated insulin secretion, the relationship between keratins and β-cell mitochondrial function and morphology was investigated. β cells in murine K8-knockout (K8(-/-)) islets of Langerhans have increased numbers of mitochondria, which are rounder and have diffuse cristae, as seen by electron microscopy. The mitochondrial network in primary cultured K8(-/-) β cells is more fragmented compared with K8(+/+) mitochondria, correlating with decreased levels of mitofusin 2 and the mitofusin 2- and keratin-binding protein trichoplein. K8(-/-) β-cell mitochondria have decreased levels of total and mitochondrial cytochrome c, which correlates with a reduction in electron transport complexes I and IV. This provokes loss of mitochondrial membrane potential and reduction of ATP and insulin amount, as seen in K8(-/-) β cells. Mitochondria in K8 wild-type β cells and MIN6 insulinoma cells overexpressing K8 and 18 are more stationary compared with mitochondria in keratin-deficient cells. In conclusion, keratins, likely through trichoplein-mitofusin interactions, regulate both structural and dynamic functions of β-cell mitochondria, which could have implications for downstream insulin secretion.-Silvander, J. S. G., Kvarnström, S. M., Kumari-Ilieva, A., Shrestha, A., Alam, C. M., Toivola, D. M. Keratins regulate β-cell mitochondrial morphology, motility, and homeostasis. © FASEB.

  12. Palmitoylation regulates epidermal homeostasis and hair follicle differentiation.

    Directory of Open Access Journals (Sweden)

    Pleasantine Mill

    2009-11-01

    Full Text Available Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs. Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity. We examined expression of Zdhhc21 protein in skin and find it restricted to specific hair lineages. Loss of Zdhhc21 function results in delayed hair shaft differentiation, at the site of expression of the gene, but also leads to hyperplasia of the interfollicular epidermis (IFE and sebaceous glands, distant from the expression site. The specific delay in follicle differentiation is associated with attenuated anagen propagation and is reflected by decreased levels of Lef1, nuclear beta-catenin, and Foxn1 in hair shaft progenitors. In the thickened basal compartment of mutant IFE, phospho-ERK and cell proliferation are increased, suggesting increased signaling through EGFR or integrin-related receptors, with a parallel reduction in expression of the key differentiation factor Gata3. We show that the Src-family kinase, Fyn, involved in keratinocyte differentiation, is a direct palmitoylation target of Zdhhc21 and is mislocalized in mutant follicles. This study is the first to demonstrate a key role for palmitoylation in regulating developmental signals in mammalian tissue homeostasis.

  13. Novel Molecules Regulating Energy Homeostasis: Physiology and Regulation by Macronutrient Intake and Weight Loss

    Directory of Open Access Journals (Sweden)

    Anna Gavrieli

    2016-09-01

    Full Text Available Excess energy intake, without a compensatory increase of energy expenditure, leads to obesity. Several molecules are involved in energy homeostasis regulation and new ones are being discovered constantly. Appetite regulating hormones such as ghrelin, peptide tyrosine-tyrosine and amylin or incretins such as the gastric inhibitory polypeptide have been studied extensively while other molecules such as fibroblast growth factor 21, chemerin, irisin, secreted frizzle-related protein-4, total bile acids, and heme oxygenase-1 have been linked to energy homeostasis regulation more recently and the specific role of each one of them has not been fully elucidated. This mini review focuses on the above mentioned molecules and discusses them in relation to their regulation by the macronutrient composition of the diet as well as diet-induced weight loss.

  14. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling

    NARCIS (Netherlands)

    Spits, Hergen; Di Santo, James P.

    2011-01-01

    Research has identified what can be considered a family of innate lymphoid cells (ILCs) that includes not only natural killer (NK) cells and lymphoid tissue-inducer (LTi) cells but also cells that produce interleukin 5 (IL-5), IL-13, IL-17 and/or IL-22. These ILC subsets are developmentally related,

  15. Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

    Science.gov (United States)

    Giacomin, Paul R.; Moy, Ryan H.; Noti, Mario; Osborne, Lisa C.; Siracusa, Mark C.; Alenghat, Theresa; Liu, Bigang; McCorkell, Kelly A.; Troy, Amy E.; Rak, Gregory D.; Hu, Yinling; May, Michael J.; Ma, Hak-Ling; Fouser, Lynette A.; Sonnenberg, Gregory F.

    2015-01-01

    Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)–specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)–dependent antibacterial immunity in the intestine. Although IKKβΔIEC mice efficiently controlled Citrobacter rodentium infection, IKKαΔIEC mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKαΔIEC mice displayed impaired IL-22 production by RORγt+ ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22–competent ILCs from control mice could protect IKKαΔIEC mice from C. rodentium–induced morbidity. Defective ILC3 responses in IKKαΔIEC mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell–intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity. PMID:26371187

  16. Regulation of intestinal homeostasis and immunity with probiotic lactobacilli

    NARCIS (Netherlands)

    Baarlen, van P.; Wells, J.; Kleerebezem, M.

    2013-01-01

    The gut microbiota provide important stimuli to the human innate and adaptive immune system and co-mediate metabolic and immune homeostasis. Probiotic bacteria can be regarded as part of the natural human microbiota, and have been associated with improving homeostasis, albeit with different levels

  17. Epigenetic regulation of non-lymphoid cells by Bisphenol-A, a model endocrine disrupter: Potential Implications for Immunoregulation

    Directory of Open Access Journals (Sweden)

    Deena eKhan

    2015-06-01

    Full Text Available Endocrine disrupting chemicals (EDC abound in the environment since many compounds are released from chemical, agricultural, pharmaceutical and consumer product industries. Many of the EDCs such as Bisphenol A (BPA have estrogenic activity or interfere with endogenous sex hormones. Experimental studies have reported a positive correlation of BPA with reproductive toxicity, altered growth and immune dysregulation. Although the precise relevance of these studies to the environmental levels is unclear, nevertheless, their potential health implications remain a concern. One possible mechanism by which BPA can alter genes is by regulating epigenetics, including microRNA, alteration of methylation and histone acetylation. There is now wealth of information on BPA effects on non-lymphoid cells and by comparison, paucity of data on effects of BPA on the immune system. In this mini review, we will highlight BPA regulation of estrogen receptor-mediated immune cell functions and in different inflammatory conditions. In addition, BPA-mediated epigenetic regulation of non-lymphoid cells is emphasized. We recognize that most of these studies are on non-lymphoid cells, and given that BPA also affects the immune system, it is plausible that BPA could have similar epigenetic regulation in immune cells. It is hoped that this review will stimulate studies in this area to ascertain whether or not BPA epigenetically regulates the cells of the immune system.

  18. Sibutramine effects on central mechanisms regulating energy homeostasis.

    Science.gov (United States)

    Araújo, João R; Martel, Fátima

    2012-03-01

    During the last 50 years the global pandemic of obesity and associated life-threatening co-morbidities strongly promoted the development of anti-obesity pharmacotherapy. Sibutramine is an anti-obesity drug that in conjunction with lifestyle modifications reduces food intake and body weight. This may result from several effects: inhibition of presynaptic reuptake of monoaminergic neurotransmitters in the central nervous system, thereby suppressing appetite, induction of an increase in anorexigenic and a decrease in orexigenic neuropeptide secretion, induction of an increase in energy expenditure, and induction of peripheral sympathomimetic effects. The effects of sibutramine on anabolic and catabolic signals that regulate energy homeostasis in the hypothalamus are not completely understood. So, the aim of this review is to summarize the central mechanisms of action of sibutramine, responsible for its weight and food intake reducing potential. Despite being a useful drug in obesity treatment, awareness about the loss of long-term effectiveness and detrimental side effects of sibutramine has recently emerged. As a consequence, new drugs that produce safer and more persistent weight loss are currently undergoing clinical trials.

  19. Hypothalamic regulation of brown adipose tissue thermogenesis and energy homeostasis

    Directory of Open Access Journals (Sweden)

    Wei eZhang

    2015-08-01

    Full Text Available Obesity and diabetes are increasing at an alarming rate worldwide, but the strategies for the prevention and treatment of these disorders remain inadequate. Brown adipose tissue (BAT is important for cold protection by producing heat using lipids and glucose as metabolic fuels. This thermogenic action causes increased energy expenditure and significant lipid/glucose disposal. In addition, BAT in white adipose tissue (WAT or beige cells have been found and they also exhibit the thermogenic action similar to BAT. These data provide evidence indicating BAT/beige cells as a potential target for combating obesity and diabetes. Recent discoveries of active BAT and beige cells in adult humans have further highlighted this potential. Growing studies have also shown the importance of central nervous system in the control of BAT thermogenesis and WAT browning using animal models. This review is focused on central neural thermoregulation, particularly addressing our current understanding of the importance of hypothalamic neural signaling in the regulation of BAT/beige thermogenesis and energy homeostasis.

  20. Human innate lymphoid cells

    NARCIS (Netherlands)

    Mjösberg, Jenny; Spits, Hergen

    2016-01-01

    Innate lymphoid cells (ILCs) are increasingly acknowledged as important mediators of immune homeostasis and pathology. ILCs act as early orchestrators of immunity, responding to epithelium-derived signals by expressing an array of cytokines and cell-surface receptors, which shape subsequent immune

  1. ERR gamma Regulates Cardiac, Gastric, and Renal Potassium Homeostasis

    NARCIS (Netherlands)

    Alaynick, William A.; Way, James M.; Wilson, Stephanie A.; Benson, William G.; Pei, Liming; Downes, Michael; Yu, Ruth; Jonker, Johan W.; Holt, Jason A.; Rajpal, Deepak K.; Li, Hao; Stuart, Joan; McPherson, Ruth; Remlinger, Katja S.; Chang, Ching-Yi; McDonnell, Donald P.; Evans, Ronald M.; Billin, Andrew N.

    Energy production by oxidative metabolism in kidney, stomach, and heart, is primarily expended in establishing ion gradients to drive renal electrolyte homeostasis, gastric acid secretion, and cardiac muscle contraction, respectively. In addition to orchestrating transcriptional control of oxidative

  2. Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.

    Directory of Open Access Journals (Sweden)

    Cecilia Gonzalez Campo

    that reelin is a trans-neuronal messenger secreted by GABAergic neurons that regulates NMDARs homeostasis in postnatal hippocampus. Defects in reelin secretion could play a major role in the development of neuropsychiatric disorders, particularly those associated with deregulation of NMDARs such as schizophrenia.

  3. KRIT1 regulates the homeostasis of intracellular reactive oxygen species.

    Directory of Open Access Journals (Sweden)

    Luca Goitre

    Full Text Available KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM, a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhage. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 functions need to be severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms are still research challenges. We found that KRIT1 plays an important role in molecular mechanisms involved in the maintenance of the intracellular Reactive Oxygen Species (ROS homeostasis to prevent oxidative cellular damage. In particular, we demonstrate that KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels. Conversely, ROS levels in KRIT1(-/- cells are significantly and dose-dependently reduced after restoration of KRIT1 expression. Moreover, we show that the modulation of intracellular ROS levels by KRIT1 loss/restoration is strictly correlated with the modulation of the expression of the antioxidant protein SOD2 as well as of the transcriptional factor FoxO1, a master regulator of cell responses to oxidative stress and a modulator of SOD2 levels. Furthermore, we show that the KRIT1-dependent maintenance of low ROS levels facilitates the downregulation of cyclin D1 expression required for cell transition from proliferative growth to quiescence. Finally, we demonstrate that the enhanced ROS levels in KRIT1(-/- cells are associated with an increased cell susceptibility to oxidative DNA damage and a marked induction of the DNA damage sensor and repair gene Gadd45alpha, as well as with a decline of mitochondrial energy metabolism. Taken together, our results point to a new model where KRIT1 limits the accumulation of intracellular oxidants and prevents oxidative stress-mediated cellular dysfunction and DNA damage by

  4. PLAP-1: A novel molecule regulating homeostasis of periodontal tissues

    Directory of Open Access Journals (Sweden)

    Satoru Yamada

    2008-10-01

    Full Text Available Periodontal ligament (PDL plays crucial roles in maintaining the homeostasis of tooth and tooth-supporting tissue, periodontium. In attempt to understand the molecular and genetic basis of PDL functions, we investigated the expression profile of active genes in human periodontal ligament obtained by collecting sequences with 3′-directed cDNA library, which faithfully represents composition of the mRNA population. We succeeded to obtain a total of 1752 cDNA sequences by sequencing randomly selected clones and a total of 1318 different species was identified as gene signatures (GS by their sequence identity. The resulting expression profile showed that collagen types I and III were the most abundant genes and osteogenesis-relating genes, such as osteonectin and periostin were highly expressed. In the gene expression profile of human PDL, we found a novel gene which was highly expressed in PDL, but not in other tissue-cDNA libraries. We cloned a full-length cDNA of the gene and identified that it codes a novel protein, which is a new member of class I of small leucine-rich repeat proteoglycan (SLRP family. We designated it periodontal ligament associated protein-1 (PLAP-1. PLAP-1 mRNA expression was confirmed in in vitro-maintained PDL cells and was enhanced during the course of the cytodifferentiation of the PDL cells into mineralized tissue-forming cells such as osteoblasts and cementoblasts. In situ mRNA hybridization analysis using mouse periodontium revealed that PLAP-1 was expressed only in PDL tissues. Over-expression of PLAP-1 in PDL-derived clone cells interfered with both naturally and bone morphogenetic protein 2 (BMP-2-induced mineralization of the PDL cells. On the other hand, knockdown of PLAP-1 transcript levels by RNA interference enhanced BMP-2-induced differentiation of PDL cells. Furthermore, co-immunoprecipitation assays showed a direct interaction between PLAP-1 and BMP-2 in vitro. These results suggest that PLAP-1 plays a

  5. Regulation of protein homeostasis in neurodegenerative diseases : the role of coding and non-coding genes

    NARCIS (Netherlands)

    Alvarenga Fernandes Sin, Olga; Nollen, Ellen A. A.

    2015-01-01

    Protein homeostasis is fundamental for cell function and survival, because proteins are involved in all aspects of cellular function, ranging from cell metabolism and cell division to the cell's response to environmental challenges. Protein homeostasis is tightly regulated by the synthesis, folding,

  6. Sexual Dimorphism and Aging Differentially Regulate Adaptive Homeostasis.

    Science.gov (United States)

    Pomatto, Laura C D; Tower, John; Davies, Kelvin J A

    2018-01-16

    External and internal stimuli cause modifications to gene and biochemical pathways. In turn, demonstrating that biological systems continuously make short-term adaptations both to set-points, and to the range of "normal" capacity, due to mild conditional changes, or to subtoxic, nondamaging levels of chemical agents. This is termed as "Adaptive Homeostasis," defined with the following: "The transient expansion or contraction of the homeostatic range in response to exposure to sub-toxic, nondamaging, signaling molecules or events, or the removal or cessation of such molecules or events." Research from several laboratories, including our own, found that adaptive homeostasis declines with age in organisms as diverse as worms, flies, and mammals, and decreases with senescence in mammalian cell cultures. We suggest that diminishing adaptive homeostasis may play a causal role as a factor responsible for the aging phenotype. Furthermore, although studies of humans, animals, and model organisms are often limited to a single sex, and cell culture studies may even be conducted with lines whose donor's sex was unknown, studies reveal distinct sexual dimorphism in adaptive homeostasis. Interestingly, although young males and females may exhibit dramatic differences in adaptive capacities and/or preferences, these distinctions are lost with age as adaptive homeostasis patterns converge. © The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Human innate lymphoid cells.

    Science.gov (United States)

    Mjösberg, Jenny; Spits, Hergen

    2016-11-01

    Innate lymphoid cells (ILCs) are increasingly acknowledged as important mediators of immune homeostasis and pathology. ILCs act as early orchestrators of immunity, responding to epithelium-derived signals by expressing an array of cytokines and cell-surface receptors, which shape subsequent immune responses. As such, ILCs make up interesting therapeutic targets for several diseases. In patients with allergy and asthma, group 2 innate lymphoid cells produce high amounts of IL-5 and IL-13, thereby contributing to type 2-mediated inflammation. Group 3 innate lymphoid cells are implicated in intestinal homeostasis and psoriasis pathology through abundant IL-22 production, whereas group 1 innate lymphoid cells are accumulated in chronic inflammation of the gut (inflammatory bowel disease) and lung (chronic obstructive pulmonary disease), where they contribute to IFN-γ-mediated inflammation. Although the ontogeny of mouse ILCs is slowly unraveling, the development of human ILCs is far from understood. In addition, the growing complexity of the human ILC family in terms of previously unrecognized functional heterogeneity and plasticity has generated confusion within the field. Here we provide an updated view on the function and plasticity of human ILCs in tissue homeostasis and disease. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  8. Myosin Vb mediated plasma membrane homeostasis regulates peridermal cell size and maintains tissue homeostasis in the zebrafish epidermis.

    Science.gov (United States)

    Sonal; Sidhaye, Jaydeep; Phatak, Mandar; Banerjee, Shamik; Mulay, Aditya; Deshpande, Ojas; Bhide, Sourabh; Jacob, Tressa; Gehring, Ines; Nuesslein-Volhard, Christiane; Sonawane, Mahendra

    2014-09-01

    The epidermis is a stratified epithelium, which forms a barrier to maintain the internal milieu in metazoans. Being the outermost tissue, growth of the epidermis has to be strictly coordinated with the growth of the embryo. The key parameters that determine tissue growth are cell number and cell size. So far, it has remained unclear how the size of epidermal cells is maintained and whether it contributes towards epidermal homeostasis. We have used genetic analysis in combination with cellular imaging to show that zebrafish goosepimples/myosin Vb regulates plasma membrane homeostasis and is involved in maintenance of cell size in the periderm, the outermost epidermal layer. The decrease in peridermal cell size in Myosin Vb deficient embryos is compensated by an increase in cell number whereas decrease in cell number results in the expansion of peridermal cells, which requires myosin Vb (myoVb) function. Inhibition of cell proliferation as well as cell size expansion results in increased lethality in larval stages suggesting that this two-way compensatory mechanism is essential for growing larvae. Our analyses unravel the importance of Myosin Vb dependent cell size regulation in epidermal homeostasis and demonstrate that the epidermis has the ability to maintain a dynamic balance between cell size and cell number.

  9. The Porphyromonas gingivalis ferric uptake regulator orthologue does not regulate iron homeostasis

    Directory of Open Access Journals (Sweden)

    Catherine Butler

    2015-09-01

    Full Text Available Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that has an absolute requirement for iron which it transports from the host as heme and/or Fe2+. Iron transport must be regulated to prevent toxic effects from excess metal in the cell. P. gingivalis has one ferric uptake regulator (Fur orthologue encoded in its genome called Har, which would be expected to regulate the transport and usage of iron within this bacterium. As a gene regulator, inactivation of Har should result in changes in gene expression of several genes compared to the wild-type. This dataset (GEO accession number GSE37099 provides information on expression levels of genes in P. gingivalis in the absence of Har. Surprisingly, these genes do not relate to iron homeostasis.

  10. Calcium and phosphate homeostasis: concerted interplay of new regulators.

    NARCIS (Netherlands)

    Renkema, K.Y.R.; Alexander, R.T.; Bindels, R.J.M.; Hoenderop, J.G.J.

    2008-01-01

    Calcium (Ca(2+)) and phosphate (P(i)) are essential to many vital physiological processes. Consequently the maintenance of Ca(2+) and P(i) homeostasis is essential to a healthy existence. This occurs through the concerted action of intestinal, renal, and skeletal regulatory mechanisms. Ca(2+) and

  11. Regulation of calcium homeostasis in activated human neutrophils ...

    African Journals Online (AJOL)

    Objectives. The objectives of the current study were to: (i) present an integrated model for the restoration of calcium homeostasis in activated human neutrophils based on current knowledge and recent research; and (ii) identify potential targets for the modulation of calcium fluxes in activated neutrophils based on this model ...

  12. A Quick-responsive DNA Nanotechnology Device for Bio-molecular Homeostasis Regulation

    National Research Council Canada - National Science Library

    Wu, Songlin; Wang, Pei; Xiao, Chen; Li, Zheng; Yang, Bing; Fu, Jieyang; Chen, Jing; Wan, Neng; Ma, Cong; Li, Maoteng; Yang, Xiangliang; Zhan, Yi

    2016-01-01

    .... To produce a quick-responsive regulatory system that can be easily utilized for various types of homeostasis, a device called nano-fingers that facilitates the regulation of physiological processes...

  13. CLMP-Mediated Regulation of Intestinal Homeostasis in IBD

    Science.gov (United States)

    2014-10-01

    properties, cell proliferation and wound repair. 15. SUBJECT TERMS CAR-Like Membrane Protein, intestinal mucosa homeostasis, cell proliferation...intestinal mucosa is composed by a single layer of epithelial cells that forms a selective physical barrier allowing the passage of nutrients and solutes...members of the Cortical Thymocyte marker in Xenopus (CTX) family. CAR-Like Membrane Protein (CLMP) belongs to the CTX family, however, its function in

  14. Ca2+ Homeostasis Regulates Xenopus Oocyte Maturation1

    Science.gov (United States)

    Sun, Lu; Hodeify, Rawad; Haun, Shirley; Charlesworth, Amanda; MacNicol, Angus M.; Ponnappan, Subramaniam; Ponnappan, Usha; Prigent, Claude; Machaca, Khaled

    2008-01-01

    In contrast to the well-defined role of Ca2+ signals during mitosis, the contribution of Ca2+ signaling to meiosis progression is controversial, despite several decades of investigating the role of Ca2+ and its effectors in vertebrate oocyte maturation. We have previously shown that during Xenopus oocyte maturation, Ca2+ signals are dispensable for entry into meiosis and for germinal vesicle breakdown. However, normal Ca2+ homeostasis is essential for completion of meiosis I and extrusion of the first polar body. In this study, we test the contribution of several downstream effectors in mediating the Ca2+ effects during oocyte maturation. We show that calmodulin and calcium-calmodulin-dependent protein kinase II (CAMK2) are not critical downstream Ca2+ effectors during meiotic maturation. In contrast, accumulation of Aurora kinase A (AURKA) protein is disrupted in cells deprived of Ca2+ signals. Since AURKA is required for bipolar spindle formation, failure to accumulate AURKA may contribute to the defective spindle phenotype following Ca2+ deprivation. These findings argue that Ca2+ homeostasis is important in establishing the oocyte’s competence to undergo maturation in preparation for fertilization and embryonic development. PMID:18094360

  15. Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system.

    Science.gov (United States)

    Walsh, Matthew C; Lee, JangEun; Choi, Yongwon

    2015-07-01

    Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adapter protein that mediates a wide array of protein-protein interactions via its TRAF domain and a RING finger domain that possesses non-conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of interleukin-1 receptor (IL-1R)-mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the Toll-like receptor (TLR) family, tumor growth factor-β receptors (TGFβR), and T-cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor pathways. In the context of the immune system, TRAF6-mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system but also for maintaining immune tolerance, and more recent work has begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Homeostatic NF-κB Signaling in Steady-State Migratory Dendritic Cells Regulates Immune Homeostasis and Tolerance.

    Science.gov (United States)

    Baratin, Myriam; Foray, Chloe; Demaria, Olivier; Habbeddine, Mohamed; Pollet, Emeline; Maurizio, Julien; Verthuy, Christophe; Davanture, Suzel; Azukizawa, Hiroaki; Flores-Langarica, Adriana; Dalod, Marc; Lawrence, Toby

    2015-04-21

    Migratory non-lymphoid tissue dendritic cells (NLT-DCs) transport antigens to lymph nodes (LNs) and are required for protective immune responses in the context of inflammation and to promote tolerance to self-antigens in steady-state. However, the molecular mechanisms that elicit steady-state NLT-DC maturation and migration are unknown. By comparing the transcriptome of NLT-DCs in the skin with their migratory counterparts in draining LNs, we have identified a novel NF-κB-regulated gene network specific to migratory DCs. We show that targeted deletion of IKKβ in DCs, a major activator of NF-κB, prevents NLT-DC accumulation in LNs and compromises regulatory T cell conversion in vivo. This was associated with impaired tolerance and autoimmunity. NF-κB is generally considered the prototypical pro-inflammatory transcription factor, but this study describes a role for NF-κB signaling in DCs for immune homeostasis and tolerance that could have implications in autoimmune diseases and immunity. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Antizyme Inhibitor 2 : A Novel Regulator of Cellular Polyamine Homeostasis

    OpenAIRE

    Kanerva, Kristiina

    2010-01-01

    Polyamines are organic polycations that participate in various physiological functions, including cell proliferation, differentiation and apoptosis. Cellular polyamines originate from endogenous biosynthesis and exogenous sources. Their subcellular pool is under strict control, achieved by regulating their uptake and metabolism. Polyamine-induced proteins called antizymes (AZ) act as key regulators of intracellular polyamine concentration. They regulate both the transport of polyamines and th...

  18. Roquin--a multifunctional regulator of immune homeostasis.

    Science.gov (United States)

    Schaefer, J S; Klein, J R

    2016-03-01

    Roquin-1 (Rc3h1) is an E3 ubiquitin ligase originally discovered in a mutational screen for genetic factors contributory to systemic lupus erythematosus-like symptoms in mice. A single base-pair mutation in the Rc3h1 gene resulted in the manifestation of autoantibody production and sustained immunological inflammation characterized by excessive T follicular helper cell activation and formation of germinal centers. Subsequent studies have uncovered a multifactorial process by which Roquin-1 contributes to the maintenance of immune homeostasis. Through its interactions with partner proteins, Roquin-1 targets mRNAs for decay with inducible costimulator being a primary target. In this review, we discuss newly discovered functions of Roquin-1 in the immune system and inflammation, and in disease manifestation, and discuss avenues of further research. A model is presented for the role of Roquin in health and disease.

  19. Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction

    Science.gov (United States)

    Brain estrogen receptor-a (ERa) is essential for estrogenic regulation of energy homeostasis and reproduction. We previously showed that ERa expressed by pro-opiomelanocortin (POMC) neurons mediates estrogen's effects on food intake, body weight, negative regulation of hypothalamic–pituitary–gonadal...

  20. The contribution of hypothalamic macroglia to the regulation of energy homeostasis.

    Science.gov (United States)

    Buckman, Laura B; Ellacott, Kate L J

    2014-01-01

    The hypothalamus is critical for the regulation of energy homeostasis. Genetic and pharmacologic studies have identified a number of key hypothalamic neuronal circuits that integrate signals controlling food intake and energy expenditure. Recently, studies have begun to emerge demonstrating a role for non-neuronal cell types in the regulation of energy homeostasis. In particular the potential importance of different glial cell types is increasingly being recognized. A number of studies have described changes in the activity of hypothalamic macroglia (principally astrocytes and tanycytes) in response to states of positive and negative energy balance, such as obesity and fasting. This article will review these studies and discuss how these findings are changing our understanding of the cellular mechanisms by which energy homeostasis is regulated.

  1. The contribution of hypothalamic macroglia to the regulation of energy homeostasis

    Directory of Open Access Journals (Sweden)

    Laura B Buckman

    2014-10-01

    Full Text Available The hypothalamus is critical for the regulation of energy homeostasis. Genetic and pharmacologic studies have identified a number of key hypothalamic neuronal circuits that integrate signals controlling food intake and energy expenditure. Recently studies have begun to emerge demonstrating a role for non-neuronal cell types in the regulation of energy homeostasis. In particular the potential importance of different glial cell types is increasingly being recognized. A number of studies have described changes in the activity of hypothalamic macroglia (principally astrocytes and tanycytes in response to states of positive and negative energy balance, such as obesity and fasting. This article will review these studies and discuss how these findings are changing our understanding of the cellular mechanisms by which energy homeostasis is regulated.

  2. Systemic regulation of mineral homeostasis by micro RNAs

    Directory of Open Access Journals (Sweden)

    Julia eKehr

    2013-05-01

    Full Text Available Plants frequently have to cope with environments with sub-optimal mineral nutrient availability. Therefore they need to constantly sense changes of ion concentrations in their environment. Nutrient availabilities and needs have to be tightly coordinated between organs to ensure a balance between uptake and demand for metabolism, growth, reproduction, and defence reactions. To this end information about the nutrient status has to flow from cell-to-cell, but also between distant organs via the long-distance transport tubes to trigger adaptive responses. This systemic signalling between roots and shoots is required to maintain mineral nutrient homeostasis in the different organs under varying environmental conditions. Recent results begin to shed light on the molecular components of the complex long-distance signalling pathways and it has been proposed that systemic signals can be transported through the xylem as well as via the phloem. Several molecules, including nutrients, hormones, sugars, and small RNAs have been suggested to be involved in systemic communication over long distance (Liu et al. 2009. Recent research has suggested that in the case of mineral nutrients, the nutrients themselves, but also macromolecules like micro RNAs (miRNAs can act as important information transmitters. The following review will summarise the current knowledge about phloem-mediated systemic signalling by miRNAs during ion nutrient allocation and adaptation to mineral nutrient deprivation, concentrating on the well-analysed responses to a lack of potassium, sulphur, and copper.

  3. CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis.

    Science.gov (United States)

    Kim, Hyunbae; Zheng, Ze; Walker, Paul D; Kapatos, Gregory; Zhang, Kezhong

    2017-07-15

    Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock. Functionally, CREBH is required in order to maintain circadian homeostasis of hepatic glycogen storage and blood glucose levels. CREBH regulates the rhythmic expression of the genes encoding the rate-limiting enzymes for glycogenolysis and gluconeogenesis, including liver glycogen phosphorylase (PYGL), phosphoenolpyruvate carboxykinase 1 (PCK1), and the glucose-6-phosphatase catalytic subunit (G6PC). CREBH interacts with peroxisome proliferator-activated receptor α (PPARα) to synergize its transcriptional activities in hepatic gluconeogenesis. The acetylation of CREBH at lysine residue 294 controls CREBH-PPARα interaction and synergy in regulating hepatic glucose metabolism in mice. CREBH deficiency leads to reduced blood glucose levels but increases hepatic glycogen levels during the daytime or upon fasting. In summary, our studies revealed that CREBH functions as a key metabolic regulator that controls glucose homeostasis across the circadian cycle or under metabolic stress. Copyright © 2017 American Society for Microbiology.

  4. Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4

    DEFF Research Database (Denmark)

    Foresti, Ombretta; Ruggiano, Annamaria; Hannibal-Bach, Hans K

    2013-01-01

    Sterol homeostasis is essential for the function of cellular membranes and requires feedback inhibition of HMGR, a rate-limiting enzyme of the mevalonate pathway. As HMGR acts at the beginning of the pathway, its regulation affects the synthesis of sterols and of other essential mevalonate...... ligase implicated in a branch of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Since the other branch of ERAD is required for HMGR regulation, our results reveal a fundamental role for ERAD in sterol homeostasis, with the two branches of this pathway acting together...

  5. microRNA Regulation of Peritoneal Cavity Homeostasis in Peritoneal Dialysis

    Directory of Open Access Journals (Sweden)

    Melisa Lopez-Anton

    2015-01-01

    Full Text Available Preservation of peritoneal cavity homeostasis and peritoneal membrane function is critical for long-term peritoneal dialysis (PD treatment. Several microRNAs (miRNAs have been implicated in the regulation of key molecular pathways driving peritoneal membrane alterations leading to PD failure. miRNAs regulate the expression of the majority of protein coding genes in the human genome, thereby affecting most biochemical pathways implicated in cellular homeostasis. In this review, we report published findings on miRNAs and PD therapy, with emphasis on evidence for changes in peritoneal miRNA expression during long-term PD treatment. Recent work indicates that PD effluent- (PDE- derived cells change their miRNA expression throughout the course of PD therapy, contributing to the loss of peritoneal cavity homeostasis and peritoneal membrane function. Changes in miRNA expression profiles will alter regulation of key molecular pathways, with the potential to cause profound effects on peritoneal cavity homeostasis during PD treatment. However, research to date has mainly adopted a literature-based miRNA-candidate methodology drawing conclusions from modest numbers of patient-derived samples. Therefore, the study of miRNA expression during PD therapy remains a promising field of research to understand the mechanisms involved in basic peritoneal cell homeostasis and PD failure.

  6. The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros.

    Science.gov (United States)

    Greif, P A; Tizazu, B; Krause, A; Kremmer, E; Bohlander, S K

    2008-05-01

    The t(10;11)(p13;q14) translocation leads to the fusion of the CALM and AF10 genes. This translocation can be found as the sole cytogenetic abnormality in acute lymphoblastic leukemia, acute myeloid leukemia and in malignant lymphomas. The expression of CALM/AF10 in primary murine bone marrow cells results in the development of an aggressive leukemia in a murine bone marrow transplantation model. Using a yeast two-hybrid screen, we identified the lymphoid regulator Ikaros as an AF10 interacting protein. Interestingly, Ikaros is required for normal development of lymphocytes, and aberrant expression of Ikaros has been found in leukemia. In a murine model, the expression of a dominant negative isoform of Ikaros causes leukemias and lymphomas. The Ikaros interaction domain of AF10 was mapped to the leucine zipper domain of AF10, which is required for malignant transformation both by the CALM/AF10 and the MLL/AF10 fusion proteins. The interaction between AF10 and Ikaros was confirmed by GST pull down and co-immunoprecipitation. Coexpression of CALM/AF10 but not of AF10 alters the subcellular localization of Ikaros in murine fibroblasts. The transcriptional repressor activity of Ikaros is reduced by AF10. These results suggest that CALM/AF10 might interfere with normal Ikaros function, and thereby block lymphoid differentiation in CALM/AF10 positive leukemias.

  7. Regulation of Intestinal Homeostasis by Innate Immune Cells

    OpenAIRE

    Kayama, Hisako; Nishimura, Junichi; Takeda, Kiyoshi

    2013-01-01

    The intestinal immune system has an ability to distinguish between the microbiota and pathogenic bacteria, and then activate pro-inflammatory pathways against pathogens for host defense while remaining unresponsive to the microbiota and dietary antigens. In the intestine, abnormal activation of innate immunity causes development of several inflammatory disorders such as inflammatory bowel diseases (IBD). Thus, activity of innate immunity is finely regulated in the intestine. To date, multiple...

  8. Cigarette Smoking and Brain Regulation of Energy Homeostasis

    OpenAIRE

    Chen, Hui; Saad, Sonia; Sandow, Shaun L.; Bertrand, Paul P.

    2012-01-01

    Cigarette smoking is an addictive behavior, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases). Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causing...

  9. CHIP Regulates Aquaporin-2 Quality Control and Body Water Homeostasis

    DEFF Research Database (Denmark)

    Wu, Qi; Moeller, Hanne B; Stevens, Donté A

    2017-01-01

    The importance of the kidney distal convoluted tubule (DCT) and cortical collecting duct (CCD) is highlighted by various water and electrolyte disorders that arise when the unique transport properties of these segments are disturbed. Despite this critical role, little is known about which proteins...... osmolality. We did not observe significant changes in other water- or sodium-transporting proteins in the gene-modified mice. In summary, these results suggest that CHIP regulates AQP2 and subsequently, renal water handling....

  10. The transcriptional repressor HIC1 regulates intestinal immune homeostasis.

    Science.gov (United States)

    Burrows, K; Antignano, F; Bramhall, M; Chenery, A; Scheer, S; Korinek, V; Underhill, T M; Zaph, C

    2017-11-01

    The intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T-cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T-cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.

  11. Serotonin 2c receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

    Science.gov (United States)

    Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor a...

  12. Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration

    Science.gov (United States)

    Sumagin, Ronen; Parkos, Charles A

    2014-01-01

    Epithelial adhesion molecules play essential roles in regulating cellular function and maintaining mucosal tissue homeostasis. Some form epithelial junctional complexes to provide structural support for epithelial monolayers and act as a selectively permeable barrier separating luminal contents from the surrounding tissue. Others serve as docking structures for invading viruses and bacteria, while also regulating the immune response. They can either obstruct or serve as footholds for the immune cells recruited to mucosal surfaces. Currently, it is well appreciated that adhesion molecules collectively serve as environmental cue sensors and trigger signaling events to regulate epithelial function through their association with the cell cytoskeleton and various intracellular adapter proteins. Immune cells, particularly neutrophils (PMN) during transepithelial migration (TEM), can modulate adhesion molecule expression, conformation, and distribution, significantly impacting epithelial function and tissue homeostasis. This review discusses the roles of key intestinal epithelial adhesion molecules in regulating PMN trafficking and outlines the potential consequences on epithelial function. PMID:25838976

  13. Cigarette smoking and brain regulation of energy homeostasis.

    Science.gov (United States)

    Chen, Hui; Saad, Sonia; Sandow, Shaun L; Bertrand, Paul P

    2012-01-01

    Cigarette smoking is an addictive behavior, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases). Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causing a negative energy state which is characterized by reduced energy intake and increased energy expenditure that are linked to low body weight. These findings have led to the public perception that smoking is associated with weight loss. However, its effects at reducing abdominal fat mass (a predisposing factor for glucose intolerance and insulin resistance) are marginal, and its promotion of lean body mass loss in animal studies suggests a limited potential for treatment in obesity. Smoking during pregnancy puts pressure on the mother's metabolic system and is a significant contributor to adverse pregnancy outcomes. Smoking is a predictor of future risk for respiratory dysfunction, social behavioral problems, cardiovascular disease, obesity, and type-2 diabetes. Catch-up growth is normally observed in children exposed to intrauterine smoke, which has been linked to subsequent childhood obesity. Nicotine can have a profound impact on the developing fetal brain, via its ability to rapidly and fully pass the placenta. In animal studies this has been linked with abnormal hypothalamic gene expression of appetite regulators such as downregulation of NPY and POMC in the arcuate nucleus of the hypothalamus. Maternal smoking or nicotine replacement leads to unhealthy eating habits (such as junk food addiction) and other behavioral disorders in the offspring.

  14. Cigarette smoking and brain regulation of energy homeostasis

    Directory of Open Access Journals (Sweden)

    Hui eChen

    2012-07-01

    Full Text Available Cigarette smoking is an addictive behaviour, and is the primary cause of cardiovascular and pulmonary disease, and cancer (among other diseases. Cigarette smoke contains thousands of components that may affect caloric intake and energy expenditure, although nicotine is the major addictive substance present, and has the best described actions. Nicotine exposure from cigarette smoke can change brain feeding regulation to reduce appetite via both energy homeostatic and reward mechanisms, causing a negative energy state which is characterized by reduced energy intake and increased energy expenditure that are linked to low body weight. These findings have led to the public perception that smoking is associated with weight loss. However, its effects at reducing abdominal fat mass (a predisposing factor for glucose intolerance and insulin resistance are marginal, and its promotion of lean body mass loss in animal studies suggests a limited potential for treatment in obesity. Smoking during pregnancy puts pressure on the mother’s metabolic system and is a significant contributor to adverse pregnancy outcomes. Smoking is a predictor of future risk for respiratory dysfunction, social behavioral problems, cardiovascular disease, obesity and type-2 diabetes. Catch-up growth is normally observed in children exposed to intrauterine smoke, which has been linked to subsequent childhood obesity. Nicotine can have a profound impact on the developing fetal brain, via its ability to rapidly and fully pass the placenta. In animal studies this has been linked with abnormal hypothalamic gene expression of appetite regulators such as downregulation of NPY and POMC in the arcuate nucleus of the hypothalamus. Maternal smoking or nicotine replacement leads to unhealthy eating habits (such as junk food addiction and other behavioral disorders in the offspring.

  15. A multi-scale model of hepcidin promoter regulation reveals factors controlling systemic iron homeostasis.

    Directory of Open Access Journals (Sweden)

    Guillem Casanovas

    2014-01-01

    Full Text Available Systemic iron homeostasis involves a negative feedback circuit in which the expression level of the peptide hormone hepcidin depends on and controls the iron blood levels. Hepcidin expression is regulated by the BMP6/SMAD and IL6/STAT signaling cascades. Deregulation of either pathway causes iron-related diseases such as hemochromatosis or anemia of inflammation. We quantitatively analyzed how BMP6 and IL6 control hepcidin expression. Transcription factor (TF phosphorylation and reporter gene expression were measured under co-stimulation conditions, and the promoter was perturbed by mutagenesis. Using mathematical modeling, we systematically analyzed potential mechanisms of cooperative and competitive promoter regulation by the transcription factors, and experimentally validated the model predictions. Our results reveal that hepcidin cross-regulation primarily occurs by combinatorial transcription factor binding to the promoter, whereas signaling crosstalk is insignificant. We find that the presence of two BMP-responsive elements enhances the steepness of the promoter response towards the iron-sensing BMP signaling axis, which promotes iron homeostasis in vivo. IL6 co-stimulation reduces the promoter sensitivity towards the BMP signal, because the SMAD and STAT transcription factors compete for recruiting RNA polymerase to the transcription start site. This may explain why inflammatory signals disturb iron homeostasis in anemia of inflammation. Taken together, our results reveal why the iron homeostasis circuit is sensitive to perturbations implicated in disease.

  16. Characteristic of innate lymphoid cells (ILC

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    Mateusz Adamiak

    2014-12-01

    Full Text Available Innate lymphoid cells (ILC is a newly described family of immune cells that are part of the natural immunity which is important not only during infections caused by microorganisms, but also in the formation of lymphoid tissue, tissue remodeling after damage due to injury and homeostasis tissue stromal cells. Family ILC cells form NK cells (natural killer and lymphoid tissue inducer T cells (LTi, which, although they have different functions, are evolutionarily related. NK cells are producing mainly IFN-γ, whereas LTi cells as NKR+LTi like, IL-17 and/or IL-22, which suggests that the last two cells, can also represent the innate versions of helper T cell - TH17 and TH22. Third population of ILC is formed by cells with characteristics such as NK cells and LTi (ILC22 - which are named NK22 cells, natural cytotoxicity receptor 22 (NCR22 cells or NK receptor-positive (LTi NKR+ LTi cells. Fourth population of ILC cells are ILC17 - producing IL-17, while the fifth is formed by natural helper type 2 T cells (nTH2, nuocyte, innate type 2 helper cells (IH2 and multi-potent progenitor type 2 cells (MPPtype2. Cells of the last population synthesize IL-5 and IL-13. It is assumed that an extraordinary functional diversity of ILC family, resembles T cells, probably because they are under the control of the corresponding transcription factors - as direct regulation factors, such as the family of lymphocytes T.

  17. Inflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota.

    Science.gov (United States)

    Gagliani, Nicola; Palm, Noah W; de Zoete, Marcel R; Flavell, Richard A

    2014-09-01

    Inflammasomes are large cytosolic protein complexes that detect infection and stress-associated signals and promote immediate inflammatory responses. In the intestine, activation of the inflammasome leads to an inflammatory response that is important for controlling enteric infections but can also result in pathological tissue damage. Recent studies have suggested that the inflammasome also regulates intestinal homeostasis through its effects on the intestinal microbiota. Notably, many conflicting studies have been published regarding the effect of inflammasome deficiencies on intestinal homeostasis. Here, we attempt to reconcile these contrasting data by highlighting the many ways that the inflammasome contributes to intestinal homeostasis and pathology and exploring the potential role of alterations in the microbiota in these conflicting studies. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Cholesterol efflux is differentially regulated in neurons and astrocytes: implications for brain cholesterol homeostasis

    Science.gov (United States)

    Chen, Jing; Zhang, Xiaolu; Kusumo, Handojo; Costa, Lucio G.; Guizzetti, Marina

    2012-01-01

    Disruption of cholesterol homeostasis in the central nervous system (CNS) has been associated with neurological, neurodegenerative, and neurodevelopmental disorders. The CNS is a closed system with regard to cholesterol homeostasis, as cholesterol-delivering lipoproteins from the periphery cannot pass the blood-brain-barrier and enter the brain. Different cell types in the brain have different functions in the regulation of cholesterol homeostasis, with astrocytes producing and releasing apolipoprotein E and lipoproteins, and neurons metabolizing cholesterol to 24(S)-hydroxycholesterol. We present evidence that astrocytes and neurons adopt different mechanisms also in regulating cholesterol efflux. We found that in astrocytes cholesterol efflux is induced by both lipid-free apolipoproteins and lipoproteins, while cholesterol removal from neurons is triggered only by lipoproteins. The main pathway by which apolipoproteins induce cholesterol efflux is through ABCA1. By upregulating ABCA1 levels and by inhibiting its activity and silencing its expression, we show that ABCA1 is involved in cholesterol efflux from astrocytes but not from neurons. Furthermore, our results suggest that ABCG1 is involved in cholesterol efflux to apolipoproteins and lipoproteins from astrocytes but not from neurons, while ABCG4, whose expression is much higher in neurons than astrocytes, is involved in cholesterol efflux from neurons but not astrocytes. These results indicate that different mechanisms regulate cholesterol efflux from neurons and astrocytes, reflecting the different roles that these cell types play in brain cholesterol homeostasis. These results are important in understanding cellular targets of therapeutic drugs under development for the treatments of conditions associated with altered cholesterol homeostasis in the CNS. PMID:23010475

  19. Regulation of Cytokine Secretion in Human CD127(+) LTi-like Innate Lymphoid Cells by Toll-like Receptor 2

    NARCIS (Netherlands)

    Crellin, Natasha K.; Trifari, Sara; Kaplan, Charles D.; Satoh-Takayama, Naoko; Di Santo, James P.; Spits, Hergen

    2010-01-01

    Lymphoid tissue inducer cells are members of an emerging family of innate lymphoid cells (ILC). Although these cells were originally reported to produce cytokines such as interleukin-17 (IL-17) and IL-22, we demonstrate here that human CD127(+)RORC(+) and CD56(+)CD127(+) LTi-like ILC also express

  20. The Innate Lymphoid Cell Precursor.

    Science.gov (United States)

    Ishizuka, Isabel E; Constantinides, Michael G; Gudjonson, Herman; Bendelac, Albert

    2016-05-20

    The discovery of tissue-resident innate lymphoid cell populations effecting different forms of type 1, 2, and 3 immunity; tissue repair; and immune regulation has transformed our understanding of mucosal immunity and allergy. The emerging complexity of these populations along with compounding issues of redundancy and plasticity raise intriguing questions about their precise lineage relationship. Here we review advances in mapping the emergence of these lineages from early lymphoid precursors. We discuss the identification of a common innate lymphoid cell precursor characterized by transient expression of the transcription factor PLZF, and the lineage relationships of innate lymphoid cells with conventional natural killer cells and lymphoid tissue inducer cells. We also review the rapidly growing understanding of the network of transcription factors that direct the development of these lineages.

  1. Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis.

    Directory of Open Access Journals (Sweden)

    Bon Jeong Ku

    Full Text Available The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6 is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Alb(cre/+Mig-6(f/f; Mig-6(d/d. Mig-6(d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6(d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6(d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6(d/d mice compared to Mig-6(f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease.

  2. Energy Metabolism Regulates Retinoic Acid Synthesis and Homeostasis in Physiological Contexts

    OpenAIRE

    Obrochta, Kristin Marie

    2014-01-01

    Mounting evidence supports a regulated and reciprocal relationship between retinoid homeostasis and energy metabolism, with a physiologically relevant consequence of disrupted energy balance. This research was motivated by an observation that all-trans-retinoic acid (atRA), and biosynthetic precursors, were responsive to acute shifts in energy status, in wild type animals with normal body weight and glucose tolerance, i.e. not consequent to metabolic syndrome. My dissertation was designed to ...

  3. Pathological and therapeutic roles of innate lymphoid cells in diverse diseases.

    Science.gov (United States)

    Kim, Jisu; Kim, Geon; Min, Hyeyoung

    2017-11-01

    Innate lymphoid cells (ILCs) are a recently defined type of innate-immunity cells that belong to the lymphoid lineage and have lymphoid morphology but do not express an antigen-specific B cell or T-cell receptor. ILCs regulate immune functions prior to the formation of adaptive immunity and exert effector functions through a cytokine release. ILCs have been classified into three groups according to the transcription factors that regulate their development and function and the effector cytokines they produce. Of note, ILCs resemble T helper (Th) cells, such as Th1, Th2, and Th17 cells, and show a similar dependence on transcription factors and distinct cytokine production. Despite their short history in immunology, ILCs have received much attention, and numerous studies have revealed biological functions of ILCs including host defense against pathogens, inflammation, tissue repair, and metabolic homeostasis. Here, we describe recent findings about the roles of ILCs in the pathogenesis of various diseases and potential therapeutic targets.

  4. Development and function of secondary and tertiary lymphoid organs in the small intestine and the colon

    Directory of Open Access Journals (Sweden)

    Manuela Buettner

    2016-09-01

    Full Text Available The immune system of the gut has evolved a number of specific lymphoid structures that contribute to homeostasis in the face of microbial colonization and food-derived antigenic challenge. These lymphoid organs encompass Peyer’s patches (PP in the small intestine and their colonic counterparts that develop in a programmed fashion before birth. In addition, the gut harbors a network of lymphoid tissues that is commonly designated as solitary intestinal lymphoid tissues (SILT. In contrast to PP, SILT develop strictly after birth and consist of a dynamic continuum of structures ranging from small cryptopatches (CP to large, mature isolated lymphoid follicles (ILF. Although the development of PP and SILT follow similar principles, such as an early clustering of lymphoid tissue inducer (LTi cells and the requirement for lymphotoxin beta (LTβ receptor-mediated signaling, the formation of CP and their further maturation into ILF is associated with additional intrinsic and environmental signals. Moreover, recent data also indicate that specific differences exist in the regulation of ILF formation between the small intestine and the colon. Importantly, intestinal inflammation in both mice and humans is associated with a strong expansion of the lymphoid network in the gut. Recent experiments in mice suggest that these structures, although they resemble large, mature ILF in appearance, may represent de novo-induced tertiary lymphoid organs (TLO. While so far it is not clear whether intestinal TLO contribute to the exacerbation of inflammatory pathology, it has been shown that ILF provide the critical microenvironment necessary for the induction of an effective host response upon infection with enteric bacterial pathogens. Regarding the importance of ILF for intestinal immunity, interfering with the development and maturation of these lymphoid tissues may offer novel means for manipulating the immune response during intestinal infection or inflammation.

  5. TOX sets the stage for innate lymphoid cells

    NARCIS (Netherlands)

    Spits, Hergen

    2015-01-01

    Like T cells and B cells, innate lymphoid cells (ILCs) develop from common lymphoid progenitors, but how commitment to the ILC lineage is regulated has remained unclear. The transcriptional regulator TOX is important in this process

  6. Regulation of aquaporin-2 in the kidney: A molecular mechanism of body-water homeostasis

    Directory of Open Access Journals (Sweden)

    Tae-Hwan Kwon

    2013-09-01

    Full Text Available The kidneys play a key role in the homeostasis of body water and electrolyte balance. Aquaporin-2 (AQP2 is the vasopressin-regulated water-channel protein expressed at the connecting tubule and collecting duct, and plays a key role in urine concentration and body-water homeostasis through short-term and long-term regulation of collecting duct water permeability. The signaling transduction pathways resulting in the AQP2 trafficking to the apical plasma membrane of the collecting duct principal cells, including AQP2 phosphorylation, RhoA phosphorylation, actin depolymerization, and calcium mobilization, and the changes of AQP2 abundance in water-balance disorders have been extensively studied. Dysregulation of AQP2 has been shown to be importantly associated with a number of clinical conditions characterized by body-water balance disturbances, including hereditary nephrogenic diabetes insipidus (NDI, lithium-induced NDI, electrolytes disturbance, acute and chronic renal failure, ureteral obstruction, nephrotic syndrome, congestive heart failure, and hepatic cirrhosis. Recent studies exploiting omics technology further demonstrated the comprehensive vasopressin signaling pathways in the collecting ducts. Taken together, these studies elucidate the underlying molecular mechanisms of body-water homeostasis and provide the basis for the treatment of body-water balance disorders.

  7. Development and regulation of chloride homeostasis in the central nervous system

    Directory of Open Access Journals (Sweden)

    Miho eWatanabe

    2015-09-01

    Full Text Available GABA (γ-aminobutyric acid is the main inhibitory neurotransmitter of the mature central nervous system. The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl- gradients, which are generated by cation-Cl- co-transporters. An accumulation of Cl- by the Na+-K+-2Cl- co-transporter (NKCC1 increases the intracellular Cl- concentration ([Cl-]i such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl--extruder KCC2, which is a neuron-specific K+-Cl- co-transporter, with or without downregulation of NKCC1, results in low [Cl-]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl- homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases in [Cl-]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including BDNF, insulin-like growth factor, and CFTR. Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl- homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors SPAK-OSR1. In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na+ and K+ ions, topographical interaction with the Na+-K+ ATPase and its modulators such as creatine kinase should modulate functions of Cl- transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl- transporters may also play a pivotal role in the development of Cl- homeostasis.

  8. DNA methylation regulates transcriptional homeostasis of algal endosymbiosis in the coral model Aiptasia

    KAUST Repository

    Li, Yong

    2017-11-03

    The symbiotic relationship between cnidarians and dinoflagellates is the cornerstone of coral reef ecosystems. Although research is focusing on the molecular mechanisms underlying this symbiosis, the role of epigenetic mechanisms, which have been implicated in transcriptional regulation and acclimation to environmental change, is unknown. To assess the role of DNA methylation in the cnidarian-dinoflagellate symbiosis, we analyzed genome-wide CpG methylation, histone associations, and transcriptomic states of symbiotic and aposymbiotic anemones in the model system Aiptasia. We find methylated genes are marked by histone H3K36me3 and show significant reduction of spurious transcription and transcriptional noise, revealing a role of DNA methylation in the maintenance of transcriptional homeostasis. Changes in DNA methylation and expression show enrichment for symbiosis-related processes such as immunity, apoptosis, phagocytosis recognition and phagosome formation, and unveil intricate interactions between the underlying pathways. Our results demonstrate that DNA methylation provides an epigenetic mechanism of transcriptional homeostasis during symbiosis.

  9. Calcineurin signaling and membrane lipid homeostasis regulates iron mediated multidrug resistance mechanisms in Candida albicans.

    Directory of Open Access Journals (Sweden)

    Saif Hameed

    2011-04-01

    Full Text Available We previously demonstrated that iron deprivation enhances drug susceptibility of Candida albicans by increasing membrane fluidity which correlated with the lower expression of ERG11 transcript and ergosterol levels. The iron restriction dependent membrane perturbations led to an increase in passive diffusion and drug susceptibility. The mechanisms underlying iron homeostasis and multidrug resistance (MDR, however, are not yet resolved. To evaluate the potential mechanisms, we used whole genome transcriptome and electrospray ionization tandem mass spectrometry (ESI-MS/MS based lipidome analyses of iron deprived Candida cells to examine the new cellular circuitry of the MDR of this pathogen. Our transcriptome data revealed a link between calcineurin signaling and iron homeostasis. Among the several categories of iron deprivation responsive genes, the down regulation of calcineurin signaling genes including HSP90, CMP1 and CRZ1 was noteworthy. Interestingly, iron deprived Candida cells as well as iron acquisition defective mutants phenocopied molecular chaperone HSP90 and calcineurin mutants and thus were sensitive to alkaline pH, salinity and membrane perturbations. In contrast, sensitivity to above stresses did not change in iron deprived DSY2146 strain with a hyperactive allele of calcineurin. Although, iron deprivation phenocopied compromised HSP90 and calcineurin, it was independent of protein kinase C signaling cascade. Notably, the phenotypes associated with iron deprivation in genetically impaired calcineurin and HSP90 could be reversed with iron supplementation. The observed down regulation of ergosterol (ERG1, ERG2, ERG11 and ERG25 and sphingolipid biosynthesis (AUR1 and SCS7 genes followed by lipidome analysis confirmed that iron deprivation not only disrupted ergosterol biosynthesis, but it also affected sphingolipid homeostasis in Candida cells. These lipid compositional changes suggested extensive remodeling of the membranes in iron

  10. The role of Wt1 in regulating mesenchyme in cancer, development, and tissue homeostasis.

    Science.gov (United States)

    Chau, You-Ying; Hastie, Nicholas D

    2012-10-01

    From both the fundamental and clinical perspectives, there is growing interest in mesenchymal cells and the mechanisms that regulate the two-way switch between mesenchymal and epithelial states. Here, we review recent findings showing that the Wilms' tumor gene (Wt1) is a key regulator of mesenchyme maintenance and the mesenchyme to epithelial balance in the development of certain mesodermal organs. We summarize recent experiments demonstrating, unexpectedly, that Wt1 is also essential for the integrity or function of multiple adult tissues, mainly, we argue, through regulating mesenchymal cells. We also discuss growing evidence that implicates Wt1 in tissue repair and regeneration. Drawing on these findings, we highlight the similarities between Wt1-expressing cells in different tissues. We believe that future studies aimed at elucidating the mechanisms underlying the functions of Wt1 in adult cells will reveal key cell types, pathways, and molecules regulating adult tissue homeostasis and repair. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. PfsR is a key regulator of iron homeostasis in Synechocystis PCC 6803.

    Directory of Open Access Journals (Sweden)

    Dan Cheng

    Full Text Available Iron is an essential cofactor in numerous cellular processes. The iron deficiency in the oceans affects the primary productivity of phytoplankton including cyanobacteria. In this study, we examined the function of PfsR, a TetR family transcriptional regulator, in iron homeostasis of the cyanobacterium Synechocystis PCC 6803. Compared with the wild type, the pfsR deletion mutant displayed stronger tolerance to iron limitation and accumulated significantly more chlorophyll a, carotenoid, and phycocyanin under iron-limiting conditions. The mutant also maintained more photosystem I and photosystem II complexes than the wild type after iron deprivation. In addition, the activities of photosystem I and photosystem II were much higher in pfsR deletion mutant than in wild-type cells under iron-limiting conditions. The transcripts of pfsR were enhanced by iron limitation and inactivation of the gene affected pronouncedly expression of fut genes (encoding a ferric iron transporter, feoB (encoding a ferrous iron transporter, bfr genes (encoding bacterioferritins, ho genes (encoding heme oxygenases, isiA (encoding a chlorophyll-binding protein, and furA (encoding a ferric uptake regulator. The iron quota in pfsR deletion mutant cells was higher than in wild-type cells both before and after exposure to iron limitation. Electrophoretic mobility shift assays showed that PfsR bound to its own promoter and thereby auto-regulated its own expression. These data suggest that PfsR is a critical regulator of iron homeostasis.

  12. Functional and phenotypic heterogeneity of group 3 innate lymphoid cells.

    Science.gov (United States)

    Melo-Gonzalez, Felipe; Hepworth, Matthew R

    2017-03-01

    Group 3 innate lymphoid cells (ILC3), defined by expression of the transcription factor retinoid-related orphan receptor γt, play key roles in the regulation of inflammation and immunity in the gastrointestinal tract and associated lymphoid tissues. ILC3 consist largely of two major subsets, NCR + ILC3 and LTi-like ILC3, but also demonstrate significant plasticity and heterogeneity. Recent advances have begun to dissect the relationship between ILC3 subsets and to define distinct functional states within the intestinal tissue microenvironment. In this review we discuss the ever-expanding roles of ILC3 in the context of intestinal homeostasis, infection and inflammation - with a focus on comparing and contrasting the relative contributions of ILC3 subsets. © 2016 The Authors. Immunology published by John Wiley & Sons Ltd.

  13. Central regulation of brown adipose tissue thermogenesis and energy homeostasis dependent on food availability.

    Science.gov (United States)

    Nakamura, Yoshiko; Nakamura, Kazuhiro

    2017-12-05

    Energy homeostasis of mammals is maintained by balancing energy expenditure within the body and energy intake through feeding. Several lines of evidence indicate that brown adipose tissue (BAT), a sympathetically activated thermogenic organ, turns excess energy into heat to maintain the energy balance in rodents and humans, in addition to its thermoregulatory role for the defense of body core temperature in cold environments. Elucidating the central circuit mechanism controlling BAT thermogenesis dependent on nutritional conditions and food availability in relation to energy homeostasis is essential to understand the etiology of symptoms caused by energy imbalance, such as obesity. The central thermogenic command outflow to BAT descends through an excitatory neural pathway mediated by hypothalamic, medullary and spinal sites. This sympathoexcitatory thermogenic drive is controlled by tonic GABAergic inhibitory signaling from the thermoregulatory center in the preoptic area, whose tone is altered by body core and cutaneous thermosensory inputs. This circuit controlling BAT thermogenesis for cold defense also functions for the development of fever and psychological stress-induced hyperthermia, indicating its important role in the defense from a variety of environmental stressors. When food is unavailable, hunger-driven neural signaling from the hypothalamus activates GABAergic neurons in the medullary reticular formation, which then block the sympathoexcitatory thermogenic outflow to BAT to reduce energy expenditure and simultaneously command the masticatory motor system to promote food intake-effectively commanding responses to survive starvation. This article reviews the central mechanism controlling BAT thermogenesis in relation to the regulation of energy and thermal homeostasis dependent on food availability.

  14. NF-κB in the regulation of epithelial homeostasis and inflammation

    Science.gov (United States)

    Wullaert, Andy; Bonnet, Marion C; Pasparakis, Manolis

    2011-01-01

    The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin. PMID:21151201

  15. Interplay of innate lymphoid cells and the microbiota.

    Science.gov (United States)

    Britanova, Liudmila; Diefenbach, Andreas

    2017-09-01

    Innate lymphoid cells (ILC) are a recently identified group of innate lymphocytes that are preferentially located at barrier surfaces. Barrier surfaces are in direct contact with complex microbial ecosystems, collectively referred to as the microbiota. It is now believed that the interplay of the microbiota with host components (i.e. epithelial cells and immune cells) promotes host fitness by regulating organ homeostasis, metabolism, and host defense against pathogens. In this review, we will give an overview of this multifaceted interplay between ILC and components of the microbiota. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. The yeast AMPK homolog SNF1 regulates acetyl coenzyme A homeostasis and histone acetylation.

    Science.gov (United States)

    Zhang, Man; Galdieri, Luciano; Vancura, Ales

    2013-12-01

    Acetyl coenzyme A (acetyl-CoA) is a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Concentration of acetyl-CoA affects histone acetylation and links intermediary metabolism and transcriptional regulation. Here we show that SNF1, the budding yeast ortholog of the mammalian AMP-activated protein kinase (AMPK), plays a role in the regulation of acetyl-CoA homeostasis and global histone acetylation. SNF1 phosphorylates and inhibits acetyl-CoA carboxylase, which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in the de novo synthesis of fatty acids. Inactivation of SNF1 results in a reduced pool of cellular acetyl-CoA, globally decreased histone acetylation, and reduced fitness and stress resistance. The histone acetylation and transcriptional defects can be partially suppressed and the overall fitness improved in snf1Δ mutant cells by increasing the cellular concentration of acetyl-CoA, indicating that the regulation of acetyl-CoA homeostasis represents another mechanism in the SNF1 regulatory repertoire.

  17. Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis.

    Science.gov (United States)

    Lawan, Ahmed; Zhang, Lei; Gatzke, Florian; Min, Kisuk; Jurczak, Michael J; Al-Mutairi, Mashael; Richter, Patric; Camporez, Joao Paulo G; Couvillon, Anthony; Pesta, Dominik; Roth Flach, Rachel J; Shulman, Gerald I; Bennett, Anton M

    2015-01-01

    The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  18. The Coordinated Positive Regulation of Topoisomerase Genes Maintains Topological Homeostasis in Streptomyces coelicolor.

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    Szafran, Marcin Jan; Gongerowska, Martyna; Gutkowski, Paweł; Zakrzewska-Czerwińska, Jolanta; Jakimowicz, Dagmara

    2016-11-01

    Maintaining an optimal level of chromosomal supercoiling is critical for the progression of DNA replication and transcription. Moreover, changes in global supercoiling affect the expression of a large number of genes and play a fundamental role in adapting to stress. Topoisomerase I (TopA) and gyrase are key players in the regulation of bacterial chromosomal topology through their respective abilities to relax and compact DNA. Soil bacteria such as Streptomyces species, which grow as branched, multigenomic hyphae, are subject to environmental stresses that are associated with changes in chromosomal topology. The topological fluctuations modulate the transcriptional activity of a large number of genes and in Streptomyces are related to the production of antibiotics. To better understand the regulation of topological homeostasis in Streptomyces coelicolor, we investigated the interplay between the activities of the topoisomerase-encoding genes topA and gyrBA We show that the expression of both genes is supercoiling sensitive. Remarkably, increased chromosomal supercoiling induces the topA promoter but only slightly influences gyrBA transcription, while DNA relaxation affects the topA promoter only marginally but strongly activates the gyrBA operon. Moreover, we showed that exposure to elevated temperatures induces rapid relaxation, which results in changes in the levels of both topoisomerases. We therefore propose a unique mechanism of S. coelicolor chromosomal topology maintenance based on the supercoiling-dependent stimulation, rather than repression, of the transcription of both topoisomerase genes. These findings provide important insight into the maintenance of topological homeostasis in an industrially important antibiotic producer. We describe the unique regulation of genes encoding two topoisomerases, topoisomerase I (TopA) and gyrase, in a model Streptomyces species. Our studies demonstrate the coordination of topoisomerase gene regulation, which is crucial

  19. The nuclear IκB family of proteins controls gene regulation and immune homeostasis.

    Science.gov (United States)

    MaruYama, Takashi

    2015-10-01

    The inhibitory IκB family of proteins is subdivided into two groups based on protein localization in the cytoplasm or in the nucleus. These proteins interact with NF-κB, a major transcription factor regulating the expression of many inflammatory cytokines, by modulating its transcriptional activity. However, nuclear IκB family proteins not only interact with NF-κB to change its transcriptional activity, but they also bind to chromatin and control gene expression. This review provides an overview of nuclear IκB family proteins and their role in immune homeostasis. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection.

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    Stacey Ann Gorski

    2013-09-01

    Full Text Available Respiratory virus infections, such as influenza, typically induce a robust type I (pro-inflammatory cytokine immune response, however, the production of type 2 cytokines has been observed. Type 2 cytokine production during respiratory virus infection is linked to asthma exacerbation; however, type 2 cytokines may also be tissue protective. Interleukin (IL-5 is a prototypical type 2 cytokine that is essential for eosinophil maturation and egress out of the bone marrow. However, little is known about the cellular source and underlying cellular and molecular basis for the regulation of IL-5 production during respiratory virus infection. Using a mouse model of influenza virus infection, we found a robust transient release of IL-5 into infected airways along with a significant and progressive accumulation of eosinophils into the lungs, particularly during the recovery phase of infection, i.e. following virus clearance. The cellular source of the IL-5 was group 2 innate lymphoid cells (ILC2 infiltrating the infected lungs. Interestingly, the progressive accumulation of eosinophils following virus clearance is reflected in the rapid expansion of c-kit⁺ IL-5 producing ILC2. We further demonstrate that the enhanced capacity for IL-5 production by ILC2 during recovery is concomitant with the enhanced expression of the IL-33 receptor subunit, ST2, by ILC2. Lastly, we show that NKT cells, as well as alveolar macrophages (AM, are endogenous sources of IL-33 that enhance IL-5 production from ILC2. Collectively, these results reveal that c-kit⁺ ILC2 interaction with IL-33 producing NKT and AM leads to abundant production of IL-5 by ILC2 and accounts for the accumulation of eosinophils observed during the recovery phase of influenza infection.

  1. Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis.

    Science.gov (United States)

    Stark, Romana; Reichenbach, Alex; Andrews, Zane B

    2015-12-15

    The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin

  2. RNA-binding protein hnRNPLL as a critical regulator of lymphocyte homeostasis and differentiation.

    Science.gov (United States)

    Chang, Xing

    2016-05-01

    RNA-binding proteins orchestrate posttranscriptional regulation of gene expression, such as messenger RNA (mRNA) splicing, RNA stability regulation, and translation regulation. Heterogeneous nuclear RNA-binding proteins (hnRNPs) refer to a collection of unrelated RNA-binding proteins predominantly located in the nucleus (Han et al. Biochem J 2010, 430:379-392). Although canonical functions of hnRNPs are to promote pre-mRNA splicing, they are involved in all the processes of RNA metabolism through recognizing specific cis-elements on RNA (Dreyfuss et al. Annu Rev Biochem 1993, 62:289-321; Huelga et al. Cell Rep 2012, 1:167-178; Krecic and Swanson. Curr Opin Cell Biol 1999, 11:363-371). Heterogeneous nuclear RNA-binding protein L like (hnRNPLL) is a tissue-specific hnRNP, which was identified as a regulator of CD45RA to CD45RO switching during memory T-cell development (Oberdoerffer et al. Science 2008, 321:686-691; Topp et al. RNA 2008, 14:2038-2049; Wu et al. Immunity 2008, 29:863-875). Since then, hnRNPLL has emerged as a critical regulator of lymphocyte homeostasis and terminal differentiation, controlling alternative splicing or expression of critical genes for the lymphocytes development (Wu et al. Immunity 2008, 29:863-875; Chang et al. Proc Natl Acad Sci USA 2015, 112:E1888-E1897). This review will summarize recent advances in understanding the functions of hnRNPLL, focusing on its biochemical functions and physiological roles in lymphocyte differentiation and homeostasis. WIREs RNA 2016, 7:295-302. doi: 10.1002/wrna.1335 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

  3. Fungal Morphology, Iron Homeostasis, and Lipid Metabolism Regulated by a GATA Transcription Factor in Blastomyces dermatitidis.

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    Amber J Marty

    2015-06-01

    Full Text Available In response to temperature, Blastomyces dermatitidis converts between yeast and mold forms. Knowledge of the mechanism(s underlying this response to temperature remains limited. In B. dermatitidis, we identified a GATA transcription factor, SREB, important for the transition to mold. Null mutants (SREBΔ fail to fully complete the conversion to mold and cannot properly regulate siderophore biosynthesis. To capture the transcriptional response regulated by SREB early in the phase transition (0-48 hours, gene expression microarrays were used to compare SREB∆ to an isogenic wild type isolate. Analysis of the time course microarray data demonstrated SREB functioned as a transcriptional regulator at 37°C and 22°C. Bioinformatic and biochemical analyses indicated SREB was involved in diverse biological processes including iron homeostasis, biosynthesis of triacylglycerol and ergosterol, and lipid droplet formation. Integration of microarray data, bioinformatics, and chromatin immunoprecipitation identified a subset of genes directly bound and regulated by SREB in vivo in yeast (37°C and during the phase transition to mold (22°C. This included genes involved with siderophore biosynthesis and uptake, iron homeostasis, and genes unrelated to iron assimilation. Functional analysis suggested that lipid droplets were actively metabolized during the phase transition and lipid metabolism may contribute to filamentous growth at 22°C. Chromatin immunoprecipitation, RNA interference, and overexpression analyses suggested that SREB was in a negative regulatory circuit with the bZIP transcription factor encoded by HAPX. Both SREB and HAPX affected morphogenesis at 22°C; however, large changes in transcript abundance by gene deletion for SREB or strong overexpression for HAPX were required to alter the phase transition.

  4. Innate Lymphoid Cells Are Depleted Irreversibly during Acute HIV-Infection in the Absence of Viral Suppression

    DEFF Research Database (Denmark)

    Kløverpris, Henrik N.; Kazer, Samuel W.; Mjösberg, Jenny

    2016-01-01

    Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-on ILCs remains unknown. We found that human blood...... ILCs were severely depleted during acute viremic HIV-infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed...... mechanistic link between acute HIV-infection, lymphoid tissue breakdown, and persistent immune dysfunction....

  5. Regulation of Phosphatidylethanolamine Homeostasis — The Critical Role of CTP:Phosphoethanolamine Cytidylyltransferase (Pcyt2

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    Zvezdan Pavlovic

    2013-01-01

    Full Text Available Phosphatidylethanolamine (PE is the most abundant lipid on the protoplasmatic leaflet of cellular membranes. It has a pivotal role in cellular processes such as membrane fusion, cell cycle regulation, autophagy, and apoptosis. CTP:phosphoethanolamine cytidylyltransferase (Pcyt2 is the main regulatory enzyme in de novo biosynthesis of PE from ethanolamine and diacylglycerol by the CDP-ethanolamine Kennedy pathway. The following is a summary of the current state of knowledge on Pcyt2 and how splicing and isoform specific differences could lead to variations in functional properties in this family of enzymes. Results from the most recent studies on Pcyt2 transcriptional regulation, promoter function, autophagy, and cell growth regulation are highlighted. Recent data obtained from Pcyt2 knockout mouse models is also presented, demonstrating the essentiality of this gene in embryonic development as well as the major physiological consequences of deletion of one Pcyt2 allele. Those include development of symptoms of the metabolic syndrome such as elevated lipogenesis and lipoprotein secretion, hypertriglyceridemia, liver steatosis, obesity, and insulin resistance. The objective of this review is to elucidate the nature of Pcyt2 regulation by linking its catalytic function with the regulation of lipid and energy homeostasis.

  6. Hypothalamic roles of mTOR complex I: Integration of nutrient and hormone signals to regulate energy homeostasis

    Science.gov (United States)

    Mammalian or mechanistic target of rapamycin (mTOR) senses nutrient, energy, and hormone signals to regulate metabolism and energy homeostasis. mTOR activity in the hypothalamus, which is associated with changes in energy status, plays a critical role in the regulation of food intake and body weight...

  7. Circulating Blood eNOS Contributes to the Regulation of Systemic Blood Pressure and Nitrite Homeostasis

    Science.gov (United States)

    Wood, Katherine C.; Cortese-Krott, Miriam M.; Kovacic, Jason C.; Noguchi, Audrey; Liu, Virginia B.; Wang, Xunde; Raghavachari, Nalini; Boehm, Manfred; Kato, Gregory J.; Kelm, Malte; Gladwin, Mark T.

    2013-01-01

    Objective Mice genetically deficient in endothelial nitric oxide synthase (eNOS−/−) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. While the current paradigm holds that this bioactivity derives specifically from expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed. Approach and Results To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted WT and eNOS−/− mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NAME and repristinated by the NOS substrate L-Arginine, and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert 14C-Arginine into 14C-Citrulline in a NOS-dependent fashion. Conclusions These are the first studies to definitively establish a role for a blood borne eNOS, using cross transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect. PMID:23702660

  8. Developmental gene x environment interactions affecting systems regulating energy homeostasis and obesity.

    Science.gov (United States)

    Levin, Barry E

    2010-07-01

    Most human obesity is inherited as a polygenic trait which is largely refractory to medical therapy because obese individuals avidly defend their elevated body weight set-point. This set-point is mediated by an integrated neural network that controls energy homeostasis. Epidemiological studies suggest that perinatal and pre-pubertal environmental factors can promote offspring obesity. Rodent studies demonstrate the important interactions between genetic predisposition and environmental factors in promoting obesity. This review covers issues of development and function of neural systems involved in the regulation of energy homeostasis and the roles of leptin and insulin in these processes, the ways in which interventions at various phases from gestation, lactation and pre-pubertal stages of development can favorably and unfavorably alter the development of obesity n offspring. These studies suggest that early identification of obesity-prone humans and of the factors that can prevent them from becoming obese could provide an effective strategy for preventing the world-wide epidemic of obesity. Published by Elsevier Inc.

  9. The broad spectrum of signaling pathways regulated by unfolded protein response in neuronal homeostasis.

    Science.gov (United States)

    Saito, Atsushi; Imaizumi, Kazunori

    2017-06-28

    The protein folding capabilities in the endoplasmic reticulum (ER) are disturbed by alternations in the cellular homeostasis such as the disruption of calcium ion homeostasis, the expression of mutated proteins and oxidative stress. In response to these ER dysfunctions, eukaryotic cells activate canonical branches of signal transduction cascades to restore the protein folding capacity and avoid irreversible damages, collectively termed the unfolded protein response (UPR). Prolonged ER dysfunctions and the downregulation of UPR signaling pathways have been accepted as a crucial trigger for the pathogenesis of various neurodegenerative diseases. Furthermore, recent studies have revealed that the UPR has a wide spectrum of signaling pathways for unique physiological roles in the diverse developmental, differential and lipidomic processes. A developed and intricate ER network exists in the neurites of neurons. Neuronal ER functions and ER-derived signaling mediate efficient communication between cell soma and distal sites through local protein synthesis, sorting and lipogenesis. However, relevant of ER-derived UPR signaling pathways in the elaborate mechanisms regulating neuronal activities, synaptic functions and protective responses against injury is not fully elucidated. In this review, we summarized our current understanding of how the UPR functions provide the appropriate signals for neuronal capabilities. We also reviewed how UPR dysfunctions lead to the pathogenesis of neurodegenerative diseases, and the possibilities ameliorating their toxic effects by targeting UPR components. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. Neuro-immune interaction and the regulation of intestinal immune homeostasis.

    Science.gov (United States)

    Verheijden, Simon; Boeckxstaens, Guy E

    2017-09-14

    Many essential gastrointestinal functions, including motility, secretion and blood flow are regulated by the autonomic nervous system (ANS), both through intrinsic enteric neurons and extrinsic (sympathetic and parasympathetic) innervation. Recently identified neuro-immune mechanisms, in particular the interplay between enteric neurons and muscularis macrophages, are now considered to be essential for fine-tuning peristalsis. These findings shed new light on how intestinal immune cells can support enteric nervous function. In addition, both intrinsic and extrinsic neural mechanisms control intestinal immune homeostasis in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. In this mini-review, we discuss recent insights on immunomodulation by intrinsic enteric neurons and extrinsic innervation, with a particular focus on intestinal macrophages. In addition, we discuss the relevance of these novel mechanisms for intestinal immune homeostasis in physiological and pathological conditions, mainly focusing on motility disorders (gastroparesis and post-operative ileus) and inflammatory disorders (colitis). Copyright © 2017, American Journal of Physiology-Gastrointestinal and Liver Physiology.

  11. Altered regulation of energy homeostasis in older rats in response to thyroid hormone administration.

    Science.gov (United States)

    Walrand, Stephane; Short, Kevin R; Heemstra, Lydia A; Novak, Colleen M; Levine, James A; Coenen-Schimke, Jill M; Nair, K Sreekumaran

    2014-03-01

    Hyperthyroidism causes increased energy intake and expenditure, although anorexia and higher weight loss have been reported in elderly individuals with hyperthyroidism. To determine the effect of age on energy homeostasis in response to experimental hyperthyroidism, we administered 200 μg tri-iodothyronine (T3) in 7- and 27-mo-old rats for 14 d. T3 increased energy expenditure (EE) in both the young and the old rats, although the old rats lost more weight (147 g) than the young rats (58 g) because of the discordant effect of T3 on food intake, with a 40% increase in the young rats, but a 40% decrease in the old ones. The increased food intake in the young rats corresponded with a T3-mediated increase in the appetite-regulating proteins agouti-related peptide, neuropeptide Y, and uncoupling protein 2 in the hypothalamus, but no increase occurred in the old rats. Evidence of mitochondrial biogenesis in response to T3 was similar in the soleus muscle and heart of the young and old animals, but less consistent in old plantaris muscle and liver. Despite the comparable increase in EE, T3's effect on mitochondrial function was modulated by age in a tissue-specific manner. We conclude that older rats lack compensatory mechanisms to increase caloric intake in response to a T3-induced increase in EE, demonstrating a detrimental effect of age on energy homeostasis.

  12. Coupling Hydroxyapatite Nanocrystals with Lactoferrin as a Promising Strategy to Fine Regulate Bone Homeostasis.

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    Monica Montesi

    Full Text Available Lactoferrin (LF is an interesting glycoprotein in the field of bone biology for its regulatory effect on cells involved in bone remodeling, that results compromised in several pathological conditions, as osteoporosis. In a previous study we observed that the coupling of LF and biomimetic hydroxyapatite nanocrystals (HA, a material well-known for its bioactivity and osteoconductive properties, leads to a combined effect in the induction of osteogenic differentiation of mesenchymal stem cells. On the basis of this evidence, the present study is an extension of our previous work aiming to investigate the synergistic effect of the coupling of HA and LF on bone homeostasis. Biomimetic HA nanocrystals were synthesized and functionalized with LF (HA-LF and then pre-osteoblasts (MC3T3-E1 and monocyte/macrophage cells lines (RAW 264.7, using as osteoclastogenesis in vitro model, were cultured separately or in co-culture in presence of HA-LF. The results clearly revealed that HA and LF act in synergism in the regulation of the bone homeostasis, working as anabolic factor for osteoblasts differentiation and bone matrix deposition, and as inhibitor of the osteoclast formation and activity.

  13. Regulation of copper and iron homeostasis by metal chelators: a possible chemotherapy for Alzheimer's disease.

    Science.gov (United States)

    Robert, Anne; Liu, Yan; Nguyen, Michel; Meunier, Bernard

    2015-05-19

    With the increase of life expectancy of humans in more than two-thirds of the countries in the World, aging diseases are becoming the frontline health problems. Alzheimer's disease (AD) is now one of the major challenges in drug discovery, since, with the exception of memantine in 2003, all clinical trials with drug candidates failed over the past decade. If we consider that the loss of neurons is due to a high level of oxidative stress produced by nonregulated redox active metal ions like copper linked to amyloids of different sizes, regulation of metal homeostasis is a key target. The difficulty for large copper-carrier proteins to directly extract copper ions from metalated amyloids might be considered as being at the origin of the rupture of the copper homeostasis regulation in AD brains. So, there is an urgent need for new specific metal chelators that should be able to regulate the homeostasis of metal ions, specially copper and iron, in AD brains. As a consequence of that concept, chelators promoting metal excretion from brain are not desired. One should favor ligands able to extract copper ions from sinks (amyloids being the major one) and to transfer these redox-active metal ions to copper-carrier proteins or copper-containing enzymes. Obviously, the affinity of these chelators for the metal ion should not be a sufficient criterion, but the metal specificity and the ability of the chelators to release the metal under specific biological conditions should be considered. Such an approach is still largely unexplored. The requirements for the chelators are very high (ability to cross the brain-blood barrier, lack of toxicity, etc.), few chemical series were proposed, and, among them, biochemical or biological data are scarce. As a matter of fact, the bioinorganic pharmacology of AD represents less than 1% of all articles dedicated to AD drug research. The major part of these articles deals with an old and rather toxic drug, clioquinol and related analogs, that

  14. Pannexins Are Potential New Players in the Regulation of Cerebral Homeostasis during Sleep-Wake Cycle

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    Valery I. Shestopalov

    2017-07-01

    Full Text Available During brain homeostasis, both neurons and astroglia release ATP that is rapidly converted to adenosine in the extracellular space. Pannexin-1 (Panx1 hemichannels represent a major conduit of non-vesicular ATP release from brain cells. Previous studies have shown that Panx1−/− mice possess severe disruption of the sleep-wake cycle. Here, we review experimental data supporting the involvement of pannexins (Panx in the coordination of fundamental sleep-associated brain processes, such as neuronal activity and regulation of cerebrovascular tone. Panx1 hemichannels are likely implicated in the regulation of the sleep-wake cycle via an indirect effect of released ATP on adenosine receptors and through interaction with other somnogens, such as IL-1β, TNFα and prostaglandin D2. In addition to the recently established role of Panx1 in the regulation of endothelium-dependent arterial dilation, similar signaling pathways are the major cellular component of neurovascular coupling. The new discovered role of Panx in sleep regulation may have broad implications in coordinating neuronal activity and homeostatic housekeeping processes during the sleep-wake cycle.

  15. Priority in selenium homeostasis involves regulation of SepSecS transcription in the chicken brain.

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    Jin-Long Li

    Full Text Available O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS is critical for the biosynthesis and transformation of selenocysteine (Sec and plays an important role in the biological function of Se through the regulation of selenoprotein synthesis. Selenium (Se and Selenoprotein play a pivotal role in brain function. However, how intake of the micronutrient Se affects gene expression and how genetic factors influence Se metabolism in the brain is unknown. To investigate the regulation of SepSecS transcription induced by Se in the chicken brain, we determined the Se content of brain tissue, SepSecS gene expression levels and mRNA stability in the chicken brain and primary cultured chicken embryos neurons receiving Se supplements. These results showed that Se content in the brain remains remarkably stable during Se supplementation. A significant increase in SepSecS mRNA levels was observed in all of the brain tissues of chickens fed diets containing 1-5 mg/kg sodium selenite. Most strikingly, significant changes in SepSecS mRNA levels were not observed in neurons treated with Se. However, Se altered the SepSecS mRNA half-life in cells. These data suggest that Se could regulate SepSecS mRNA stability in the avian brain and that SepSecS plays an important role in Se homeostasis regulation.

  16. Modeling the role of negative cooperativity in metabolic regulation and homeostasis.

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    Eliot C Bush

    Full Text Available A significant proportion of enzymes display cooperativity in binding ligand molecules, and such effects have an important impact on metabolic regulation. This is easiest to understand in the case of positive cooperativity. Sharp responses to changes in metabolite concentrations can allow organisms to better respond to environmental changes and maintain metabolic homeostasis. However, despite the fact that negative cooperativity is almost as common as positive, it has been harder to imagine what advantages it provides. Here we use computational models to explore the utility of negative cooperativity in one particular context: that of an inhibitor binding to an enzyme. We identify several factors which may contribute, and show that acting together they can make negative cooperativity advantageous.

  17. The Mitochondrial Permeability Transition Pore Regulator Cyclophilin D Exhibits Tissue-Specific Control of Metabolic Homeostasis.

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    Rhianna C Laker

    Full Text Available The mitochondrial permeability transition pore (mPTP is a key regulator of mitochondrial function that has been implicated in the pathogenesis of metabolic disease. Cyclophilin D (CypD is a critical regulator that directly binds to mPTP constituents to facilitate the pore opening. We previously found that global CypD knockout mice (KO are protected from diet-induced glucose intolerance; however, the tissue-specific function of CypD and mPTP, particularly in the control of glucose homeostasis, has not been ascertained. To this end, we performed calcium retention capacity (CRC assay to compare the importance of CypD in the liver versus skeletal muscle. We found that liver mitochondria are more dependent on CypD for mPTP opening than skeletal muscle mitochondria. To ascertain the tissue-specific role of CypD in metabolic homeostasis, we generated liver-specific and muscle-specific CypD knockout mice (LKO and MKO, respectively and fed them either a chow diet or 45% high-fat diet (HFD for 14 weeks. MKO mice displayed similar body weight gain and glucose intolerance compared with wild type littermates (WT, whereas LKO mice developed greater visceral obesity, glucose intolerance and pyruvate intolerance compared with WT mice. These findings demonstrate that loss of muscle CypD is not sufficient to alter whole body glucose metabolism, while the loss of liver CypD exacerbates obesity and whole-body metabolic dysfunction in mice fed HFD.

  18. Transient expression of neuropeptide W in postnatal mouse hypothalamus--a putative regulator of energy homeostasis.

    Science.gov (United States)

    Motoike, T; Skach, A G; Godwin, J K; Sinton, C M; Yamazaki, M; Abe, M; Natsume, R; Sakimura, K; Yanagisawa, M

    2015-08-20

    Neuropeptide B and W (NPB and NPW) are cognate peptide ligands for NPBWR1 (GPR7), a G protein-coupled receptor. In rodents, they have been implicated in the regulation of energy homeostasis, neuroendocrine/autonomic responses, and social interactions. Although localization of these peptides and their receptors in adult rodent brain has been well documented, their expression in mouse brain during development is unknown. Here we demonstrate the transient expression of NPW mRNA in the dorsomedial hypothalamus (DMH) of postnatal mouse brain and its co-localization with neuropeptide Y (NPY) mRNA. Neurons expressing both NPW and NPY mRNAs begin to emerge in the DMH at about postnatal day 0 (P-0) through P-3. Their expression is highest around P-14, declines after P-21, and by P-28 only a faint expression of NPW and NPY mRNA remains. In P-18 brains, we detected NPW neurons in the region spanning the subincertal nucleus (SubI), the lateral hypothalamic (LH) perifornical (PF) areas, and the DMH, where the highest expression of NPW mRNA was observed. The majority of these postnatal hypothalamic NPW neurons co-express NPY mRNA. A cross of NPW-iCre knock-in mice with a Cre-dependent tdTomato reporter line revealed that more than half of the reporter-positive neurons in the adult DMH, which mature from the transiently NPW-expressing neurons, are sensitive to peripherally administrated leptin. These data suggest that the DMH neurons that transiently co-express NPW and NPY in the peri-weaning period might play a role in regulating energy homeostasis during postnatal development. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Regulation of Genes Involved in Carnitine Homeostasis by PPARα across Different Species (Rat, Mouse, Pig, Cattle, Chicken, and Human

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    Robert Ringseis

    2012-01-01

    Full Text Available Recent studies in rodents convincingly demonstrated that PPARα is a key regulator of genes involved in carnitine homeostasis, which serves as a reasonable explanation for the phenomenon that energy deprivation and fibrate treatment, both of which cause activation of hepatic PPARα, causes a strong increase of hepatic carnitine concentration in rats. The present paper aimed to comprehensively analyse available data from genetic and animal studies with mice, rats, pigs, cows, and laying hens and from human studies in order to compare the regulation of genes involved in carnitine homeostasis by PPARα across different species. Overall, our comparative analysis indicates that the role of PPARα as a regulator of carnitine homeostasis is well conserved across different species. However, despite demonstrating a well-conserved role of PPARα as a key regulator of carnitine homeostasis in general, our comprehensive analysis shows that this assumption particularly applies to the regulation by PPARα of carnitine uptake which is obviously highly conserved across species, whereas regulation by PPARα of carnitine biosynthesis appears less well conserved across species.

  20. Hypothalamic Y2 Receptors: Central Coordination of Energy Homeostasis and Bone Mass Regulation.

    Science.gov (United States)

    Herzog, Herbert

    2002-10-01

    Neuropeptide Y (NPY) in the central nervous system is a major regulator of food consumption and energy homeostasis. It also regulates blood pressure, induces anxiolysis, enhances memory retention and affects circadian rhythms, as well as modulates hormone release. Five Y receptors are known that mediate the action of NPY and its two other family members, peptide YY and pancreatic polypeptide. Increased NPY signaling due to elevated NPY expression in the hypothalamus leads to the development of obesity and its related phenotypes, type 2 diabetes and cardiovascular disease. Dysregulation in NPY signaling also causes alterations in bone formation. The large number of Y receptors has made it difficult to delineate their individual contributions to these physiological processes. However, recent studies analyzing Y-receptor knockout models have started to unravel some of the individual functions of these Y receptors. Particularly, the use of conditional knockout models has made it possible to pinpoint a specific functional contribution to an individual Y receptor in a particular location. From these studies, the predominantly presynaptically expressed Y2 receptor in the arcuate nucleus of the hypothalamus has emerged as a prime candidate for mediating satiety as well as a candidate for regulating bone formation. (c) 2002 Prous Science. All rights reserved.

  1. TDP-43, an ALS linked protein, regulates fat deposition and glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Nancy R Stallings

    Full Text Available The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS. While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism. Here we report, that over-expression of TDP-43 in transgenic mice can result in a phenotype characterized by increased fat deposition and adipocyte hypertrophy. In addition, TDP-43 over-expression in skeletal muscle results in increased steady state levels of Tbc1d1, a RAB-GTPase activating protein involved in Glucose 4 transporter (Glut4 translocation. Skeletal muscle fibers isolated from TDP-43 transgenic mice show altered Glut4 translocation in response to insulin and impaired insulin mediated glucose uptake. These results indicate that levels of TDP-43 regulate body fat composition and glucose homeostasis in vivo.

  2. AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species

    Directory of Open Access Journals (Sweden)

    Rebecca C. Rabinovitch

    2017-10-01

    Full Text Available Reactive oxygen species (ROS are continuously produced as a by-product of mitochondrial metabolism and eliminated via antioxidant systems. Regulation of mitochondrially produced ROS is required for proper cellular function, adaptation to metabolic stress, and bypassing cellular senescence. Here, we report non-canonical regulation of the cellular energy sensor AMP-activated protein kinase (AMPK by mitochondrial ROS (mROS that functions to maintain cellular metabolic homeostasis. We demonstrate that mitochondrial ROS are a physiological activator of AMPK and that AMPK activation triggers a PGC-1α-dependent antioxidant response that limits mitochondrial ROS production. Cells lacking AMPK activity display increased mitochondrial ROS levels and undergo premature senescence. Finally, we show that AMPK-PGC-1α-dependent control of mitochondrial ROS regulates HIF-1α stabilization and that mitochondrial ROS promote the Warburg effect in cells lacking AMPK signaling. These data highlight a key function for AMPK in sensing and resolving mitochondrial ROS for stress resistance and maintaining cellular metabolic balance.

  3. Transcriptional Regulation of Rod Photoreceptor Homeostasis Revealed by In Vivo NRL Targetome Analysis

    Science.gov (United States)

    Hao, Hong; Kim, Douglas S.; Klocke, Bernward; Johnson, Kory R.; Cui, Kairong; Gotoh, Norimoto; Zang, Chongzhi; Gregorski, Janina; Gieser, Linn; Peng, Weiqun; Fann, Yang; Seifert, Martin; Zhao, Keji; Swaroop, Anand

    2012-01-01

    A stringent control of homeostasis is critical for functional maintenance and survival of neurons. In the mammalian retina, the basic motif leucine zipper transcription factor NRL determines rod versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. Here, we report an integrated analysis of NRL-centered gene regulatory network by coupling chromatin immunoprecipitation followed by high-throughput sequencing (ChIP–Seq) data from Illumina and ABI platforms with global expression profiling and in vivo knockdown studies. We identified approximately 300 direct NRL target genes. Of these, 22 NRL targets are associated with human retinal dystrophies, whereas 95 mapped to regions of as yet uncloned retinal disease loci. In silico analysis of NRL ChIP–Seq peak sequences revealed an enrichment of distinct sets of transcription factor binding sites. Specifically, we discovered that genes involved in photoreceptor function include binding sites for both NRL and homeodomain protein CRX. Evaluation of 26 ChIP–Seq regions validated their enhancer functions in reporter assays. In vivo knockdown of 16 NRL target genes resulted in death or abnormal morphology of rod photoreceptors, suggesting their importance in maintaining retinal function. We also identified histone demethylase Kdm5b as a novel secondary node in NRL transcriptional hierarchy. Exon array analysis of flow-sorted photoreceptors in which Kdm5b was knocked down by shRNA indicated its role in regulating rod-expressed genes. Our studies identify candidate genes for retinal dystrophies, define cis-regulatory module(s) for photoreceptor-expressed genes and provide a framework for decoding transcriptional regulatory networks that dictate rod homeostasis. PMID:22511886

  4. Ouabain-induced perturbations in intracellular ionic homeostasis regulate death receptor-mediated apoptosis

    Science.gov (United States)

    Panayiotidis, Mihalis I.; Franco, Rodrigo; Bortner, Carl D.; Cidlowski, John A.

    2012-01-01

    Apoptosis is defined by specific morphological and biochemical characteristics including cell shrinkage (termed apoptotic volume decrease), a process that results from the regulation of ion channels and plasma membrane transporter activity. The Na+-K+-ATPase is the predominant pump that controls cell volume and plasma membrane potential in cells and alterations in its function have been suggested to be associated with apoptosis. We report here that the Na+-K+-ATPase inhibitor ouabain, potentiates apoptosis in the human lymphoma Jurkat cells exposed to Fas ligand (FasL) or Tumor necrosis factor--related apoptosis-inducing ligand (TRAIL) but not other apoptotic agents such as H2O2, thapsigargin or UV-C implicating a role for the Na+-K+-ATPase in death receptor-induced apoptosis. Interestingly, ouabain also potentiated perturbations in cell Ca2+ homeostasis only in conjunction with the apoptotic inducer FasL but not TRAIL. Ouabain did not affect alterations in the intracellular Ca2+ levels in response to H2O2, thapsigargin or UV-C. FasL-induced alterations in Ca2+ were not abolished in Ca2+-free medium but incubation of cells with BAPTA-AM inhibited both Ca2+ perturbations and the ouabain-induced potentiation of FasL-induced apoptosis. Our data suggest that the impairment of the Na+-K+-ATPase activity during apoptosis is linked to perturbations in cell Ca2+ homeostasis that modulate apoptosis induced by the activation of Fas by FasL. PMID:20422450

  5. Transcriptional regulation of rod photoreceptor homeostasis revealed by in vivo NRL targetome analysis.

    Directory of Open Access Journals (Sweden)

    Hong Hao

    Full Text Available A stringent control of homeostasis is critical for functional maintenance and survival of neurons. In the mammalian retina, the basic motif leucine zipper transcription factor NRL determines rod versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. Here, we report an integrated analysis of NRL-centered gene regulatory network by coupling chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq data from Illumina and ABI platforms with global expression profiling and in vivo knockdown studies. We identified approximately 300 direct NRL target genes. Of these, 22 NRL targets are associated with human retinal dystrophies, whereas 95 mapped to regions of as yet uncloned retinal disease loci. In silico analysis of NRL ChIP-Seq peak sequences revealed an enrichment of distinct sets of transcription factor binding sites. Specifically, we discovered that genes involved in photoreceptor function include binding sites for both NRL and homeodomain protein CRX. Evaluation of 26 ChIP-Seq regions validated their enhancer functions in reporter assays. In vivo knockdown of 16 NRL target genes resulted in death or abnormal morphology of rod photoreceptors, suggesting their importance in maintaining retinal function. We also identified histone demethylase Kdm5b as a novel secondary node in NRL transcriptional hierarchy. Exon array analysis of flow-sorted photoreceptors in which Kdm5b was knocked down by shRNA indicated its role in regulating rod-expressed genes. Our studies identify candidate genes for retinal dystrophies, define cis-regulatory module(s for photoreceptor-expressed genes and provide a framework for decoding transcriptional regulatory networks that dictate rod homeostasis.

  6. Regulation of copper homeostasis and biotic interactions by microRNA 398b in common bean.

    Directory of Open Access Journals (Sweden)

    Loreto Naya

    Full Text Available MicroRNAs are recognized as important post-transcriptional regulators in plants. Information about the roles of miRNAs in common bean (Phaseolus vulgaris L., an agronomically important legume, is yet scant. The objective of this work was to functionally characterize the conserved miRNA: miR398b and its target Cu/Zn Superoxide Dismutase 1 (CSD1 in common bean. We experimentally validated a novel miR398 target: the stress up-regulated Nodulin 19 (Nod19. Expression analysis of miR398b and target genes -CSD1 and Nod19- in bean roots, nodules and leaves, indicated their role in copper (Cu homeostasis. In bean plants under Cu toxicity miR398b was decreased and Nod19 and CSD1, that participates in reactive oxygen species (ROS detoxification, were up-regulated. The opposite regulation was observed in Cu deficient bean plants; lower levels of CSD1 would allow Cu delivery to essential Cu-containing proteins. Composite common bean plants with transgenic roots over-expressing miR398 showed ca. 20-fold higher mature miR398b and almost negligible target transcript levels as well as increased anthocyanin content and expression of Cu-stress responsive genes, when subjected to Cu deficiency. The down-regulation of miR398b with the consequent up-regulation of its targets was observed in common bean roots during the oxidative burst resulting from short-time exposure to high Cu. A similar response occurred at early stage of bean roots inoculated with Rhizobium tropici, where an increase in ROS was observed. In addition, the miR398b down-regulation and an increase in CSD1 and Nod19 were observed in bean leaves challenged with Sclerotinia scleortiorum fungal pathogen. Transient over-expression of miR398b in Nicotiana benthamiana leaves infected with S. sclerotiorum resulted in enhanced fungal lesions. We conclude that the miR398b-mediated up-regulation of CSD and Nod19 is relevant for common bean plants to cope with oxidative stress generated in abiotic and biotic

  7. Transcriptional repressor Blimp1 regulates follicular regulatory T-cell homeostasis and function.

    Science.gov (United States)

    Yang, Guang; Yang, Xiaosu; Zhang, Junmei; Li, Guancheng; Zheng, Dandan; Peng, Anjiao; Hu, Jue; Xu, Liqun; Yang, Baifeng; Yang, Huan; Zhou, Wenbin; Tuzun, Erdem; Li, Jing

    2018-01-01

    The B-lymphocyte-induced maturation protein 1 (Blimp1) regulates T-cell homeostasis and function. Loss of Blimp1 could double the proportion of follicular regulatory T (Tfr) cells. However, the effects that Blimp1 may have on the function of Tfr cells remain unknown. Here we document the function for Blimp1 in Tfr cells in vitro and in vivo. Data presented in this study demonstrate that Tfr cells indirectly inhibit the activation and differentiation of B cells by negatively regulating follicular helper T cells, so lowering the secretion of antibody. Lack of Blimp1 makes the immune suppression function of Tfr cells impaired in vitro. In the in vivo study, adoptive transfer of Tfr cells could reduce immune responses in germinal centres and relieve the muscle weakness symptoms of mice with experimental autoimmune myasthenia gravis. Blimp1 deficiency resulted in reduced suppressive ability of Tfr cells. This study identifies that Tfr cells are potent suppressors of immunity and are controlled by Blimp1. © 2017 John Wiley & Sons Ltd.

  8. Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis.

    Science.gov (United States)

    Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E; Seidman, J G; Pu, William T; Wang, Da-Zhi

    2015-11-02

    Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.

  9. [The discovery of neuromedin U and its pivotal role in the central regulation of energy homeostasis].

    Science.gov (United States)

    Kirsz, Katarzyna; Zięba, Dorota A

    2012-04-16

     Neuromedin U (NMU) is a structurally highly conserved neuropeptide and has been paired with the G-protein-coupled receptors (GPCRs) NMUR1 and NMUR2, which were formerly classified in the orphan receptor family. Activation of the G protein Gq/11 subunit causes a pertussis toxin (PTX)-insensitive activation of both phospholipase C and mitogen-activated protein kinase (MAP), and activation of the Go subunit causes a PTX-sensitive inhibition of adenyl cyclase. Additionally, NMU selectively inhibits L-type high-voltage-gated Ca2+ channels in mouse hippocampus, as well as low-voltage-activated T-type Ca2+ channels in mouse dorsal root ganglia (DRG). NMU peptide and its receptors are predominantly expressed in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy homeostasis. A novel neuropeptide, neuromedin S (NMS), is structurally related to NMU. They share a C-terminal core structure and both have been implicated in the regulation of food intake, as well as the circadian rhythms. The acute anorectic and weight-reducing effects of NMU and NMS are mediated by NMUR2. This suggests that NMUR2-selective agonists may be useful for the treatment of obesity.

  10. Complement emerges as a masterful regulator of CNS homeostasis, neural synaptic plasticity and cognitive function.

    Science.gov (United States)

    Mastellos, Dimitrios C

    2014-11-01

    Growing evidence points to a previously elusive role of complement-modulated pathways in CNS development, neurogenesis and synaptic plasticity. Distinct complement effectors appear to play a multifaceted role in brain homeostasis by regulating synaptic pruning in the retinogeniculate system and sculpting functional neural circuits both in the developing and adult mammalian brain. A recent study by Perez-Alcazar et al. (2014) provides novel insights into this intricate interplay between complement and the dynamically regulated brain synaptic circuitry, by reporting that mice deficient in C3 exhibit enhanced hippocampus-dependent spatial learning and cognitive performance. This behavioral pattern is associated with an impact of C3 on the functional capacity of glutamatergic synapses, supporting a crucial role for complement in excitatory synapse elimination in the hippocampus. These findings add a fresh twist to this rapidly evolving research field, suggesting that discrete complement components may differentially modulate synaptic connectivity by wiring up with diverse neural effectors in different regions of the brain. The emerging role of complement in synaptogenesis and neural network plasticity opens new conceptual avenues for considering complement interception as a potential therapeutic modality for ameliorating progressive cognitive impairment in age-related, debilitating brain diseases with a prominent inflammatory signature. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Innate Lymphoid Cells in HIV/SIV Infections.

    Science.gov (United States)

    Shah, Spandan V; Manickam, Cordelia; Ram, Daniel R; Reeves, R Keith

    2017-01-01

    Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC) have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s) in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.

  12. Innate Lymphoid Cells in HIV/SIV Infections

    Directory of Open Access Journals (Sweden)

    Spandan V. Shah

    2017-12-01

    Full Text Available Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.

  13. NPY Neuron-Specific Y2 Receptors Regulate Adipose Tissue and Trabecular Bone but Not Cortical Bone Homeostasis in Mice

    OpenAIRE

    Yan-Chuan Shi; Shu Lin; Wong, Iris P. L.; Baldock, Paul A.; Aygul Aljanova; Enriquez, Ronaldo F.; Lesley Castillo; Natalie F Mitchell; Ji-Ming Ye; Lei Zhang; Laurence Macia; Ernie Yulyaningsih; Amy D Nguyen; Riepler, Sabrina J.; Herbert Herzog

    2010-01-01

    BACKGROUND: Y2 receptor signalling is known to be important in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone physiology. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPY-expressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear. METHODOLOGY/PRINCIPAL FINDINGS: We thus generated two conditional knockout mouse models, Y2(lox/lox) and NPY...

  14. Neuronal calcium sensor synaptotagmin-9 is not involved in the regulation of glucose homeostasis or insulin secretion

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Wang, Xiaorui; Wang, Yue

    2010-01-01

    /PRINCIPAL FINDINGS: In this study we tested whether synaptotagmin-9 participates in the regulation of glucose-stimulated insulin release by using pancreas-specific synaptotagmin-9 knockout (p-S9X) mice. Deletion of synaptotagmin-9 in the pancreas resulted in no changes in glucose homeostasis or body weight. Glucose......, is not involved in the regulation of glucose-stimulated insulin release from pancreatic β-cells....

  15. Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue*

    Science.gov (United States)

    Guo, Hong; Foncea, Rocio; O'Byrne, Sheila M.; Jiang, Hongfeng; Zhang, Yuanyuan; Deis, Jessica A.; Blaner, William S.; Bernlohr, David A.; Chen, Xiaoli

    2016-01-01

    We have recently characterized the role of lipocalin 2 (Lcn2) as a new adipose-derived cytokine in the regulation of adaptive thermogenesis via a non-adrenergic pathway. Herein, we explored a potential non-adrenergic mechanism by which Lcn2 regulates thermogenesis and lipid metabolism. We found that Lcn2 is a retinoic acid target gene, and retinoic acid concurrently stimulated UCP1 and Lcn2 expression in adipocytes. Lcn2 KO mice exhibited a blunted effect of all-trans-retinoic acid (ATRA) on body weight and fat mass, lipid metabolism, and retinoic acid signaling pathway activation in adipose tissue under the high fat diet-induced obese condition. We further demonstrated that Lcn2 is required for the full action of ATRA on the induction of UCP1 and PGC-1α expression in brown adipocytes and the restoration of cold intolerance in Lcn2 KO mice. Interestingly, we discovered that Lcn2 KO mice have decreased levels of retinoic acid and retinol in adipose tissue. The protein levels of STRA6 responsible for retinol uptake were significantly decreased in adipose tissue. The retinol transporter RBP4 was increased in adipose tissue but decreased in the circulation, suggesting the impairment of RBP4 secretion in Lcn2 KO adipose tissue. Moreover, Lcn2 deficiency abolished the ATRA effect on RBP4 expression in adipocytes. All the data suggest that the decreased retinoid level and action are associated with impaired retinol transport and storage in adipose tissue in Lcn2 KO mice. We conclude that Lcn2 plays a critical role in regulating metabolic homeostasis of retinoids and retinoid-mediated thermogenesis in adipose tissue. PMID:27008859

  16. Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue.

    Science.gov (United States)

    Guo, Hong; Foncea, Rocio; O'Byrne, Sheila M; Jiang, Hongfeng; Zhang, Yuanyuan; Deis, Jessica A; Blaner, William S; Bernlohr, David A; Chen, Xiaoli

    2016-05-20

    We have recently characterized the role of lipocalin 2 (Lcn2) as a new adipose-derived cytokine in the regulation of adaptive thermogenesis via a non-adrenergic pathway. Herein, we explored a potential non-adrenergic mechanism by which Lcn2 regulates thermogenesis and lipid metabolism. We found that Lcn2 is a retinoic acid target gene, and retinoic acid concurrently stimulated UCP1 and Lcn2 expression in adipocytes. Lcn2 KO mice exhibited a blunted effect of all-trans-retinoic acid (ATRA) on body weight and fat mass, lipid metabolism, and retinoic acid signaling pathway activation in adipose tissue under the high fat diet-induced obese condition. We further demonstrated that Lcn2 is required for the full action of ATRA on the induction of UCP1 and PGC-1α expression in brown adipocytes and the restoration of cold intolerance in Lcn2 KO mice. Interestingly, we discovered that Lcn2 KO mice have decreased levels of retinoic acid and retinol in adipose tissue. The protein levels of STRA6 responsible for retinol uptake were significantly decreased in adipose tissue. The retinol transporter RBP4 was increased in adipose tissue but decreased in the circulation, suggesting the impairment of RBP4 secretion in Lcn2 KO adipose tissue. Moreover, Lcn2 deficiency abolished the ATRA effect on RBP4 expression in adipocytes. All the data suggest that the decreased retinoid level and action are associated with impaired retinol transport and storage in adipose tissue in Lcn2 KO mice. We conclude that Lcn2 plays a critical role in regulating metabolic homeostasis of retinoids and retinoid-mediated thermogenesis in adipose tissue. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. The E3 ligase AtCHIP positively regulates Clp proteolytic subunit homeostasis.

    Science.gov (United States)

    Wei, Jia; Qiu, Xiaoyun; Chen, Lin; Hu, Wenjun; Hu, Rongbin; Chen, Jian; Sun, Li; Li, Li; Zhang, Hong; Lv, Zhiqiang; Shen, Guoxin

    2015-09-01

    The caseinolytic peptidase (Clp) core proteins are essential for plant growth and development, especially for chloroplast function. Antisense or overexpression of ClpP4, which is one of the Clp core subunits, causes chlorotic phenotypes in Arabidopsis. An E3 ligase gene, AtCHIP, has previously been found to ubiquitylate ClpP4 in vitro. ClpP4 antisense and overexpressing plants that also overexpressed AtCHIP were constructed to explore the effect of AtCHIP on ClpP4. Overexpression of AtCHIP was found to rescue the chlorotic phenotypes of both ClpP4 antisense and overexpressing plants. The unbalanced levels of Clp core proteins in ClpP4 antisense and overexpressing plants with overexpression of AtCHIP were similar to wild-type levels, suggesting that AtCHIP regulates Clp core proteins. The results also show that AtCHIP can interact with ClpP3 and ClpP5 in yeast and ubiquitylate ClpP3 and ClpP5 in vitro. This suggests that AtCHIP is directly related to ClpP3 and ClpP5. Given these results, the inference is that through selective degradation of Clp subunits, AtCHIP could positively regulate homeostasis of Clp proteolytic subunits and maximize the production of functional chloroplasts. Similar results were obtained from transgenic tobacco plants, suggesting that regulation of the Clp protease by AtCHIP is conserved. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  18. Characteristics of innate lymphoid cells (ILCs) and their role in immunological disorders (an update).

    Science.gov (United States)

    Yazdani, Reza; Sharifi, Mehri; Shirvan, Aylar Saba; Azizi, Gholamreza; Ganjalikhani-Hakemi, Mazdak

    2015-01-01

    Innate lymphoid cells (ILCs) are a novel family of hematopoietic effectors and regulators of innate immunity. Although these cells are morphologically similar to B cells and T cells, however they do not express antigen receptors. ILCs seems to have emerging roles in innate immune responses against infectious or non-infectious microorganisms, protection of the epithelial barrier, lymphoid organogenesis and inflammation, tissue remodeling and regulating homeostasis of tissue stromal cells. In addition, it has recently been reported that ILCs have a crucial role in several disorders such as allergy and autoimmunity. Based on their phenotype and functions, ILCs are classified into three major groups called ILCs1, ILCs2, and ILCs3. Here we reviewed the most recent data concerning diverse ILC phenotypes, subclasses, functions in immune responses as well as in immune mediated disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Tertiary lymphoid tissue

    Science.gov (United States)

    Di Caro, Giuseppe; Marchesi, Federica

    2014-01-01

    Tumor-infiltrating lymphocytes influence colorectal cancer progression. We have recently documented that tertiary lymphoid tissue in the colorectal cancer microenvironment orchestrates lymphocyte infiltration and that tertiary lymphoid tissue and lymphocytes cooperate in a coordinated antitumor immune response to improve patient outcome. Thus, tertiary lymphoid tissue represents a potential target in the design of tailored immune-based therapeutic approaches. PMID:25083321

  20. miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle

    Directory of Open Access Journals (Sweden)

    Duo Zhang

    2016-07-01

    Full Text Available Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC. Short-term high-fat diet (HFD feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα, which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control.

  1. The Vestibular System: A Newly Identified Regulator of Bone Homeostasis Acting Through the Sympathetic Nervous System.

    Science.gov (United States)

    Vignaux, G; Besnard, S; Denise, P; Elefteriou, F

    2015-08-01

    The vestibular system is a small bilateral structure located in the inner ear, known as the organ of balance and spatial orientation. It senses head orientation and motion, as well as body motion in the three dimensions of our environment. It is also involved in non-motor functions such as postural control of blood pressure. These regulations are mediated via anatomical projections from vestibular nuclei to brainstem autonomic centers and are involved in the maintenance of cardiovascular function via sympathetic nerves. Age-associated dysfunction of the vestibular organ contributes to an increased incidence of falls, whereas muscle atrophy, reduced physical activity, cellular aging, and gonadal deficiency contribute to bone loss. Recent studies in rodents suggest that vestibular dysfunction might also alter bone remodeling and mass more directly, by affecting the outflow of sympathetic nervous signals to the skeleton and other tissues. This review will summarize the findings supporting the influence of vestibular signals on bone homeostasis, and the potential clinical relevance of these findings.

  2. Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis

    Science.gov (United States)

    Tarussio, David; Metref, Salima; Seyer, Pascal; Mounien, Lourdes; Vallois, David; Magnan, Christophe; Foretz, Marc; Thorens, Bernard

    2013-01-01

    How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function. PMID:24334455

  3. Plasma-membrane Cnh1 Na+/H+ antiporter regulates potassium homeostasis in Candida albicans.

    Science.gov (United States)

    Kinclova-Zimmermannova, Olga; Sychrová, Hana

    2007-08-01

    The physiological role of Candida albicans Cnh1, a member of the Na+/H+ antiporter family, was characterized. Though CaCnh1p had broad substrate specificity and mediated efflux of at least four alkali metal cations upon heterologous expression in Saccharomyces cerevisiae, its presence in C. albicans cells was important especially for potassium homeostasis. In C. albicans, CaCnh1p tagged with GFP was localized in the plasma membrane of cells growing as both yeasts and hyphae. Deletion of CNH1 alleles did not affect tolerance to NaCl, LiCl or CsCl, but resulted in increased sensitivity to high external concentrations of KCl and RbCl. The potassium and rubidium tolerance of a cnh1 homozygous mutant was fully restored by reintegration of CNH1 into the genome. The higher sensitivity of the cnh1/cnh1 mutant to external KCl was caused by a lower K+ efflux from these cells. Together, the functional characterization of the CaCnh1 antiporter in C. albicans revealed that this antiporter plays a significant role in C. albicans physiology. It ensures potassium and rubidium tolerance and participates in the regulation of intracellular potassium content of C. albicans cells.

  4. The Causative Gene in Chanarian Dorfman Syndrome Regulates Lipid Droplet Homeostasis in C. elegans.

    Directory of Open Access Journals (Sweden)

    Meng Xie

    2015-06-01

    Full Text Available AMP-activated kinase (AMPK is a key regulator of many cellular mechanisms required for adjustment to various stresses induced by the changing environment. In C. elegans dauer larvae AMPK-null mutants expire prematurely due to hyperactive Adipose Triglyceride Lipase (ATGL-1 followed by rapid depletion of triglyceride stores. We found that the compromise of one of the three C. elegans orthologues of human cgi-58 significantly improves the survival of AMPK-deficient dauers. We also provide evidence that C. elegans CGI-58 acts as a co-activator of ATGL-1, while it also functions cooperatively to maintain regular lipid droplet structure. Surprisingly, we show that it also acts independently of ATGL-1 to restrict lipid droplet coalescence by altering the surface abundance and composition of long chain (C20 polyunsaturated fatty acids (PUFAs. Our data reveal a novel structural role of CGI-58 in maintaining lipid droplet homeostasis through its effects on droplet composition, morphology and lipid hydrolysis; a conserved function that may account for some of the ATGL-1-independent features unique to Chanarin-Dorfman Syndrome.

  5. Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating Tff3 Expression.

    Science.gov (United States)

    Zhu, Yi; Zhao, Shangang; Deng, Yingfeng; Gordillo, Ruth; Ghaben, Alexandra L; Shao, Mengle; Zhang, Fang; Xu, Ping; Li, Yang; Cao, Huachuan; Zagnitko, Olga; Scott, David A; Gupta, Rana K; Xing, Chao; Zhang, Bei B; Lin, Hua V; Scherer, Philipp E

    2017-11-01

    Transcripts of key enzymes in the Leloir pathway of galactose metabolism in mouse livers are significantly increased after chronic high-fat/high-sucrose feeding. UDP-galactose-4-epimerase (GALE) is the last enzyme in this pathway that converts UDP-galactose to UDP-glucose and was previously identified as a downstream target of the endoplasmic reticulum (ER) stress effector spliced X-box binding protein 1, suggesting an interesting cross talk between galactose and glucose metabolism in the context of hepatic ER stress and whole-body metabolic fitness. However, its specific role in glucose metabolism is not established. Using an inducible and tissue-specific mouse model, we report that hepatic overexpression of Gale increases gluconeogenesis from pyruvate and impairs glucose tolerance. Conversely, genetic reduction of Gale in liver improves glucose tolerance. Transcriptional profiling identifies trefoil factor 3 (Tff3) as one of the downstream targets of GALE. Restoration of Tff3 expression corrects glucose intolerance in Gale-overexpressing mice. These studies reveal a new link between hepatic GALE activity and whole-body glucose homeostasis via regulation of hepatic Tff3 expression. © 2017 by the American Diabetes Association.

  6. Regulation of TRH neurons and energy homeostasis-related signals under stress.

    Science.gov (United States)

    Joseph-Bravo, Patricia; Jaimes-Hoy, Lorraine; Charli, Jean-Louis

    2015-03-01

    Energy homeostasis relies on a concerted response of the nervous and endocrine systems to signals evoked by intake, storage, and expenditure of fuels. Glucocorticoids (GCs) and thyroid hormones are involved in meeting immediate energy demands, thus placing the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-adrenal axes at a central interface. This review describes the mode of regulation of hypophysiotropic TRHergic neurons and the evidence supporting the concept that they act as metabolic integrators. Emphasis has been be placed on i) the effects of GCs on the modulation of transcription of Trh in vivo and in vitro, ii) the physiological and molecular mechanisms by which acute or chronic situations of stress and energy demands affect the activity of TRHergic neurons and the HPT axis, and iii) the less explored role of non-hypophysiotropic hypothalamic TRH neurons. The partial evidence gathered so far is indicative of a contrasting involvement of distinct TRH cell types, manifested through variability in cellular phenotype and physiology, including rapid responses to energy demands for thermogenesis or physical activity and nutritional status that may be modified according to stress history. © 2015 Society for Endocrinology.

  7. The Clubroot Pathogen (Plasmodiophora brassicae Influences Auxin Signaling to Regulate Auxin Homeostasis in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Linda Jahn

    2013-11-01

    Full Text Available The clubroot disease, caused by the obligate biotrophic protist Plasmodiophora brassicae, affects cruciferous crops worldwide. It is characterized by root swellings as symptoms, which are dependent on the alteration of auxin and cytokinin metabolism. Here, we describe that two different classes of auxin receptors, the TIR family and the auxin binding protein 1 (ABP1 in Arabidopsis thaliana are transcriptionally upregulated upon gall formation. Mutations in the TIR family resulted in more susceptible reactions to the root pathogen. As target genes for the different pathways we have investigated the transcriptional regulation of selected transcriptional repressors (Aux/IAA and transcription factors (ARF. As the TIR pathway controls auxin homeostasis via the upregulation of some auxin conjugate synthetases (GH3, the expression of selected GH3 genes was also investigated, showing in most cases upregulation. A double gh3 mutant showed also slightly higher susceptibility to P. brassicae infection, while all tested single mutants did not show any alteration in the clubroot phenotype. As targets for the ABP1-induced cell elongation the effect of potassium channel blockers on clubroot formation was investigated. Treatment with tetraethylammonium (TEA resulted in less severe clubroot symptoms. This research provides evidence for the involvement of two auxin signaling pathways in Arabidopsis needed for the establishment of the root galls by P. brassicae.

  8. Participation of the central melanocortin system in metabolic regulation and energy homeostasis.

    Science.gov (United States)

    Jeong, Jin Kwon; Kim, Jae Geun; Lee, Byung Ju

    2014-10-01

    Obesity and metabolic disorders, such as type 2 diabetes and hypertension, have attracted considerable attention as life-threatening diseases not only in developed countries but also worldwide. Additionally, the rate of obesity in young people all over the world is rapidly increasing. Accumulated evidence suggests that the central nervous system may participate in the development of and/or protection from obesity. For example, in the brain, the hypothalamic melanocortin system senses and integrates central and peripheral metabolic signals and controls the degree of energy expenditure and feeding behavior, in concert with metabolic status, to regulate whole-body energy homeostasis. Currently, researchers are studying the mechanisms by which peripheral metabolic molecules control feeding behavior and energy balance through the central melanocortin system. Accordingly, recent studies have revealed that some inflammatory molecules and transcription factors participate in feeding behavior and energy balance by controlling the central melanocortin pathway, and have thus become new candidates as therapeutic targets to fight metabolic diseases such as obesity and diabetes.

  9. Presenilins regulate synaptic plasticity and mitochondrial calcium homeostasis in the hippocampal mossy fiber pathway.

    Science.gov (United States)

    Lee, Sang Hun; Lutz, David; Mossalam, Mohanad; Bolshakov, Vadim Y; Frotscher, Michael; Shen, Jie

    2017-06-15

    plasticity impairment observed at MF and SC synapses in acute PS cDKO hippocampal slices, PS cDKO mice exhibit profound spatial learning and memory deficits in the Morris water maze. Our findings demonstrate the importance of PS in the regulation of synaptic plasticity and mitochondrial Ca 2+ homeostasis in the hippocampal MF pathway.

  10. (Pro)Renin receptor regulates potassium homeostasis through a local mechanism.

    Science.gov (United States)

    Xu, Chuanming; Lu, Aihua; Wang, Hong; Fang, Hui; Zhou, Li; Sun, Peng; Yang, Tianxin

    2017-09-01

    (Pro)renin receptor (PRR) is highly expressed in the distal nephron, but it has an unclear functional implication. The present study was conducted to explore a potential role of renal PRR during high K(+) (HK) loading. In normal Sprague-Dawley rats, a 1-wk HK intake increased renal expression of full-length PRR and urinary excretion of soluble PRR (sPRR). Administration of PRO20, a decoy peptide antagonist of PRR, in K(+)-loaded animals elevated plasma K(+) level and decreased urinary K(+) excretion, accompanied with suppressed urinary aldosterone excretion and intrarenal aldosterone levels. HK downregulated Na(+)-Cl(-) cotransporter (NCC) expression but upregulated CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2), renal outer medullary K(+) channel (ROMK), calcium-activated potassium channel subunit α1 (α-BK), α-Na(+)-K(+)-ATPase (α-NKA), and epithelial Na(+) channel subunit β (β-ENaC), all of which were blunted by PRO20. After HK loading was completed, urinary, but not plasma renin, was upregulated, which was blunted by PRO20. The same experiments that were performed using adrenalectomized (ADX) rats yielded similar results. Interestingly, spironolactone treatment in HK-loaded ADX rats attenuated kaliuresis but promoted natriuresis, which was associated with the suppressed responses of β-ENaC, α-NKA, ROMK, and α-BK protein expression. Taken together, we discovered a novel role of renal PRR in regulation of K(+) homeostasis through a local mechanism involving intrarenal renin-angiotensin-aldosterone system and coordinated regulation of membrane Na(+)- and K(+)-transporting proteins.

  11. Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis.

    Science.gov (United States)

    Colomer-Winter, C; Gaca, A O; Lemos, J A

    2017-07-01

    In Enterococcus faecalis, the regulatory nucleotides pppGpp and ppGpp, collectively, (p)ppGpp, are required for growth in blood, survival within macrophages, and virulence. However, a clear understanding of how (p)ppGpp promotes virulence in E. faecalis and other bacterial pathogens is still lacking. In the host, the essential transition metals iron (Fe) and manganese (Mn) are not readily available to invading pathogens because of a host-driven process called nutritional immunity. Considering its central role in adaptation to nutritional stresses, we hypothesized that (p)ppGpp mediates E. faecalis virulence through regulation of metal homeostasis. Indeed, supplementation of serum with either Fe or Mn restored growth and survival of the Δrel ΔrelQ [(p)ppGpp(0)] strain to wild-type levels. Using a chemically defined medium, we found that (p)ppGpp accumulates in response to either Fe depletion or Mn depletion and that the (p)ppGpp(0) strain has a strong growth requirement for Mn that is alleviated by Fe supplementation. Although inactivation of the nutrient-sensing regulator codY restored some phenotypes of the (p)ppGpp(0) strain, transcriptional analysis showed that the (p)ppGpp/CodY network does not promote transcription of known metal transporters. Interestingly, physiologic and enzymatic investigations suggest that the (p)ppGpp(0) strain requires higher levels of Mn in order to cope with high levels of endogenously produced reactive oxygen species (ROS). Because (p)ppGpp mediates antibiotic persistence and virulence in several bacteria, our findings have broad implications and provide new leads for the development of novel therapeutic and preventive strategies against E. faecalis and beyond. Copyright © 2017 American Society for Microbiology.

  12. Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control

    Science.gov (United States)

    Han, Sumin; Lone, Museer A.; Schneiter, Roger; Chang, Amy

    2010-01-01

    Yeast members of the ORMDL family of endoplasmic reticulum (ER) membrane proteins play a central role in lipid homeostasis and protein quality control. In the absence of yeast Orm1 and Orm2, accumulation of long chain base, a sphingolipid precursor, suggests dysregulation of sphingolipid synthesis. Physical interaction between Orm1 and Orm2 and serine palmitoyltransferase, responsible for the first committed step in sphingolipid synthesis, further supports a role for the Orm proteins in regulating sphingolipid synthesis. Phospholipid homeostasis is also affected in orm1Δ orm2Δ cells: the cells are inositol auxotrophs with impaired transcriptional regulation of genes encoding phospholipid biosynthesis enzymes. Strikingly, impaired growth of orm1Δ orm2Δ cells is associated with constitutive unfolded protein response, sensitivity to stress, and slow ER-to-Golgi transport. Inhibition of sphingolipid synthesis suppresses orm1Δ orm2Δ phenotypes, including ER stress, suggesting that disrupted sphingolipid homeostasis accounts for pleiotropic phenotypes. Thus, the yeast Orm proteins control membrane biogenesis by coordinating lipid homeostasis with protein quality control. PMID:20212121

  13. Astrocyte control of fetal cortical neuron glutathione homeostasis: up-regulation by ethanol.

    Science.gov (United States)

    Rathinam, Mary Latha; Watts, Lora Talley; Stark, Avishay A; Mahimainathan, Lenin; Stewart, Jennifer; Schenker, Steven; Henderson, George I

    2006-03-01

    Ethanol increases apoptotic neuron death in the developing brain and at least part of this may be mediated by oxidative stress. In cultured fetal rat cortical neurons, Ethanol increases levels of reactive oxygen species (ROS) within minutes of exposure and reduces total cellular glutathione (GSH) shortly thereafter. This is followed by onset of apoptotic cell death. These responses to Ethanol can be blocked by elevating neuron GSH with N-acetylcysteine or by co-culturing neurons with neonatal cortical astrocytes. We describe here mechanisms by which the astrocyte-neuron gamma-glutamyl cycle is up-regulated by Ethanol, enhancing control of neuron GSH in response to the pro-oxidant, Ethanol. Up to 6 days of Ethanol exposure had no consistent effects on activities of gamma-glutamyl cysteine ligase or glutathione synthetase, and GSH content remained unchanged (p glutathione reductase was increased with 1 and 2 day Ethanol exposures, 25% and 39% for 2.5 and 4.0 mg/mL Ethanol by 1 day, and 11% and 16% for 2.5 and 4.0 mg/mL at 2 days, respectively (p Ethanol increased GSH efflux from astrocyte up to 517% (p Ethanol increased both gamma-glutamyl transpeptidase expression and activity on astrocyte within 24 h of exposure (40%, p = 0.05 with 4.0 mg/mL) and this continued for at least 4 days of Ethanol treatment. Aminopeptidase N activity on neurons increased by 62% and 55% within 1 h of Ethanol for 2.5 and 4.0 mg/mL concentration, respectively (p Ethanol, the net effect being to enhance neuron GSH homeostasis, thereby protecting neurons from Ethanol-mediated oxidative stress and apoptotic death.

  14. Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

    Science.gov (United States)

    Acharya, Nandini; Penukonda, Sasi; Shcheglova, Tatiana; Hagymasi, Adam T; Basu, Sreyashi; Srivastava, Pramod K

    2017-05-09

    Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1(hi) macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1(-/-) or CB2(-/-) mice have fewer CX3CR1(hi) Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4(+) cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4(+) T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.

  15. Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control

    OpenAIRE

    Han, Sumin; Lone, Museer A.; Schneiter, Roger; CHANG, Amy

    2010-01-01

    Yeast members of the ORMDL family of endoplasmic reticulum (ER) membrane proteins play a central role in lipid homeostasis and protein quality control. In the absence of yeast Orm1 and Orm2, accumulation of long chain base, a sphingolipid precursor, suggests dysregulation of sphingolipid synthesis. Physical interaction between Orm1 and Orm2 and serine palmitoyltransferase, responsible for the first committed step in sphingolipid synthesis, further supports a role for the Orm proteins in regul...

  16. Identification of novel genetic regulations associated with airway epithelial homeostasis using next-generation sequencing data and bioinformatics approaches.

    Science.gov (United States)

    Sheu, Chau-Chyun; Tsai, Ming-Ju; Chen, Feng-Wei; Chang, Kuo-Feng; Chang, Wei-An; Chong, Inn-Wen; Kuo, Po-Lin; Hsu, Ya-Ling

    2017-10-10

    Airway epithelial cells play important roles in airway remodeling. Understanding gene regulations in airway epithelial homeostasis may provide new insights into pathogenesis and treatment of asthma. This study aimed to combine gene expression (GE) microarray, next generation sequencing (NGS), and bioinformatics to explore genetic regulations associated with airway epithelial homeostasis. We analyzed expression profiles of mRNAs (GE microarray) and microRNAs (NGS) in normal and asthmatic bronchial epithelial cells, and identified 9 genes with potential microRNA-mRNA interactions. Of these 9 dysregulated genes, downregulation of MEF2C and MDGA1 were validated in a representative microarray (GSE43696) from the gene expression omnibus (GEO) database. Our findings suggested that upregulated mir-203a may repress MEF2C, a transcription factor, leading to decreased cellular proliferation. In addition, upregulated mir-3065-3p may repress MDGA1, a cell membrane anchor protein, resulting in suppression of cell-cell adhesion. We also found that KCNJ2, a potassium channel, was downregulated in severe asthma and may promote epithelial cell apoptosis. We proposed that aberrant regulations of mir-203a-MEF2C and mir-3065-3p-MDGA1, as well as downregulation of KCNJ2, play important roles in airway epithelial homeostasis in asthma. These findings provide new perspectives on diagnostic or therapeutic strategies targeting bronchial epithelium for asthma. The approach in this study also provides a new aspect of studying asthma.

  17. Molecular deregulation of signaling in lymphoid tumors.

    Science.gov (United States)

    Spina, Valeria; Martuscelli, Lavinia; Rossi, Davide

    2015-10-01

    Genomic studies have led to a significant impact both on the pace and the nature of understanding the molecular and biological bases of a variety of lymphoid tumors. An increasingly emerging aspect from genomic studies is that malignant lymphoid cells manipulate signaling pathways that are central to the homeostasis of their normal counterpart, including B- and T-cell receptor signaling, NF-κB signaling, Toll-like receptor signaling, cytokine signaling, MAP kinase signaling, and NOTCH signaling. This review aims at covering the signaling pathways that are affected by mutations in lymphoid tumors, and how genetic alteration of these pathways may contribute to disease pathogenesis and management. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box.

    Science.gov (United States)

    Williams, G; Harrold, J A; Cutler, D J

    2000-08-01

    The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of 'feeding' and 'satiety' centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY 'feeding' receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as alpha-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as 'agouti' protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY

  19. Infection Programs Sustained Lymphoid Stromal Cell Responses and Shapes Lymph Node Remodeling upon Secondary Challenge

    Directory of Open Access Journals (Sweden)

    Julia L. Gregory

    2017-01-01

    Full Text Available Lymph nodes (LNs are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner. Infection induced rapid transcriptional responses in LSCs. This transcriptional program was transient, returning to homeostasis within 1 month of infection, yet expanded fibroblastic reticular cell networks persisted for more than 3 months after infection, and this altered LN composition reduced the magnitude of LSC responses to subsequent heterologous infection. Our results reveal the complexity of LSC responses during infection and suggest that amplified networks of LN stromal cells support successive immune responses.

  20. Reactive Oxygen Species and Mitochondrial Homeostasis as Regulators of Stem Cell Fate and Function.

    Science.gov (United States)

    Tan, Darren Q; Suda, Toshio

    2017-10-26

    The precise role and impact of reactive oxygen species (ROS) in stem cells, which are essential for lifelong tissue homeostasis and regeneration, remain of significant interest to the field. The long-term regenerative potential of a stem cell compartment is determined by the delicate balance between quiescence, self-renewal, and differentiation, all of which can be influenced by ROS levels. Recent Advances: The past decade has seen a growing appreciation for the importance of ROS and redox homeostasis in various stem cell compartments, particularly those of hematopoietic, neural, and muscle tissues. In recent years, the importance of proteostasis and mitochondria in relation to stem cell biology and redox homeostasis has garnered considerable interest. Here, we explore the reciprocal relationship between ROS and stem cells, with significant emphasis on mitochondria as a core component of redox homeostasis. We discuss how redox signaling, involving cell-fate determining protein kinases and transcription factors, can control stem cell function and fate. We also address the impact of oxidative stress on stem cells, especially oxidative damage of lipids, proteins, and nucleic acids. We further discuss ROS management in stem cells, and present recent evidence supporting the importance of mitochondrial activity and its modulation (via mitochondrial clearance, biogenesis, dynamics, and distribution [i.e., segregation and transfer]) in stem cell redox homeostasis. Therefore, elucidating the intricate links between mitochondria, cellular metabolism, and redox homeostasis is envisioned to be critical for our understanding of ROS in stem cell biology and its therapeutic relevance in regenerative medicine. Antioxid. Redox Signal. 00, 000-000.

  1. The Interplay between Wnt Mediated Expansion and Negative Regulation of Growth Promotes Robust Intestinal Crypt Structure and Homeostasis.

    Directory of Open Access Journals (Sweden)

    Huijing Du

    2015-08-01

    Full Text Available The epithelium of the small intestinal crypt, which has a vital role in protecting the underlying tissue from the harsh intestinal environment, is completely renewed every 4-5 days by a small pool of stem cells at the base of each crypt. How is this renewal controlled and homeostasis maintained, particularly given the rapid nature of this process? Here, based on the recent observations from in vitro "mini gut" studies, we use a hybrid stochastic model of the crypt to investigate how exogenous niche signaling (from Wnt and BMP combines with auto-regulation to promote homeostasis. This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals. Results show that Paneth cell derived Wnt signals, which have been observed experimentally to sustain crypts in cultured organs, have a dramatically different influence on niche dynamics than does mesenchyme derived Wnt. While this signaling can indeed act as a redundant backup to the exogenous gradient, it introduces a positive feedback that destabilizes the niche and causes its uncontrolled expansion. We find that in this setting, BMP has a critical role in constraining this expansion, consistent with observations that its removal leads to crypt fission. Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt's spatial structure. Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check.

  2. The Interplay between Wnt Mediated Expansion and Negative Regulation of Growth Promotes Robust Intestinal Crypt Structure and Homeostasis.

    Science.gov (United States)

    Du, Huijing; Nie, Qing; Holmes, William R

    2015-08-01

    The epithelium of the small intestinal crypt, which has a vital role in protecting the underlying tissue from the harsh intestinal environment, is completely renewed every 4-5 days by a small pool of stem cells at the base of each crypt. How is this renewal controlled and homeostasis maintained, particularly given the rapid nature of this process? Here, based on the recent observations from in vitro "mini gut" studies, we use a hybrid stochastic model of the crypt to investigate how exogenous niche signaling (from Wnt and BMP) combines with auto-regulation to promote homeostasis. This model builds on the sub-cellular element method to account for the three-dimensional structure of the crypt, external regulation by Wnt and BMP, internal regulation by Notch signaling, as well as regulation by internally generated diffusible signals. Results show that Paneth cell derived Wnt signals, which have been observed experimentally to sustain crypts in cultured organs, have a dramatically different influence on niche dynamics than does mesenchyme derived Wnt. While this signaling can indeed act as a redundant backup to the exogenous gradient, it introduces a positive feedback that destabilizes the niche and causes its uncontrolled expansion. We find that in this setting, BMP has a critical role in constraining this expansion, consistent with observations that its removal leads to crypt fission. Further results also point to a new hypothesis for the role of Ephrin mediated motility of Paneth cells, specifically that it is required to constrain niche expansion and maintain the crypt's spatial structure. Combined, these provide an alternative view of crypt homeostasis where the niche is in a constant state of expansion and the spatial structure of the crypt arises as a balance between this expansion and the action of various sources of negative regulation that hold it in check.

  3. Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

    NARCIS (Netherlands)

    Beumer, Joep; Clevers, Hans

    2016-01-01

    The intestinal epithelium is the fastest renewing tissue in mammals and has a large flexibility to adapt to different types of damage. Lgr5(+) crypt base columnar (CBC) cells act as stem cells during homeostasis and are essential during regeneration. Upon perturbation, the activity of CBCs is

  4. Migration and Tissue Tropism of Innate Lymphoid Cells

    Science.gov (United States)

    Kim, Chang H.; Hashimoto-Hill, Seika; Kim, Myunghoo

    2016-01-01

    Innate lymphoid cell (ILCs) subsets differentially populate various barrier and non-barrier tissues, where they play important roles in tissue homeostasis and tissue-specific responses to pathogen attack. Recent findings have provided insight into the molecular mechanisms that guide ILC migration into peripheral tissues, revealing common features among different ILC subsets as well as important distinctions. Recent studies have also highlighted the impact of tissue-specific cues on ILC migration, and the importance of the local immunological milieu. We review these findings here and discuss how the migratory patterns and tissue tropism of different ILC subsets relate to the development and differentiation of these cells, and to ILC-mediated tissue-specific regulation of innate and adaptive immune responses. In this context we outline open questions and important areas of future research. PMID:26708278

  5. Card9-dependent IL-1β regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer.

    Science.gov (United States)

    Bergmann, Hanna; Roth, Susanne; Pechloff, Konstanze; Kiss, Elina A; Kuhn, Sabine; Heikenwälder, Mathias; Diefenbach, Andreas; Greten, Florian R; Ruland, Jürgen

    2017-08-01

    Inflammatory bowel diseases (IBD) are key risk factors for the development of colorectal cancer, but the mechanisms that link intestinal inflammation with carcinogenesis are insufficiently understood. Card9 is a myeloid cell-specific signaling protein that regulates inflammatory responses downstream of various pattern recognition receptors and which cooperates with the inflammasomes for IL-1β production. Because polymorphisms in Card9 were recurrently associated with human IBD, we investigated the function of Card9 in a colitis-associated cancer (CAC) model. Card9 -/- mice develop smaller, less proliferative and less dysplastic tumors compared to their littermates and in the regenerating mucosa we detected dramatically impaired IL-1β generation and defective IL-1β controlled IL-22 production from group 3 innate lymphoid cells. Consistent with the key role of immune-derived IL-22 in activating STAT3 signaling during normal and pathological intestinal epithelial cell (IEC) proliferation, Card9 -/- mice also exhibit impaired tumor cell intrinsic STAT3 activation. Our results imply a Card9-controlled, ILC3-mediated mechanism regulating healthy and malignant IEC proliferation and demonstrates a role of Card9-mediated innate immunity in inflammation-associated carcinogenesis. © 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. The virus-induced HSPs regulate the apoptosis of operatus APCs that result in autoimmunity, not in homeostasis.

    Science.gov (United States)

    Temajo, Norbert O; Howard, Neville

    2014-12-01

    The viruses stand salient as environmental factors that trigger autoimmunity. The virus realizes its effects through induction of heat-shock proteins (HSPs) as well as by the viral IE-axis-mediated conversion of organ epithelial cells into virgin de novo professional antigen-presenting cells (APCs). The HSP is the accomplished operator in homeostasis by the logic of it being the regulator of apoptosis. By virtue of its regulation of apoptosis, the HSP is also involved in autoimmunity: (1) adornment of viral IE-axis-generated virgin de novo professional APCs with HSP-induced co-stimulatory molecules which transform these otherwise epithelial cells to competent antigen presenters, the operatus APCs, liable to apoptosis that becomes the initiator of organ damages; (2) molecular mimicry mechanism: epitopes on the HSP may be mistaken for viral peptides and be presented by operatus APCs to autoreactive TCRs resulting in the apoptosis of the operatus APCs; (3) regulation of MHC class II DR-mediated apoptosis of operatus APCS which can result in organ-specific autoimmune syndromes. We should remember, however, that Nature's intended purpose for apoptosis of the professional APCs is benevolence: as a principal regulator of immune homeostasis. But the apoptosis of our postulated operatus APCs can result in autoimmunity. The transformation of virgin de novo professional APCs to operatus APCs mirrors the maturation of DCs through their acquisition of HSP-induced costimulatory molecules. What happens to mature DCs as antigen presenters that end in homeostasis is replicated by what happens to operatus APCs that ends instead in autoimmunity.

  7. Leptin and the regulation of food intake, energy homeostasis and immunity with special focus on periparturient ruminants.

    Science.gov (United States)

    Ingvartsen, K L; Boisclair, Y R

    2001-11-01

    The biology of leptin has been studied most extensively in rodents and in humans. Leptin is involved in the regulation of food intake, energy homeostasis and immunity. Leptin is primarily produced in white adipose tissue and acts via a family of membrane bound receptors, including an isoform with a long intracellular domain (OB-Rb), and many isoforms with short intracellular domains (Ob-Rs). OB-Rb is predominantly expressed in the hypothalamic regions involved in the regulation of food intake and energy homeostasis. The other isoforms are distributed ubiquitously and are found in most peripheral tissues in far greater abundance than OB-Rb. The effects of leptin on food intake and energy homeostasis are central and are mediated via a network of orexigenic neuropeptides (neuropeptide Y, galanin, galanin-like peptide, melanin-concentrating hormone, orexins, agouti-related peptide) and anorexigenic neuropeptides (corticotropin-releasing hormone, pro-opiomelanocortin, alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript). In addition, leptin acts directly on immune cells to stimulate hematopoesis, T-cell immunity, phagocytosis, cytokine production, and to attenuate susceptibility to infectious insults. Emerging data in ruminants suggest that leptin is dynamically regulated by many factors and physiological states. Thus, leptin is secreted in a pulsatile fashion, but without a marked diurnal rhythm. A positive relationship between adiposity and plasma leptin concentration exists in growing and lactating ruminants. The concentration of plasma leptin increases during pregnancy, starts to decline 1--2 wk before parturition, and reaches a nadir in early lactation. The reduction of plasma leptin at parturition is likely to promote centrally mediated adaptations required in periods of energy deficit, but could have negative effects on immune cell function. Future research is needed in ruminants to address the roles played by leptin and the

  8. A Conserved Splicing Silencer Dynamically Regulates O-GlcNAc Transferase Intron Retention and O-GlcNAc Homeostasis

    Directory of Open Access Journals (Sweden)

    Sung-Kyun Park

    2017-08-01

    Full Text Available Modification of nucleocytoplasmic proteins with O-GlcNAc regulates a wide variety of cellular processes and has been linked to human diseases. The enzymes O-GlcNAc transferase (OGT and O-GlcNAcase (OGA add and remove O-GlcNAc, but the mechanisms regulating their expression remain unclear. Here, we demonstrate that retention of the fourth intron of OGT is regulated in response to O-GlcNAc levels. We further define a conserved intronic splicing silencer (ISS that is necessary for OGT intron retention. Deletion of the ISS in colon cancer cells leads to increases in OGT, but O-GlcNAc homeostasis is maintained by concomitant increases in OGA protein. However, the ISS-deleted cells are hypersensitive to OGA inhibition in culture and in soft agar. Moreover, growth of xenograft tumors from ISS-deleted cells is compromised in mice treated with an OGA inhibitor. Thus, ISS-mediated regulation of OGT intron retention is a key component in OGT expression and maintaining O-GlcNAc homeostasis.

  9. Human innate lymphoid cells

    NARCIS (Netherlands)

    Hazenberg, Mette D.; Spits, Hergen

    2014-01-01

    Innate lymphoid cells (ILCs) are lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity and tissue remodeling. ILCs are categorized into 3 groups based on their distinct patterns of cytokine production and the requirement of

  10. Amyloid precursor protein maintains constitutive and adaptive plasticity of dendritic spines in adult brain by regulating D-serine homeostasis.

    Science.gov (United States)

    Zou, Chengyu; Crux, Sophie; Marinesco, Stephane; Montagna, Elena; Sgobio, Carmelo; Shi, Yuan; Shi, Song; Zhu, Kaichuan; Dorostkar, Mario M; Müller, Ulrike C; Herms, Jochen

    2016-10-17

    Dynamic synapses facilitate activity-dependent remodeling of neural circuits, thereby providing the structural substrate for adaptive behaviors. However, the mechanisms governing dynamic synapses in adult brain are still largely unknown. Here, we demonstrate that in the cortex of adult amyloid precursor protein knockout (APP-KO) mice, spine formation and elimination were both reduced while overall spine density remained unaltered. When housed under environmental enrichment, APP-KO mice failed to respond with an increase in spine density. Spine morphology was also altered in the absence of APP The underlying mechanism of these spine abnormalities in APP-KO mice was ascribed to an impairment in D-serine homeostasis. Extracellular D-serine concentration was significantly reduced in APP-KO mice, coupled with an increase of total D-serine. Strikingly, chronic treatment with exogenous D-serine normalized D-serine homeostasis and restored the deficits of spine dynamics, adaptive plasticity, and morphology in APP-KO mice. The cognitive deficit observed in APP-KO mice was also rescued by D-serine treatment. These data suggest that APP regulates homeostasis of D-serine, thereby maintaining the constitutive and adaptive plasticity of dendritic spines in adult brain. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

  11. Essential Regulation of Lung Surfactant Homeostasis by the Orphan G Protein-Coupled Receptor GPR116

    Directory of Open Access Journals (Sweden)

    Mi Young Yang

    2013-05-01

    Full Text Available GPR116 is an orphan seven-pass transmembrane receptor whose function has been unclear. Global disruption of the Gpr116 gene in mice revealed an unexpected, critical role for this receptor in lung surfactant homeostasis, resulting in progressive accumulation of surfactant lipids and proteins in the alveolar space, labored breathing, and a reduced lifespan. GPR116 expression analysis, bone marrow transplantation studies, and characterization of conditional knockout mice revealed that GPR116 expression in ATII cells is required for maintaining normal surfactant levels. Aberrant packaging of surfactant proteins with lipids in the Gpr116 mutant mice resulted in compromised surfactant structure, function, uptake, and processing. Thus, GPR116 plays an indispensable role in lung surfactant homeostasis with important ramifications for the understanding and treatment of lung surfactant disorders.

  12. Arabidopsis ABI5 plays a role in regulating ROS homeostasis by activating CATALASE 1 transcription in seed germination.

    Science.gov (United States)

    Bi, Chao; Ma, Yu; Wu, Zhen; Yu, Yong-Tao; Liang, Shan; Lu, Kai; Wang, Xiao-Fang

    2017-05-01

    It has been known that ABA INSENSITIVE 5 (ABI5) plays a vital role in regulating seed germination. In the present study, we showed that inhibition of the catalase activity with 3-amino-1,2,4-triazole (3-AT) inhibits seed germination of Col-0, abi5 mutants and ABI5-overexpression transgenic lines. Compared with Col-0, the seeds of abi5 mutants showed more sensitive to 3-AT during seed germination, while the seeds of ABI5-overexpression transgenic lines showed more insensitive. H 2 O 2 showed the same effect on seed germination of Col-0, abi5 mutants and ABI5-overexpression transgenic lines as 3-AT. These results suggest that ROS is involved in the seed germination mediated by ABI5. Further, we observed that T-DNA insertion mutants of the three catalase members in Arabidopsis displayed 3-AT-insensitive or -hypersensitive phenotypes during seed germination, suggesting that these catalase members regulate ROS homeostasis in a highly complex way. ABI5 affects reactive oxygen species (ROS) homeostasis by affecting CATALASE expression and catalase activity. Furthermore, we showed that ABI5 directly binds to the CAT1 promoter and activates CAT1 expression. Genetic evidence supports the idea that CAT1 functions downstream of ABI5 in ROS signaling during seed germination. RNA-sequencing analysis indicates that the transcription of the genes involved in ROS metabolic process or genes responsive to ROS stress is impaired in abi5-1 seeds. Additionally, expression changes in some genes correlative to seed germination were showed due to the change in ABI5 expression under 3-AT treatment. Together, all the findings suggest that ABI5 regulates seed germination at least partly by affecting ROS homeostasis.

  13. Dynamic regulation of auxin oxidase and conjugating enzymes AtDAO1 and GH3 modulates auxin homeostasis.

    Science.gov (United States)

    Mellor, Nathan; Band, Leah R; Pěnčík, Aleš; Novák, Ondřej; Rashed, Afaf; Holman, Tara; Wilson, Michael H; Voß, Ute; Bishopp, Anthony; King, John R; Ljung, Karin; Bennett, Malcolm J; Owen, Markus R

    2016-09-27

    The hormone auxin is a key regulator of plant growth and development, and great progress has been made understanding auxin transport and signaling. Here, we show that auxin metabolism and homeostasis are also regulated in a complex manner. The principal auxin degradation pathways in Arabidopsis include oxidation by Arabidopsis thaliana gene DIOXYGENASE FOR AUXIN OXIDATION 1/2 (AtDAO1/2) and conjugation by Gretchen Hagen3s (GH3s). Metabolic profiling of dao1-1 root tissues revealed a 50% decrease in the oxidation product 2-oxoindole-3-acetic acid (oxIAA) and increases in the conjugated forms indole-3-acetic acid aspartic acid (IAA-Asp) and indole-3-acetic acid glutamic acid (IAA-Glu) of 438- and 240-fold, respectively, whereas auxin remains close to the WT. By fitting parameter values to a mathematical model of these metabolic pathways, we show that, in addition to reduced oxidation, both auxin biosynthesis and conjugation are increased in dao1-1 Transcripts of AtDAO1 and GH3 genes increase in response to auxin over different timescales and concentration ranges. Including this regulation of AtDAO1 and GH3 in an extended model reveals that auxin oxidation is more important for auxin homoeostasis at lower hormone concentrations, whereas auxin conjugation is most significant at high auxin levels. Finally, embedding our homeostasis model in a multicellular simulation to assess the spatial effect of the dao1-1 mutant shows that auxin increases in outer root tissues in agreement with the dao1-1 mutant root hair phenotype. We conclude that auxin homeostasis is dependent on AtDAO1, acting in concert with GH3, to maintain auxin at optimal levels for plant growth and development.

  14. Regulation of brain copper homeostasis by the brain barrier systems: Effects of Fe-overload and Fe-deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Monnot, Andrew D.; Behl, Mamta; Ho, Sanna; Zheng, Wei, E-mail: wzheng@purdue.edu

    2011-11-15

    Maintaining brain Cu homeostasis is vital for normal brain function. The role of systemic Fe deficiency (FeD) or overload (FeO) due to metabolic diseases or environmental insults in Cu homeostasis in the cerebrospinal fluid (CSF) and brain tissues remains unknown. This study was designed to investigate how blood-brain barrier (BBB) and blood-SCF barrier (BCB) regulated Cu transport and how FeO or FeD altered brain Cu homeostasis. Rats received an Fe-enriched or Fe-depleted diet for 4 weeks. FeD and FeO treatment resulted in a significant increase (+ 55%) and decrease (- 56%) in CSF Cu levels (p < 0.05), respectively; however, neither treatment had any effect on CSF Fe levels. The FeD, but not FeO, led to significant increases in Cu levels in brain parenchyma and the choroid plexus. In situ brain perfusion studies demonstrated that the rate of Cu transport into the brain parenchyma was significantly faster in FeD rats (+ 92%) and significantly slower (- 53%) in FeO rats than in controls. In vitro two chamber Transwell transepithelial transport studies using primary choroidal epithelial cells revealed a predominant efflux of Cu from the CSF to blood compartment by the BCB. Further ventriculo-cisternal perfusion studies showed that Cu clearance by the choroid plexus in FeD animals was significantly greater than control (p < 0.05). Taken together, our results demonstrate that both the BBB and BCB contribute to maintain a stable Cu homeostasis in the brain and CSF. Cu appears to enter the brain primarily via the BBB and is subsequently removed from the CSF by the BCB. FeD has a more profound effect on brain Cu levels than FeO. FeD increases Cu transport at the brain barriers and prompts Cu overload in the CNS. The BCB plays a key role in removing the excess Cu from the CSF.

  15. Innate lymphoid cells in atherosclerosis.

    Science.gov (United States)

    Engelbertsen, Daniel; Lichtman, Andrew H

    2017-12-05

    The family of innate lymphoid cells (ILCs) consisting of NK cells, lymphoid tissue inducer cells and the 'helper'-like ILC subsets ILC1, ILC2 and ILC3 have been shown to have important roles in protection against microbes, regulation of inflammatory diseases and involved in allergic reactions. ILC1s produce IFN-γ upon stimulation with IL-12 and IL-18, ILC2s produce IL-5 and IL-13 responding to IL-33 and IL-25 while ILC3s produce IL-17 and IL-22 after stimulation with IL-23 or IL-1. Although few studies have directly investigated the role for ILCs in atherosclerosis, several studies have investigated transcription factors and cytokines shared by ILCs and T helper cells. In this review we summarize our current understanding of the role of ILC in atherosclerosis and discuss future directions. Copyright © 2017. Published by Elsevier B.V.

  16. A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Ke Xu

    2011-12-01

    Full Text Available Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into "whole-body" contextual models that mimic in vivo conditions.

  17. Emerging concepts and future challenges in innate lymphoid cell biology

    Science.gov (United States)

    Artis, David

    2016-01-01

    Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role. PMID:27811053

  18. The Yin and Yang of Innate Lymphoid Cells in Cancer.

    Science.gov (United States)

    Carrega, Paolo; Campana, Stefania; Bonaccorsi, Irene; Ferlazzo, Guido

    2016-11-01

    The recent appreciation of novel subsets of innate lymphoid cells (ILCs) as important regulators of tissue homeostasis, inflammation and repair, raise questions regarding the presence and role of these cells in cancer tissues. In addition to natural killer and fetal lymphoid tissue inducer (LTi) cells, the ILC family comprises non-cytolytic, cytokine-producing cells that are classified into ILC1, ILC2 and ILC3 based on phenotypic and functional characteristics. Differently from natural killer cells, which are the prototypical members of ILC1 and whose role in tumors is better established, the involvement of other ILC subsets in cancer progression or resistance is still fuzzy and in several instances controversial, since current studies indicate both context-dependent beneficial or pathogenic effects. Here, we review the current knowledge regarding the involvement of these novel ILC subsets in the context of tumor immunology, highlighting how ILC subsets might behave either as friends or foes. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  19. Emerging concepts and future challenges in innate lymphoid cell biology.

    Science.gov (United States)

    Tait Wojno, Elia D; Artis, David

    2016-10-17

    Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role. © 2016 Tait Wojno and Artis.

  20. Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways.

    Science.gov (United States)

    Rouault, Tracey A; Maio, Nunziata

    2017-08-04

    Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Redox and Ionic Homeostasis Regulations against Oxidative, Salinity and Drought Stress in Wheat (A Systems Biology Approach

    Directory of Open Access Journals (Sweden)

    Zahid Hussain Shah

    2017-10-01

    Full Text Available Systems biology and omics has provided a comprehensive understanding about the dynamics of the genome, metabolome, transcriptome, and proteome under stress. In wheat, abiotic stresses trigger specific networks of pathways involved in redox and ionic homeostasis as well as osmotic balance. These networks are considerably more complicated than those in model plants, and therefore, counter models are proposed by unifying the approaches of omics and stress systems biology. Furthermore, crosstalk among these pathways is monitored by the regulation and streaming of transcripts and genes. In this review, we discuss systems biology and omics as a promising tool to study responses to oxidative, salinity, and drought stress in wheat.

  2. Human CD5+ Innate Lymphoid Cells Are Functionally Immature and Their Development from CD34+ Progenitor Cells Is Regulated by Id2

    Directory of Open Access Journals (Sweden)

    Maho Nagasawa

    2017-08-01

    Full Text Available Innate lymphoid cells (ILCs have emerged as a key cell type involved in surveillance and maintenance of mucosal tissues. Mouse ILCs rely on the transcriptional regulator Inhibitor of DNA-binding protein 2 (Id2 for their development. Here, we show that Id2 also drives development of human ILC because forced expression of Id2 in human thymic progenitors blocked T cell commitment, upregulated CD161 and promyelocytic leukemia zinc finger (PLZF, and maintained CD127 expression, markers that are characteristic for human ILCs. Surprisingly CD5 was also expressed on these in vitro generated ILCs. This was not an in vitro artifact because CD5 was also found on ex vivo isolated ILCs from thymus and from umbilical cord blood. CD5 was also expressed on small proportions of ILC2 and ILC3. CD5+ ILCs were functionally immature, but could further differentiate into mature CD5− cytokine-secreting ILCs. Our data show that Id2 governs human ILC development from thymic progenitor cells toward immature CD5+ ILCs.

  3. The role of innate lymphoid cells in healthy and inflamed skin

    DEFF Research Database (Denmark)

    Bonefeld, Charlotte M.; Geisler, Carsten

    2016-01-01

    system. During the last years, it has become clear that innate lymphoid cells play a role in homeostasis and inflammation of the skin in humans and mice. In this review, we will discuss the role of innate lymphoid cells in healthy and inflamed skin with special focus on their role in atopic dermatitis....

  4. Human IGF1 regulates midgut oxidative stress and epithelial homeostasis to balance lifespan and Plasmodium falciparum resistance in Anopheles stephensi.

    Directory of Open Access Journals (Sweden)

    Anna L Drexler

    2014-06-01

    Full Text Available Insulin and insulin-like growth factor signaling (IIS regulates cell death, repair, autophagy, and renewal in response to stress, damage, and pathogen challenge. Therefore, IIS is fundamental to lifespan and disease resistance. Previously, we showed that insulin-like growth factor 1 (IGF1 within a physiologically relevant range (0.013-0.13 µM in human blood reduced development of the human parasite Plasmodium falciparum in the Indian malaria mosquito Anopheles stephensi. Low IGF1 (0.013 µM induced FOXO and p70S6K activation in the midgut and extended mosquito lifespan, whereas high IGF1 (0.13 µM did not. In this study the physiological effects of low and high IGF1 were examined in detail to infer mechanisms for their dichotomous effects on mosquito resistance and lifespan. Following ingestion, low IGF1 induced phosphorylation of midgut c-Jun-N-terminal kinase (JNK, a critical regulator of epithelial homeostasis, but high IGF1 did not. Low and high IGF1 induced midgut mitochondrial reactive oxygen species (ROS synthesis and nitric oxide (NO synthase gene expression, responses which were necessary and sufficient to mediate IGF1 inhibition of P. falciparum development. However, increased ROS and apoptosis-associated caspase-3 activity returned to baseline levels following low IGF1 treatment, but were sustained with high IGF1 treatment and accompanied by aberrant expression of biomarkers for mitophagy, stem cell division and proliferation. Low IGF1-induced ROS are likely moderated by JNK-induced epithelial cytoprotection as well as p70S6K-mediated growth and inhibition of apoptosis over the lifetime of A. stephensi to facilitate midgut homeostasis and enhanced survivorship. Hence, mitochondrial integrity and homeostasis in the midgut, a key signaling center for IIS, can be targeted to coordinately optimize mosquito fitness and anti-pathogen resistance for improved control strategies for malaria and other vector-borne diseases.

  5. Human IGF1 Regulates Midgut Oxidative Stress and Epithelial Homeostasis to Balance Lifespan and Plasmodium falciparum resistance in Anopheles stephensi

    Science.gov (United States)

    Drexler, Anna L.; Pietri, Jose E.; Pakpour, Nazzy; Hauck, Eric; Wang, Bo; Glennon, Elizabeth K. K.; Georgis, Martha; Riehle, Michael A.; Luckhart, Shirley

    2014-01-01

    Insulin and insulin-like growth factor signaling (IIS) regulates cell death, repair, autophagy, and renewal in response to stress, damage, and pathogen challenge. Therefore, IIS is fundamental to lifespan and disease resistance. Previously, we showed that insulin-like growth factor 1 (IGF1) within a physiologically relevant range (0.013–0.13 µM) in human blood reduced development of the human parasite Plasmodium falciparum in the Indian malaria mosquito Anopheles stephensi. Low IGF1 (0.013 µM) induced FOXO and p70S6K activation in the midgut and extended mosquito lifespan, whereas high IGF1 (0.13 µM) did not. In this study the physiological effects of low and high IGF1 were examined in detail to infer mechanisms for their dichotomous effects on mosquito resistance and lifespan. Following ingestion, low IGF1 induced phosphorylation of midgut c-Jun-N-terminal kinase (JNK), a critical regulator of epithelial homeostasis, but high IGF1 did not. Low and high IGF1 induced midgut mitochondrial reactive oxygen species (ROS) synthesis and nitric oxide (NO) synthase gene expression, responses which were necessary and sufficient to mediate IGF1 inhibition of P. falciparum development. However, increased ROS and apoptosis-associated caspase-3 activity returned to baseline levels following low IGF1 treatment, but were sustained with high IGF1 treatment and accompanied by aberrant expression of biomarkers for mitophagy, stem cell division and proliferation. Low IGF1-induced ROS are likely moderated by JNK-induced epithelial cytoprotection as well as p70S6K-mediated growth and inhibition of apoptosis over the lifetime of A. stephensi to facilitate midgut homeostasis and enhanced survivorship. Hence, mitochondrial integrity and homeostasis in the midgut, a key signaling center for IIS, can be targeted to coordinately optimize mosquito fitness and anti-pathogen resistance for improved control strategies for malaria and other vector-borne diseases. PMID:24968248

  6. Oxygen in health and disease: regulation of oxygen homeostasis--clinical implications.

    Science.gov (United States)

    Maltepe, Emin; Saugstad, Ola Didrik

    2009-03-01

    Oxygen is critical for multicellular existence. Its reduction to water by the mitochondrial electron transport chain helps supply the metabolic demands of human life. The incompletely reduced, reactive oxygen byproducts of this reaction, however, can be quite toxic. In this review, we explore the mechanisms responsible for maintaining oxygen homeostasis and the consequences of their dysfunction. With an eye toward defining clinical care guidelines for the management of critically ill neonates, we present evidence describing the role of physiologic hypoxia during development and the adverse consequences of hyperoxia in-term as well as preterm infants.

  7. Vitamin A Controls the Presence of RORγ+ Innate Lymphoid Cells and Lymphoid Tissue in the Small Intestine.

    Science.gov (United States)

    Goverse, Gera; Labao-Almeida, Carlos; Ferreira, Manuela; Molenaar, Rosalie; Wahlen, Sigrid; Konijn, Tanja; Koning, Jasper; Veiga-Fernandes, Henrique; Mebius, Reina E

    2016-06-15

    Changes in diet and microbiota have determining effects on the function of the mucosal immune system. For example, the active metabolite of vitamin A, retinoic acid (RA), has been described to maintain homeostasis in the intestine by its influence on both lymphocytes and myeloid cells. Additionally, innate lymphoid cells (ILCs), important producers of cytokines necessary for intestinal homeostasis, are also influenced by vitamin A in the small intestines. In this study, we show a reduction of both NCR(-) and NCR(+) ILC3 subsets in the small intestine of mice raised on a vitamin A-deficient diet. Additionally, the percentages of IL-22-producing ILCs were reduced in the absence of dietary vitamin A. Conversely, mice receiving additional RA had a specific increase in the NCR(-) ILC3 subset, which contains the lymphoid tissue inducer cells. The dependence of lymphoid tissue inducer cells on vitamin A was furthermore illustrated by impaired development of enteric lymphoid tissues in vitamin A-deficient mice. These effects were a direct consequence of ILC-intrinsic RA signaling, because retinoic acid-related orphan receptor γt-Cre × RARα-DN mice had reduced numbers of NCR(-) and NCR(+) ILC3 subsets within the small intestine. However, lymphoid tissue inducer cells were not affected in these mice nor was the formation of enteric lymphoid tissue, demonstrating that the onset of RA signaling might take place before retinoic acid-related orphan receptor γt is expressed on lymphoid tissue inducer cells. Taken together, our data show an important role for vitamin A in controlling innate lymphoid cells and, consequently, postnatal formed lymphoid tissues within the small intestines. Copyright © 2016 by The American Association of Immunologists, Inc.

  8. The perilipin homologue, lipid storage droplet 2, regulates sleep homeostasis and prevents learning impairments following sleep loss.

    Directory of Open Access Journals (Sweden)

    Matthew S Thimgan

    2010-08-01

    Full Text Available Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. Recently, two genes, brummer (bmm and Lipid storage droplet 2 (Lsd2, have been shown to modulate the response to starvation. bmm mutants have excess fat and are resistant to starvation, whereas Lsd2 mutants are lean and sensitive to starvation. Thus, we hypothesized that bmm and Lsd2 may play a role in sleep regulation. Indeed, bmm mutant flies display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking.

  9. Regulation of retinoid-mediated signaling involved in skin homeostasis by RAR and RXR agonists/antagonists in mouse skin.

    Science.gov (United States)

    Gericke, Janine; Ittensohn, Jan; Mihály, Johanna; Alvarez, Susana; Alvarez, Rosana; Töröcsik, Dániel; de Lera, Angel R; Rühl, Ralph

    2013-01-01

    Endogenous retinoids like all-trans retinoic acid (ATRA) play important roles in skin homeostasis and skin-based immune responses. Moreover, retinoid signaling was found to be dysregulated in various skin diseases. The present study used topical application of selective agonists and antagonists for retinoic acid receptors (RARs) α and γ and retinoid-X receptors (RXRs) for two weeks on mouse skin in order to determine the role of retinoid receptor subtypes in the gene regulation in skin. We observed pronounced epidermal hyperproliferation upon application of ATRA and synthetic agonists for RARγ and RXR. ATRA and the RARγ agonist further increased retinoid target gene expression (Rbp1, Crabp2, Krt4, Cyp26a1, Cyp26b1) and the chemokines Ccl17 and Ccl22. In contrast, a RARα agonist strongly decreased the expression of ATRA-synthesis enzymes, of retinoid target genes, markers of skin homeostasis, and various cytokines in the skin, thereby markedly resembling the expression profile induced by RXR and RAR antagonists. Our results indicate that RARα and RARγ subtypes possess different roles in the skin and may be of relevance for the auto-regulation of endogenous retinoid signaling in skin. We suggest that dysregulated retinoid signaling in the skin mediated by RXR, RARα and/or RARγ may promote skin-based inflammation and dysregulation of skin barrier properties.

  10. Cul3 and the BTB adaptor insomniac are key regulators of sleep homeostasis and a dopamine arousal pathway in Drosophila.

    Directory of Open Access Journals (Sweden)

    Cory Pfeiffenberger

    Full Text Available Sleep is homeostatically regulated, such that sleep drive reflects the duration of prior wakefulness. However, despite the discovery of genes important for sleep, a coherent molecular model for sleep homeostasis has yet to emerge. To better understand the function and regulation of sleep, we employed a reverse-genetics approach in Drosophila. An insertion in the BTB domain protein CG32810/insomniac (inc exhibited one of the strongest baseline sleep phenotypes thus far observed, a ~10 h sleep reduction. Importantly, this is coupled to a reduced homeostatic response to sleep deprivation, consistent with a disrupted sleep homeostat. Knockdown of the INC-interacting protein, the E3 ubiquitin ligase Cul3, results in reduced sleep duration, consolidation, and homeostasis, suggesting an important role for protein turnover in mediating INC effects. Interestingly, inc and Cul3 expression in post-mitotic neurons during development contributes to their adult sleep functions. Similar to flies with increased dopaminergic signaling, loss of inc and Cul3 result in hyper-arousability to a mechanical stimulus in adult flies. Furthermore, the inc sleep duration phenotype can be rescued by pharmacological inhibition of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. Taken together, these results establish inc and Cul3 as important new players in setting the sleep homeostat and a dopaminergic arousal pathway in Drosophila.

  11. Innate lymphoid cells and their stromal microenvironments.

    Science.gov (United States)

    Kellermayer, Zoltán; Vojkovics, Dóra; Balogh, Péter

    2017-09-01

    In addition to the interaction between antigen presenting cells, T and B lymphocytes, recent studies have revealed important roles for a diverse set of auxiliary cells that profoundly influence the induction and regulation of immune responses against pathogens. Of these the stromal cells composed of various non-hematopoietic constituents are crucial for the creation and maintenance of specialized semi-static three-dimensional lymphoid tissue microenvironment, whereas the more recently described innate lymphoid cells are generated by the diversification of committed lymphoid precursor cells independently from clonally rearranged antigen receptor genes. Recent findings have revealed important contributions by innate lymphoid cells in inflammation and protection against pathogens in a tissue-specific manner. Importantly, lymphoid stromal cells also influence the onset of immune responses in tissue-specific fashion, raising the possibility of tissue-specific stromal - innate lymphoid cell collaboration. In this review we summarize the main features and interactions between these two cells types, with particular emphasis on ILC type 3 cells and their microenvironmental partners. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  12. The virus-induced HSPs regulate the apoptosis of operatus APCs that results in autoimmunity, not in homeostasis.

    Science.gov (United States)

    Temajo, Norbert O; Howard, Neville

    2014-10-01

    The viruses are salient in the roles of environmental factors that trigger autoimmunity. The virus realizes its effects by the power of its induction of heat shock proteins (HSPs) as well as by the viral IE-axis-mediated conversion of organ epithelial cells into virgin de novo professional antigen-presenting cells (APCs). The HSP is the accomplished operator in homeostasis by the logic of it being the regulator of apoptosis. That HSP which regulates and controls different points in the pathways of apoptosis is rationally propitious as both HSP and apoptosis are highly conserved in multicellular organisms. By virtue of its regulation of apoptosis, the HSP is also involved in human autoimmunity and this involvement is tripartite: (i) adornment of viral IE-axis-generated virgin de novo professional APCs with HSP-induced co-stimulatory molecules which transform these otherwise epithelial cells to achieve the status of fledged competent antigen-presenters, the operatus APCs, which are liable to apoptosis that becomes the initiator of organ damages that can culminate in the autoimmune syndrome(s); apoptosis is a routine fate that befalls all APCs following their antigen presentation; (ii) molecular mimicry mechanism: epitopes on the HSP may be mistaken for viral peptides and be presented by operatus APCs to autoreactive TCRs resulting in the apoptosis of the operatus APCs; and (iii) regulation of MHC class II-DR-mediated apoptosis of operatus APCs which can ultimately consequent in organ-specific autoimmune syndromes. We should remember, however, that Nature's intended purpose for the apoptosis of the professional APCs is benevolence: as a principal regulator of homeostasis. It is only from the apoptosis of our postulated operatus APCs that the apoptotic consequence can be deleterious, an autoimmune syndrome(s). The transformation of virgin de novo professional APCs to operatus APCs mirrors the maturation of DCs, through their acquisition of HSP-induced co

  13. Salt tolerance and regulation of gas exchange and hormonal homeostasis by auxin-priming in wheat

    Directory of Open Access Journals (Sweden)

    Muhammad Iqbal

    2013-09-01

    Full Text Available The objective of this work was to assess the regulatory effects of auxin-priming on gas exchange and hormonal homeostasis in spring wheat subjected to saline conditions. Seeds of MH-97 (salt-intolerant and Inqlab-91 (salt-tolerant cultivars were subjected to 11 priming treatments (three hormones x three concentrations + two controls and evaluated under saline (15 dS m-1 and nonsaline (2.84 dS m-1 conditions. The priming treatments consisted of: 5.71, 8.56, and 11.42 × 10-4 mol L-1 indoleacetic acid; 4.92, 7.38, and 9.84 × 10-4 mol L-1 indolebutyric acid; 4.89, 7.34, and 9.79 × 10-4 mol L-1 tryptophan; and a control with hydroprimed seeds. A negative control with nonprimed seeds was also evaluated. All priming agents diminished the effects of salinity on endogenous abscisic acid concentration in the salt-intolerant cultivar. Grain yield was positively correlated with net CO2 assimilation rate and endogenous indoleacetic acid concentration, and it was negatively correlated with abscisic acid and free polyamine concentrations. In general, the priming treatment with tryptophan at 4.89 × 10-4 mol L-1 was the most effective in minimizing yield losses and reductions in net CO2 assimilation rate, under salt stress conditions. Hormonal homeostasis increases net CO2 assimilation rate and confers tolerance to salinity on spring wheat.

  14. IL-13 promotes collagen accumulation in Crohn's disease fibrosis by down-regulation of fibroblast MMP synthesis: a role for innate lymphoid cells?

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    Jennifer R Bailey

    Full Text Available BACKGROUND: Fibrosis is a serious consequence of Crohn's disease (CD, often necessitating surgical resection. We examined the hypothesis that IL-13 may promote collagen accumulation within the CD muscle microenvironment. METHODS: Factors potentially modulating collagen deposition were examined in intestinal tissue samples from fibrotic (f CD and compared with cancer control (C, ulcerative colitis (UC and uninvolved (u CD. Mechanisms attributable to IL-13 were analysed using cell lines derived from uninvolved muscle tissue and tissue explants. RESULTS: In fCD muscle extracts, collagen synthesis was significantly increased compared to other groups, but MMP-2 was not co-ordinately increased. IL-13 transcripts were highest in fCD muscle compared to muscle from other groups. IL-13 receptor (R α1 was expressed by intestinal muscle smooth muscle, nerve and KIR(+ cells. Fibroblasts from intestinal muscle expressed Rα1, phosphorylated STAT6 in response to IL-13, and subsequently down-regulated MMP-2 and TNF-α-induced MMP-1 and MMP-9 synthesis. Cells with the phenotype KIR(+CD45(+CD56(+/-CD3(- were significantly increased in fCD muscle compared to all other groups, expressed Rα1 and membrane IL-13, and transcribed high levels of IL-13. In explanted CD muscle, these cells did not phosphorylate STAT6 in response to exogenous IL-13. CONCLUSIONS: The data indicate that in fibrotic intestinal muscle of Crohn's patients, the IL-13 pathway is stimulated, involving a novel population of infiltrating IL-13Rα1(+, KIR(+ innate lymphoid cells, producing IL-13 which inhibits fibroblast MMP synthesis. Consequently, matrix degradation is down-regulated and this leads to excessive collagen deposition.

  15. EsGLUT4 and CHHBP are involved in the regulation of glucose homeostasis in the crustacean Eriocheir sinensis

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    Ran Li

    2017-09-01

    Full Text Available Glucose is an essential energy source for both vertebrates and invertebrates. In mammals, glucose uptake is mediated primarily by glucose transporters (GLUTs, members of the major facilitator superfamily (MFS of passive transporters. Among the GLUTs, GLUT4 is the main glucose transporter in muscles and adipocytes. In skeletal muscle cells, GLUT4 interacts with the lipid raft protein flotillin to transport glucose upon stimulation by insulin. Although several studies have examined GLUT4 function in mammals, few have been performed in crustaceans, which also use glucose as their main energy source. Crustacean hyperglycemic hormone (CHH is a multifunctional neurohormone found only in arthropods, and one of its roles is to regulate glucose homeostasis. However, the molecular mechanism that underlies CHH regulation and whether GLUT4 is involved in its regulation in crustaceans remain unclear. In the present study, we identified a full-length GLUT4 cDNA sequence (defined herein as EsGLUT4 from the Chinese mitten crab Eriocheir sinensis and analyzed its tissue distribution and cellular localization. By the ForteBio Octet system, two large hydrophilic regions within EsGLUT4 were found to interact with the CHH binding protein (CHHBP, an E. sinensis flotillin-like protein. Interestingly, live-cell imaging indicated that EsGLUT4 and CHHBP responded simultaneously upon stimulation by CHH, resulting in glucose release. In contrast to insulin-dependent GLUT4, however, EsGLUT4 and CHHBP were present within cytoplasmic vesicles, both translocating to the plasma membrane upon CHH stimulation. In conclusion, our results provide new evidence for the involvement of EsGLUT4 and CHHBP in the regulation of glucose homeostasis in crustacean carbohydrate metabolism.

  16. Innate lymphoid cells, precursors and plasticity.

    Science.gov (United States)

    Gronke, Konrad; Kofoed-Nielsen, Michael; Diefenbach, Andreas

    2016-11-01

    Innate lymphoid cells (ILC) have only recently been recognized as a separate entity of the lymphoid lineage. Their subpopulations share common characteristics in terms of early development and major transcriptional circuitry with their related cousins of the T cell world. It is currently hypothesized that ILCs constitute an evolutionary older version of the lymphoid immune system. They are found at all primary entry points for pathogens such as mucosal surfaces of the lung and gastrointestinal system, the skin and the liver, which is the central contact point for pathogens that breach the intestinal barrier and enter the circulation. There, ILC contribute to the first line defense as well as to organ homeostasis. However, ILC are not only involved in classical defense tasks, but also contribute to the organogenesis of lymphoid organs as well as tissue remodeling and even stem cell regeneration. ILC may, therefore, implement different functions according to their emergence in ontogeny, their development and their final tissue location. We will review here their early development from precursors of the fetal liver and the adult bone marrow as well as their late plasticity in adaptation to their environment. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  17. Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation

    DEFF Research Database (Denmark)

    Agudelo, Leandro Z; Ferreira, Duarte M S; Cervenka, Igor

    2018-01-01

    accumulation. Here we show that kynurenic acid increases energy utilization by activating G protein-coupled receptor Gpr35, which stimulates lipid metabolism, thermogenic, and anti-inflammatory gene expression in adipose tissue. This suppresses weight gain in animals fed a high-fat diet and improves glucose...... tolerance. Kynurenic acid and Gpr35 enhance Pgc-1α1 expression and cellular respiration, and increase the levels of Rgs14 in adipocytes, which leads to enhanced beta-adrenergic receptor signaling. Conversely, genetic deletion of Gpr35 causes progressive weight gain and glucose intolerance, and sensitizes...... to the effects of high-fat diets. Finally, exercise-induced adipose tissue browning is compromised in Gpr35 knockout animals. This work uncovers kynurenine metabolism as a pathway with therapeutic potential to control energy homeostasis....

  18. [Regulation Mechanism of Ginkgo-Dipyridamolum for Calcium Homeostasis on Cardioprotective Effect During Ischemia Reperfusion Injury].

    Science.gov (United States)

    Wang, Jing; Wang, Hai-hua; Zhou, Ping-ping; Jiang, Yu-xin

    2015-12-01

    To explore regulatory mechanism of Ginkgo-dipyridamolum (GD) for calcium homeostasis on cardioprotective effect during ischemia reperfusion injury in the isolated rat heart. 40 male SD-rats were randomly divided into five groups (n = 8): normal control group (NC), ischemia reperfusion group (IR), GD precondition group (GD + IR), Nicardipine and GD precondition group( Nic + GD + IR), and LaCl3 and GD precondition group (LaCl, + GD +IR). The hearts of rats were isolated after anesthesia and performed to profuse with Langendorff equipment. The heart functional indexes (HR, LVSP and ± dp/dt(max)) were detected at the five time points (stabilize point, ischemia 30 min, reperfusion 5 min, reperfusion 30 min, and reperfusion 60 min). The coronary effluents were also collected at the five time points. The activities of LDH and CK were measured, respectively, as well as the Ca2+ contents. After the experiments were finished,the myocardial mitochondria were isolated, homogenated and then the Ca2+ concentrations, the activities of IDH and α-OGDH were detected. The pathologic changes in myocardial tissues were also observed by histologic section. Compared with IR group, the heart functional indexes ( LVSP x HR and ± dp/dt(max)) of GD + IR group were improved at the five time points; the enzymes (LDH and CK) release, the Ca2+ concentrations, the activities of IDH and α-OGDH were reduced in mitochondrion. However, the protective effects above could be inhibited by Nic and LaCl3. Histologic sections showed that the myocardial tissue in IR group was damaged obviously, the damaged myocardial tissues were repaired in GD + IR, Nic + GD + IR and LaCl, + GD + IR) groups, especially in GD + IR group. Ginkgo-dipyridamolum can alleviate the myocardial ischemia reperfusion injury, the mechanism is probobaly related to maintaining calcium homeostasis and mitochondrial energy metabolism function.

  19. Metformin regulates glycemic homeostasis in patients with type 2 diabetes mellitus as an NO donor

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    Ivan Sergeevich Kuznetsov

    2013-11-01

    Full Text Available Aim. To evaluate the influence of metformin on nitric oxide bioavailability in patients with type 2 diabetes mellitus (T2DM regarding glycemic homeostasis, and to investigate a correlation between metformin dosage and NO levels in vivo.Materials and Methods. Two groups – primary and control – were assembled for the clinical section of this study. Patients with newly diagnosed T2DM on metformin therapy were included to the primary group, while drug-naïve T2DM patients were enrolled as control subjects. Glycemic parameters and NO bioavailability was tested in both groups prior to and after the follow-up period. Experimental section was dedicated to the elucidation of potential dose-dependent effects of metformin on NO bioavailability. Mice were intraperitoneally infused with metformin at 0.5; 1.1; 5.6 mg per subject. Tissue detection of NO was performed with diethyldithiocarbamate (DETC iron complexes to form mononitrosyl iron compounds (MIC with paramagnetic properties. Control rodents were intraperitoneally infused with metformin without spin trapping.Results. We found nitrite and methaemoglobin (a marker for NO bioavailability to increase in parallel along with glycemic compensation in the primary but not control group. In vivo rodent models showed linear correlation between accumulation of DETC/MIC and dose of metformin, as well as formation of dinitrosyl iron complexes, known as endogenous NO transporters.Conclusion. Our data suggests that metformin benefits glycemic homeostasis in T2DM as an NO donor via formation of dinitrosyl iron complexes.

  20. NFAT5 regulates T lymphocyte homeostasis and CD24-dependent T cell expansion under pathologic hypernatremia.

    Science.gov (United States)

    Berga-Bolaños, Rosa; Drews-Elger, Katherine; Aramburu, Jose; López-Rodríguez, Cristina

    2010-12-01

    Immune cells rely on the transcription factor NFAT5 to adapt to hypertonic stress. The hypertonicity-dependent role of NFAT5 in T cells in vivo remains unclear because mouse models of NFAT5 deficiency have produced substantially different T cell phenotypes. In this study, we analyzed the T cell compartment in NFAT5-null and T cell-specific NFAT5 knockout mice. We found that NFAT5-null mice had constitutive, pronounced hypernatremia and suffered a severe immunodeficiency, with T cell lymphopenia, altered CD8 naive/memory homeostasis, and inability to reject allogeneic tumors. By contrast, T cell-specific NFAT5 knockout mice had normal plasma tonicity, rejected allogeneic tumors, and exhibited only a mild, low-penetrance memory bias in CD8 cells. Notably, when T cells from these mice were cultured ex vivo in hypernatremic media, they exhibited features found in NFAT5-null mice, with pronounced naive/memory imbalance and impaired homeostatic survival in response to IL-7, as well as a severe inhibition of their mitogen-induced proliferation. By analyzing surface receptors whose expression might be affected in NFAT5-deficient cells, we identified CD24 as a novel NFAT5 target induced by hypertonicity both in vitro and in vivo, and required to sustain T cell expansion under osmostress. NFAT5 bound to the Cd24 promoter in response to hypertonicity facilitated the local derepression of chromatin and enhanced the expression of CD24 mRNA and protein. Altogether, our results indicate that the systemic hypernatremia of NFAT5-null mice is a major contributor to their immunodeficiency, and highlight the role of NFAT5 and CD24 in the homeostasis of T cells under osmostress in vivo.

  1. Developmental acquisition of regulomes underlies innate lymphoid cell functionality

    Science.gov (United States)

    Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis, and they mirror adaptive CD4+ T helper (Th) cell subtypes in both usages of effector molecules and ·transcription factors. To better understand ILC subsets and their relationship with Th cells, we measur...

  2. Revealing localization and regulation of GTPase PmRab7 in lymphoid cells of Penaeus monodon after WSSV infection

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    Amrendra Kumar

    2016-10-01

    Full Text Available Objective: To identify white spot syndrome virus (WSSV entry into the host-cells of the cultured shrimp Penaeus monodon, we have attempted to localize PmRab7 (Ras-related in brain which is playing a vital role in the WSSV internalization. Methods: In this study, we have cloned PmRab7 and expressed in Escherichia coli, further purified rPmRab7 was used for antibody production, isolation of lysosomal sub-cellular fractions and western blot against lysosomal protein. Moreover, high fold-change in PmRab7 regulation with increasing copy number of WSSV has been studied by using real-time PCR. Results: 651 bp amplicon size gene was successfully amplified, ligated amplicon with pTZ T-tail vector confirmed by colony PCR and retriction enzyme digestion on agarose gel. Subcloned (pRSET-B 651 bp gene transformed successfully in Rosetta and after 6 h of induction expressed rPmRab7 was on SDS page, furthermore soluble fraction of rPmRab7 (26 kDa was purified by ni-NTA column. AntiPmRab7 antibody was received by Merk Pvt. Ltd., and western blot analysis revealed that PmRab7 is present in the lysosomal sub-cellular fraction. Copy number of WSSV was increased 5 fold in 24 h and 20 fold in 72 h of infection and subsequently transcrtipt of PmRab7 was Ct = 1.0 to Ct = 8.5. Conclusions: Presence of PmRab7 on lysosome clearly indicating PmRab7 participating in lysosomal maturation, other hand WSSV may follow the same route of entry. WSSV internalization has directly linked with regulation of PmRab7.

  3. Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis.

    Science.gov (United States)

    Wood, Katherine C; Cortese-Krott, Miriam M; Kovacic, Jason C; Noguchi, Audrey; Liu, Virginia B; Wang, Xunde; Raghavachari, Nalini; Boehm, Manfred; Kato, Gregory J; Kelm, Malte; Gladwin, Mark T

    2013-08-01

    Mice genetically deficient in endothelial nitric oxide synthase (eNOS(-/-)) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. Although the current paradigm holds that this bioactivity derives specifically from the expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed. To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted wild-type and eNOS(-/-) mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NG-nitroarginine methyl ester and repristinated by the NOS substrate L-arginine and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert (14)C-arginine into (14)C-citrulline in NOS-dependent fashion. These are the first studies to definitively establish a role for a blood-borne eNOS, using cross-transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect.

  4. Genetic regulation by NLA and microRNA827 for maintaining nitrate-dependent phosphate homeostasis in arabidopsis.

    Directory of Open Access Journals (Sweden)

    Surya Kant

    2011-03-01

    Full Text Available Plants need abundant nitrogen and phosphorus for higher yield. Improving plant genetics for higher nitrogen and phosphorus use efficiency would save potentially billions of dollars annually on fertilizers and reduce global environmental pollution. This will require knowledge of molecular regulators for maintaining homeostasis of these nutrients in plants. Previously, we reported that the NITROGEN LIMITATION ADAPTATION (NLA gene is involved in adaptive responses to low-nitrogen conditions in Arabidopsis, where nla mutant plants display abrupt early senescence. To understand the molecular mechanisms underlying NLA function, two suppressors of the nla mutation were isolated that recover the nla mutant phenotype to wild type. Map-based cloning identified these suppressors as the phosphate (Pi transport-related genes PHF1 and PHT1.1. In addition, NLA expression is shown to be regulated by the low-Pi induced microRNA miR827. Pi analysis revealed that the early senescence in nla mutant plants was due to Pi toxicity. These plants accumulated over five times the normal Pi content in shoots specifically under low nitrate and high Pi but not under high nitrate conditions. Also the Pi overaccumulator pho2 mutant shows Pi toxicity in a nitrate-dependent manner similar to the nla mutant. Further, the nitrate and Pi levels are shown to have an antagonistic crosstalk as displayed by their differential effects on flowering time. The results demonstrate that NLA and miR827 have pivotal roles in regulating Pi homeostasis in plants in a nitrate-dependent fashion.

  5. ILK Induction in Lymphoid Organs by a TNFα-NF-κB-Regulated Pathway Promotes the Development of Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Krenn, Peter W; Hofbauer, Sebastian W; Pucher, Susanne; Hutterer, Evelyn; Hinterseer, Elisabeth; Denk, Ursula; Asslaber, Daniela; Ganghammer, Sylvia; Sternberg, Christina; Neureiter, Daniel; Aberger, Fritz; Wickström, Sara A; Egle, Alexander; Greil, Richard; Hartmann, Tanja N

    2016-04-15

    The proliferation of chronic lymphocytic leukemia (CLL) cells requires communication with the lymphoid organ microenvironment. Integrin-linked kinase (ILK) is a multifunctional intracellular adaptor protein that transmits extracellular signals to regulate malignant cell motility, metastasis, and cell-cycle progression, but is poorly characterized in hematologic malignancies. In this study, we investigated the role of ILK in the context of CLL and observed high ILK expression in patient samples, particularly in tumor cells harboring prognostic high-risk markers such as unmutated IGHV genes, high Zap70, or CD38 expression, or a signature of recent proliferation. We also found increased numbers of Ki67 (MKI67)-positive cells in regions of enhanced ILK expression in lymph nodes from CLL patients. Using coculture conditions mimicking the proliferative lymph node microenvironment, we detected a parallel induction of ILK and cyclin D1 (CCND1) expression in CLL cells that was dependent on the activation of NF-κB signaling by soluble TNFα. The newly synthesized ILK protein colocalized to centrosomal structures and was required for correct centrosome clustering and mitotic spindle organization. Furthermore, we established a mouse model of CLL in which B-cell-specific genetic ablation of ILK resulted in decelerated leukemia development due to reduced organ infiltration and proliferation of CLL cells. Collectively, our findings describe a TNFα-NF-κB-mediated mechanism by which ILK expression is induced in the lymph node microenvironment and propose that ILK promotes leukemogenesis by enabling CLL cells to cope with centrosomal defects acquired during malignant transformation. Cancer Res; 76(8); 2186-96. ©2016 AACR. ©2016 American Association for Cancer Research.

  6. Interleukin-7 Availability Is Maintained by a Hematopoietic Cytokine Sink Comprising Innate Lymphoid Cells and T Cells.

    Science.gov (United States)

    Martin, Christopher E; Spasova, Darina S; Frimpong-Boateng, Kwesi; Kim, Hee-Ok; Lee, Minji; Kim, Kwang Soon; Surh, Charles D

    2017-07-18

    Interleukin-7 (IL-7) availability determines the size and proliferative state of the resting T cell pool. However, the mechanisms that regulate steady-state IL-7 amounts are unclear. Using experimental lymphopenic mouse models and IL-7-induced homeostatic proliferation to measure IL-7 availability in vivo, we found that radioresistant cells were the source of IL-7 for both CD4 + and CD8 + T cells. Hematopoietic lineage cells, although irrelevant as a source of IL-7, were primarily responsible for limiting IL-7 availability via their expression of IL-7R. Unexpectedly, innate lymphoid cells were found to have a potent influence on IL-7 amounts in the primary and secondary lymphoid tissues. These results demonstrate that IL-7 homeostasis is achieved through consumption by multiple subsets of innate and adaptive immune cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Mga2 transcription factor regulates an oxygen-responsive lipid homeostasis pathway in fission yeast

    DEFF Research Database (Denmark)

    Burr, Risa; Stewart, Emerson V; Shao, Wei

    2016-01-01

    -regulated under low oxygen. To identify new regulators of low oxygen adaptation, we screened the S. pombe nonessential haploid deletion collection and identified 27 gene deletions sensitive to both low oxygen and cobalt chloride, a hypoxia mimetic. One of these genes, mga2, is a putative transcriptional activator...

  8. Phosphatidylcholines as regulators of glucose and lipid homeostasis: Promises and potential risks

    NARCIS (Netherlands)

    Hohenester, Simon; Beuers, Ulrich

    2011-01-01

    Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an

  9. Physiology of hemodynamic homeostasis

    NARCIS (Netherlands)

    de Hert, Stefan

    2012-01-01

    Homeostasis of hemodynamics refers to the regulation of the blood circulation to meet the demands of the different organ and tissue systems. This homeostasis involves an intimate interaction between peripheral metabolic needs, vascular adaptations to meet these needs and cardiac adaptation to

  10. Twilight, a Novel Circadian-Regulated Gene, Integrates Phototropism with Nutrient and Redox Homeostasis during Fungal Development.

    Directory of Open Access Journals (Sweden)

    Yi Zhen Deng

    2015-06-01

    Full Text Available Phototropic regulation of circadian clock is important for environmental adaptation, organismal growth and differentiation. Light plays a critical role in fungal development and virulence. However, it is unclear what governs the intracellular metabolic response to such dark-light rhythms in fungi. Here, we describe a novel circadian-regulated Twilight (TWL function essential for phototropic induction of asexual development and pathogenesis in the rice-blast fungus Magnaporthe oryzae. The TWL transcript oscillates during circadian cycles and peaks at subjective twilight. GFP-Twl remains acetylated and cytosolic in the dark, whereas light-induced phosphorylation (by the carbon sensor Snf1 kinase drives it into the nucleus. The mRNA level of the transcription/repair factor TFB5, was significantly down regulated in the twl∆ mutant. Overexpression of TFB5 significantly suppressed the conidiation defects in the twl∆ mutant. Furthermore, Tfb5-GFP translocates to the nucleus during the phototropic response and under redox stress, while it failed to do so in the twl∆ mutant. Thus, we provide mechanistic insight into Twl-based regulation of nutrient and redox homeostasis in response to light during pathogen adaptation to the host milieu in the rice blast pathosystem.

  11. Metformin impairs systemic bile acid homeostasis through regulating SIRT1 protein levels.

    Science.gov (United States)

    Chen, Qi; Yang, Xiaoying; Zhang, Huabing; Kong, Xingxing; Yao, Lu; Cui, Xiaona; Zou, Yongkang; Fang, Fude; Yang, Jichun; Chang, Yongsheng

    2017-01-01

    Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Yeast Lipin 1 Orthologue Pah1p Regulates Vacuole Homeostasis and Membrane Fusion*

    Science.gov (United States)

    Sasser, Terry; Qiu, Quan-Sheng; Karunakaran, Surya; Padolina, Mark; Reyes, Anna; Flood, Blake; Smith, Sheena; Gonzales, Chad; Fratti, Rutilio A.

    2012-01-01

    Vacuole homotypic fusion requires a group of regulatory lipids that includes diacylglycerol, a fusogenic lipid that is produced through multiple metabolic pathways including the dephosphorylation of phosphatidic acid (PA). Here we examined the relationship between membrane fusion and PA phosphatase activity. Pah1p is the single yeast homologue of the Lipin family of PA phosphatases. Deletion of PAH1 was sufficient to cause marked vacuole fragmentation and abolish vacuole fusion. The function of Pah1p solely depended on its phosphatase activity as complementation studies showed that wild type Pah1p restored fusion, whereas the phosphatase dead mutant Pah1pD398E had no effect. We discovered that the lack of PA phosphatase activity blocked fusion by inhibiting the binding of SNAREs to Sec18p, an N-ethylmaleimide-sensitive factor homologue responsible for priming inactive cis-SNARE complexes. In addition, pah1Δ vacuoles were devoid of the late endosome/vacuolar Rab Ypt7p, the phosphatidylinositol 3-kinase Vps34p, and Vps39p, a subunit of the HOPS (homotypic fusion and vacuole protein sorting) tethering complex, all of which are required for vacuole fusion. The lack of Vps34p resulted in the absence of phosphatidylinositol 3-phosphate, a lipid required for SNARE activity and vacuole fusion. These findings demonstrate that Pah1p and PA phosphatase activity are critical for vacuole homeostasis and fusion. PMID:22121197

  13. Yeast lipin 1 orthologue pah1p regulates vacuole homeostasis and membrane fusion.

    Science.gov (United States)

    Sasser, Terry; Qiu, Quan-Sheng; Karunakaran, Surya; Padolina, Mark; Reyes, Anna; Flood, Blake; Smith, Sheena; Gonzales, Chad; Fratti, Rutilio A

    2012-01-13

    Vacuole homotypic fusion requires a group of regulatory lipids that includes diacylglycerol, a fusogenic lipid that is produced through multiple metabolic pathways including the dephosphorylation of phosphatidic acid (PA). Here we examined the relationship between membrane fusion and PA phosphatase activity. Pah1p is the single yeast homologue of the Lipin family of PA phosphatases. Deletion of PAH1 was sufficient to cause marked vacuole fragmentation and abolish vacuole fusion. The function of Pah1p solely depended on its phosphatase activity as complementation studies showed that wild type Pah1p restored fusion, whereas the phosphatase dead mutant Pah1p(D398E) had no effect. We discovered that the lack of PA phosphatase activity blocked fusion by inhibiting the binding of SNAREs to Sec18p, an N-ethylmaleimide-sensitive factor homologue responsible for priming inactive cis-SNARE complexes. In addition, pah1Δ vacuoles were devoid of the late endosome/vacuolar Rab Ypt7p, the phosphatidylinositol 3-kinase Vps34p, and Vps39p, a subunit of the HOPS (homotypic fusion and vacuole protein sorting) tethering complex, all of which are required for vacuole fusion. The lack of Vps34p resulted in the absence of phosphatidylinositol 3-phosphate, a lipid required for SNARE activity and vacuole fusion. These findings demonstrate that Pah1p and PA phosphatase activity are critical for vacuole homeostasis and fusion.

  14. Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway.

    Science.gov (United States)

    Grisanti, Laura; Revenkova, Ekaterina; Gordon, Ronald E; Iomini, Carlo

    2016-06-15

    Primary cilia have been linked to signaling pathways involved in cell proliferation, cell motility and cell polarity. Defects in ciliary function result in developmental abnormalities and multiple ciliopathies. Patients affected by severe ciliopathies, such as Meckel syndrome, present several ocular surface disease conditions of unclear pathogenesis. Here, we show that primary cilia are predominantly present on basal cells of the mouse corneal epithelium (CE) throughout development and in the adult. Conditional ablation of cilia in the CE leads to an increase in proliferation and vertical migration of basal corneal epithelial cells (CECs). A consequent increase in cell density of suprabasal layers results in a thicker than normal CE. Surprisingly, in cilia-deficient CE, cilia-mediated signaling pathways, including Hh and Wnt pathways, were not affected but the intensity of Notch signaling was severely diminished. Although Notch1 and Notch2 receptors were expressed normally, nuclear Notch1 intracellular domain (N1ICD) expression was severely reduced. Postnatal development analysis revealed that in cilia-deficient CECs downregulation of the Notch pathway precedes cell proliferation defects. Thus, we have uncovered a function of the primary cilium in maintaining homeostasis of the CE by balancing proliferation and vertical migration of basal CECs through modulation of Notch signaling. © 2016. Published by The Company of Biologists Ltd.

  15. Plant natriuretic peptides: Systemic regulators of plant homeostasis and defense that can affect cardiomyoblasts

    KAUST Repository

    Gehring, Christoph A.

    2010-09-01

    Immunologic evidence has suggested the presence of biologically active natriuretic peptide (NPs) hormones in plants because antiatrial NP antibodies affinity purify biologically active plant NPs (PNP). In the model plant, an Arabidopsis thaliana PNP (AtPNP-A) has been identified and characterized. AtPNP-A belongs to a novel class of molecules that share some similarity with the cell wall loosening expansins but do not contain the carbohydrate-binding wall anchor thus suggesting that PNPs and atrial natriuretic peptides are heterologs. AtPNP-A acts systemically, and this is consistent with its localization in the apoplastic extracellular space and the conductive tissue. Furthermore, AtPNP-A signals via the second messenger cyclic guanosine 3′,5′-monophosphate and modulates ion and water transport and homeostasis. It also plays a critical role in host defense against pathogens. AtPNP-A can be classified as novel paracrine plant hormone because it is secreted into the apoplastic space in response to stress and can enhance its own expression. Interestingly, purified recombinant PNP induces apo-ptosis in a dose-dependent manner and was most effective on cardiac myoblast cell lines. Because PNP is mimicking the effect of ANP in some instances, PNP may prove to provide useful leads for development of novel therapeutic NPs. Copyright © 2013 by The American Federation for Medical Research.

  16. Sulfate uptake in photosynthetic Euglena gracilis. Mechanisms of regulation and contribution to cysteine homeostasis.

    Science.gov (United States)

    García-García, Jorge Donato; Olin-Sandoval, Viridiana; Saavedra, Emma; Girard, Lourdes; Hernández, Georgina; Moreno-Sánchez, Rafael

    2012-10-01

    Sulfate uptake was analyzed in photosynthetic Euglena gracilis grown in sulfate sufficient or sulfate deficient media, or under Cd(2+) exposure or Cys overload, to determine its regulatory mechanisms and contribution to Cys homeostasis. In control and sulfate deficient or Cd(2+)-stressed cells, one high affinity and two low affinity sulfate transporters were revealed, which were partially inhibited by photophosphorylation and oxidative phosphorylation inhibitors and ionophores, as well as by chromate and molybdate; H(+) efflux also diminished in presence of sulfate. In both sulfate deficient and Cd(2+)-exposed cells, the activity of the sulfate transporters was significantly increased. However, the content of thiol-metabolites was lower in sulfate-deficient cells, and higher in Cd(2+)-exposed cells, in comparison to control cells. In cells incubated with external Cys, sulfate uptake was strongly inhibited correlating with 5-times increased intracellular Cys. Re-supply of sulfate to sulfate deficient cells increased the Cys, γ-glutamylcysteine and GSH pools, and to Cys-overloaded cells resulted in the consumption of previously accumulated Cys. In contrast, in Cd(2+) exposed cells none of the already elevated thiol-metabolites changed. (i) Sulfate transport is an energy-dependent process; (ii) sulfate transporters are over-expressed under sulfate deficiency or Cd(2+) stress and their activity can be inhibited by high internal Cys; and (iii) sulfate uptake exerts homeostatic control of the Cys pool. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. The Hippo pathway regulates stem cells during homeostasis and regeneration of the flatworm Macrostomum lignano.

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    Demircan, Turan; Berezikov, Eugene

    2013-08-01

    The Hippo pathway orchestrates activity of stem cells during development and tissue regeneration and is crucial for controlling organ size. However, roles of the Hippo pathway in highly regenerative organisms, such as flatworms, are unknown. Here we show that knockdown of the Hippo pathway core genes in the flatworm Macrostomum lignano affects tissue homeostasis and causes formation of outgrowths through hyperproliferation of stem cells (neoblasts), and leads to disruption of allometric scaling during regeneration and increased size of regenerated parts. We further show that Yap, the downstream effector of the Hippo pathway, is a potential neoblast marker gene, as it is expressed in dividing cells in M. lignano and is essential for neoblast self-renewal. The phenotypes we observe in M. lignano upon knockdown of the Hippo pathway core genes and Yap are consistent with the known functions of the pathway in other model organisms and demonstrate that the Hippo pathway is functionally conserved between flatworms and mammals. This work establishes M. lignano as a productive model for investigation of the Hippo pathway.

  18. Augmentation of bacterial homeostasis by regulating in situ buffer capacity: Significance of total dissolved salts over acidogenic metabolism.

    Science.gov (United States)

    Venkata Mohan, S; Srikanth, S; Nikhil, G N

    2017-02-01

    During anaerobic fermentation, consequent accumulation of acidic fermented products leads to the failure of pH homeostasis. The present study aimed to comprehend the changes in buffering capacity with addition of sodium salts of hydroxide, bicarbonate and phosphate. The results showed notable augmentation in buffer capacity and cumulative hydrogen production (CHP) compared to control. The influential factor is the amount of undissociated volatile fatty acids released that affected the cell metabolism and consequently biohydrogen generation. It is inferred that among the tested salts, sodium bicarbonate has substantial buffering capacity (β, 0.035± mol) ensuing maximum CHP (468± mL). Besides, bioelectrochemical analysis revealed variations in redox currents that aligned with biohydrogen production. The study provides valuable information on the role of inorganic dissolved salts that would be required to regulate H2 generation and acidogenesis in the aspects of acid-gas phase system. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice

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    Mark A. Smith

    2015-04-01

    Full Text Available Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC and agouti-related protein (AgRP neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons.

  20. Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice.

    Science.gov (United States)

    Smith, Mark A; Katsouri, Loukia; Irvine, Elaine E; Hankir, Mohammed K; Pedroni, Silvia M A; Voshol, Peter J; Gordon, Matthew W; Choudhury, Agharul I; Woods, Angela; Vidal-Puig, Antonio; Carling, David; Withers, Dominic J

    2015-04-21

    Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Neuronal calcium sensor synaptotagmin-9 is not involved in the regulation of glucose homeostasis or insulin secretion.

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    Natalia Gustavsson

    Full Text Available BACKGROUND: Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define the identities of proteins that are responsible for sensing calcium changes and for transmitting the calcium signal to release machineries. Synaptotagmins are primarily expressed in brain and endocrine cells and exhibit diverse calcium binding properties. Synaptotagmin-1, -2 and -9 are calcium sensors for fast neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium-dependent insulin secretion, thus suggesting that other calcium-sensors must participate in the regulation of insulin secretion. Of the other synaptotagmin isoforms that are present in pancreatic islets, the neuronal calcium sensor synaptotagmin-9 is expressed at the highest level after synaptotagmin-7. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested whether synaptotagmin-9 participates in the regulation of glucose-stimulated insulin release by using pancreas-specific synaptotagmin-9 knockout (p-S9X mice. Deletion of synaptotagmin-9 in the pancreas resulted in no changes in glucose homeostasis or body weight. Glucose tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice. CONCLUSIONS: Thus, synaptotagmin-9, although a major calcium sensor in the brain, is not involved in the regulation of glucose-stimulated insulin release from pancreatic β-cells.

  2. Propofol Affects Neurodegeneration and Neurogenesis by Regulation of Autophagy via Effects on Intracellular Calcium Homeostasis.

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    Qiao, Hui; Li, Yun; Xu, Zhendong; Li, Wenxian; Fu, Zhijian; Wang, Yuezhi; King, Alexander; Wei, Huafeng

    2017-09-01

    In human cortical neural progenitor cells, we investigated the effects of propofol on calcium homeostasis in both the ryanodine and inositol 1,4,5-trisphosphate calcium release channels. We also studied propofol-mediated effects on autophagy, cell survival, and neuro- and gliogenesis. The dose-response relationship between propofol concentration and duration was studied in neural progenitor cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays. The effects of propofol on cytosolic calcium concentration were evaluated using Fura-2, and autophagy activity was determined by LC3II expression levels with Western blot. Proliferation and differentiation were evaluated by bromodeoxyuridine incorporation and immunostaining with neuronal and glial markers. Propofol dose- and time-dependently induced cell damage and elevated LC3II expression, most robustly at 200 µM for 24 h (67 ± 11% of control, n = 12 to 19) and 6 h (2.4 ± 0.5 compared with 0.6 ± 0.1 of control, n = 7), respectively. Treatment with 200 μM propofol also increased cytosolic calcium concentration (346 ± 71% of control, n = 22 to 34). Propofol at 10 µM stimulated neural progenitor cell proliferation and promoted neuronal cell fate, whereas propofol at 200 µM impaired neuronal proliferation and promoted glial cell fate (n = 12 to 20). Cotreatment with ryanodine and inositol 1,4,5-trisphosphate receptor antagonists and inhibitors, cytosolic Ca chelators, or autophagy inhibitors mostly mitigated the propofol-mediated effects on survival, proliferation, and differentiation. These results suggest that propofol-mediated cell survival or neurogenesis is closely associated with propofol's effects on autophagy by activation of ryanodine and inositol 1,4,5-trisphosphate receptors.

  3. The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity.

    Science.gov (United States)

    Xiao, Yichuan; Zou, Qiang; Xie, Xiaoping; Liu, Ting; Li, Haiyan S; Jie, Zuliang; Jin, Jin; Hu, Hongbo; Manyam, Ganiraju; Zhang, Li; Cheng, Xuhong; Wang, Hui; Marie, Isabelle; Levy, David E; Watowich, Stephanie S; Sun, Shao-Cong

    2017-05-01

    Dendritic cells (DCs) are crucial for mediating immune responses but, when deregulated, also contribute to immunological disorders, such as autoimmunity. The molecular mechanism underlying the function of DCs is incompletely understood. In this study, we have identified TANK-binding kinase 1 (TBK1), a master innate immune kinase, as an important regulator of DC function. DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell-priming activity. We further demonstrate that TBK1 negatively regulates the induction of a subset of genes by type I interferon receptor (IFNAR). Deletion of IFNAR1 could largely prevent aberrant T cell activation and autoimmunity in DC-conditional Tbk1 knockout mice. These findings identify a DC-specific function of TBK1 in the maintenance of immune homeostasis and tolerance. © 2017 Xiao et al.

  4. Mycobacterium tuberculosis WhiB3 maintains redox homeostasis by regulating virulence lipid anabolism to modulate macrophage response.

    Science.gov (United States)

    Singh, Amit; Crossman, David K; Mai, Deborah; Guidry, Loni; Voskuil, Martin I; Renfrow, Matthew B; Steyn, Adrie J C

    2009-08-01

    The metabolic events associated with maintaining redox homeostasis in Mycobacterium tuberculosis (Mtb) during infection are poorly understood. Here, we discovered a novel redox switching mechanism by which Mtb WhiB3 under defined oxidizing and reducing conditions differentially modulates the assimilation of propionate into the complex virulence polyketides polyacyltrehaloses (PAT), sulfolipids (SL-1), phthiocerol dimycocerosates (PDIM), and the storage lipid triacylglycerol (TAG) that is under control of the DosR/S/T dormancy system. We developed an in vivo radio-labeling technique and demonstrated for the first time the lipid profile changes of Mtb residing in macrophages, and identified WhiB3 as a physiological regulator of virulence lipid anabolism. Importantly, MtbDeltawhiB3 shows enhanced growth on medium containing toxic levels of propionate, thereby implicating WhiB3 in detoxifying excess propionate. Strikingly, the accumulation of reducing equivalents in MtbDeltawhiB3 isolated from macrophages suggests that WhiB3 maintains intracellular redox homeostasis upon infection, and that intrabacterial lipid anabolism functions as a reductant sink. MtbDeltawhiB3 infected macrophages produce higher levels of pro- and anti-inflammatory cytokines, indicating that WhiB3-mediated regulation of lipids is required for controlling the innate immune response. Lastly, WhiB3 binds to pks2 and pks3 promoter DNA independent of the presence or redox state of its [4Fe-4S] cluster. Interestingly, reduction of the apo-WhiB3 Cys thiols abolished DNA binding, whereas oxidation stimulated DNA binding. These results confirmed that WhiB3 DNA binding is reversibly regulated by a thiol-disulfide redox switch. These results introduce a new paradigmatic mechanism that describes how WhiB3 facilitates metabolic switching to fatty acids by regulating Mtb lipid anabolism in response to oxido-reductive stress associated with infection, for maintaining redox balance. The link between the WhiB3

  5. A family business: stem cell progeny join the niche to regulate homeostasis.

    Science.gov (United States)

    Hsu, Ya-Chieh; Fuchs, Elaine

    2012-01-23

    Stem cell niches, the discrete microenvironments in which the stem cells reside, play a dominant part in regulating stem cell activity and behaviours. Recent studies suggest that committed stem cell progeny become indispensable components of the niche in a wide range of stem cell systems. These unexpected niche inhabitants provide versatile feedback signals to their stem cell parents. Together with other heterologous cell types that constitute the niche, they contribute to the dynamics of the microenvironment. As progeny are often located in close proximity to stem cell niches, similar feedback regulations may be the underlying principles shared by different stem cell systems.

  6. Profiling the lymphoid-resident T cell pool reveals modulation by age and microbiota.

    Science.gov (United States)

    Durand, Aurélie; Audemard-Verger, Alexandra; Guichard, Vincent; Mattiuz, Raphaël; Delpoux, Arnaud; Hamon, Pauline; Bonilla, Nelly; Rivière, Matthieu; Delon, Jérôme; Martin, Bruno; Auffray, Cédric; Boissonnas, Alexandre; Lucas, Bruno

    2018-01-04

    Despite being implicated in non-lymphoid tissues, non-recirculating T cells may also exist in secondary lymphoid organs (SLO). However, a detailed characterization of this lymphoid-resident T cell pool has not yet been done. Here we show that a substantial proportion of CD4 regulatory (Treg) and memory (Tmem) cells establish long-term residence in the SLOs of specific pathogen-free mice. Of these SLOs, only T cell residence within Peyer's patches is affected by microbiota. Resident CD4 Treg and CD4 Tmem cells from lymph nodes and non-lymphoid tissues share many phenotypic and functional characteristics. The percentage of resident T cells in SLOs increases considerably with age, with S1PR1 downregulation possibly contributing to this altered homeostasis. Our results thus show that T cell residence is not only a hallmark of non-lymphoid tissues, but can be extended to secondary lymphoid organs.

  7. Osteoblastic Actions of the Neuropeptide Y System to Regulate Bone and Energy Homeostasis.

    Science.gov (United States)

    Horsnell, Harry; Baldock, Paul A

    2016-02-01

    Neural pathways are now a well-appreciated factor in the regulatory milieu controlling the maintenance of bone mass. A number of neural pathways from the brain to bone have been identified. These pathways often involve elements of the energy homeostatic apparatus, indicating links between the regulation of bone metabolism and energy balance. Neuropeptide Y is one such factor that co-regulates these two processes. Initial studies outlined the skeletal actions of NPY from within the brain and the interactions with energy homeostatic processes. However, in recent years, an appreciation for the actions of NPY within bone cells has expanded. Cells of the osteoblastic lineage express both NPY ligand and a cognate receptor NPY, Y1R. Murine studies have demonstrated that both ligand and receptor actively control bone mass and osteoblast activity and interact with mechanical signals to integrate with the local loading environment. Local NPY signalling regulates osteoprogenitor production and differentiation, to cover the entire osteoblastic lineage. In addition, several recent studies have demonstrated extra-skeletal actions of osteoblastic NPY signalling, to regulate energy expenditure and with it adiposity, and in a separate study, to control release of a factor-controlling beta cell mass and insulin production/release and with it glucose tolerance. Thus, osteoblastic neuropeptide production and signalling illustrates the rapidly widening sphere of influence of skeletal tissue, and suggests a far more complex and interconnected physiology then is currently appreciated.

  8. A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis.

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    Joshua M Baughman

    2009-08-01

    Full Text Available The human oxidative phosphorylation (OxPhos system consists of approximately 90 proteins encoded by nuclear and mitochondrial genomes and serves as the primary cellular pathway for ATP biosynthesis. While the core protein machinery for OxPhos is well characterized, many of its assembly, maturation, and regulatory factors remain unknown. We exploited the tight transcriptional control of the genes encoding the core OxPhos machinery to identify novel regulators. We developed a computational procedure, which we call expression screening, which integrates information from thousands of microarray data sets in a principled manner to identify genes that are consistently co-expressed with a target pathway across biological contexts. We applied expression screening to predict dozens of novel regulators of OxPhos. For two candidate genes, CHCHD2 and SLIRP, we show that silencing with RNAi results in destabilization of OxPhos complexes and a marked loss of OxPhos enzymatic activity. Moreover, we show that SLIRP plays an essential role in maintaining mitochondrial-localized mRNA transcripts that encode OxPhos protein subunits. Our findings provide a catalogue of potential novel OxPhos regulators that advance our understanding of the coordination between nuclear and mitochondrial genomes for the regulation of cellular energy metabolism.

  9. The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis.

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    Ellacott, Kate L J; Cone, Roger D

    2004-01-01

    The importance of the central melanocortin system in the regulation of energy balance is highlighted by studies in transgenic animals and humans with defects in this system. Mice that are engineered to be deficient for the melanocortin-4 receptor (MC4R) or pro-opiomelanocortin (POMC) and those that overexpress agouti or agouti-related protein (AgRP) all have a characteristic obese phenotype typified by hyperphagia, increased linear growth, and metabolic defects. Similar attributes are seen in humans with haploinsufficiency of the MC4R. The central melanocortin system modulates energy homeostasis through the actions of the agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), a POMC cleavage product, and the endogenous antagonist AgRP on the MC3R and MC4R. POMC is expressed at only two locations in the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the tractus solitarius (NTS) of the brainstem. This chapter will discuss these two populations of POMC neurons and their contribution to energy homeostasis. We will examine the involvement of the central melanocortin system in the incorporation of information from the adipostatic hormone leptin and acute hunger and satiety factors such as peptide YY (PYY(3-36)) and ghrelin via a neuronal network involving POMC/cocaine and amphetamine-related transcript (CART) and neuropeptide Y (NPY)/AgRP neurons. We will discuss evidence for the existence of a similar network of neurons in the NTS and propose a model by which this information from the ARC and NTS centers may be integrated directly or via adipostatic centers such as the paraventricular nucleus of the hypothalamus (PVH).

  10. The chloroplast permease PIC1 regulates plant growth and development by directing homeostasis and transport of iron.

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    Duy, Daniela; Stübe, Roland; Wanner, Gerhard; Philippar, Katrin

    2011-04-01

    The membrane-spanning protein PIC1 (for permease in chloroplasts 1) in Arabidopsis (Arabidopsis thaliana) was previously described to mediate iron transport across the inner envelope membrane of chloroplasts. The albino phenotype of pic1 knockout mutants was reminiscent of iron-deficiency symptoms and characterized by severely impaired plastid development and plant growth. In addition, plants lacking PIC1 showed a striking increase in chloroplast ferritin clusters, which function in protection from oxidative stress by sequestering highly reactive free iron in their spherical protein shell. In contrast, PIC1-overexpressing lines (PIC1ox) in this study rather resembled ferritin loss-of-function plants. PIC1ox plants suffered from oxidative stress and leaf chlorosis, most likely originating from iron overload in chloroplasts. Later during growth, plants were characterized by reduced biomass as well as severely defective flower and seed development. As a result of PIC1 protein increase in the inner envelope membrane of plastids, flower tissue showed elevated levels of iron, while the content of other transition metals (copper, zinc, manganese) remained unchanged. Seeds, however, specifically revealed iron deficiency, suggesting that PIC1 overexpression sequestered iron in flower plastids, thereby becoming unavailable for seed iron loading. In addition, expression of genes associated with metal transport and homeostasis as well as photosynthesis was deregulated in PIC1ox plants. Thus, PIC1 function in plastid iron transport is closely linked to ferritin and plastid iron homeostasis. In consequence, PIC1 is crucial for balancing plant iron metabolism in general, thereby regulating plant growth and in particular fruit development.

  11. NKS1, Na+- and K+-sensitive 1, regulates ion homeostasis in an SOS-independent pathway in Arabidopsis

    KAUST Repository

    Choi, Wonkyun

    2011-04-01

    An Arabidopsis thaliana mutant, nks1-1, exhibiting enhanced sensitivity to NaCl was identified in a screen of a T-DNA insertion population in the genetic background of Col-0 gl1 sos3-1. Analysis of the genome sequence in the region flanking the T-DNA left border indicated two closely linked mutations in the gene encoded at locus At4g30996. A second allele, nks1-2, was obtained from the Arabidopsis Biological Resource Center. NKS1 mRNA was detected in all parts of wild-type plants but was not detected in plants of either mutant, indicating inactivation by the mutations. Both mutations in NKS1 were associated with increased sensitivity to NaCl and KCl, but not to LiCl or mannitol. NaCl sensitivity was associated with nks1 mutations in Arabidopsis lines expressing either wild type or alleles of SOS1, SOS2 or SOS3. The NaCl-sensitive phenotype of the nks1-2 mutant was complemented by expression of a full-length NKS1 allele from the CaMV35S promoter. When grown in medium containing NaCl, nks1 mutants accumulated more Na+ than wild type and K +/Na+ homeostasis was perturbed. It is proposed NKS1, a plant-specific gene encoding a 19 kDa endomembrane-localized protein of unknown function, is part of an ion homeostasis regulation pathway that is independent of the SOS pathway. © 2011 Elsevier Ltd. All rights reserved.

  12. Astragaloside IV Prevents Cardiac Remodeling in the Apolipoprotein E-Deficient Mice by Regulating Cardiac Homeostasis and Oxidative Stress

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    Xiong-Zhi Li

    2017-12-01

    Full Text Available Background: Hypercholesterolemia is a risk factor for the development of cardiac hypertrophy. Astragaloside IV (AST-IV possesses cardiovascular protective properties. We hypothesize that AST-IV prevents cardiac remodeling with hypercholesterolemia via modulating tissue homeostasis and alleviating oxidative stress. Methods: The ApoE-/- mice were treated with AST-IV at 1 or 10 mg/kg for 8 weeks. The blood lipids tests, echocardiography, and TUNEL were performed. The mRNA expression profile was detected by real-time PCR. The myocytes size and number, and the expressions of proliferation (ki67, senescence (p16INK4a, oxidant (NADPH oxidase 4, NOX4 and antioxidant (superoxide dismutase, SOD were observed by immunofluorescence staining. Results: Neither 1 mg/kg nor 10 mg/kg AST-IV treatment could decrease blood lipids in ApoE-/- mice. However, the decreased left ventricular ejection fraction (LVEF and fractional shortening (FS in ApoE–/– mice were significantly improved after AST-IV treatment. The cardiac collagen volume fraction declined nearly in half after AST-IV treatment. The enlarged myocyte size was suppressed, and myocyte number was recovered, and the alterations of genes expressions linked to cell cycle, proliferation, senescence, p53-apoptosis pathway and oxidant-antioxidants in the hearts of ApoE-/- mice were reversed after AST-IV treatment. The decreased ki67 and increased p16INK4a in the hearts of ApoE-/- mice were recovered after AST-IV treatment. The percentages of apoptotic myocytes and NOX4-positive cells in AST-IV treated mice were decreased, which were consistent with the gene expressions. Conclusion: AST-IV treatment could prevent cardiac remodeling and recover the impaired ventricular function induced by hypercholesterolemia. The beneficial effect of AST-IV might partly be through regulating cardiac homeostasis and anti-oxidative stress.

  13. GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis.

    Science.gov (United States)

    Lan, Hong; Vassileva, Galya; Corona, Aaron; Liu, Li; Baker, Hana; Golovko, Andrei; Abbondanzo, Susan J; Hu, Weiwen; Yang, Shijun; Ning, Yun; Del Vecchio, Robert A; Poulet, Frederique; Laverty, Maureen; Gustafson, Eric L; Hedrick, Joseph A; Kowalski, Timothy J

    2009-05-01

    G protein-coupled receptor 119 (GPR119) is expressed in pancreatic islets and intestine, and is involved in insulin and incretin hormone release. GPR119-knockout (Gpr119(-/-)) mice were reported to have normal islet morphology and normal size, body weight (BW), and fed/fasted glucose levels. However, the physiological function of GPR119 and its role in maintaining glucose homeostasis under metabolic stress remain unknown. Here, we report the phenotypes of an independently generated line of Gpr119(-/-) mice under basal and high-fat diet (HFD)-induced obesity. Under low-fat diet feeding, Gpr119(-/-) mice show normal plasma glucose and lipids, but have lower BWs and lower post-prandial levels of active glucagon-like peptide 1 (GLP-1). Nutrient-stimulated GLP-1 release is attenuated in Gpr119(-/-) mice, suggesting that GPR119 plays a role in physiological regulation of GLP-1 secretion. Under HFD-feeding, both Gpr119(+)(/)(+) and Gpr119(-/-) mice gain weight similarly, develop hyperinsulinemia and hyperleptinemia, but not hyperglycemia or dyslipidemia. Glucose and insulin tolerance tests did not reveal a genotypic difference. These data show that GPR119 is not essential for the maintenance of glucose homeostasis. Moreover, we found that oleoylethanolamide (OEA), reported as a ligand for GPR119, was able to suppress food intake in both Gpr119(+)(/)(+) and Gpr119(-/-) mice, indicating that GPR119 is not required for the hypophagic effect of OEA. Our results demonstrate that GPR119 is important for incretin and insulin secretion, but not for appetite suppression.

  14. Involvement of the iron regulatory protein from Eisenia andrei earthworms in the regulation of cellular iron homeostasis.

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    Petra Procházková

    Full Text Available Iron homeostasis in cells is regulated by iron regulatory proteins (IRPs that exist in different organisms. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs of the 5'- or 3'-untranslated regions (UTR of mRNAs that encode many proteins involved in iron metabolism. In this study, we have cloned and described a new regulatory protein belonging to the family of IRPs from the earthworm Eisenia andrei (EaIRP. The earthworm IRE site in 5'-UTR of ferritin mRNA most likely folds into a secondary structure that differs from the conventional IRE structures of ferritin due to the absence of a typically unpaired cytosine that participates in protein binding. Prepared recombinant EaIRP and proteins from mammalian liver extracts are able to bind both mammalian and Eisenia IRE structures of ferritin mRNA, although the affinity of the rEaIRP/Eisenia IRE structure is rather low. This result suggests the possible contribution of a conventional IRE structure. When IRP is supplemented with a Fe-S cluster, it can function as a cytosolic aconitase. Cellular cytosolic and mitochondrial fractions, as well as recombinant EaIRP, exhibit aconitase activity that can be abolished by the action of oxygen radicals. The highest expression of EaIRP was detected in parts of the digestive tract. We can assume that earthworms may possess an IRE/IRP regulatory network as a potential mechanism for maintaining cellular iron homeostasis, although the aconitase function of EaIRP is most likely more relevant.

  15. Fibroblast α11β1 integrin regulates tensional homeostasis in fibroblast/A549 carcinoma heterospheroids.

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    Ning Lu

    Full Text Available We have previously shown that fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. To understand the molecular mechanisms whereby a collagen receptor on fibroblast can regulate tumor growth we have used a 3D heterospheroid system composed of A549 tumor cells and fibroblasts without (α11+/+ or with a deletion (α11-/- in integrin α11 gene. Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids. Gene expression profiling of differentially expressed genes in fibroblast/A549 spheroids identified CXCL5 as one molecule down-regulated in A549 cells in the absence of α11 on the fibroblasts. Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5. We furthermore suggest that fibroblast α11β1 in fibroblast/A549 spheroids regulates interstitial fluid pressure by compacting the collagen matrix, in turn implying a role for stromal collagen receptors in regulating tensional hemostasis in tumors. In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy.

  16. Regulation of sulphur assimilation is essential for virulence and affects iron homeostasis of the human-pathogenic mould Aspergillus fumigatus.

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    Jorge Amich

    Full Text Available Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

  17. Regulation of nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways.

    Directory of Open Access Journals (Sweden)

    Seok Hyun Cho

    Full Text Available Allergic rhinitis is a chronic inflammatory disease orchestrated by Th2 lymphocytes. Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1 is known to be a negative regulator in the IL-4α/STAT-6 signaling pathway of the lung. However, the role of SHP-1 enzyme and its functional relationship with Th2 and Th1 cytokines are not known in the nasal airway. In this study, we aimed to study the nasal inflammation as a result of SHP-1 deficiency in viable motheaten (mev mice and to investigate the molecular mechanisms involved. Cytology, histology, and expression of cytokines and chemokines were analyzed to define the nature of the nasal inflammation. Targeted gene depletion of Th1 (IFN-γ and Th2 (IL-4 and IL-13 cytokines was used to identify the critical pathways involved. Matrix metalloproteinases (MMPs were studied to demonstrate the clearance mechanism of recruited inflammatory cells into the nasal airway. We showed here that mev mice had a spontaneous allergic rhinitis-like inflammation with eosinophilia, mucus metaplasia, up-regulation of Th2 cytokines (IL-4 and IL-13, chemokines (eotaxin, and MMPs. All of these inflammatory mediators were clearly counter-regulated by Th2 and Th1 cytokines. Deletion of IFN-γ gene induced a strong Th2-skewed inflammation with transepithelial migration of the inflammatory cells. These findings suggest that SHP-1 enzyme and Th2/Th1 paradigm may play a critical role in the maintenance of nasal immune homeostasis and in the regulation of allergic rhinitis.

  18. The Proteome of the Red Blood Cell: An Auspicious Source of New Insights into Membrane-Centered Regulation of Homeostasis.

    Science.gov (United States)

    Bosman, Giel J C G M

    2016-11-25

    During the past decade, the hand-in-hand development of biotechnology and bioinformatics has enabled a view of the function of the red blood cell that surpasses the supply of oxygen and removal of carbon dioxide. Comparative proteomic inventories have yielded new clues to the processes that regulate membrane-cytoskeleton interactions in health and disease, and to the ways by which red blood cells communicate with their environment. In addition, proteomic data have revealed the possibility that many, hitherto unsuspected, metabolic processes are active in the red blood cell cytoplasm. Recent metabolomic studies have confirmed and expanded this notion. Taken together, the presently available data point towards the red blood cell membrane as the hub at which all regulatory processes come together. Thus, alterations in the association of regulatory proteins with the cell membrane may be a sine qua non for the functional relevance of any postulated molecular mechanism. From this perspective, comparative proteomics centered on the red blood cell membrane constitute a powerful tool for the identification and elucidation of the physiologically and pathologically relevant pathways that regulate red blood cell homeostasis. Additionally, this perspective provides a focus for the interpretation of metabolomic studies, especially in the development of biomarkers in the blood.

  19. Altered structural and effective connectivity in anorexia and bulimia nervosa in circuits that regulate energy and reward homeostasis

    Science.gov (United States)

    Frank, G K W; Shott, M E; Riederer, J; Pryor, T L

    2016-01-01

    Anorexia and bulimia nervosa are severe eating disorders that share many behaviors. Structural and functional brain circuits could provide biological links that those disorders have in common. We recruited 77 young adult women, 26 healthy controls, 26 women with anorexia and 25 women with bulimia nervosa. Probabilistic tractography was used to map white matter connectivity strength across taste and food intake regulating brain circuits. An independent multisample greedy equivalence search algorithm tested effective connectivity between those regions during sucrose tasting. Anorexia and bulimia nervosa had greater structural connectivity in pathways between insula, orbitofrontal cortex and ventral striatum, but lower connectivity from orbitofrontal cortex and amygdala to the hypothalamus (Pbulimia nervosa effective connectivity was directed from anterior cingulate via ventral striatum to the hypothalamus. Across all groups, sweetness perception was predicted by connectivity strength in pathways connecting to the middle orbitofrontal cortex. This study provides evidence that white matter structural as well as effective connectivity within the energy-homeostasis and food reward-regulating circuitry is fundamentally different in anorexia and bulimia nervosa compared with that in controls. In eating disorders, anterior cingulate cognitive–emotional top down control could affect food reward and eating drive, override hypothalamic inputs to the ventral striatum and enable prolonged food restriction. PMID:27801897

  20.  The discovery of neuromedin U and its pivotal role in the central regulation of energy homeostasis

    Directory of Open Access Journals (Sweden)

    Katarzyna Kirsz

    2012-04-01

    Full Text Available  Neuromedin U (NMU is a structurally highly conserved neuropeptide and has been paired with the G-protein-coupled receptors (GPCRs NMUR1 and NMUR2, which were formerly classified in the orphan receptor family. Activation of the G protein Gq/11 subunit causes a pertussis toxin (PTX-insensitive activation of both phospholipase C and mitogen-activated protein kinase (MAP, and activation of the Go subunit causes a PTX-sensitive inhibition of adenyl cyclase. Additionally, NMU selectively inhibits L-type high-voltage-gated Ca2 channels in mouse hippocampus, as well as low-voltage-activated T-type Ca2 channels in mouse dorsal root ganglia (DRG. NMU peptide and its receptors are predominantly expressed in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy homeostasis. A novel neuropeptide, neuromedin S (NMS, is structurally related to NMU. They share a C-terminal core structure and both have been implicated in the regulation of food intake, as well as the circadian rhythms. The acute anorectic and weight-reducing effects of NMU and NMS are mediated by NMUR2. This suggests that NMUR2-selective agonists may be useful for the treatment of obesity.

  1. Beneficial autoimmunity at body surfaces– immune surveillance and rapid type 2 immunity regulate tissue homeostasis and cancer

    Directory of Open Access Journals (Sweden)

    Tim eDalessandri

    2014-07-01

    Full Text Available Epithelial cells line body surface tissues and provide a physicochemical barrier to the external environment. Frequent microbial and non-microbial challenges such as those imposed by mechanical disruption, injury or exposure to noxious environmental substances including chemicals, carcinogens, ultraviolet-irradiation or toxins cause activation of epithelial cells with release of cytokines and chemokines as well as alterations in the expression of cell surface ligands. Such display of epithelial stress is rapidly sensed by tissue resident immunocytes, which can directly interact with self-moieties on epithelial cells and initiate both local and systemic immune responses. Epithelial cells are thus key drivers of immune surveillance at body surface tissues. However, epithelial cells have a propensity to drive type 2 immunity (rather than type 1 upon non-invasive challenge or stress – a type of immunity whose regulation and function still remain enigmatic. Here we review the induction and possible role of type 2 immunity in epithelial tissues and propose that rapid immune surveillance and type 2 immunity are key regulators of tissue homeostasis and carcinogenesis.

  2. Wrinkled1 accelerates flowering and regulates lipid homeostasis between oil accumulation and membrane lipid anabolism in Brassica napus

    Directory of Open Access Journals (Sweden)

    Qing eLi

    2015-11-01

    Full Text Available Wrinkled1 (WRI1 belongs to the APETALA2 transcription factor family; it is unique to plants and is a central regulator of oil synthesis in Arabidopsis. The effects of WRI1 on comprehensive lipid metabolism and plant development were unknown, especially in crop plants. This study found that BnWRI1 in Brassica napus accelerated flowering and enhanced oil accumulation in both seeds and leaves without leading to a visible growth inhibition. BnWRI1 decreased storage carbohydrates and increased soluble sugars to facilitate the carbon flux to lipid anabolism. BnWRI1 is localized to the nucleus and directly binds to the AW-box at proximal upstream regions of genes involved in fatty acid synthesis and lipid assembly. The overexpression (OE of BnWRI1 resulted in the up-regulation of genes involved in glycolysis, fatty acid synthesis, lipid assembly, and flowering. Lipid profiling revealed increased galactolipid monogalactosyldiacylglycerol (MGDG, digalactosyldiacylglycerol (DGDG, and phosphatidylcholine (PC in the leaves of OE plants, whereas it exhibited a reduced level of the galactolipids DGDG and MGDG and increased levels of PC, phosphatidylethanolamide (PE, and oil (triacylglycerol, TAG in the siliques of OE plants during the early seed development stage. These results suggest that BnWRI1 is important for homeostasis among TAG, membrane lipids and sugars, and thus facilitates flowering and oil accumulation in B. napus.

  3. Wrinkled1 Accelerates Flowering and Regulates Lipid Homeostasis between Oil Accumulation and Membrane Lipid Anabolism in Brassica napus.

    Science.gov (United States)

    Li, Qing; Shao, Jianhua; Tang, Shaohua; Shen, Qingwen; Wang, Tiehu; Chen, Wenling; Hong, Yueyun

    2015-01-01

    Wrinkled1 (WRI1) belongs to the APETALA2 transcription factor family; it is unique to plants and is a central regulator of oil synthesis in Arabidopsis. The effects of WRI1 on comprehensive lipid metabolism and plant development were unknown, especially in crop plants. This study found that BnWRI1 in Brassica napus accelerated flowering and enhanced oil accumulation in both seeds and leaves without leading to a visible growth inhibition. BnWRI1 decreased storage carbohydrates and increased soluble sugars to facilitate the carbon flux to lipid anabolism. BnWRI1 is localized to the nucleus and directly binds to the AW-box at proximal upstream regions of genes involved in fatty acid (FA) synthesis and lipid assembly. The overexpression (OE) of BnWRI1 resulted in the up-regulation of genes involved in glycolysis, FA synthesis, lipid assembly, and flowering. Lipid profiling revealed increased galactolipids monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), and phosphatidylcholine (PC) in the leaves of OE plants, whereas it exhibited a reduced level of the galactolipids DGDG and MGDG and increased levels of PC, phosphatidylethanolamide, and oil [triacylglycerol (TAG)] in the siliques of OE plants during the early seed development stage. These results suggest that BnWRI1 is important for homeostasis among TAG, membrane lipids and sugars, and thus facilitates flowering and oil accumulation in B. napus.

  4. Altered structural and effective connectivity in anorexia and bulimia nervosa in circuits that regulate energy and reward homeostasis.

    Science.gov (United States)

    Frank, G K W; Shott, M E; Riederer, J; Pryor, T L

    2016-11-01

    Anorexia and bulimia nervosa are severe eating disorders that share many behaviors. Structural and functional brain circuits could provide biological links that those disorders have in common. We recruited 77 young adult women, 26 healthy controls, 26 women with anorexia and 25 women with bulimia nervosa. Probabilistic tractography was used to map white matter connectivity strength across taste and food intake regulating brain circuits. An independent multisample greedy equivalence search algorithm tested effective connectivity between those regions during sucrose tasting. Anorexia and bulimia nervosa had greater structural connectivity in pathways between insula, orbitofrontal cortex and ventral striatum, but lower connectivity from orbitofrontal cortex and amygdala to the hypothalamus (Panorexia and bulimia nervosa effective connectivity was directed from anterior cingulate via ventral striatum to the hypothalamus. Across all groups, sweetness perception was predicted by connectivity strength in pathways connecting to the middle orbitofrontal cortex. This study provides evidence that white matter structural as well as effective connectivity within the energy-homeostasis and food reward-regulating circuitry is fundamentally different in anorexia and bulimia nervosa compared with that in controls. In eating disorders, anterior cingulate cognitive-emotional top down control could affect food reward and eating drive, override hypothalamic inputs to the ventral striatum and enable prolonged food restriction.

  5. Innate lymphoid cells and natural killer T cells in the gastrointestinal tract immune system.

    Science.gov (United States)

    Montalvillo, Enrique; Garrote, José Antonio; Bernardo, David; Arranz, Eduardo

    2014-05-01

    The gastrointestinal tract is equipped with a highly specialized intrinsic immune system. However, the intestine is exposed to a high antigenic burden that requires a fast, nonspecific response -so-called innate immunity- to maintain homeostasis and protect the body from incoming pathogens. In the last decade multiple studies helped to unravel the particular developmental requirements and specific functions of the cells that play a role in innate immunity. In this review we shall focus on innate lymphoid cells, a newly discovered, heterogeneous set of cells that derive from an Id2-dependent lymphoid progenitor cell population. These cells have been categorized on the basis of the pattern of cytokines that they secrete, and the transcription factors that regulate their development and functions. Innate lymphoid cells play a role in the early response to pathogens, the anatomical contention of the commensal flora, and the maintenance of epithelial integrity.Amongst the various innate lymphoid cells we shall lay emphasis on a subpopulation with several peculiarities, namely that of natural killer T cells, a subset of T lymphocytes that express both T-cell and NK-cell receptors. The most numerous fraction of the NKT population are the so-called invariant NKT or iNKT cells. These iNKT cells have an invariant TCR and recognize the glycolipidic structures presented by the CD1d molecule, a homolog of class-I MHC molecules. Following activation they rapidly acquire cytotoxic activity and secrete both Th1 and Th2 cytokines, including IL-17. While their specific role is not yet established, iNKT cells take part in a great variety of intestinal immune responses ranging from oral tolerance to involvement in a number of gastrointestinal conditions.

  6. Innate lymphoid cells and natural killer T cells in the gastrointestinal tract immune system

    Directory of Open Access Journals (Sweden)

    Enrique Montalvillo

    2014-05-01

    Full Text Available The gastrointestinal tract is equipped with a highly specialized intrinsic immune system. However, the intestine is exposed to a high antigenic burden that requires a fast, nonspecific response -so-called innate immunity- to maintain homeostasis and protect the body from incoming pathogens. In the last decade multiple studies helped to unravel the particular developmental requirements and specific functions of the cells that play a role in innate immunity. In this review we shall focus on innate lymphoid cells, a newly discovered, heterogeneous set of cells that derive from an Id2-dependent lymphoid progenitor cell population. These cells have been categorized on the basis of the pattern of cytokines that they secrete, and the transcription factors that regulate their development and functions. Innate lymphoid cells play a role in the early response to pathogens, the anatomical contention of the commensal flora, and the maintenance of epithelial integrity. Amongst the various innate lymphoid cells we shall lay emphasis on a subpopulation with several peculiarities, namely that of natural killer T cells, a subset of T lymphocytes that express both T-cell and NK-cell receptors. The most numerous fraction of the NKT population are the so-called invariant NKT or iNKT cells. These iNKT cells have an invariant TCR and recognize the glycolipidic structures presented by the CD1d molecule, a homolog of class-I MHC molecules. Following activation they rapidly acquire cytotoxic activity and secrete both Th1 and Th2 cytokines, including IL-17. While their specific role is not yet established, iNKT cells take part in a great variety of intestinal immune responses ranging from oral tolerance to involvement in a number of gastrointestinal conditions.

  7. The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body.

    Directory of Open Access Journals (Sweden)

    Christal A Worthen

    2014-03-01

    Full Text Available Fine tuning of body iron is required to prevent diseases such as iron-overload and anemia. The putative iron-sensor, transferrin receptor 2 (TfR2, is expressed in the liver and mutations in this protein result in the iron-overload disease Type III hereditary hemochromatosis (HH. With the loss of functional TfR2, the liver produces about two-fold less of the peptide hormone hepcidin, which is responsible for negatively regulating iron uptake from the diet. This reduction in hepcidin expression leads to the slow accumulation of iron in the liver, heart, joints, and pancreas and subsequent cirrhosis, heart disease, arthritis, and diabetes. TfR2 can bind iron-loaded transferrin in the bloodstream, and hepatocytes treated with transferrin respond with a two-fold increase in hepcidin expression through stimulation of the BMP-signaling pathway. Loss of functional TfR2 or its binding partner, the original HH protein (HFE, results in a loss of this transferrin-sensitivity. While much is known about the trafficking and regulation of TfR2, the mechanism of its transferrin-sensitivity through the BMP-signaling pathway is still not known.

  8. The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body.

    Science.gov (United States)

    Worthen, Christal A; Enns, Caroline A

    2014-01-01

    Fine-tuning of body iron is required to prevent diseases such as iron-overload and anemia. The putative iron sensor, transferrin receptor 2 (TfR2), is expressed in the liver and mutations in this protein result in the iron-overload disease Type III hereditary hemochromatosis (HH). With the loss of functional TfR2, the liver produces about 2-fold less of the peptide hormone hepcidin, which is responsible for negatively regulating iron uptake from the diet. This reduction in hepcidin expression leads to the slow accumulation of iron in the liver, heart, joints, and pancreas and subsequent cirrhosis, heart disease, arthritis, and diabetes. TfR2 can bind iron-loaded transferrin (Tf) in the bloodstream, and hepatocytes treated with Tf respond with a 2-fold increase in hepcidin expression through stimulation of the bone morphogenetic protein (BMP)-signaling pathway. Loss of functional TfR2 or its binding partner, the original HH protein, results in a loss of this transferrin-sensitivity. While much is known about the trafficking and regulation of TfR2, the mechanism of its transferrin-sensitivity through the BMP-signaling pathway is still not known.

  9. RFX6 Regulates Insulin Secretion by Modulating Ca2+ Homeostasis in Human β Cells

    Directory of Open Access Journals (Sweden)

    Vikash Chandra

    2014-12-01

    Full Text Available Development and function of pancreatic β cells involve the regulated activity of specific transcription factors. RFX6 is a transcription factor essential for mouse β cell differentiation that is mutated in monogenic forms of neonatal diabetes. However, the expression and functional roles of RFX6 in human β cells, especially in pathophysiological conditions, are poorly explored. We demonstrate the presence of RFX6 in adult human pancreatic endocrine cells. Using the recently developed human β cell line EndoC-βH2, we show that RFX6 regulates insulin gene transcription, insulin content, and secretion. Knockdown of RFX6 causes downregulation of Ca2+-channel genes resulting in the reduction in L-type Ca2+-channel activity that leads to suppression of depolarization-evoked insulin exocytosis. We also describe a previously unreported homozygous missense RFX6 mutation (p.V506G that is associated with neonatal diabetes, which lacks the capacity to activate the insulin promoter and to increase Ca2+-channel expression. Our data therefore provide insights for understanding certain forms of neonatal diabetes.

  10. FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase

    Science.gov (United States)

    Doan, Khanh V.; Kinyua, Ann W.; Yang, Dong Joo; Ko, Chang Mann; Moh, Sang Hyun; Shong, Ko Eun; Kim, Hail; Park, Sang-Kyu; Kim, Dong-Hoon; Kim, Inki; Paik, Ji-Hye; DePinho, Ronald A.; Yoon, Seul Gi; Kim, Il Yong; Seong, Je Kyung; Choi, Yun-Hee; Kim, Ki Woo

    2016-01-01

    Dopaminergic (DA) neurons are involved in the integration of neuronal and hormonal signals to regulate food consumption and energy balance. Forkhead transcriptional factor O1 (FoxO1) in the hypothalamus plays a crucial role in mediation of leptin and insulin function. However, the homoeostatic role of FoxO1 in DA system has not been investigated. Here we report that FoxO1 is highly expressed in DA neurons and mice lacking FoxO1 specifically in the DA neurons (FoxO1 KODAT) show markedly increased energy expenditure and interscapular brown adipose tissue (iBAT) thermogenesis accompanied by reduced fat mass and improved glucose/insulin homoeostasis. Moreover, FoxO1 KODAT mice exhibit an increased sucrose preference in concomitance with higher dopamine and norepinephrine levels. Finally, we found that FoxO1 directly targets and negatively regulates tyrosine hydroxylase (TH) expression, the rate-limiting enzyme of the catecholamine synthesis, delineating a mechanism for the KO phenotypes. Collectively, these results suggest that FoxO1 in DA neurons is an important transcriptional factor that directs the coordinated control of energy balance, thermogenesis and glucose homoeostasis. PMID:27681312

  11. Urokinase plasminogen activator receptor affects bone homeostasis by regulating osteoblast and osteoclast function

    DEFF Research Database (Denmark)

    Furlan, Federico; Galbiati, Clara; Jørgensen, Niklas R

    2007-01-01

    reorganization in mature osteoclasts. INTRODUCTION: Urokinase receptor (uPAR) is actively involved in the regulation of important cell functions, such as proliferation, adhesion, and migration. It was previously shown that the major players in bone remodeling, osteoblasts and osteoclasts, express u...... to mechanical tests. UPAR KO calvaria osteoblasts were characterized by proliferation assays, RT-PCR for important proteins secreted during differentiation, and immunoblot for activator protein 1 (AP-1) family members. In vitro osteoclast formation was tested with uPAR KO bone marrow monocytes in the presence...... a proliferative advantage with no difference in apoptosis, higher matrix mineralization, and earlier appearance of alkaline phosphatase (ALP). Surface RANKL expression at different stages of differentiation was not altered. AP-1 components, such as JunB and Fra-1, were upregulated in uPAR KO osteoblasts, along...

  12. The GATOR1 Complex Regulates Metabolic Homeostasis and the Response to Nutrient Stress in Drosophila melanogaster

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    Youheng Wei

    2016-12-01

    Full Text Available TORC1 regulates metabolism and growth in response to a large array of upstream inputs. The evolutionarily conserved trimeric GATOR1 complex inhibits TORC1 activity in response to amino acid limitation. In humans, the GATOR1 complex has been implicated in a wide array of pathologies including cancer and hereditary forms of epilepsy. However, the precise role of GATOR1 in animal physiology remains largely undefined. Here, we characterize null mutants of the GATOR1 components nprl2, nprl3, and iml1 in Drosophila melanogaster. We demonstrate that all three mutants have inappropriately high baseline levels of TORC1 activity and decreased adult viability. Consistent with increased TORC1 activity, GATOR1 mutants exhibit a cell autonomous increase in cell growth. Notably, escaper nprl2 and nprl3 mutant adults have a profound locomotion defect. In line with a nonautonomous role in the regulation of systemic metabolism, expressing the Nprl3 protein in the fat body, a nutrient storage organ, and hemocytes but not muscles and neurons rescues the motility of nprl3 mutants. Finally, we show that nprl2 and nprl3 mutants fail to activate autophagy in response to amino acid limitation and are extremely sensitive to both amino acid and complete starvation. Thus, in Drosophila, in addition to maintaining baseline levels of TORC1 activity, the GATOR1 complex has retained a critical role in the response to nutrient stress. In summary, the TORC1 inhibitor GATOR1 contributes to multiple aspects of the development and physiology of Drosophila.

  13. Glucocorticoids and microbiota regulate ontogeny of intestinal fucosyltransferase 2 requisite for gut homeostasis.

    Science.gov (United States)

    Nanthakumar, N Nanda; Meng, Di; Newburg, David S

    2013-10-01

    At weaning, the intestinal mucosa surface glycans change from predominantly sialylated to fucosylated. Intestinal adaptation from milk to solid food is regulated by intrinsic and extrinsic factors. The contribution by glucocorticoid, an intrinsic factor, and colonization by microbiota, an extrinsic factor, was measured as the induction of α1,2/3-fucosyltransferase and sucrase-isomaltase (SI) activity and gene expression in conventionally raised, germ-free, and bacteria-depleted mice. In conventionally raised mice, cortisone acetate (CA) precociously accelerated SI gene expression up to 3 weeks and fut2 to 4 weeks of age. In germ-free mice, CA treatment induces only SI expression but not fucosyltransferase. In post-weaning bacteria-deficient (germ-free and bacteria-depleted) mice, fut2 expression remains at low suckling levels. In microbiota deficient mice, intestinal fut2 (but not fut1, fut4 or fut7) was induced only by adult microbiota, but not immature microbiota or CA. Fut2 induction could also be restored by colonization by Bacteroides fragilis, but not by a B. fragilis mutant unable to utilize fucose. Restoration of fut2 expression (by either microbiota or B. fragilis) in bacteria-depleted mice is necessary for recovery from dextran sulfate sodium-induced mucosal injury. Thus, glucocorticoids and microbes regulate distinct aspects of gut ontogeny: CA precociously accelerates SI expression and, only in colonized mice, fut2 early expression. The adult microbiota is required for the fut2 induction responsible for the highly fucosylated adult gut phenotype and is necessary for recovery from intestinal injury. Fut2-dependent recovery from inflammation may explain the high incidence of inflammatory disease (Crohn's and necrotizing enterocolitis) in populations with mutant FUT2 polymorphic alleles.

  14. T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation. | Center for Cancer Research

    Science.gov (United States)

    The process by which self-reactive CD4+ T cells infiltrate the central nervous system (CNS) and trigger neuroinflammation is not fully understood. Lazarevic and colleagues show that NKp46+innate lymphoid cells dependent on the transcription factor T-bet are critical mediators in facilitating the entry of autoreactive CD4+ cells of the TH17 subset of helper T cells into the CNS, which leads to autoimmunity. Artwork by Lewis Long.

  15. Laccases involved in 1,8-dihydroxynaphthalene melanin biosynthesis in Aspergillus fumigatus are regulated by developmental factors and copper homeostasis.

    Science.gov (United States)

    Upadhyay, Srijana; Torres, Guadalupe; Lin, Xiaorong

    2013-12-01

    Aspergillus fumigatus produces heavily melanized infectious conidia. The conidial melanin is associated with fungal virulence and resistance to various environmental stresses. This 1,8-dihydroxynaphthalene (DHN) melanin is synthesized by enzymes encoded in a gene cluster in A. fumigatus, including two laccases, Abr1 and Abr2. Although this gene cluster is not conserved in all aspergilli, laccases are critical for melanization in all species examined. Here we show that the expression of A. fumigatus laccases Abr1/2 is upregulated upon hyphal competency and drastically increased during conidiation. The Abr1 protein is localized at the surface of stalks and conidiophores, but not in young hyphae, consistent with the gene expression pattern and its predicted role. The induction of Abr1/2 upon hyphal competency is controlled by BrlA, the master regulator of conidiophore development, and is responsive to the copper level in the medium. We identified a developmentally regulated putative copper transporter, CtpA, and found that CtpA is critical for conidial melanization under copper-limiting conditions. Accordingly, disruption of CtpA enhanced the induction of abr1 and abr2, a response similar to that induced by copper starvation. Furthermore, nonpigmented ctpAΔ conidia elicited much stronger immune responses from the infected invertebrate host Galleria mellonella than the pigmented ctpAΔ or wild-type conidia. Such enhancement in eliciting Galleria immune responses was independent of the ctpAΔ conidial viability, as previously observed for the DHN melanin mutants. Taken together, our findings indicate that both copper homeostasis and developmental regulators control melanin biosynthesis, which affects conidial surface properties that shape the interaction between this pathogen and its host.

  16. MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase-Mediated Gluconeogenesis.

    Science.gov (United States)

    Zhuo, Shu; Yang, Mengmei; Zhao, Yanan; Chen, Xiaofang; Zhang, Feifei; Li, Na; Yao, Pengle; Zhu, Tengfei; Mei, Hong; Wang, Shanshan; Li, Yu; Chen, Shiting; Le, Yingying

    2016-11-01

    MicroRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes, which is characterized by insulin resistance and hepatic glucose overproduction. We show that miRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through an adenovirus-mediated gain- and loss-of-function study, we found that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice and identified glycerol kinase (Gyk) as a direct target of miR-451. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, the glycerol gluconeogenesis axis, and the AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibited hepatic gluconeogenesis, alleviated hyperglycemia, and improved glucose tolerance. Further studies showed that miR-451 is upregulated by glucose and insulin in hepatocytes; the elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. This study provides the first evidence that miR-451 and Gyk regulate the AKT-FOXO1-PEPCK/G6Pase pathway and play critical roles in hepatic gluconeogenesis and glucose homeostasis and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes. © 2016 by the American Diabetes Association.

  17. Fatigue is a Brain-Derived Emotion that Regulates the Exercise Behavior to Ensure the Protection of Whole Body Homeostasis.

    Science.gov (United States)

    Noakes, Timothy David

    2012-01-01

    An influential book written by A. Mosso in the late nineteenth century proposed that fatigue that "at first sight might appear an imperfection of our body, is on the contrary one of its most marvelous perfections. The fatigue increasing more rapidly than the amount of work done saves us from the injury which lesser sensibility would involve for the organism" so that "muscular fatigue also is at bottom an exhaustion of the nervous system." It has taken more than a century to confirm Mosso's idea that both the brain and the muscles alter their function during exercise and that fatigue is predominantly an emotion, part of a complex regulation, the goal of which is to protect the body from harm. Mosso's ideas were supplanted in the English literature by those of A. V. Hill who believed that fatigue was the result of biochemical changes in the exercising limb muscles - "peripheral fatigue" - to which the central nervous system makes no contribution. The past decade has witnessed the growing realization that this brainless model cannot explain exercise performance. This article traces the evolution of our modern understanding of how the CNS regulates exercise specifically to insure that each exercise bout terminates whilst homeostasis is retained in all bodily systems. The brain uses the symptoms of fatigue as key regulators to insure that the exercise is completed before harm develops. These sensations of fatigue are unique to each individual and are illusionary since their generation is largely independent of the real biological state of the athlete at the time they develop. The model predicts that attempts to understand fatigue and to explain superior human athletic performance purely on the basis of the body's known physiological and metabolic responses to exercise must fail since subconscious and conscious mental decisions made by winners and losers, in both training and competition, are the ultimate determinants of both fatigue and athletic performance.

  18. Fatigue is a brain-derived emotion that regulates the exercise behavior to ensure the protection of whole body homeostasis

    Directory of Open Access Journals (Sweden)

    Timothy David Noakes

    2012-04-01

    Full Text Available An influential book written by A. Mosso in the late 19th century proposed that fatigue that at first sight might appear an imperfection of our body, is on the contrary one of its most marvellous perfections. The fatigue increasing more rapidly than the amount of work done saves us from the injury which lesser sensibility would involve for the organism so that muscular fatigue also is at bottom an exhaustion of the nervous system.It has taken more than a century to confirm Mosso’s idea that both the brain and the muscles alter their function during exercise and that fatigue is predominantly an emotion, part of a complex regulation, the goal of which is to protect the body from harm. Mosso’s ideas were supplanted in the English literature by those of A.V. Hill who believed that fatigue was the result of biochemical changes in the exercising limb muscles - peripheral fatigue - to which the central nervous system makes no contribution. The past decade has witnessed the growing realization that this brainless model cannot explain exercise performance. This article traces the evolution of our modern understanding of how the CNS regulates exercise specifically to insure that each exercise bout terminates whilst homeostasis is retained in all bodily systems. The brain uses the symptoms of fatigue as key regulators to insure that the exercise is completed before harm develops. These sensations of fatigue are unique to each individual and are illusionary since their generation is largely independent of the real biological state of the athlete at the time they develop. The model predicts that attempts to understand fatigue and to explain superior human athletic performance purely on the basis of the body’s known physiological and metabolic responses to exercise must fail since subconscious and conscious mental decisions made by winners and losers, in both training and competition, are the ultimate determinants of both fatigue and athletic performance.

  19. Chromatin Dynamics and the RNA Exosome Function in Concert to Regulate Transcriptional Homeostasis

    Directory of Open Access Journals (Sweden)

    Mayuri Rege

    2015-11-01

    Full Text Available The histone variant H2A.Z is a hallmark of nucleosomes flanking promoters of protein-coding genes and is often found in nucleosomes that carry lysine 56-acetylated histone H3 (H3-K56Ac, a mark that promotes replication-independent nucleosome turnover. Here, we find that H3-K56Ac promotes RNA polymerase II occupancy at many protein-coding and noncoding loci, yet neither H3-K56Ac nor H2A.Z has a significant impact on steady-state mRNA levels in yeast. Instead, broad effects of H3-K56Ac or H2A.Z on RNA levels are revealed only in the absence of the nuclear RNA exosome. H2A.Z is also necessary for the expression of divergent, promoter-proximal noncoding RNAs (ncRNAs in mouse embryonic stem cells. Finally, we show that H2A.Z functions with H3-K56Ac to facilitate formation of chromosome interaction domains (CIDs. Our study suggests that H2A.Z and H3-K56Ac work in concert with the RNA exosome to control mRNA and ncRNA expression, perhaps in part by regulating higher-order chromatin structures.

  20. The Mycobacterial Transcriptional Regulator whiB7 Gene Links Redox Homeostasis and Intrinsic Antibiotic Resistance*

    Science.gov (United States)

    Burian, Ján; Ramón-García, Santiago; Sweet, Gaye; Gómez-Velasco, Anaximandro; Av-Gay, Yossef; Thompson, Charles J.

    2012-01-01

    Intrinsic drug resistance in Mycobacterium tuberculosis limits therapeutic options for treating tuberculosis. The mycobacterial transcriptional regulator whiB7 contributes to intrinsic resistance by activating its own expression and many drug resistance genes in response to antibiotics. To investigate whiB7 activation, we constructed a GFP reporter to monitor its expression, and we used it to investigate the whiB7 promoter and to screen our custom library of almost 600 bioactive compounds, including the majority of clinical antibiotics. Results showed whiB7 was transcribed from a promoter that was conserved across mycobacteria and other actinomycetes, including an AT-rich sequence that was likely targeted by WhiB7. Expression was induced by compounds having diverse structures and targets, independent of the ability of whiB7 to mediate resistance, and was dependent on media composition. Pretreatment with whiB7 activators resulted in clinically relevant increases in intrinsic drug resistance. Antibiotic-induced transcription was synergistically increased by the reductant dithiothreitol, an effect mirrored by a whiB7-dependent shift to a highly reduced cytoplasm reflected by the ratio of reduced/oxidized mycothiol. These data provided evidence that intrinsic resistance resulting from whiB7 activation is linked to fundamental changes in cell metabolism. PMID:22069311

  1. The contribution of skin glycosaminoglycans to the regulation of sodium homeostasis in rats.

    Science.gov (United States)

    Sugár, D; Agócs, R; Tatár, E; Tóth, G; Horváth, P; Sulyok, E; Szabó, A J

    2017-08-07

    The glycosaminoglycan (GAG) molecules are a group of high molecular weight, negatively charged polysaccharides present abundantly in the mammalian organism. By their virtue of ion and water binding capacity, they may affect the redistribution of body fluids and ultimately the blood pressure. Data from the literature suggests that the mitogens Vascular Endothelial Growth Factor (VEGF)-A and VEGF-C are able to regulate the amount and charge density of GAGs and their detachment from the cell surface. Based on these findings we investigated the relationship between the level of dietary sodium intake, the expression levels of VEGF-A and VEGF-C, and the amount of the skin GAGs hyaluronic acid and chondroitin sulphate in an in vivo rat model. Significant correlation between dietary sodium intake, skin sodium levels and GAG content was found. We confirmed the GAG synthesizing role of VEGF-C but failed to prove that GAGs are degraded by VEGF-A. No significant difference in blood pressure was registered between the different dietary groups. A quotient calculated form the ion and water content of the skin tissue samples suggests that - in contrast to previous findings - the osmotically inactive ions and bound water fractions are proportional.

  2. Abscisic Acid Regulates Auxin Homeostasis in Rice Root Tips to Promote Root Hair Elongation

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    Tao Wang

    2017-06-01

    Full Text Available Abscisic acid (ABA plays an essential role in root hair elongation in plants, but the regulatory mechanism remains to be elucidated. In this study, we found that exogenous ABA can promote rice root hair elongation. Transgenic rice overexpressing SAPK10 (Stress/ABA-activated protein kinase 10 had longer root hairs; rice plants overexpressing OsABIL2 (OsABI-Like 2 had attenuated ABA signaling and shorter root hairs, suggesting that the effect of ABA on root hair elongation depends on the conserved PYR/PP2C/SnRK2 ABA signaling module. Treatment of the DR5-GUS and OsPIN-GUS lines with ABA and an auxin efflux inhibitor showed that ABA-induced root hair elongation depends on polar auxin transport. To examine the transcriptional response to ABA, we divided rice root tips into three regions: short root hair, long root hair and root tip zones; and conducted RNA-seq analysis with or without ABA treatment. Examination of genes involved in auxin transport, biosynthesis and metabolism indicated that ABA promotes auxin biosynthesis and polar auxin transport in the root tip, which may lead to auxin accumulation in the long root hair zone. Our findings shed light on how ABA regulates root hair elongation through crosstalk with auxin biosynthesis and transport to orchestrate plant development.

  3. TOR Complex 2-Ypk1 Signaling Maintains Sphingolipid Homeostasis by Sensing and Regulating ROS Accumulation

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    Brad J. Niles

    2014-02-01

    Full Text Available Reactive oxygen species (ROS are produced during normal metabolism and can function as signaling molecules. However, ROS at elevated levels can damage cells. Here, we identify the conserved target of rapamycin complex 2 (TORC2/Ypk1 signaling module as an important regulator of ROS in the model eukaryotic organism, S. cerevisiae. We show that TORC2/Ypk1 suppresses ROS produced both by mitochondria as well as by nonmitochondrial sources, including changes in acidification of the vacuole. Furthermore, we link vacuole-related ROS to sphingolipids, essential components of cellular membranes, whose synthesis is also controlled by TORC2/Ypk1 signaling. In total, our data reveal that TORC2/Ypk1 act within a homeostatic feedback loop to maintain sphingolipid levels and that ROS are a critical regulatory signal within this system. Thus, ROS sensing and signaling by TORC2/Ypk1 play a central physiological role in sphingolipid biosynthesis and in the maintenance of cell growth and viability.

  4. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions

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    Kentaro Kaneko

    2016-09-01

    Full Text Available The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment.

  5. Stem cells are differentially regulated during development, regeneration and homeostasis in flatworms.

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    De Mulder, Katrien; Pfister, Daniela; Kuales, Georg; Egger, Bernhard; Salvenmoser, Willi; Willems, Maxime; Steger, Jessica; Fauster, Katja; Micura, Ronald; Borgonie, Gaetan; Ladurner, Peter

    2009-10-01

    The flatworm stem cell system is exceptional within the animal kingdom, as totipotent stem cells (neoblasts) are the only dividing cells within the organism. In contrast to most organisms, piwi-like gene expression in flatworms is extended from germ cells to somatic stem cells. We describe the isolation and characterization of the piwi homologue macpiwi in the flatworm Macrostomum lignano. We use in situ hybridization, antibody staining and RNA interference to study macpiwi expression and function in adults, during postembryonic development, regeneration and upon starvation. We found novelties regarding piwi function and observed differences to current piwi functions in flatworms. First, macpiwi was essential for the maintenance of somatic stem cells in adult animals. A knock-down of macpiwi led to a complete elimination of stem cells and death of the animals. Second, the regulation of stem cells was different in adults and regenerates compared to postembryonic development. Third, sexual reproduction of M. lignano allowed to follow germline formation during postembryonic development, regeneration, and starvation. Fourth, piwi expression in hatchlings further supports an embryonic formation of the germline in M. lignano. Our findings address new questions in flatworm stem cell research and provide a basis for comparison with higher organisms.

  6. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions.

    Science.gov (United States)

    Kaneko, Kentaro; Xu, Pingwen; Cordonier, Elizabeth L; Chen, Siyu S; Ng, Amy; Xu, Yong; Morozov, Alexei; Fukuda, Makoto

    2016-09-13

    The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Nuclear and Membrane Actions of Estrogen Receptor Alpha: Contribution to the Regulation of Energy and Glucose Homeostasis.

    Science.gov (United States)

    Guillaume, Maeva; Montagner, Alexandra; Fontaine, Coralie; Lenfant, Françoise; Arnal, Jean-François; Gourdy, Pierre

    2017-01-01

    Estrogen receptor alpha (ERα) has been demonstrated to play a key role in reproduction but also to exert numerous functions in nonreproductive tissues. Accordingly, ERα is now recognized as a key regulator of energy homeostasis and glucose metabolism and mediates the protective effects of estrogens against obesity and type 2 diabetes. This chapter attempts to summarize our current understanding of the mechanisms of ERα activation and their involvement in the modulation of energy balance and glucose metabolism. We first focus on the experimental studies that constitute the basis of the understanding of ERα as a nuclear receptor and more specifically on the key roles played by its two activation functions (AFs). We depict the consequences of the selective inactivation of these AFs in mouse models, which further underline the prominent role of nuclear ERα in the prevention of obesity and diabetes, as on the reproductive tract and the vascular system. Besides these nuclear actions, a fraction of ERα is associated with the plasma membrane and activates nonnuclear signaling from this site. Such rapid effects, called membrane-initiated steroid signals (MISS), have been characterized in a variety of cell lines and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS as well as the generation of mice expressing an ERα protein impeded for membrane localization has just begun to unravel the physiological role of MISS in vivo and their contribution to ERα-mediated metabolic protection. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators.

  8. Neuronal Cholesterol Accumulation Induced by Cyp46a1 Down-Regulation in Mouse Hippocampus Disrupts Brain Lipid Homeostasis

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    Sophie Ayciriex

    2017-07-01

    Full Text Available Impairment in cholesterol metabolism is associated with many neurodegenerative disorders including Alzheimer's disease (AD. However, the lipid alterations underlying neurodegeneration and the connection between altered cholesterol levels and AD remains not fully understood. We recently showed that cholesterol accumulation in hippocampal neurons, induced by silencing Cyp46a1 gene expression, leads to neurodegeneration with a progressive neuronal loss associated with AD-like phenotype in wild-type mice. We used a targeted and non-targeted lipidomics approach by liquid chromatography coupled to high-resolution mass spectrometry to further characterize lipid modifications associated to neurodegeneration and cholesterol accumulation induced by CYP46A1 inhibition. Hippocampus lipidome of normal mice was profiled 4 weeks after cholesterol accumulation due to Cyp46a1 gene expression down-regulation at the onset of neurodegeneration. We showed that major membrane lipids, sphingolipids and specific enzymes involved in phosphatidylcholine and sphingolipid metabolism, were rapidly increased in the hippocampus of AAV-shCYP46A1 injected mice. This lipid accumulation was associated with alterations in the lysosomal cargoe, accumulation of phagolysosomes and impairment of endosome-lysosome trafficking. Altogether, we demonstrated that inhibition of cholesterol 24-hydroxylase, key enzyme of cholesterol metabolism leads to a complex dysregulation of lipid homeostasis. Our results contribute to dissect the potential role of lipids in severe neurodegenerative diseases like AD.

  9. A P-Loop NTPase Regulates Quiescent Center Cell Division and Distal Stem Cell Identity through the Regulation of ROS Homeostasis in Arabidopsis Root.

    Science.gov (United States)

    Yu, Qianqian; Tian, Huiyu; Yue, Kun; Liu, Jiajia; Zhang, Bing; Li, Xugang; Ding, Zhaojun

    2016-09-01

    Reactive oxygen species (ROS) are recognized as important regulators of cell division and differentiation. The Arabidopsis thaliana P-loop NTPase encoded by APP1 affects root stem cell niche identity through its control of local ROS homeostasis. The disruption of APP1 is accompanied by a reduction in ROS level, a rise in the rate of cell division in the quiescent center (QC) and the promotion of root distal stem cell (DSC) differentiation. Both the higher level of ROS induced in the app1 mutant by exposure to methyl viologen (MV), and treatment with hydrogen peroxide (H2O2) rescued the mutant phenotype, implying that both the increased rate of cell division in the QC and the enhancement in root DSC differentiation can be attributed to a low level of ROS. APP1 is expressed in the root apical meristem cell mitochondria, and its product is associated with ATP hydrolase activity. The key transcription factors, which are defining root distal stem niche, such as SCARECROW (SCR) and SHORT ROOT (SHR) are both significantly down-regulated at both the transcriptional and protein level in the app1 mutant, indicating that SHR and SCR are important downstream targets of APP1-regulated ROS signaling to control the identity of root QC and DSCs.

  10. Non-classical mechanisms of transcriptional regulation by the vitamin D receptor: insights into calcium homeostasis, immune system regulation and cancer chemoprevention.

    Science.gov (United States)

    Dimitrov, Vassil; Salehi-Tabar, Reyhaneh; An, Beum-Soo; White, John H

    2014-10-01

    Hormonal 1,25-dihydroxyvitamin D [1,25(OH)2D] signals through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor. Gene expression profiling studies have revealed that 1,25(OH)2D signaling through the VDR can lead to activation or repression of target gene transcription in roughly equal proportions. Classically, transcriptional regulation by the VDR, similar to other nuclear receptors, has been characterized by its capacity to recognize high affinity cognate vitamin D response elements (VDREs), located in the regulatory regions of target genes. Several biochemical studies revealed that the VDRE-bound receptor recruits a series of coregulatory proteins, leading to transactivation of adjacent target genes. However, genome-wide and other analyses of VDR binding have revealed that a subset of VDR binding sites does not contain VDREs, and that VDREs are not associated with transcriptionally repressed VDR target genes. Work over the last ∼20 years and in particular recent findings have revealed a diverse array of mechanisms by which VDR can form complexes with several other classes of transcriptional activators, leading to repression of gene transcription. Moreover, these efforts have led to several insights into the molecular basis for the physiological regulation of calcium homeostasis, immune system function and cancer chemoprevention by 1,25(OH)2D/VDR signaling. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Molecular and cellular regulation of water homeostasis in anuran amphibians by aquaporins.

    Science.gov (United States)

    Suzuki, Masakazu; Tanaka, Shigeyasu

    2009-07-01

    Aquaporins (AQPs) are water channel proteins important for transcellular water transport. Anuran AQP family consists of at least AQP0-AQP5, AQP7-AQP10, and two anuran-specific types, designated as AQPa1 and AQPa2. In Hyla japonica, AQP2 (AQP-h2K) and two forms of AQPa2 (AQP-h2 and AQP-h3) reside in the tight-junctioned epithelial cells of three major osmoregulatory organs, i.e. AQP-h2K in the kidney, AQP-h2 in the urinary bladder, and both AQP-h2 and AQP-h3 in the ventral pelvic skin. They show translocation from the cytoplasmic pool to the apical plasma membrane in response to arginine vasotocin (AVT), thereby regulating water transport across the apical membrane. Tissue distribution of AQPa2 in five anuran species, from aquatic to arboreal habitats, suggests that AQP-h2 is a urinary bladder-type AQP, while AQP-h3 is a ventral pelvic skin-type AQP. Further, AQP-h2K seems to be specific to the kidney. On the other hand, Hyla AQP3 (AQPh3BL)is located in the basolateral plasma membrane of the tight epithelial cells, irrespective of AVT stimulation. These findings suggest that anuran AVT-dependent osmoregulatory organs utilize AQP3 at the exit site of the transepithelial water transport, whereas at the entry site they basically adopt different AQPs as translocatable water channels: h2-like AQPa2 in the urinary bladder, h3-like AQPa2 in the pelvic skin, andAQP2 in the kidney. Anuran AQP3 also shows an extensive distribution over the integument, and is located along the basolateral plasma membrane of principal cells of the epidermis. It is possible that anuran AQP3might protect the epidermis against cutaneous water loss by supplying water and glycerol. In addition,immunohistochemical studies suggest that anuran AQP3 and AQP5 might be involved in the isoosmotic fluid secretion from the mucous glands and Xenopus small granular glands, possibly aiding maintenance of the moist skin, cutaneous gas exchange, and thermoregulation. Intriguingly, genomic and molecular

  12. A Novel Egr-1-Agrin Pathway and Potential Implications for Regulation of Synaptic Physiology and Homeostasis at the Neuromuscular Junction

    Directory of Open Access Journals (Sweden)

    Ryen MacDonald

    2017-08-01

    Full Text Available Synaptic transmission requires intricate coordination of the components involved in processing of incoming signals, formation and stabilization of synaptic machinery, neurotransmission and in all related signaling pathways. Changes to any of these components cause synaptic imbalance and disruption of neuronal circuitry. Extensive studies at the neuromuscular junction (NMJ have greatly aided in the current understanding of synapses and served to elucidate the underlying physiology as well as associated adaptive and homeostatic processes. The heparan sulfate proteoglycan agrin is a vital component of the NMJ, mediating synaptic formation and maintenance in both brain and muscle, but very little is known about direct control of its expression. Here, we investigated the relationship between agrin and transcription factor early growth response-1 (Egr-1, as Egr-1 regulates the expression of many genes involved in synaptic homeostasis and plasticity. Using chromatin immunoprecipitation (ChIP, cell culture with cell lines derived from brain and muscle, and animal models, we show that Egr-1 binds to the AGRN gene locus and suppresses its expression. When compared with wild type (WT, mice deficient in Egr-1 (Egr-1−/− display a marked increase in AGRN mRNA and agrin full-length and cleavage fragment protein levels, including the 22 kDa, C-terminal fragment in brain and muscle tissue homogenate. Because agrin is a crucial component of the NMJ, we explored possible physiological implications of the Egr-1-agrin relationship. In the diaphragm, Egr-1−/− mice display increased NMJ motor endplate density, individual area and area of innervation. In addition to increased density, soleus NMJs also display an increase in fragmented and faint endplates in Egr-1−/− vs. WT mice. Moreover, the soleus NMJ electrophysiology of Egr-1−/− mice revealed increased quantal content and motor testing showed decreased movement and limb muscle strength compared with

  13. NPY neuron-specific Y2 receptors regulate adipose tissue and trabecular bone but not cortical bone homeostasis in mice.

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    Yan-Chuan Shi

    Full Text Available BACKGROUND: Y2 receptor signalling is known to be important in neuropeptide Y (NPY-mediated effects on energy homeostasis and bone physiology. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPY-expressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear. METHODOLOGY/PRINCIPAL FINDINGS: We thus generated two conditional knockout mouse models, Y2(lox/lox and NPYCre/+;Y2(lox/lox, in which Y2 receptors can be selectively ablated either in the hypothalamus or specifically in hypothalamic NPY-producing neurons of adult mice. Specific deletion of hypothalamic Y2 receptors increases food intake and body weight compared to controls. Importantly, specific ablation of hypothalamic Y2 receptors on NPY-containing neurons results in a significantly greater adiposity in female but not male mice, accompanied by increased hepatic triglyceride levels, decreased expression of liver carnitine palmitoyltransferase (CPT1 and increased expression of muscle phosphorylated acetyl-CoA carboxylase (ACC. While food intake, body weight, femur length, bone mineral content, density and cortical bone volume and thickness are not significantly altered, trabecular bone volume and number were significantly increased by hypothalamic Y2 deletion on NPY-expressing neurons. Interestingly, in situ hybridisation reveals increased NPY and decreased proopiomelanocortin (POMC mRNA expression in the arcuate nucleus of mice with hypothalamus-specific deletion of Y2 receptors in NPY neurons, consistent with a negative feedback mechanism between NPY expression and Y2 receptors on NPY-ergic neurons. CONCLUSIONS/SIGNIFICANCE: Taken together these data demonstrate the anti-obesogenic role of Y2 receptors in the brain, notably on NPY-ergic neurons, possibly via inhibition of NPY neurons and concomitant stimulation of POMC-expressing neurons in the arcuate nucleus of

  14. A Novel Egr-1-Agrin Pathway and Potential Implications for Regulation of Synaptic Physiology and Homeostasis at the Neuromuscular Junction.

    Science.gov (United States)

    MacDonald, Ryen; Barbat-Artigas, Sebastien; Cho, Chulmin; Peng, Huashan; Shang, Jijun; Moustaine, Ayman; Carbonetto, Salvatore; Robitaille, Richard; Chalifour, Lorraine E; Paudel, Hemant

    2017-01-01

    Synaptic transmission requires intricate coordination of the components involved in processing of incoming signals, formation and stabilization of synaptic machinery, neurotransmission and in all related signaling pathways. Changes to any of these components cause synaptic imbalance and disruption of neuronal circuitry. Extensive studies at the neuromuscular junction (NMJ) have greatly aided in the current understanding of synapses and served to elucidate the underlying physiology as well as associated adaptive and homeostatic processes. The heparan sulfate proteoglycan agrin is a vital component of the NMJ, mediating synaptic formation and maintenance in both brain and muscle, but very little is known about direct control of its expression. Here, we investigated the relationship between agrin and transcription factor early growth response-1 (Egr-1), as Egr-1 regulates the expression of many genes involved in synaptic homeostasis and plasticity. Using chromatin immunoprecipitation (ChIP), cell culture with cell lines derived from brain and muscle, and animal models, we show that Egr-1 binds to the AGRN gene locus and suppresses its expression. When compared with wild type (WT), mice deficient in Egr-1 (Egr-1-/-) display a marked increase in AGRN mRNA and agrin full-length and cleavage fragment protein levels, including the 22 kDa, C-terminal fragment in brain and muscle tissue homogenate. Because agrin is a crucial component of the NMJ, we explored possible physiological implications of the Egr-1-agrin relationship. In the diaphragm, Egr-1-/- mice display increased NMJ motor endplate density, individual area and area of innervation. In addition to increased density, soleus NMJs also display an increase in fragmented and faint endplates in Egr-1-/- vs. WT mice. Moreover, the soleus NMJ electrophysiology of Egr-1-/- mice revealed increased quantal content and motor testing showed decreased movement and limb muscle strength compared with WT. This study provides

  15. CCR10 regulates balanced maintenance and function of resident regulatory and effector T cells to promote immune homeostasis in skin

    Science.gov (United States)

    Xia, Mingcan; Hu, Shaomin; Fu, Yaoyao; Jin, Wensen; Yi, Qiyi; Matsui, Yurika; Yang, Jie; McDowell, Mary Ann; Sarkar, Surojit; Kalia, Vandana; Xiong, Na

    2014-01-01

    Background CCR10 and CCL27 are the most skin-specific chemokine receptor/ligand pair implicated in skin allergy and inflammatory diseases including atopic dermatitis and psoriasis. This pair is thought to regulate migration and/or maintenance of skin T cells and suggested as therapeutic targets for treatment of skin diseases. However, the functional importance of CCR10/CCL27 in vivo remains elusive. Objective We sought to determine expression and function of CCR10 in different subsets of skin T cells under both homeostatic and inflammatory conditions to gain a mechanistic insight into potential roles of CCR10 during skin inflammation. Methods Using heterozygous and homozygous CCR10-knockout/EGFP-knockin mice, we assessed expression of CCR10 on regulatory and effector T cells of healthy and inflamed skin induced by chemicals, pathogens and auto-reactive T cells. In addition, we assessed the effect of CCR10-knockout on the maintenance and functions of different T cells and inflammatory status in the skin during different phases of the immune response. Results CCR10 expression is preferentially induced on memory-like skin-resident T cells and their progenitors for their maintenance in homeostatic skin but not expressed on most skin-infiltrating effector T cells during inflammation. In CCR10-knockout mice, the imbalanced presence and dysregulated function of resident regulatory and effector T cells result in over-reactive and prolonged innate and memory responses in the skin, leading to increased clearance of Leishmamia infection in the skin. Conclusion CCR10 is a critical regulator of skin immune homeostasis. PMID:24767879

  16. Overexpression of RING domain E3 ligase ZmXerico1 confers drought tolerance through regulation of ABA homeostasis.

    Science.gov (United States)

    Brugiere, Norbert; Zhang, Wenjing; Xu, John; Scolaro, Eric J; Lu, Cheng; Kahsay, Robel Y; Kise, Rie; Trecker, Libby; Williams, Robert W; Hakimi, Salim; Niu, Xiping; Lafitte, Renee; Habben, Jeffrey E

    2017-09-12

    Drought stress is one of the main environmental problems encountered by crop growers. Reduction in arable land area and reduced water availability make it paramount to identify and develop strategies to allow crops to be more resilient in water limiting environments. The plant hormone abscisic acid (ABA) plays an important role in the plants' response to drought stress through its control of stomatal aperture and water transpiration; and transgenic modulation of ABA levels therefore represents an attractive avenue to improve the drought tolerance of crops. Several steps in the ABA signaling pathway are controlled by ubiquitination involving RING domain containing proteins. We characterized the maize RING protein family and identified two novel RING-H2 genes called ZmXerico1 and ZmXerico2. Expression of ZmXerico genes is induced by drought stress and we show that overexpression of ZmXerico1 and ZmXerico2 in Arabidopsis and maize confers ABA hypersensitivity and improved water use efficiency which can lead to enhanced maize yield performance in a controlled drought stress environment. Overexpression of ZmXerico1 and ZmXerico2 in maize results in increased ABA levels and decreased levels of ABA degradation products diphaseic acid and phaseic acid. We show that ZmXerico1 is localized in the endoplasmic reticulum, where ABA 8'-hydroxylases have been shown to be localized, and that it functions as an E3 ubiquitin ligase. We demonstrate that ZmXerico1 plays a role in the control of ABA homeostasis through regulation of ABA 8'-hydroxylase protein stability, representing a novel control point in the regulation of the ABA pathway. {copyright, serif} 2017 American Society of Plant Biologists. All rights reserved.

  17. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice.

    Science.gov (United States)

    Qian, Su; Chen, Howard; Weingarth, Drew; Trumbauer, Myrna E; Novi, Dawn E; Guan, Xiaoming; Yu, Hong; Shen, Zhu; Feng, Yue; Frazier, Easter; Chen, Airu; Camacho, Ramon E; Shearman, Lauren P; Gopal-Truter, Shobhna; MacNeil, Douglas J; Van der Ploeg, Lex H T; Marsh, Donald J

    2002-07-01

    Agouti-related protein (AgRP), a neuropeptide abundantly expressed in the arcuate nucleus of the hypothalamus, potently stimulates feeding and body weight gain in rodents. AgRP is believed to exert its effects through the blockade of signaling by alpha-melanocyte-stimulating hormone at central nervous system (CNS) melanocortin-3 receptor (Mc3r) and Mc4r. We generated AgRP-deficient (Agrp(-/-)) mice to examine the physiological role of AgRP. Agrp(-/-) mice are viable and exhibit normal locomotor activity, growth rates, body composition, and food intake. Additionally, Agrp(-/-) mice display normal responses to starvation, diet-induced obesity, and the administration of exogenous leptin or neuropeptide Y (NPY). In situ hybridization failed to detect altered CNS expression levels for proopiomelanocortin, Mc3r, Mc4r, or NPY mRNAs in Agrp(-/-) mice. As AgRP and the orexigenic peptide NPY are coexpressed in neurons of the arcuate nucleus, we generated AgRP and NPY double-knockout (Agrp(-/-);Npy(-/-)) mice to determine whether NPY or AgRP plays a compensatory role in Agrp(-/-) or NPY-deficient (Npy(-/-)) mice, respectively. Similarly to mice deficient in either AgRP or NPY, Agrp(-/-);Npy(-/-) mice suffer no obvious feeding or body weight deficits and maintain a normal response to starvation. Our results demonstrate that neither AgRP nor NPY is a critically required orexigenic factor, suggesting that other pathways capable of regulating energy homeostasis can compensate for the loss of both AgRP and NPY.

  18. Crosstalk between nuclear factor I-C and transforming growth factor-β1 signaling regulates odontoblast differentiation and homeostasis.

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    Dong-Seol Lee

    Full Text Available Transforming growth factor-β1 (TGF-β1 signaling plays a key role in vertebrate development, homeostasis, and disease. Nuclear factor I-C (NFI-C has been implicated in TGF-β1 signaling, extracellular matrix gene transcription, and tooth root development. However, the functional relationship between NFI-C and TGF-β1 signaling remains uncharacterized. The purpose of this study was to identify the molecular interactions between NFI-C and TGF-β1 signaling in mouse odontoblasts. Real-time polymerase chain reaction and western analysis demonstrated that NFI-C expression levels were inversely proportional to levels of TGF-β1 signaling molecules during in vitro odontoblast differentiation. Western blot and immunofluorescence results showed that NFI-C was significantly degraded after TGF-β1 addition in odontoblasts, and the formation of the Smad3 complex was essential for NFI-C degradation. Additionally, ubiquitination assay results showed that Smurf1 and Smurf2 induced NFI-C degradation and polyubiquitination in a TGF-β1-dependent manner. Both kinase and in vitro binding assays revealed that the interaction between NFI-C and Smurf1/Smurf2 requires the activation of the mitogen-activated protein kinase pathway by TGF-β1. Moreover, degradation of NFI-C induced by TGF-β1 occurred generally in cell types other than odontoblasts in normal human breast epithelial cells. In contrast, NFI-C induced dephosphorylation of p-Smad2/3. These results show that crosstalk between NFI-C and TGF-β1 signaling regulates cell differentiation and homeostatic processes in odontoblasts, which might constitute a common cellular mechanism.

  19. ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia.

    Science.gov (United States)

    Buendia, Izaskun; Tenti, Giammarco; Michalska, Patrycja; Méndez-López, Iago; Luengo, Enrique; Satriani, Michele; Padín-Nogueira, Fernando; López, Manuela G; Ramos, M Teresa; García, Antonio G; Menéndez, J Carlos; León, Rafael

    2017-01-18

    During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na(+)/Ca(2+) exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca(2+) overload, such as toxicity induced by high K(+) in the SH-SY5Y cell line (60% protection at 30 μM) and veratridine in hippocampal slices (26% protection at 10 μM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 μM) and oxygen and glucose deprivation (76% protection at 10 μM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine.

  20. TRPV4 and AQP4 Channels Synergistically Regulate Cell Volume and Calcium Homeostasis in Retinal Müller Glia.

    Science.gov (United States)

    Jo, Andrew O; Ryskamp, Daniel A; Phuong, Tam T T; Verkman, Alan S; Yarishkin, Oleg; MacAulay, Nanna; Križaj, David

    2015-09-30

    that fine-tunes astroglial volume regulation by integrating osmosensing, calcium signaling, and water transport and, when overactivated, triggers pathological swelling. Significance statement: We characterize the physiological features of interactions between the astroglial swelling sensor transient receptor potential isoform 4 (TRPV4) and the aquaporin 4 (AQP4) water channel in retinal Müller cells. Our data reveal an elegant and complex set of mechanisms involving reciprocal interactions at the level of glial gene expression, calcium homeostasis, swelling, and volume regulation. Specifically, water influx through AQP4 drives calcium influx via TRPV4 in the glial end foot, which regulates expression of Aqp4 and Kir4.1 genes and facilitates the time course and amplitude of hypotonicity-induced swelling and regulatory volume decrease. We confirm the crucial facets of the signaling mechanism in heterologously expressing oocytes. These results identify the molecular mechanism that contributes to dynamic regulation of glial volume but also provide new insights into the pathophysiology of glial reactivity and edema formation. Copyright © 2015 the authors 0270-6474/15/3513526-13$15.00/0.

  1. Sleep homeostasis regulated by 5HT2b receptor in a small subset of neurons in the dorsal fan-shaped body of drosophila

    Science.gov (United States)

    Qian, Yongjun; Cao, Yue; Deng, Bowen; Yang, Guang; Li, Jiayun; Xu, Rui; zhang, Dandan

    2017-01-01

    Our understanding of the molecular mechanisms underlying sleep homeostasis is limited. We have taken a systematic approach to study neural signaling by the transmitter 5-hydroxytryptamine (5-HT) in drosophila. We have generated knockout and knockin lines for Trh, the 5-HT synthesizing enzyme and all five 5-HT receptors, making it possible for us to determine their expression patterns and to investigate their functional roles. Loss of the Trh, 5HT1a or 5HT2b gene decreased sleep time whereas loss of the Trh or 5HT2b gene diminished sleep rebound after sleep deprivation. 5HT2b expression in a small subset of, probably a single pair of, neurons in the dorsal fan-shaped body (dFB) is functionally essential: elimination of the 5HT2b gene from these neurons led to loss of sleep homeostasis. Genetic ablation of 5HT2b neurons in the dFB decreased sleep and impaired sleep homeostasis. Our results have shown that serotonergic signaling in specific neurons is required for the regulation of sleep homeostasis. PMID:28984573

  2. C/ebpα controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1.

    Science.gov (United States)

    Chen, Wei; Zhu, Guochun; Tang, Jun; Zhou, Hou-De; Li, Yi-Ping

    2017-10-30

    Osteoclast lineage commitment and differentiation have been studied extensively, although the mechanism by which transcription factor(s) control osteoclast terminal differentiation, activation and function remains unclear. CCAAT/enhancer-binding protein α (C/ebpα) has been reported to be a key regulator of osteoclast cell lineage commitment, yet C/ebpα's roles in osteoclast terminal differentiation, activation and function and bone homeostasis, under physiological or pathological conditions, have not been studied because newborn C/ebpα null mice die within several hours after birth. Furthermore, the function of C/ebpα in osteoclast terminal differentiation, activation and function are largely unknown. Herein, we generated and analyzed an osteoclast-specific C/ebpα conditional knockout (CKO) mouse model via Ctsk-Cre mice and found that C/ebpα-deficient mice exhibited a severe osteopetrosis phenotype due to impaired osteoclast terminal differentiation, activation and function, including mildly reduced osteoclast number, impaired osteoclast polarization, actin formation, and bone resorption, which demonstrated the novel function of C/ebpα in cell function and terminal differentiation. Interestingly, C/ebpα deficiency did not affect bone formation or monocyte/macrophage development. Our results further demonstrated that C/ebpα deficiency suppressed the expression of osteoclast functional genes, e.g. encoding Cathepsin K (Ctsk), Atp6i (Tcirg1) and osteoclast regulator genes, e.g. encoding c-fos (Fos), and nuclear factor of activated T-cells 1 (Nfatc1), while having no effect on Pu.1 (Spi1) expression. Promoter activity mapping and ChIP assay defined the critical cis-regulatory element (CCRE) in the promoter region of Nfatc1, and also showed that the CCREs were directly associated with C/ebpα, which enhanced the promoter's activity. The deficiency of C/ebpα in osteoclasts completely blocked ovariectomy-induced bone loss, indicating C/ebpα is a promising new

  3. The Role of Innate Lymphoid Cells in Immune-Mediated Liver Diseases

    Science.gov (United States)

    Liu, Meifang; Zhang, Cai

    2017-01-01

    Innate lymphoid cells (ILCs) are a recently identified group of innate immune cells lacking antigen-specific receptors that can mediate immune responses and regulate tissue homeostasis and inflammation. ILCs comprise group 1 ILCs, group 2 ILCs, and group 3 ILCs. These ILCs usually localize at mucosal surfaces and combat pathogens by the rapid release of certain cytokines. However, the uncontrolled activation of ILCs can also lead to damaging inflammation, especially in the gut, lung, and skin. Although the physiological and pathogenic roles of ILCs in liver diseases have been attracting increasing attention recently, there has been no systematic review regarding the roles of ILCs in immune-mediated liver diseases. Here, we review the relationships between the ILC subsets and their functions in immune-mediated liver diseases, and discuss their therapeutic potential based on current knowledge about the functional roles of these cells in liver diseases. PMID:28659927

  4. Transcriptome analysis by GeneTrail revealed regulation of functional categories in response to alterations of iron homeostasis in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Lenhof Hans-Peter

    2011-05-01

    Full Text Available Abstract Background High-throughput technologies have opened new avenues to study biological processes and pathways. The interpretation of the immense amount of data sets generated nowadays needs to be facilitated in order to enable biologists to identify complex gene networks and functional pathways. To cope with this task multiple computer-based programs have been developed. GeneTrail is a freely available online tool that screens comparative transcriptomic data for differentially regulated functional categories and biological pathways extracted from common data bases like KEGG, Gene Ontology (GO, TRANSPATH and TRANSFAC. Additionally, GeneTrail offers a feature that allows screening of individually defined biological categories that are relevant for the respective research topic. Results We have set up GeneTrail for the use of Arabidopsis thaliana. To test the functionality of this tool for plant analysis, we generated transcriptome data of root and leaf responses to Fe deficiency and the Arabidopsis metal homeostasis mutant nas4x-1. We performed Gene Set Enrichment Analysis (GSEA with eight meaningful pairwise comparisons of transcriptome data sets. We were able to uncover several functional pathways including metal homeostasis that were affected in our experimental situations. Representation of the differentially regulated functional categories in Venn diagrams uncovered regulatory networks at the level of whole functional pathways. Over-Representation Analysis (ORA of differentially regulated genes identified in pairwise comparisons revealed specific functional plant physiological categories as major targets upon Fe deficiency and in nas4x-1. Conclusion Here, we obtained supporting evidence, that the nas4x-1 mutant was defective in metal homeostasis. It was confirmed that nas4x-1 showed Fe deficiency in roots and signs of Fe deficiency and Fe sufficiency in leaves. Besides metal homeostasis, biotic stress, root carbohydrate, leaf

  5. Large scale comparative proteomics of a chloroplast Clp protease mutant reveals folding stress, altered protein homeostasis, and feedback regulation of metabolism.

    Science.gov (United States)

    Zybailov, Boris; Friso, Giulia; Kim, Jitae; Rudella, Andrea; Rodríguez, Verenice Ramírez; Asakura, Yukari; Sun, Qi; van Wijk, Klaas J

    2009-08-01

    The clpr2-1 mutant is delayed in development due to reduction of the chloroplast ClpPR protease complex. To understand the role of Clp proteases in plastid biogenesis and homeostasis, leaf proteomes of young seedlings of clpr2-1 and wild type were compared using large scale mass spectrometry-based quantification using an LTQ-Orbitrap and spectral counting with significance determined by G-tests. Virtually only chloroplast-localized proteins were significantly affected, indicating that the molecular phenotype was confined to the chloroplast. A comparative chloroplast stromal proteome analysis of fully developed plants was used to complement the data set. Chloroplast unfoldase ClpB3 was strongly up-regulated in both young and mature leaves, suggesting widespread and persistent protein folding stress. The importance of ClpB3 in the clp2-1 mutant was demonstrated by the observation that a CLPR2 and CLPB3 double mutant was seedling-lethal. The observed up-regulation of chloroplast chaperones and protein sorting components further illustrated destabilization of protein homeostasis. Delayed rRNA processing and up-regulation of a chloroplast DEAD box RNA helicase and polynucleotide phosphorylase, but no significant change in accumulation of ribosomal subunits, suggested a bottleneck in ribosome assembly or RNA metabolism. Strong up-regulation of a chloroplast translational regulator TypA/BipA GTPase suggested a specific response in plastid gene expression to the distorted homeostasis. The stromal proteases PreP1,2 were up-regulated, likely constituting compensation for reduced Clp protease activity and possibly shared substrates between the ClpP and PreP protease systems. The thylakoid photosynthetic apparatus was decreased in the seedlings, whereas several structural thylakoid-associated plastoglobular proteins were strongly up-regulated. Two thylakoid-associated reductases involved in isoprenoid and chlorophyll synthesis were up-regulated reflecting feedback from rate

  6. Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine

    DEFF Research Database (Denmark)

    Nguyen, Duc Ninh; Sangild, Per Torp; Østergaard, Mette Viberg

    2014-01-01

    A balance between pro- and anti-inflammatory signals from the milk and microbiota controls intestinal homeostasis just after birth, and an optimal balance is particularly important for preterm neonates that are sensitive to necrotizing enterocolis (NEC). We suggest that the intestinal cytokine IL-8...... plays an important role and hypothesize that transforming growth factor β2 (TGF-β2) acts in synergy with bacterial LPS to control IL-8 levels, thereby supporting intestinal homeostasis. Preterm pigs were fed colostrum (containing TGF-β2) or infant formula with or without antibiotics (COLOS, n = 27; ANTI...

  7. Insulin regulation of beta-cell function involves a feedback loop on SERCA gene expression, Ca(2+) homeostasis, and insulin expression and secretion.

    Science.gov (United States)

    Xu, G G; Gao, Z Y; Borge, P D; Jegier, P A; Young, R A; Wolf, B A

    2000-12-05

    The insulin receptor signaling pathway is present in beta-cells and is believed to be important in beta-cell function. We show here that insulin directly regulates beta-cell function in isolated rodent islets. Long-term insulin treatment caused a sustained increase in [Ca(2+)](i) and enhanced glucose-stimulated insulin secretion in rat islets, but failed to increase insulin content. Chronic activation of insulin receptor signaling by IRS-1 overexpression in the beta-cell inhibited gene expression of SERCA3, an endoplasmic reticulum Ca(2+)-ATPase. Insulin gene transcription was stimulated by insulin receptor signaling and insulin mimetic compound (L-783 281) in a glucose- and Grb2-dependent manner. Thus, beta-cell SERCA3 is a target for insulin regulation, which implies that beta-cell Ca(2+) homeostasis is regulated in an autocrine feedback loop by insulin. This study identifies a novel regulatory pathway of insulin secretion at the molecular level with two main components: (1) regulation of intracellular Ca(2+) homeostasis via SERCA3 and (2) regulation of insulin gene expression.

  8. Characterization and Quantification of Innate Lymphoid Cell Subsets in Human Lung.

    Directory of Open Access Journals (Sweden)

    Katrien C De Grove

    Full Text Available Innate lymphoid cells (ILC are a new family of innate immune cells that have emerged as important regulators of tissue homeostasis and inflammation. However, limited data are available concerning the relative abundance and characteristics of ILC in the human lung.The aim of this study was to characterize and enumerate the different ILC subsets in human lung by multi-color flow cytometry.Within the CD45+ Lin- CD127+ pulmonary ILC population, we identified group 1 (ILC1, group 2 (ILC2 and group 3 (ILC3 innate lymphoid cells using specific surface markers (i.e. IL12Rβ2, CRTH2 and CD117 respectively and key transcription factors (i.e. T-bet, GATA-3 and RORγT respectively. Based on the presence of NKp44, ILC3 were further subdivided in natural cytotoxicity receptor (NCR+ and NCR- ILC3. In addition, we demonstrated the production of signature cytokines IFN-γ, IL-5, IL-17A, IL-22 and GM-CSF in the pulmonary ILC population. Interestingly, we observed a tendency to a higher frequency of NCR- ILC3 in lungs of patients with chronic obstructive pulmonary disease (COPD compared with controls.We show that the three main ILC subsets are present in human lung. Importantly, the relative abundance of ILC subsets tended to change in COPD patients in comparison to control individuals.

  9. Innate lymphoid cells: the role in respiratory infections and lung tissue damage.

    Science.gov (United States)

    Głobińska, Anna; Kowalski, Marek L

    2017-10-01

    Innate lymphoid cells (ILCs) represent a diverse family of cells of the innate immune system, which play an important role in regulation of tissue homeostasis, immunity and inflammation. Emerging evidence has highlighted the importance of ILCs in both protective immunity to respiratory infections and their pathological roles in the lungs. Therefore, the aim of this review is to summarize the current knowledge, interpret and integrate it into broader perspective, enabling greater insight into the role of ILCs in respiratory diseases. Areas covered: In this review we highlighted the role of ILCs in the lungs, citing the most recent studies in this area. PubMed searches (2004- July 2017) were conducted using the term 'innate lymphoid cells respiratory viral infections' in combination with other relevant terms including various respiratory viruses. Expert commentary: Since studies of ILCs have opened new areas of investigation, understanding the role of ILCs in respiratory infections may help to clarify the mechanisms underlying viral-induced exacerbations of lung diseases, providing the basis for novel therapeutic strategies. Potential therapeutic targets have already been identified. So far, the most promising strategy is cytokine-targeting, although further clinical trials are needed to verify its effectiveness.

  10. Regulation of lipid and glucose homeostasis by mango tree leaf extract is mediated by AMPK and PI3K/AKT signaling pathways.

    Science.gov (United States)

    Zhang, Yi; Liu, Xuefeng; Han, Lifeng; Gao, Xiumei; Liu, Erwei; Wang, Tao

    2013-12-01

    Ethanolic extract of Mangifera indica (mango) dose-dependently decreased serum glucose and triglyceride in KK-A(y) mice. Our in vitro and in vivo investigations revealed that the effect of mango leave extract (ME) on glucose and lipid homeostasis is mediated, at least in part, through the PI3K/AKT and AMPK signaling pathway. ME up-regulated the expression of PI3K, AKT and GYS genes by 2.0-fold, 3.2-fold, and 2.7-fold, respectively, leading to a decrease in glucose level. On the other hand, ME up-regulated AMPK and altered lipid metabolism. ME also down-regulated ACC (2.8-fold), HSL (1.6-fold), FAS (1.8-fold) and PPAR-γ (4.0-fold). Finally, we determined that active metabolites of benzophenone C-glucosides, Iriflophenone 3-C-β-glucoside and Foliamangiferoside A from ME, may play a dominant role in this integrated regulation of sugar and lipid homeostasis. Copyright © 2013. Published by Elsevier Ltd.

  11. Context dependent development of lymphoid organ mesenchymal subsets fromBP3-Gp38+ PDGFRβ+/α+CD34+ vascular adventitial precursors

    DEFF Research Database (Denmark)

    Sitnik, Katarzyna Maria; Wendland, Kerstin; Weishaupt, Holger

    Lymphoid associated mesenchymal stromal cells are believed to play essential roles in immune and organ homeostasis however our knowledge regarding the functional heterogenity and ontogeny of these cells remains limited....

  12. Epithelial Control of Gut-Associated Lymphoid Tissue Formation through p38α-Dependent Restraint of NF-κB Signaling.

    Science.gov (United States)

    Caballero-Franco, Celia; Guma, Monica; Choo, Min-Kyung; Sano, Yasuyo; Enzler, Thomas; Karin, Michael; Mizoguchi, Atsushi; Park, Jin Mo

    2016-03-01

    The protein kinase p38α mediates cellular responses to environmental and endogenous cues that direct tissue homeostasis and immune responses. Studies of mice lacking p38α in several different cell types have demonstrated that p38α signaling is essential to maintaining the proliferation-differentiation balance in developing and steady-state tissues. The mechanisms underlying these roles involve cell-autonomous control of signaling and gene expression by p38α. In this study, we show that p38α regulates gut-associated lymphoid tissue (GALT) formation in a noncell-autonomous manner. From an investigation of mice with intestinal epithelial cell-specific deletion of the p38α gene, we find that p38α serves to limit NF-κB signaling and thereby attenuate GALT-promoting chemokine expression in the intestinal epithelium. Loss of this regulation results in GALT hyperplasia and, in some animals, mucosa-associated B cell lymphoma. These anomalies occur independently of luminal microbial stimuli and are most likely driven by direct epithelial-lymphoid interactions. Our study illustrates a novel p38α-dependent mechanism preventing excessive generation of epithelial-derived signals that drive lymphoid tissue overgrowth and malignancy. Copyright © 2016 by The American Association of Immunologists, Inc.

  13. Cellular magnesium homeostasis.

    Science.gov (United States)

    Romani, Andrea M P

    2011-08-01

    Magnesium, the second most abundant cellular cation after potassium, is essential to regulate numerous cellular functions and enzymes, including ion channels, metabolic cycles, and signaling pathways, as attested by more than 1000 entries in the literature. Despite significant recent progress, however, our understanding of how cells regulate Mg(2+) homeostasis and transport still remains incomplete. For example, the occurrence of major fluxes of Mg(2+) in either direction across the plasma membrane of mammalian cells following metabolic or hormonal stimuli has been extensively documented. Yet, the mechanisms ultimately responsible for magnesium extrusion across the cell membrane have not been cloned. Even less is known about the regulation in cellular organelles. The present review is aimed at providing the reader with a comprehensive and up-to-date understanding of the mechanisms enacted by eukaryotic cells to regulate cellular Mg(2+) homeostasis and how these mechanisms are altered under specific pathological conditions. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Pimenta, Erica M. [Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States); Barnes, Betsy J., E-mail: barnesbe@njms.rutgers.edu [Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States)

    2014-04-23

    Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin{sup ®}) and rituximab (Rituxan{sup ®})) and the first approved cancer vaccine, Provenge{sup ®} (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

  15. Role of Tertiary Lymphoid Structures (TLS in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Directory of Open Access Journals (Sweden)

    Erica M. Pimenta

    2014-04-01

    Full Text Available Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin® and rituximab (Rituxan® and the first approved cancer vaccine, Provenge® (sipuleucel-T, investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS within the tumor microenvironment may be used to enhance immunotherapy response.

  16. Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

    Directory of Open Access Journals (Sweden)

    Jennifer A. Felsted

    2017-12-01

    Full Text Available Summary: The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1 neurons of the ventromedial hypothalamus (VMH. These effects are body weight independent and involve regulation of SF1+ neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate α2δ-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease. : Felsted et al. show a required role of the calcium channel subunit and thrombospondin receptor α2δ-1 in regulating glucose and lipid homeostasis in the ventromedial hypothalamus (VMH. These effects are caused by regulation of SF1+ neuronal activity in the VMH through non-canonical mechanisms and concomitant influences on sympathetic output. Keywords: diabetes, VMH, hypothalamus, glucose, norepinephrine, serotonin, excitability, lipid, SF1

  17. Regulation of polar auxin transport in grapevine fruitlets (Vitis vinifera L.) and the proposed role of auxin homeostasis during fruit abscission.

    Science.gov (United States)

    Kühn, Nathalie; Serrano, Alejandra; Abello, Carlos; Arce, Aníbal; Espinoza, Carmen; Gouthu, Satyanarayana; Deluc, Laurent; Arce-Johnson, Patricio

    2016-10-28

    Indole-3-acetic acid (IAA), the most abundant auxin, is a growth promoter hormone involved in several developmental processes. Auxin homeostasis is very important to its function and this is achieved through the regulation of IAA biosynthesis, conjugation, degradation and transport. In grapevine, IAA plays an essential role during initial stages of berry development, since it delays fruitlet abscission by reducing the ethylene sensitivity in the abscission zone. For this reason, Continuous polar IAA transport to the pedicel is required. This kind of transport is controlled by IAA, which regulates its own movement by modifying the expression and localization of PIN-FORMED (PIN) auxin efflux facilitators that localize asymmetrically within the cell. On the other hand, the hormone gibberellin (GA) also activates the polar auxin transport by increasing PIN stability. In Vitis vinifera, fruitlet abscission occurs during the first two to three weeks after flowering. During this time, IAA and GA are present, however the role of these hormones in the control of polar auxin transport is unknown. In this work, the use of radiolabeled IAA showed that auxin is basipetally transported during grapevine fruitlet abscission. This observation was further supported by immunolocalization of putative VvPIN proteins that display a basipetal distribution in pericarp cells. Polar auxin transport and transcripts of four putative VvPIN genes decreased in conjunction with increased abscission, and the inhibition of polar auxin transport resulted in fruit drop. GA3 and IAA treatments reduced polar auxin transport, but only GA3 treatment decreased VvPIN transcript abundance. When GA biosynthesis was blocked, IAA was capable to increase polar auxin transport, suggesting that its effect depends on GA content. Finally, we observed significant changes in the content of several IAA-related compounds during the abscission period. These results provide evidence that auxin homeostasis plays a central

  18. Brief report: Enrichment of activated group 3 innate lymphoid cells in psoriatic arthritis synovial fluid

    NARCIS (Netherlands)

    Leijten, Emmerik F A; van Kempen, Tessa S.; Boes, Marianne; Michels-van Amelsfort, Jocea M R; Hijnen, Dirkjan; Hartgring, Sarita A Y; van Roon, Joel A G; Wenink, Mark H.; Radstake, Timothy R D J

    2015-01-01

    OBJECTIVE: Innate lymphoid cells (ILCs) are a recently discovered group of cells that are essential to epithelial homeostasis and are implicated in psoriasis pathogenesis, yet they have never been reported in psoriatic arthritis (PsA). METHODS: ILC classes and subsets were characterized in the

  19. Prions and lymphoid organs

    Science.gov (United States)

    O’Connor, Tracy; Aguzzi, Adriano

    2013-01-01

    Prion colonization of secondary lymphoid organs (SLOs) is a critical step preceding neuroinvasion in prion pathogenesis. Follicular dendritic cells (FDCs), which depend on both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin β receptor (LTβR) signaling for maintenance, are thought to be the primary sites of prion accumulation in SLOs. However, prion titers in RML-infected TNFR1−/− lymph nodes and rates of neuroinvasion in TNFR1−/− mice remain high despite the absence of mature FDCs. Recently, we discovered that TNFR1-independent prion accumulation in lymph nodes relies on LTβR signaling. Loss of LTβR signaling in TNFR1−/− lymph nodes coincided with the de-differentiation of high endothelial venules (HEVs)—the primary sites of lymphocyte entry into lymph nodes. These findings suggest that HEVs are the sites through which prions initially invade lymph nodes from the bloodstream. Identification of HEVs as entry portals for prions clarifies a number of previous observations concerning peripheral prion pathogenesis. However, a number of questions still remain: What is the mechanism by which prions are taken up by HEVs? Which cells are responsible for delivering prions to lymph nodes? Are HEVs the main entry site for prions into lymph nodes or do alternative routes also exist? These questions and others are considered in this article. PMID:23357827

  20. Surgical control of obesity and diabetes: the role of intestinal vs. gastric mechanisms in the regulation of body weight and glucose homeostasis.

    Science.gov (United States)

    Patel, Rajesh T; Shukla, Alpana P; Ahn, Soo Min; Moreira, Marlus; Rubino, Francesco

    2014-01-01

    To elucidate the specific role of gastric vs. intestinal manipulations in the regulation of body weight and glucose homeostasis. The effects of intestinal bypass alone (duodenal-jejunal bypass -DJB) and gastric resection alone (SG) in Zucker Diabetic Fatty (ZDF) rats were compared. Additional animals underwent a combination procedure (SG + DJB). Outcome measures included changes in weight, food intake (FI), oral glucose tolerance (GT) and gut hormones. DJB did not substantially affect weight and FI, whereas SG significantly reduced weight gain and food consumption. DJB rats showed weight-independent improvement in GT, which improved less after SG. Furthermore, SG significantly suppressed plasma ghrelin and increased insulin, glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide and peptide YY response to oral glucose whereas DJB had no effects on postprandial levels of these hormones. DJB restored postprandial glucagon suppression in diabetic rats whereas SG did not affect glucagon response. The combination procedure (SG + DJB) induced greater weight loss and better GT than SG alone without reducing food intake further. These findings reveal a dominant role of the stomach in the regulation of body weight and incretin response to oral glucose whereas intestinal bypass primarily affects glucose homeostasis by a weight-, insulin- and incretin-independent mechanism. Copyright © 2013 The Obesity Society.

  1. Isolation and characterization of endophytic plant growth-promoting (PGPB) or stress homeostasis-regulating (PSHB) bacteria associated to the halophyte Prosopis strombulifera.

    Science.gov (United States)

    Sgroy, Verónica; Cassán, Fabricio; Masciarelli, Oscar; Del Papa, María Florencia; Lagares, Antonio; Luna, Virginia

    2009-11-01

    This study was designed to isolate and characterize endophytic bacteria from halophyte Prosopis strombulifera grown under extreme salinity and to evaluate in vitro the bacterial mechanisms related to plant growth promotion or stress homeostasis regulation. Isolates obtained from P. strombulifera were compared genotypically by BOX-polymerase chain reaction, grouped according to similarity, and identified by amplification and partial sequences of 16S DNAr. Isolates were grown until exponential growth phase to evaluate the atmospheric nitrogen fixation, phosphate solubilization, siderophores, and phytohormones, such as indole-3-acetic acid, zeatin, gibberellic acid and abscisic acid production, as well as antifungal, protease, and 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity. A total of 29 endophytic strains were grouped into seven according to similarity. All bacteria were able to grow and to produce some phytohormone in chemically defined medium with or without addition of a nitrogen source. Only one was able to produce siderophores, and none of them solubilized phosphate. ACC deaminase activity was positive for six strains. Antifungal and protease activity were confirmed for two of them. In this work, we discuss the possible implications of these bacterial mechanisms on the plant growth promotion or homeostasis regulation in natural conditions.

  2. Type-2 innate lymphoid cells in asthma and allergy.

    Science.gov (United States)

    McKenzie, Andrew N J

    2014-12-01

    Type-2 innate lymphoid cells (ILC2) belong to an expanding family of innate lymphocytes that provide a potent source of immune effector cytokines at the initiation of immune responses. ILC2 arise, under the control of the transcription factors RORα and GATA3, from lymphoid progenitors in the bone marrow, to secrete type-2 cytokines including IL-5 and IL-13. Using experimental models, ILC2 have been implicated in allergic diseases, such as asthma and atopic dermatitis, but also in metabolic homeostasis. Furthermore, recent reports have indicated that ILC2 not only play roles at the initiation of type-2 immunity but can also contribute to chronic pathology, such as fibrosis, and can impact on the priming of the adaptive T-cell response. The identification of ILC2 in patients with allergic dermatitis and allergic rhinitis indicates that these cells may represent new therapeutic targets.

  3. Development, differentiation and diversity of innate lymphoid cells

    Science.gov (United States)

    Diefenbach, Andreas; Colonna, Marco; Koyasu, Shigeo

    2014-01-01

    Recent years have witnessed the discovery of an unprecedented complexity in innate lymphocyte lineages, now collectively referred to as innate lymphoid cells (ILC). ILC are preferentially located at barrier surfaces and are important for protection against pathogens and for the maintenance of organ homeostasis. Inappropriate activation of ILC has been linked to the pathogenesis of inflammatory and autoimmune disorders. Recent evidence suggests that ILC can be grouped into two separate lineages, cytotoxic ILC represented by conventional natural killer (cNK) cells and cytokine-producing helper-like ILC (i.e., ILC1, ILC2, ILC3). We will focus here on current work in humans and mice that has identified core transcriptional circuitry required for the commitment of lymphoid progenitors to the ILC lineage. The striking similarities in transcriptional control of ILC and T cell lineages reveal important insights into the evolution of transcriptional programs required to protect multicellular organisms against infections and to fortify barrier surfaces. PMID:25238093

  4. Beyond NK Cells: The Expanding Universe of Innate Lymphoid Cells

    Science.gov (United States)

    Cella, Marina; Miller, Hannah; Song, Christina

    2014-01-01

    For a long time, natural killer (NK) cells were thought to be the only innate immune lymphoid population capable of responding to invading pathogens under the influence of changing environmental cues. In the last few years, an increasing amount of evidence has shown that a number of different innate lymphoid cell (ILC) populations found at mucosal sites rapidly respond to locally produced cytokines in order to establish or maintain homeostasis. These ILC populations closely mirror the phenotype of adaptive T helper subsets in their repertoire of secreted soluble factors. Early in the immune response, ILCs are responsible for setting the stage to mount an adaptive T cell response that is appropriate for the incoming insult. Here, we review the diversity of ILC subsets and discuss similarities and differences between ILCs and NK cells in function and key transcriptional factors required for their development. PMID:24982658

  5. Novel roles of folic acid as redox regulator: Modulation of reactive oxygen species sinker protein expression and maintenance of mitochondrial redox homeostasis on hepatocellular carcinoma.

    Science.gov (United States)

    Lai, Kun-Goung; Chen, Chi-Fen; Ho, Chun-Te; Liu, Jun-Jen; Liu, Tsan-Zon; Chern, Chi-Liang

    2017-06-01

    We provide herein several lines of evidence to substantiate that folic acid (or folate) is a micronutrient capable of functioning as a novel redox regulator on hepatocellular carcinoma. First, we uncovered that folate deficiency could profoundly downregulate two prominent anti-apoptotic effectors including survivin and glucose-regulated protein-78. Silencing of either survivin or glucose-regulated protein-78 via small interfering RNA interfering technique established that both effectors could serve as reactive oxygen species sinker proteins. Second, folate deficiency-triggered oxidative-nitrosative stress could strongly induce endoplasmic reticulum stress that in turn could provoke cellular glutathione depletion through the modulation of the following two crucial events: (1) folate deficiency could strongly inhibit Bcl-2 expression leading to severe suppression of the mitochondrial glutathione pool and (2) folate deficiency could also profoundly inhibit two key enzymes that governing cellular glutathione redox regulation including γ-glutamylcysteinyl synthetase heavy chain, a catalytic enzyme for glutathione biosynthesis, and mitochondrial isocitrate dehydrogenase 2, an enzyme responsible for providing nicotinamide adenine dinucleotide phosphate necessary for regenerating oxidized glutathione disulfide back to glutathione via mitochondrial glutathione reductase. Collectively, we add to the literature new data to strengthen the notion that folate is an essential micronutrient that confers a novel role to combat reactive oxygen species insults and thus serves as a redox regulator via upregulating reactive oxygen species sinker proteins and averting mitochondrial glutathione depletion through proper maintenance of redox homeostasis via positively regulating glutathione biosynthesis, glutathione transporting system, and mitochondrial glutathione recycling process.

  6. Preferential intracellular pH regulation represents a general pattern of pH homeostasis during acid-base disturbances in the armoured catfish, Pterygoplichthys pardalis.

    Science.gov (United States)

    Harter, T S; Shartau, R B; Baker, D W; Jackson, D C; Val, A L; Brauner, C J

    2014-08-01

    Preferential intracellular pH (pHi) regulation, where pHi is tightly regulated in the face of a blood acidosis, has been observed in a few species of fish, but only during elevated blood PCO2. To determine whether preferential pHi regulation may represent a general pattern for acid-base regulation during other pH disturbances we challenged the armoured catfish, Pterygoplichthys pardalis, with anoxia and exhaustive exercise, to induce a metabolic acidosis, and bicarbonate injections to induce a metabolic alkalosis. Fish were terminally sampled 2-3 h following the respective treatments and extracellular blood pH, pHi of red blood cells (RBC), brain, heart, liver and white muscle, and plasma lactate and total CO2 were measured. All treatments resulted in significant changes in extracellular pH and RBC pHi that likely cover a large portion of the pH tolerance limits of this species (pH 7.15-7.86). In all tissues other than RBC, pHi remained tightly regulated and did not differ significantly from control values, with the exception of a decrease in white muscle pHi after anoxia and an increase in liver pHi following a metabolic alkalosis. Thus preferential pHi regulation appears to be a general pattern for acid-base homeostasis in the armoured catfish and may be a common response in Amazonian fishes.

  7. Plasma membrane Ca2+-ATPase isoforms composition regulates cellular pH homeostasis in differentiating PC12 cells in a manner dependent on cytosolic Ca2+ elevations

    DEFF Research Database (Denmark)

    Boczek, Tomasz; Lisek, Malwina; Ferenc, Bozena

    2014-01-01

    cellular acidification during KCl-stimulated Ca2+ influx. Because SERCA and NCX modulated cellular pH response in neglectable manner, and all conditions used to inhibit PMCA prevented KCl-induced pH drop, we considered PMCA2 and PMCA3 as mainly responsible for transport of protons to intracellular milieu......+-driven opening of mitochondrial permeability transition pore as putative underlying mechanism. The findings presented here demonstrate a crucial role of PMCA2 and PMCA3 in regulation of cellular pH and indicate PMCA membrane composition important for preservation of electrochemical gradient......Plasma membrane Ca2+-ATPase (PMCA) by extruding Ca2+ outside the cell, actively participates in the regulation of intracellular Ca2+ concentration. Acting as Ca2+/H+ counter-transporter, PMCA transports large quantities of protons which may affect organellar pH homeostasis. PMCA exists in four...

  8. DR2539 is a novel DtxR-like regulator of Mn/Fe ion homeostasis and antioxidant enzyme in Deinococcus radiodurans

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Huan [Key Laboratory for Nuclear-Agricultural Sciences of Chinese Ministry of Agriculture and Zhejiang Province, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou 310029 (China); Zhejiang Institute of Microbiology, Zhejiang Province, Hangzhou 310012 (China); Wu, Rongrong [Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009 (China); Xu, Guangzhi [Key Laboratory for Nuclear-Agricultural Sciences of Chinese Ministry of Agriculture and Zhejiang Province, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou 310029 (China); Fang, Xu; Qiu, Xiaoli; Guo, Hongyin [Zhejiang Institute of Microbiology, Zhejiang Province, Hangzhou 310012 (China); Tian, Bing, E-mail: tianbing@zju.edu.cn [Key Laboratory for Nuclear-Agricultural Sciences of Chinese Ministry of Agriculture and Zhejiang Province, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou 310029 (China); Hua, Yuejin, E-mail: yjhua@zju.edu.cn [Key Laboratory for Nuclear-Agricultural Sciences of Chinese Ministry of Agriculture and Zhejiang Province, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou 310029 (China)

    2010-05-28

    Transcriptional regulators of the diphtheria toxin repressor (DtxR) family control the expression of genes involved in the uptake of iron and manganese, which is not only necessitous nutrients but also was suggested to be essential for intracellular redox cycling of microorganisms. We identified a unique DtxR homologue (DR2539) with special characteristics from Deinococcus radiodurans, which is known for its extreme resistance to radiation and oxidants. The dr2539 mutant showed higher resistance to hydrogen peroxide than the wild-type strain R1. Intracellular catalase activity assay and semiquantitative PCR analysis demonstrated that this DtxR is a negative regulator of catalase (katE). Furthermore, quantitative real-time PCR, global transcription profile and inductively coupled plasma-mass spectrometry analysis showed that the DtxR is involved in the regulation of antioxidant system by maintaining the intracellular Mn/Fe ion homeostasis of D. radiodurans. However, unlike the other DtxR homologues, the DtxR of D. radiodurans acts as a negative regulator of a Mn transporter gene (dr2283) and as a positive regulator of Fe-dependent transporter genes (dr1219, drb0125) in D. radiodurans.

  9. Hormonal regulation of energy-protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes.

    Science.gov (United States)

    Suneja, Manish; Murry, Daryl J; Stokes, John B; Lim, Victoria S

    2011-01-01

    To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with

  10. Effects of 24-epibrassinolide on plant growth, osmotic regulation and ion homeostasis of salt-stressed canola.

    Science.gov (United States)

    Liu, J; Gao, H; Wang, X; Zheng, Q; Wang, C; Wang, X; Wang, Q

    2014-03-01

    This study evaluated effects of foliar spraying 24-epibrassinoide (24-EBL) on the growth of salt-stressed canola. Seedlings at the four-leaf stage were treated with 150 mM NaCl and different concentrations of 24-EBL (10(-6), 10(-8), 10(-10), 10(-12) M) for 15 days. A concentration of 10(-10) M 24-EBL was chosen as optimal and used in a subsequent experiment on plant biomass and leaf water potential parameters. The results showed that 24-EBL mainly promoted shoot growth of salt-stressed plants and also ameliorated leaf water status. Foliar spraying of salt-stressed canola with 24-EBL increased osmotic adjustment ability in all organs, especially in younger leaves and roots. This was mainly due to an increase of free amino acid content in upper leaves, soluble sugars in middle leaves, organic acids and proline in lower leaves, all of these compounds in roots, as well as essential inorganic ions. Na(+) and Cl(-) sharply increased in different organs under salt stress, and 24-EBL reduced their accumulation. 24-EBL improved the uptake of K(+), Ca(2+), Mg(2+) and NO3(-) in roots, which were mainly transported to upper leaves, while NO3(-) was mainly transported to middle leaves. Thus, 24-EBL improvements in ion homeostasis of K(+)/Na(+), Ca(2+)/Na(+), Mg(2+)/Na(+) and NO3(-)/Cl(-), especially in younger leaves and roots, could be explained. As most important parts, younger leaves and roots were the main organs protected by 24-EBL via improvement in osmotic adjustment ability and ion homeostasis. Further, physiological status of growth of salt-stressed canola was ameliorated after 24-EBL treatment. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

  11. Skin CCR10+ CD8+ T cells support resident Treg cells through the B7.2/receptor axis to regulate local immune homeostasis and response

    Science.gov (United States)

    Fu, Yaoyao; Yang, Jie; Xiong, Na

    2016-01-01

    Resident T cells in barrier tissues are important in protecting against foreign agents but could also contribute to inflammatory diseases if dysregulated. How T cell homeostasis is maintained in barrier tissues is still poorly understood. Herein we report that resident CD8+ T cells directly support maintenance of regulatory T (Treg) cells in the skin to promote immune homeostasis. Impaired establishment of resident CD8+ T cells due to knockout of the skin-homing chemokine receptor CCR10 resulted in altered balance of resident Treg and CD4+ effector T (Teff) cells in the skin and over-reactive inflammatory responses to cutaneous stimulations. Furthermore, B7.2 expressed on skin CD8+ T cells is involved in supporting survival of Treg cells, likely through interaction with its receptor CTLA-4, which is highly expressed on skin Treg cells. Our findings provide novel insight into T cell homeostatic regulation in the skin and may help understand pathobiology of tissue inflammatory diseases. PMID:27183612

  12. Transcriptome Sequencing Identifies SPL7-Regulated Copper Acquisition Genes FRO4/FRO5 and the Copper Dependence of Iron Homeostasis in Arabidopsis[C][W

    Science.gov (United States)

    Bernal, María; Casero, David; Singh, Vasantika; Wilson, Grandon T.; Grande, Arne; Yang, Huijun; Dodani, Sheel C.; Pellegrini, Matteo; Huijser, Peter; Connolly, Erin L.; Merchant, Sabeeha S.; Krämer, Ute

    2012-01-01

    The transition metal copper (Cu) is essential for all living organisms but is toxic when present in excess. To identify Cu deficiency responses comprehensively, we conducted genome-wide sequencing-based transcript profiling of Arabidopsis thaliana wild-type plants and of a mutant defective in the gene encoding SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7), which acts as a transcriptional regulator of Cu deficiency responses. In response to Cu deficiency, FERRIC REDUCTASE OXIDASE5 (FRO5) and FRO4 transcript levels increased strongly, in an SPL7-dependent manner. Biochemical assays and confocal imaging of a Cu-specific fluorophore showed that high-affinity root Cu uptake requires prior FRO5/FRO4-dependent Cu(II)-specific reduction to Cu(I) and SPL7 function. Plant iron (Fe) deficiency markers were activated in Cu-deficient media, in which reduced growth of the spl7 mutant was partially rescued by Fe supplementation. Cultivation in Cu-deficient media caused a defect in root-to-shoot Fe translocation, which was exacerbated in spl7 and associated with a lack of ferroxidase activity. This is consistent with a possible role for a multicopper oxidase in Arabidopsis Fe homeostasis, as previously described in yeast, humans, and green algae. These insights into root Cu uptake and the interaction between Cu and Fe homeostasis will advance plant nutrition, crop breeding, and biogeochemical research. PMID:22374396

  13. Group 3 Innate Lymphoid Cells: Communications Hubs of the Intestinal Immune System

    Directory of Open Access Journals (Sweden)

    David R. Withers

    2017-10-01

    Full Text Available The maintenance of mammalian health requires the generation of appropriate immune responses against a broad range of environmental and microbial challenges, which are continually encountered at barrier tissue sites including the skin, lung, and gastrointestinal tract. Dysregulated barrier immune responses result in inflammation, both locally and systemically in peripheral organs. Group 3 innate lymphoid cells (ILC3 are constitutively present at barrier sites and appear to be highly specialized in their ability to sense a range of environmental and host-derived signals. Under homeostatic conditions, ILC3 respond to local cues to maintain tissue homeostasis and restrict inflammatory responses. In contrast, perturbations in the tissue microenvironment resulting from disease, infection, or tissue damage can drive dysregulated pro-inflammatory ILC3 responses and contribute to immunopathology. The tone of the ILC3 response is dictated by a balance of “exogenous” signals, such as dietary metabolites and commensal microbes, and “endogenous” host-derived signals from stromal cells, immune cells, and the nervous system. ILC3 must therefore have the capacity to simultaneously integrate a wide array of complex and dynamic inputs in order to regulate barrier function and tissue health. In this review, we discuss the concept of ILC3 as a “communications hub” in the intestinal tract and associated lymphoid tissues and address the variety of signals, derived from multiple biological systems, which are interpreted by ILC3 to modulate the release of downstream effector molecules and regulate cell–cell crosstalk. Successful integration of environmental cues by ILC3 and downstream propagation to the broader immune system is required to maintain a tolerogenic and anti-inflammatory tone and reinforce barrier function, whereas dysregulation of ILC3 responses can contribute to the onset or progression of clinically relevant chronic inflammatory diseases.

  14. Group 3 Innate Lymphoid Cells: Communications Hubs of the Intestinal Immune System.

    Science.gov (United States)

    Withers, David R; Hepworth, Matthew R

    2017-01-01

    The maintenance of mammalian health requires the generation of appropriate immune responses against a broad range of environmental and microbial challenges, which are continually encountered at barrier tissue sites including the skin, lung, and gastrointestinal tract. Dysregulated barrier immune responses result in inflammation, both locally and systemically in peripheral organs. Group 3 innate lymphoid cells (ILC3) are constitutively present at barrier sites and appear to be highly specialized in their ability to sense a range of environmental and host-derived signals. Under homeostatic conditions, ILC3 respond to local cues to maintain tissue homeostasis and restrict inflammatory responses. In contrast, perturbations in the tissue microenvironment resulting from disease, infection, or tissue damage can drive dysregulated pro-inflammatory ILC3 responses and contribute to immunopathology. The tone of the ILC3 response is dictated by a balance of "exogenous" signals, such as dietary metabolites and commensal microbes, and "endogenous" host-derived signals from stromal cells, immune cells, and the nervous system. ILC3 must therefore have the capacity to simultaneously integrate a wide array of complex and dynamic inputs in order to regulate barrier function and tissue health. In this review, we discuss the concept of ILC3 as a "communications hub" in the intestinal tract and associated lymphoid tissues and address the variety of signals, derived from multiple biological systems, which are interpreted by ILC3 to modulate the release of downstream effector molecules and regulate cell-cell crosstalk. Successful integration of environmental cues by ILC3 and downstream propagation to the broader immune system is required to maintain a tolerogenic and anti-inflammatory tone and reinforce barrier function, whereas dysregulation of ILC3 responses can contribute to the onset or progression of clinically relevant chronic inflammatory diseases.

  15. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues

    Energy Technology Data Exchange (ETDEWEB)

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China); Chou, Guixin; Wang, Zhengtao [Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Kong, Lingyi [Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009 (China); Dai, Yue, E-mail: yuedaicpu@hotmail.com [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China); Xia, Yufeng, E-mail: yfxiacpu@126.com [Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009 (China)

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic–pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3{sup +} cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR. - Highlights: • Norisoboldine, administered orally, markedly attenuates the clinical signs of CIA. • Norisoboldine regulates the balance of Th17/Treg cells in the intestinal lymph node. • Norisoboldine induces the migration of Treg cells from the gut to joint.

  16. MicroRNA-125b expands hematopoietic stem cells and enriches for the lymphoid-balanced and lymphoid-biased subsets

    Science.gov (United States)

    Ooi, A. G. Lisa; Sahoo, Debashis; Adorno, Maddalena; Wang, Yulei; Weissman, Irving L.; Park, Christopher Y.

    2010-01-01

    MicroRNAs profoundly impact hematopoietic cells by regulating progenitor cell-fate decisions, as well as mature immune effector function. However to date, microRNAs that regulate hematopoietic stem cell (HSC) function have been less well characterized. Here we show that microRNA-125b (miR-125b) is highly expressed in HSCs and its expression decreases in committed progenitors. Overexpression of miR-125b in mouse HSC enhances their function, demonstrated through serial transplantation of highly purified HSC, and enriches for the previously described Slamf1loCD34− lymphoid-balanced and the Slamf1negCD34− lymphoid-biased cell subsets within the multipotent HSC (CD34-KLS) fraction. Mature peripheral blood cells derived from the miR-125b–overexpressing HSC are skewed toward the lymphoid lineage. Consistent with this observation, miR-125b overexpression significantly increases the number of early B-progenitor cells within the spleen and induces the expansion and enrichment of the lymphoid-balanced and lymphoid-biased HSC subset via an antiapoptotic mechanism, reducing the mRNA expression levels of two proapoptotic targets, Bmf and KLF13. The antiapoptotic effect of miR-125b is more pronounced in the lymphoid-biased HSC subset because of their intrinsic higher baseline levels of apoptosis. These effects of miR-125b are associated with the development of lymphoproliferative disease, marked by expansion of CD8+ T lymphocytes. Taken together, these data reveal that miR-125b regulates HSC survival and can promote lymphoid-fate decisions at the level of the HSC by preferentially expanding lymphoid-balanced and lymphoid-biased HSC. PMID:21118986

  17. Role of N-Arachidonoyl-Serotonin (AA-5-HT in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation

    Directory of Open Access Journals (Sweden)

    Eric Murillo-Rodríguez

    2017-05-01

    Full Text Available The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA and 2-arachidonoylglycerol (2-AG], receptors (CB1 and CB2, enzymes such as [fatty acid amide hydrolase (FAHH and monoacylglycerol lipase (MAGL], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep–wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1, N-arachidonoyl-serotonin (AA-5-HT in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p. injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W and increased slow wave sleep (SWS as well as rapid eye movement sleep (REMS. Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA, norepinephrine (NE, epinephrine (EP, serotonin (5-HT whereas the levels of adenosine (AD were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol (CBD or modafinil (MOD during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD. The

  18. Role of N-Arachidonoyl-Serotonin (AA-5-HT) in Sleep-Wake Cycle Architecture, Sleep Homeostasis, and Neurotransmitters Regulation

    Science.gov (United States)

    Murillo-Rodríguez, Eric; Di Marzo, Vincenzo; Machado, Sergio; Rocha, Nuno B.; Veras, André B.; Neto, Geraldo A. M.; Budde, Henning; Arias-Carrión, Oscar; Arankowsky-Sandoval, Gloria

    2017-01-01

    The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB1 and CB2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep–wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD). The

  19. Innate lymphoid cells and the skin

    OpenAIRE

    Salimi, Maryam; Ogg, Graham

    2014-01-01

    Innate lymphoid cells are an emerging family of effector cells that contribute to lymphoid organogenesis, metabolism, tissue remodelling and protection against infections. They maintain homeostatic immunity at barrier surfaces such as lung, skin and gut (Nature 464:1367?1371, 2010, Nat Rev Immunol 13: 145?149, 2013). Several human and mouse studies suggest a role for innate lymphoid cells in inflammatory skin conditions including atopic eczema and psoriasis. Here we review the innate lymphoid...

  20. Dietary Glycation Products Regulate Immune Homeostasis: Early Glycation Products Promote Prostate Cancer Cell Proliferation through Modulating Macrophages.

    Science.gov (United States)

    Chen, Yingjia; Filipov, Nikolay M; Guo, Tai L

    2017-10-30

    Well-controlled glycation (generally limited to the early stages) has been proposed as a strategy to improve the physiochemical properties of dietary proteins, but the functional studies of glycation products were mostly on advanced glycation end-products (AGEs) rather than early glycation products (EGPs). Since cytokines are important modulators of various biological processes, this study aimed to determine whether EGPs and AGEs affected immune homeostasis differentially and did so through modulating macrophage-derived factors. Two systems (glycine-glucose and whey protein isolate (WPI)-glucose) were established to generate glycation products. They were applied to human macrophages (PMA-differentiated U937 cells), and cell viability and cytokine production were measured. Furthermore, EGPs, AGEs and their conditioned medium (CM) from macrophages were applied to human prostate cancer (PCa) cells with different etiology (LNCaP and PC-3) and murine PCa cells (TRAMP-C2) to determine their direct and indirect effects on PCa cell proliferation. EGPs enhanced the production of anti-inflammatory and immunosuppressive cytokines, and this enhancement was associated with increased PCa cell proliferation. In contrast, AGEs inhibited macrophages to secret cytokines, but increased PCa cell proliferation directly. Our data suggest that EGPs promote the prostate tumor proliferation indirectly through modulating macrophages, while AGEs have a direct effect. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  1. Transcription factors Asg1p and Hal9p regulate pH homeostasis in Candida glabrata

    Directory of Open Access Journals (Sweden)

    Jing eWu

    2015-08-01

    Full Text Available Candida glabrata is an important microorganism used in commercial fermentation to produce pyruvate, but very little is known about its mechanisms for surviving acid stress in culture. In this study, it was shown that transcription factors Asg1p and Hal9p play essential roles in C. glabrata in the tolerance of acid stress, as the deletion of CgASG1 or CgHAL9 resulted in the inability to survive in an acidic environment. Cgasg1 and Cghal9 mutant strains are unable to maintain pH homeostasis, as evidenced by a decrease in intracellular pH and an increase in reactive oxygen species production, which results in metabolic disorders. The results showed that intracellular acidification was partly due to the diminished activity of the plasma membrane proton pump, CgPma1p. In addition, transcriptome sequencing revealed that Cgasg1 and Cghal9 mutant strains displayed a variety of changes in gene expression under acidic conditions, including genes in the MAPK signaling pathway, plasma membrane or cell wall organization, trehalose accumulation, and the RIM101 signaling pathway. Lastly, quantitative reverse-transcribed PCR and cellular localization showed that CgAsg1p and CgHal9p played independent roles in response to acid stress.

  2. The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor.

    Science.gov (United States)

    Seehus, Corey R; Aliahmad, Parinaz; de la Torre, Brian; Iliev, Iliyan D; Spurka, Lindsay; Funari, Vincent A; Kaye, Jonathan

    2015-06-01

    Diverse innate lymphoid cell (ILC) subtypes have been defined on the basis of effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways that lead to ILC-lineage specification remain poorly characterized. Here we found that the transcriptional regulator TOX was required for the in vivo differentiation of common lymphoid progenitors into ILC lineage-restricted cells. In vitro modeling demonstrated that TOX deficiency resulted in early defects in the survival or proliferation of progenitor cells, as well as ILC differentiation at a later stage. In addition, comparative transcriptome analysis of bone marrow progenitors revealed that TOX-deficient cells failed to upregulate many genes of the ILC program, including genes that are targets of Notch, which indicated that TOX is a key determinant of early specification to the ILC lineage.

  3. A Thyroid Hormone Challenge in Hypothyroid Rats Identifies T3 Regulated Genes in the Hypothalamus and in Models with Altered Energy Balance and Glucose Homeostasis

    Science.gov (United States)

    Herwig, Annika; Campbell, Gill; Mayer, Claus-Dieter; Boelen, Anita; Anderson, Richard A.; Ross, Alexander W.; Mercer, Julian G.

    2014-01-01

    Background: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms. Methods: Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA. Results: Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (±1.3-fold change, phypothalamus, a key area of the brain involved in homeostasis and neuroendocrine functions. These include genes hitherto not known to be regulated by thyroid status. PMID:25087834

  4. Interplay of nutrients and microbial metabolites in intestinal immune homeostasis: distinct and common mechanisms of immune regulation in the small bowel and colon.

    Science.gov (United States)

    Perrigoue, Jacqueline; Das, Anuk; Mora, J Rodrigo

    2014-01-01

    The intestinal mucosa is the largest body surface exposed to the environment. While there are common features when comparing immune responses along the intestinal mucosa, the small bowel and colon exhibit striking differences in their mechanisms driving immune regulation. The vitamin A (VA) metabolite all-trans retinoic acid (RA) signaling via RA nuclear receptors plays a key role in immune homeostasis in the small bowel, and recent work indicates that RA is required for establishing immune tolerance to dietary antigens in the upper intestinal tract by inducing α4β7(+)CCR9(+) gut-tropic TREG. In contrast, microbiota-specific TREG in the colon do not appear to require RA, but can be regulated by short-chain fatty acids (SCFA), microbial metabolites that signal through the G protein-coupled receptor GPR43. Moreover, TREG do not need CCR9 to home to the colon, but utilize another G protein-coupled receptor, GPR15, which is upregulated by SCFA. Thus, the mechanisms governing intestinal tolerance to dietary antigens in the upper digestive tract differ from those controlling tolerance to the microbiota in the colon, with RA and SCFA playing key complementary roles in their respective compartments. In addition to VA and SCFA, recent studies have highlighted the roles of other dietary and microbial metabolites that influence immune cell homeostasis across the small and large bowel including dietary ligands for aryl hydrocarbon receptor and microbiota-modified bile acids. Understanding the complex and dynamic interplay between dietary metabolites and commensal microbiota within the intestinal microenvironment could therefore inform novel strategies for the treatment of food allergies and inflammatory bowel diseases. 2014 Nestec Ltd., Vevey/S. Karger AG, Basel.

  5. A novel role of microglial NADPH oxidase in mediating extra-synaptic function of norepinephrine in regulating brain immune homeostasis.

    Science.gov (United States)

    Jiang, Lulu; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Shi-Jun; Oyarzabal, Esteban; Wilson, Belinda; Sanders, Virginia; Xie, Keqin; Wang, Qingshan; Hong, Jau-Shyong

    2015-06-01

    Although the peripheral anti-inflammatory effect of norepinephrine (NE) is well documented, the mechanism by which this neurotransmitter functions as an anti-inflammatory/neuroprotective agent in the central nervous system (CNS) is unclear. This article aimed to determine the anti-inflammatory/neuroprotective effects and underlying mechanisms of NE in inflammation-based dopaminergic neurotoxicity models. In mice, NE-depleting toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected at 6 months of lipopolysaccharide (LPS)-induced neuroinflammation. It was found that NE depletion enhanced LPS-induced dopaminergic neuron loss in the substantia nigra. This piece of in vivo data prompted us to conduct a series of studies in an effort to elucidate the mechanism as to how NE affects dopamine neuron survival by using primary midbrain neuron/glia cultures. Results showed that submicromolar concentrations of NE dose-dependently protected dopaminergic neurons from LPS-induced neurotoxicity by inhibiting microglia activation and subsequent release of pro-inflammatory factors. However, NE-elicited neuroprotection was not totally abolished in cultures from β2-adrenergic receptor (β2-AR)-deficient mice, suggesting that novel pathways other than β2-AR are involved. To this end, It was found that submicromolar NE dose-dependently inhibited NADPH oxidase (NOX2)-generated superoxide, which contributes to the anti-inflammatory and neuroprotective effects of NE. This novel mechanism was indeed adrenergic receptors independent since both (+) and (-) optic isomers of NE displayed the same potency. We further demonstrated that NE inhibited LPS-induced NOX2 activation by blocking the translocation of its cytosolic subunit to plasma membranes. In summary, we revealed a potential physiological role of NE in maintaining brain immune homeostasis and protecting neurons via a novel mechanism. © 2015 Wiley Periodicals, Inc.

  6. Normal and pathological V(D)J recombination: contribution to the understanding of human lymphoid malignancies.

    Science.gov (United States)

    Dadi, Saïda; Le Noir, Sandrine; Asnafi, Vahid; Beldjord, Kheïra; Macintyre, Elizabeth A

    2009-01-01

    The majority of haematological cancers involve the lymphoid system. They include acute lymphoblastic leukemias (ALL), which are arrested at variable stages of development and present with blood and bone marrow involvement and chronic leukemias, lymphomas and myelomas, which present with infiltration of a large variety of hematopoietic and non hematopoietic tissues by mature lymphoid cells which express a surface antigen receptor. The majority involve the B-cell lineage and the vast majority have undergone clonal rearrangement of their Ig and/or TCR rearrangements. Analysis of Ig/TCR genomic V(D)J repertoires by PCR based lymphoid clonality analysis within a diagnostic setting allows distinction of clonal from reactive lymphoproliferative disorders, clonal tracking for evidence of tumor dissemination and follow-up, identification of a lymphoid origin in undiagnosed tumors and evaluation of clonal evolution. Ig/TCR VDJ errors are also at the origin of recombinase mediated deregulated expression of a variety of proto-oncogenes in ALL, whereas in lymphoma it is increasingly clear that IgH containing translocations result from abnormalities other than VDJ errors (somatic hypermutation and/or isotype switching). In addition to this mechanistic contribution to lymphoid oncogenesis, it is possible that failure to successfully complete expression of an appropriate Ig or TCR may lead to maturation arrest in a lymphoid precursor, which may in itself contribute to altered tissue homeostasis, particularly if the arrest occurs at a stage of cellular expansion.

  7. Functional Differences between Human NKp44(-) and NKp44(+) RORC(+) Innate Lymphoid Cells.

    Science.gov (United States)

    Hoorweg, Kerim; Peters, Charlotte P; Cornelissen, Ferry; Aparicio-Domingo, Patricia; Papazian, Natalie; Kazemier, Geert; Mjösberg, Jenny M; Spits, Hergen; Cupedo, Tom

    2012-01-01

    Human RORC(+) lymphoid tissue inducer cells are part of a rapidly expanding family of innate lymphoid cells (ILC) that participate in innate and adaptive immune responses as well as in lymphoid tissue (re) modeling. The assessment of a potential role for innate lymphocyte-derived cytokines in human homeostasis and disease is hampered by a poor characterization of RORC(+) innate cell subsets and a lack of knowledge on the distribution of these cells in adults. Here we show that functionally distinct subsets of human RORC(+) innate lymphoid cells are enriched for secretion of IL-17a or IL-22. Both subsets have an activated phenotype and can be distinguished based on the presence or absence of the natural cytotoxicity receptor NKp44. NKp44(+) IL-22 producing cells are present in tonsils while NKp44(-) IL-17a producing cells are present in fetal developing lymph nodes. Development of human intestinal NKp44(+) ILC is a programmed event that is independent of bacterial colonization and these cells colonize the fetal intestine during the first trimester. In the adult intestine, NKp44(+) ILC are the main ILC subset producing IL-22. NKp44(-) ILC remain present throughout adulthood in peripheral non-inflamed lymph nodes as resting, non-cytokine producing cells. However, upon stimulation lymph node ILC can swiftly initiate cytokine transcription suggesting that secondary human lymphoid organs may function as a reservoir for innate lymphoid cells capable of participating in inflammatory responses.

  8. 1-alpha,25-Dihydroxyvitamin D3 up-regulates the expression of 2 types of human intestinal alkaline phosphatase alternative splicing variants in Caco-2 cells and may be an important regulator of their expression in gut homeostasis.

    Science.gov (United States)

    Noda, Seiko; Yamada, Asako; Nakaoka, Kanae; Goseki-Sone, Masae

    2017-10-01

    Vitamin D insufficiency is associated with a greater risk of osteoporosis and also influences skeletal muscle functions, differentiation, and development. The principal function of vitamin D in calcium homeostasis is to increase the absorption of calcium from the intestine, and the level of alkaline phosphatase (ALP) activity, a differentiation marker for intestinal epithelial cells, is regulated by vitamin D. Intestinal-type ALP is expressed at a high concentration in the brush border membrane of intestinal epithelial cells, and is known to be affected by several kinds of nutrients. Recent reviews have highlighted the importance of intestinal-type ALP in gut homeostasis. Intestinal-type ALP controls bacterial endotoxin-induced inflammation by dephosphorylating lipopolysaccharide and is a gut mucosal defense factor. In this study, we investigated the influence of vitamin D on the expression of 2 types of alternative mRNA variants encoding the human alkaline phosphatase, intestinal (ALPI) gene in human Caco-2 cells as an in vitro model of the small intestinal epithelium. After treatment with 1-alpha,25-dihydroxyvitamin D3, the biologically active form of vitamin D3, there were significant increases in the ALP activities of Caco-2 cells. Inhibitor and thermal inactivation experiments showed that the increased ALP had properties of intestinal-type ALP. Reverse transcription-polymerase chain reaction analysis revealed that expression of the 2 types of alternative mRNA variants from the ALPI gene was markedly enhanced by vitamin D in Caco-2 cells. In conclusion, these findings agree with the hypothesis: vitamin D up-regulated the expression of 2 types of human intestinal alkaline phosphatase alternative splicing variants in Caco-2 cells; vitamin D may be an important regulator of ALPI gene expression in gut homeostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Transcription factor WRKY46 modulates the development of Arabidopsis lateral roots in osmotic/salt stress conditions via regulation of ABA signaling and auxin homeostasis.

    Science.gov (United States)

    Ding, Zhong Jie; Yan, Jing Ying; Li, Chun Xiao; Li, Gui Xin; Wu, Yun Rong; Zheng, Shao Jian

    2015-10-01

    The development of lateral roots (LR) is known to be severely inhibited by salt or osmotic stress. However, the molecular mechanisms underlying LR development in osmotic/salt stress conditions are poorly understood. Here we show that the gene encoding the WRKY transcription factor WRKY46 (WRKY46) is expressed throughout lateral root primordia (LRP) during early LR development and that expression is subsequently restricted to the stele of the mature LR. In osmotic/salt stress conditions, lack of WRKY46 (in loss-of-function wrky46 mutants) significantly reduces, while overexpression of WRKY46 enhances, LR development. We also show that exogenous auxin largely restores LR development in wrky46 mutants, and that the auxin transport inhibitor 2,3,5-triiodobenzoic acid (TIBA) inhibits LR development in both wild-type (WT; Col-0) and in a line overexpressing WRKY46 (OV46). Subsequent analysis of abscisic acid (ABA)-related mutants indicated that WRKY46 expression is down-regulated by ABA signaling, and up-regulated by an ABA-independent signal induced by osmotic/salt stress. Next, we show that expression of the DR5:GUS auxin response reporter is reduced in roots of wrky46 mutants, and that both wrky46 mutants and OV46 display altered root levels of free indole-3-acetic acid (IAA) and IAA conjugates. Subsequent RT-qPCR and ChIP-qPCR experiments indicated that WRKY46 directly regulates the expression of ABI4 and of genes regulating auxin conjugation. Finally, analysis of wrky46 abi4 double mutant plants confirms that ABI4 acts downstream of WRKY46. In summary, our results demonstrate that WRKY46 contributes to the feedforward inhibition of osmotic/salt stress-dependent LR inhibition via regulation of ABA signaling and auxin homeostasis. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

  10. The flexible clock : Predictive and reactive homeostasis, energy balance and the circadian regulation of sleep-wake timing

    NARCIS (Netherlands)

    Riede, Sjaak J.; van der Vinne, Vincent; Hut, Roelof A.

    2017-01-01

    The Darwinian fitness of mammals living in a rhythmic environment depends on endogenous daily (circadian) rhythms in behavior and physiology. Here, we discuss the mechanisms underlying the circadian regulation of physiology and behavior in mammals. We also review recent efforts to understand

  11. Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation.

    Science.gov (United States)

    Emgård, Johanna; Kammoun, Hana; García-Cassani, Bethania; Chesné, Julie; Parigi, Sara M; Jacob, Jean-Marie; Cheng, Hung-Wei; Evren, Elza; Das, Srustidhar; Czarnewski, Paulo; Sleiers, Natalie; Melo-Gonzalez, Felipe; Kvedaraite, Egle; Svensson, Mattias; Scandella, Elke; Hepworth, Matthew R; Huber, Samuel; Ludewig, Burkhard; Peduto, Lucie; Villablanca, Eduardo J; Veiga-Fernandes, Henrique; Pereira, João P; Flavell, Richard A; Willinger, Tim

    2018-01-16

    Group 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Inflammatory group 2 innate lymphoid cells.

    Science.gov (United States)

    Huang, Yuefeng; Paul, William E

    2016-01-01

    Group 2 innate lymphoid cells (ILC2 cells) are able to produce type 2 cytokines and to mediate type 2 immune protection and tissue homeostasis. ILC2 cells have often been considered to be a single set of cells that respond to IL-33 and/or IL-25. Recent evidence now indicates that ILC2 cells can be grouped into two distinct subsets: homeostatic or natural ILC2s (nILC2 cells); and inflammatory ILC2 cells (iILC2 cells). nILC2 cells reside in barrier tissues and primarily respond to IL-33. They play critical roles not only in immune protection but also in tissue repair and beige fat biogenesis. iILC2 cells are not present in peripheral tissues in the steady state but can be elicited at many sites by helminth infection or IL-25 treatment. IL-25-elicited ilLC2 cells act as transient ILC progenitors with multipotency. They can be mobilized by distinct types of infections to develop into nILC2-like or ILC3-like cells, functioning in corresponding immune responses. The demonstration of the existence of iILC2 cells adds to our understanding of the complexity of ILC2 biology and makes necessary an analysis of the relationship between nILC2 cells and iILC2 cells. Published by Oxford University Press on behalf of The Japanese Society for Immunology 2015.

  13. Innate lymphoid cells, possible interaction with microbiota.

    Science.gov (United States)

    Moro, Kazuyo; Koyasu, Shigeo

    2015-01-01

    Recent studies have identified novel lymphocyte subsets named innate lymphoid cells (ILCs) lacking antigen-specific receptors. ILCs are present in a wide variety of epithelial compartments and occupy an intermediate position between acquired immune cells and myeloid cells. ILCs are now classified into three groups: group 1 ILC, group 2 ILC, and group 3 ILC based on their cytokine production patterns that correspond to the helper T cell subsets Th1, Th2, and Th17, respectively. ILCs play important roles in protection against various invading microbes including multicellular parasites, and in the maintenance of homeostasis and repair of epithelial layers. Excessive activation of ILCs, however, leads to various inflammatory disease conditions. ILCs have thus attracted interests of many researchers in the fields of infectious immunity, inflammatory diseases, and allergic diseases. Because epithelial cells sense alterations in environmental cues, it is important to understand the functional interaction between epithelial cells, ILCs, and environmental factors such as commensal microbiota. We discuss in this review developmental pathways of ILCs, their functions, and contribution of commensal microbiota to the differentiation and function of ILCs.

  14. Proteomic profiling in Drosophila reveals potential Dube3a regulation of the actin cytoskeleton and neuronal homeostasis.

    Directory of Open Access Journals (Sweden)

    Laura Jensen

    Full Text Available The molecular defects associated with Angelman syndrome (AS and 15q duplication autism are directly correlated to expression levels of the E3 ubiquitin ligase protein UBE3A. Here we used Drosophila melanogaster to screen for the targets of this ubiquitin ligase under conditions of both decreased (as in AS or increased (as in dup(15 levels of the fly Dube3a or human UBE3A proteins. Using liquid phase isoelectric focusing of proteins from whole fly head extracts we identified a total of 50 proteins that show changes in protein, and in some cases transcriptional levels, when Dube3a fluctuates. We analyzed head extracts from cytoplasmic, nuclear and membrane fractions for Dube3a regulated proteins. Our results indicate that Dube3a is involved in the regulation of cellular functions related to ATP synthesis/metabolism, actin cytoskeletal integrity, both catabolism and carbohydrate metabolism as well as nervous system development and function. Sixty-two percent of the proteins were >50% identical to homologous human proteins and 8 have previously be shown to be ubiquitinated in the fly nervous system. Eight proteins may be regulated by Dube3a at the transcript level through the transcriptional co-activation function of Dube3a. We investigated one autism-associated protein, ATPα, and found that it can be ubiquitinated in a Dube3a dependent manner. We also found that Dube3a mutants have significantly less filamentous actin than wild type larvae consistent with the identification of actin targets regulated by Dube3a. The identification of UBE3A targets is the first step in unraveling the molecular etiology of AS and duplication 15q autism.

  15. Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia

    OpenAIRE

    Olsson, Mattias; Bruhns, Pierre; Frazier, William A.; Ravetch, Jeffrey V.; Oldenborg, Per-Arne

    2005-01-01

    Interaction between target cell CD47 and the inhibitory macrophage receptor signal regulatory protein α (SIRPα) counteracts macrophage phagocytosis of CD47-expressing host cells. As platelets also express CD47, we asked whether inhibitory CD47/SIRPα signaling regulates normal platelet turnover and clearance of platelets in immune thrombocytopenic purpura (ITP). CD47-/- mice had a mild spontaneous thrombocytopenia, which was not due to a decreased platelet half-life as a result of increased ex...

  16. Diseases of Pulmonary Surfactant Homeostasis

    Science.gov (United States)

    Whitsett, Jeffrey A.; Wert, Susan E.; Weaver, Timothy E.

    2015-01-01

    Advances in physiology and biochemistry have provided fundamental insights into the role of pulmonary surfactant in the pathogenesis and treatment of preterm infants with respiratory distress syndrome. Identification of the surfactant proteins, lipid transporters, and transcriptional networks regulating their expression has provided the tools and insights needed to discern the molecular and cellular processes regulating the production and function of pulmonary surfactant prior to and after birth. Mutations in genes regulating surfactant homeostasis have been associated with severe lung disease in neonates and older infants. Biophysical and transgenic mouse models have provided insight into the mechanisms underlying surfactant protein and alveolar homeostasis. These studies have provided the framework for understanding the structure and function of pulmonary surfactant, which has informed understanding of the pathogenesis of diverse pulmonary disorders previously considered idiopathic. This review considers the pulmonary surfactant system and the genetic causes of acute and chronic lung disease caused by disruption of alveolar homeostasis. PMID:25621661

  17. The Regulation of the CNS Innate Immune Response Is Vital for the Restoration of Tissue Homeostasis (Repair after Acute Brain Injury: A Brief Review

    Directory of Open Access Journals (Sweden)

    M. R. Griffiths

    2010-01-01

    Full Text Available Neurons and glia respond to acute injury by participating in the CNS innate immune response. This involves the recognition and clearance of “not self ” pathogens and “altered self ” apoptotic cells. Phagocytic receptors (CD14, CD36, TLR–4 clear “not self” pathogens; neurons and glia express “death signals” to initiate apoptosis in T cells.The complement opsonins C1q, C3, and iC3b facilitate the clearance of apoptotic cells by interacting with CR3 and CR4 receptors. Apoptotic cells are also cleared by the scavenger receptors CD14, Prs-R, TREM expressed by glia. Serpins also expressed by glia counter the neurotoxic effects of thrombin and other systemic proteins that gain entry to the CNS following injury. Complement pathway and T cell activation are both regulated by complement regulatory proteins expressed by glia and neurons. CD200 and CD47 are NIRegs expressed by neurons as “don't eat me” signals and they inhibit microglial activity preventing host cell attack. Neural stem cells regulate T cell activation, increase the Treg population, and suppress proinflammatory cytokine expression. Stem cells also interact with the chemoattractants C3a, C5a, SDF-1, and thrombin to promote stem cell migration into damaged tissue to support tissue homeostasis.

  18. AtbHLH68 transcription factor contributes to the regulation of ABA homeostasis and drought stress tolerance in Arabidopsis thaliana.

    Science.gov (United States)

    Le Hir, Rozenn; Castelain, Mathieu; Chakraborti, Dipankar; Moritz, Thomas; Dinant, Sylvie; Bellini, Catherine

    2017-07-01

    Basic helix-loop-helix (bHLH) transcription factors are involved in a wide range of developmental processes and in response to biotic and abiotic stresses. They represent one of the biggest families of transcription factors but only few of them have been functionally characterized. Here we report the characterization of AtbHLH68 and show that, although the knock out mutant did not have an obvious development phenotype, it was slightly more sensitive to drought stress than the Col-0, and AtbHLH68 overexpressing lines displayed defects in lateral root (LR) formation and a significant increased tolerance to drought stress, likely related to an enhanced sensitivity to abscisic acid (ABA) and/or increased ABA content. AtbHLH68 was expressed in the vascular system of Arabidopsis and its expression was modulated by exogenously applied ABA in an organ-specific manner. We showed that the expression of genes involved in ABA metabolism [AtAAO3 (AtALDEHYDE OXIDASE 3) and AtCYP707A3 (AtABSCISIC ACID 8'HYDROXYLASE 3)], in ABA-related response to drought-stress (AtMYC2, AtbHLH122 and AtRD29A) or during LRs development (AtMYC2 and AtABI3) was de-regulated in the overexpressing lines. We propose that AtbHLH68 has a function in the regulation of LR elongation, and in the response to drought stress, likely through an ABA-dependent pathway by regulating directly or indirectly components of ABA signaling and/or metabolism. © 2017 Scandinavian Plant Physiology Society.

  19. CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis

    Directory of Open Access Journals (Sweden)

    M. Chiara Manzini

    2014-08-01

    Full Text Available Autism spectrum disorder (ASD and intellectual disability (ID are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive “founder” mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB. Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients.

  20. Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis.

    Science.gov (United States)

    Gray, Lawrence R; Sultana, Mst Rasheda; Rauckhorst, Adam J; Oonthonpan, Lalita; Tompkins, Sean C; Sharma, Arpit; Fu, Xiaorong; Miao, Ren; Pewa, Alvin D; Brown, Kathryn S; Lane, Erin E; Dohlman, Ashley; Zepeda-Orozco, Diana; Xie, Jianxin; Rutter, Jared; Norris, Andrew W; Cox, James E; Burgess, Shawn C; Potthoff, Matthew J; Taylor, Eric B

    2015-10-06

    Gluconeogenesis is critical for maintenance of euglycemia during fasting. Elevated gluconeogenesis during type 2 diabetes (T2D) contributes to chronic hyperglycemia. Pyruvate is a major gluconeogenic substrate and requires import into the mitochondrial matrix for channeling into gluconeogenesis. Here, we demonstrate that the mitochondrial pyruvate carrier (MPC) comprising the Mpc1 and Mpc2 proteins is required for efficient regulation of hepatic gluconeogenesis. Liver-specific deletion of Mpc1 abolished hepatic MPC activity and markedly decreased pyruvate-driven gluconeogenesis and TCA cycle flux. Loss of MPC activity induced adaptive utilization of glutamine and increased urea cycle activity. Diet-induced obesity increased hepatic MPC expression and activity. Constitutive Mpc1 deletion attenuated the development of hyperglycemia induced by a high-fat diet. Acute, virally mediated Mpc1 deletion after diet-induced obesity decreased hyperglycemia and improved glucose tolerance. We conclude that the MPC is required for efficient regulation of gluconeogenesis and that the MPC contributes to the elevated gluconeogenesis and hyperglycemia in T2D. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Innate lymphoid cells and asthma.

    Science.gov (United States)

    Yu, Sanhong; Kim, Hye Young; Chang, Ya-Jen; DeKruyff, Rosemarie H; Umetsu, Dale T

    2014-04-01

    Asthma is a complex and heterogeneous disease with several phenotypes, including an allergic asthma phenotype characterized by TH2 cytokine production and associated with allergen sensitization and adaptive immunity. Asthma also includes nonallergic asthma phenotypes, such as asthma associated with exposure to air pollution, infection, or obesity, that require innate rather than adaptive immunity. These innate pathways that lead to asthma involve macrophages, neutrophils, natural killer T cells, and innate lymphoid cells, newly described cell types that produce a variety of cytokines, including IL-5 and IL-13. We review the recent data regarding innate lymphoid cells and their role in asthma. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  2. Structure-function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease.

    Science.gov (United States)

    Tamir, Sagi; Paddock, Mark L; Darash-Yahana-Baram, Merav; Holt, Sarah H; Sohn, Yang Sung; Agranat, Lily; Michaeli, Dorit; Stofleth, Jason T; Lipper, Colin H; Morcos, Faruck; Cabantchik, Ioav Z; Onuchic, Jose' N; Jennings, Patricia A; Mittler, Ron; Nechushtai, Rachel

    2015-06-01

    A novel family of 2Fe-2S proteins, the NEET family, was discovered during the last decade in numerous organisms, including archea, bacteria, algae, plant and human; suggesting an evolutionary-conserved function, potentially mediated by their CDGSH Iron-Sulfur Domain. In human, three NEET members encoded by the CISD1-3 genes were identified. The structures of CISD1 (mitoNEET, mNT), CISD2 (NAF-1), and the plant At-NEET uncovered a homodimer with a unique "NEET fold", as well as two distinct domains: a beta-cap and a 2Fe-2S cluster-binding domain. The 2Fe-2S clusters of NEET proteins were found to be coordinated by a novel 3Cys:1His structure that is relatively labile compared to other 2Fe-2S proteins and is the reason of the NEETs' clusters could be transferred to apo-acceptor protein(s) or mitochondria. Positioned at the protein surface, the NEET's 2Fe-2S's coordinating His is exposed to protonation upon changes in its environment, potentially suggesting a sensing function for this residue. Studies in different model systems demonstrated a role for NAF-1 and mNT in the regulation of cellular iron, calcium and ROS homeostasis, and uncovered a key role for NEET proteins in critical processes, such as cancer cell proliferation and tumor growth, lipid and glucose homeostasis in obesity and diabetes, control of autophagy, longevity in mice, and senescence in plants. Abnormal regulation of NEET proteins was consequently found to result in multiple health conditions, and aberrant splicing of NAF-1 was found to be a causative of the neurological genetic disorder Wolfram Syndrome 2. Here we review the discovery of NEET proteins, their structural, biochemical and biophysical characterization, and their most recent structure-function analyses. We additionally highlight future avenues of research focused on NEET proteins and propose an essential role for NEETs in health and disease. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function

  3. Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals

    DEFF Research Database (Denmark)

    Pedersen, Bente K; Pedersen, Maria; Krabbe, Karen S

    2009-01-01

    identifies BDNF as a player not only in central metabolism, but also in regulating energy metabolism in peripheral organs. Low levels of BDNF are found in patients with neurodegenerative diseases, including Alzheimer's disease and major depression. In addition, BDNF levels are low in obesity...... and independently so in patients with type 2 diabetes. Brain-derived neurotrophic factor is expressed in non-neurogenic tissues, including skeletal muscle, and exercise increases BDNF levels not only in the brain and in plasma, but in skeletal muscle as well. Brain-derived neurotrophic factor mRNA and protein...... expression was increased in muscle cells that were electrically stimulated, and BDNF increased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl coenzyme A carboxylase-beta (ACCbeta) and enhanced fatty oxidation both in vitro and ex vivo. These data identify BDNF as a contraction...

  4. TRPV4 and AQP4 Channels Synergistically Regulate Cell Volume and Calcium Homeostasis in Retinal Müller Glia

    DEFF Research Database (Denmark)

    Jo, Andrew O; Ryskamp, Daniel A; Phuong, Tam T T

    2015-01-01

    (-/-) mice exhibited suppressed transcription of genes encoding Trpv4, Aqp4, and the Kir4.1 subunit of inwardly rectifying potassium channels. Swelling and [Ca(2+)]i elevations evoked in Müller cells by hypotonic stimulation were antagonized by the selective TRPV4 antagonist HC-067047 (2-methyl-1......-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide]. Glial cells lacking TRPV4 but not AQP4 showed deficits in hypotonic swelling and regulatory volume decrease. Functional synergy between TRPV4 and AQP4 during cell swelling was confirmed...... and facilitates the time course and amplitude of hypotonicity-induced swelling and regulatory volume decrease. We confirm the crucial facets of the signaling mechanism in heterologously expressing oocytes. These results identify the molecular mechanism that contributes to dynamic regulation of glial volume...

  5. Lipoic acid mitigates oxidative stress and recovers metabolic distortions in salt-stressed wheat seedlings by modulating ion homeostasis, the osmo-regulator level and antioxidant system.

    Science.gov (United States)

    Gorcek, Zeynep; Erdal, Serkan

    2015-11-01

    Soil salinity is one of the most detrimental environmental factors affecting the growth of plants and limiting their agricultural productivity. This study investigated whether exogenous lipoic acid (LA) pretreatment plays a role in promoting salt tolerance in wheat seedlings. The seedlings were treated with LA (1.75 mmol L(-1)) and salt (100 mmol L(-1) NaCl) separately and a combination of them. Salt stress significantly reduced relative water content, leaf surface area, ribulose bisphosphate carboxylase expression, and chlorophyll content but increased the content of osmo-regulator protein, carbohydrates and proline. In addition, salinity led to an imbalance in the inorganic composition of wheat leaves. While it elevated Na(+) content compared to control, Ca content and K(+)/Na(+) ratio were reduced. Under saline conditions, despite increases in antioxidant enzyme activity and levels of antioxidant compounds (ascorbate and glutathione), the content of reactive oxygen species (superoxide anion, hydrogen peroxide) and malondialdehyde were higher than in control seedlings. LA significantly promoted osmo-regulator level and antioxidant enzyme activities compared to stressed seedlings alone. Also, it both increased levels of ascorbate and glutathione and regenerated their oxidised forms, thus contributing to maintaining cellular redox status. Similarly, LA prevented excessive accumulation of Na(+) and promoted K(+)/Na(+) ratio and Ca content. Reactive oxygen species content was significantly reduced, and the inhibitions in the above parameters markedly recovered. LA reduced salinity-induced oxidative damage and thus contributed to the growth and development of plants in saline soils by modulating ion homeostasis between plant and soil as well as in osmo-regulator content and antioxidant system. © 2014 Society of Chemical Industry.

  6. Plasma membrane Ca2+-ATPase isoforms composition regulates cellular pH homeostasis in differentiating PC12 cells in a manner dependent on cytosolic Ca2+ elevations.

    Science.gov (United States)

    Boczek, Tomasz; Lisek, Malwina; Ferenc, Bozena; Kowalski, Antoni; Stepinski, Dariusz; Wiktorska, Magdalena; Zylinska, Ludmila

    2014-01-01

    Plasma membrane Ca(2+)-ATPase (PMCA) by extruding Ca(2+) outside the cell, actively participates in the regulation of intracellular Ca(2+) concentration. Acting as Ca(2+)/H(+) counter-transporter, PMCA transports large quantities of protons which may affect organellar pH homeostasis. PMCA exists in four isoforms (PMCA1-4) but only PMCA2 and PMCA3, due to their unique localization and features, perform more specialized function. Using differentiated PC12 cells we assessed the role of PMCA2 and PMCA3 in the regulation of intracellular pH in steady-state conditions and during Ca(2+) overload evoked by 59 mM KCl. We observed that manipulation in PMCA expression elevated pHmito and pHcyto but only in PMCA2-downregulated cells higher mitochondrial pH gradient (ΔpH) was found in steady-state conditions. Our data also demonstrated that PMCA2 or PMCA3 knock-down delayed Ca(2+) clearance and partially attenuated cellular acidification during KCl-stimulated Ca(2+) influx. Because SERCA and NCX modulated cellular pH response in neglectable manner, and all conditions used to inhibit PMCA prevented KCl-induced pH drop, we considered PMCA2 and PMCA3 as mainly responsible for transport of protons to intracellular milieu. In steady-state conditions, higher TMRE uptake in PMCA2-knockdown line was driven by plasma membrane potential (Ψp). Nonetheless, mitochondrial membrane potential (Ψm) in this line was dissipated during Ca(2+) overload. Cyclosporin and bongkrekic acid prevented Ψm loss suggesting the involvement of Ca(2+)-driven opening of mitochondrial permeability transition pore as putative underlying mechanism. The findings presented here demonstrate a crucial role of PMCA2 and PMCA3 in regulation of cellular pH and indicate PMCA membrane composition important for preservation of electrochemical gradient.

  7. Deciphering the Innate Lymphoid Cell Transcriptional Program

    Directory of Open Access Journals (Sweden)

    Cyril Seillet

    2016-10-01

    Full Text Available Innate lymphoid cells (ILCs are enriched at mucosal surfaces, where they provide immune surveillance. All ILC subsets develop from a common progenitor that gives rise to pre-committed progenitors for each of the ILC lineages. Currently, the temporal control of gene expression that guides the emergence of these progenitors is poorly understood. We used global transcriptional mapping to analyze gene expression in different ILC progenitors. We identified PD-1 to be specifically expressed in PLZF+ ILCp and revealed that the timing and order of expression of the transcription factors NFIL3, ID2, and TCF-1 was critical. Importantly, induction of ILC lineage commitment required only transient expression of NFIL3 prior to ID2 and TCF-1 expression. These findings highlight the importance of the temporal program that permits commitment of progenitors to the ILC lineage, and they expand our understanding of the core transcriptional program by identifying potential regulators of ILC development.

  8. Innate lymphoid cells: the new kids on the block.

    Science.gov (United States)

    Withers, David R; Mackley, Emma C; Jones, Nick D

    2015-08-01

    The purpose of this article is to review recent advances in our understanding of innate lymphoid cell function and to speculate on how these cells may become activated and influence the immune response to allogeneic tissues and cells following transplantation. Innate lymphoid cells encompass several novel cell types whose wide-ranging roles in the immune system are only now being uncovered. Through cytokine production, cross-talk with both haematopoietic and nonhaematopoietic populations and antigen presentation to T cells, these cells have been shown to be key regulators in maintaining tissue integrity, as well as initiating and then sustaining immune responses. It is now clear that innate lymphoid cells markedly contribute to immune responses and tissue repair in a number of disease contexts. Although experimental and clinical data on the behaviour of these cells following transplantation are scant, it is highly likely that innate lymphoid cells will perform similar functions in the alloimmune response following transplantation and therefore may be potential therapeutic targets for manipulation to prevent allograft rejection.

  9. A potential mechanism of metformin-mediated regulation of glucose homeostasis: inhibition of Thioredoxin-interacting protein (Txnip) gene expression.

    Science.gov (United States)

    Chai, Tin Fan; Hong, Shin Yee; He, Hongpeng; Zheng, Liling; Hagen, Thilo; Luo, Yan; Yu, Fa-Xing

    2012-08-01

    Metformin (dimethylbiguanide) is widely used among diabetic patients to lower the blood sugar level. Although several mechanisms have been proposed, its mode of action in enhancing peripheral glucose uptake and inhibiting hepatic glucose production is not fully understood. Thioredoxin-interacting protein (Txnip) is known to play important roles in glucose metabolism by inhibiting cellular glucose uptake and metabolism and promoting hepatic gluconeogenesis. The expression of the gene encoding Txnip is regulated in a glucose dependent manner via the Mondo:MLX transcription factor complex. In the present study, we report that Txnip mRNA as well as protein expression in cultured cells is markedly reduced upon metformin administration. The binding of Mondo:MLX to the Txnip gene promoter is reduced, suggesting that the transcription of the Txnip gene is repressed by metformin. Moreover, we show that the effect of metformin on Txnip gene transcription is due to the inhibition of mitochondrial complex I and increased glycolysis, and is partially mediated by the AMP activated kinase (AMPK). These observations prompt us to propose that the novel action of metformin on the Txnip gene expression may contribute to its therapeutic effects in the treatment of type II diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Root gravitropism and root hair development constitute coupled developmental responses regulated by auxin homeostasis in the Arabidopsis root apex.

    Science.gov (United States)

    Rigas, Stamatis; Ditengou, Franck Anicet; Ljung, Karin; Daras, Gerasimos; Tietz, Olaf; Palme, Klaus; Hatzopoulos, Polydefkis

    2013-03-01

    Active polar transport establishes directional auxin flow and the generation of local auxin gradients implicated in plant responses and development. Auxin modulates gravitropism at the root tip and root hair morphogenesis at the differentiation zone. Genetic and biochemical analyses provide evidence for defective basipetal auxin transport in trh1 roots. The trh1, pin2, axr2 and aux1 mutants, and transgenic plants overexpressing PIN1, all showing impaired gravity response and root hair development, revealed ectopic PIN1 localization. The auxin antagonist hypaphorine blocked root hair elongation and caused moderate agravitropic root growth, also leading to PIN1 mislocalization. These results suggest that auxin imbalance leads to proximal and distal developmental defects in Arabidopsis root apex, associated with agravitropic root growth and root hair phenotype, respectively, providing evidence that these two auxin-regulated processes are coupled. Cell-specific subcellular localization of TRH1-YFP in stele and epidermis supports TRH1 engagement in auxin transport, and hence impaired function in trh1 causes dual defects of auxin imbalance. The interplay between intrinsic cues determining root epidermal cell fate through the TTG/GL2 pathway and environmental cues including abiotic stresses modulates root hair morphogenesis. As a consequence of auxin imbalance in Arabidopsis root apex, ectopic PIN1 mislocalization could be a risk aversion mechanism to trigger root developmental responses ensuring root growth plasticity. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

  11. Molecular effects of ER alpha- and beta-selective agonists on regulation of energy homeostasis in obese female Wistar rats.

    Science.gov (United States)

    Weigt, Carmen; Hertrampf, Torsten; Kluxen, Felix M; Flenker, Ulrich; Hülsemann, Frank; Fritzemeier, Karl Heinrich; Diel, Patrick

    2013-09-05

    The molecular mechanisms underlying the effects of selective ER subtype activation on lipogenesis, adipogenesis, lipid utilization and storage as well as glucose metabolism are currently largely unknown and were analyzed in female OVX Wistar rats on a high-fat diet. Rats received estradiol (E2), ER subtype-selective agonists (Alpha and Beta), and genistein (Gen) for 10 weeks. In adipose tissue, treatment with E2, Alpha, and Beta significantly decreased lipogenic (SREBP-1c, FAS) and adipogenic genes (LPL, PPAR gamma). In liver and skeletal muscle of E2-, Alpha-, Beta-, and Gen-treated animals, lipogenesis and triglyceride accumulation were significantly reduced. Increased hepatic and muscular PPAR gamma mRNA expression was observed in untreated, Beta- and Gen-treated animals, which correlates with increased hepatic glucose uptake. However, only untreated animals showed impaired insulin sensitivity compared to all other groups. Therefore, PPAR gamma up-regulation in untreated animals suggests a compensatory mechanism, probably due to increased triglyceride accumulation in non-adipose tissues. Beta- and Gen-treated animals may benefit from the anabolic potency of ER beta that ameliorates lipid and glucose utilization in muscle. Activation of either ER subtype reduces fat enrichment and improves insulin sensitivity. Depending on the investigated tissue, different molecular pathways seem to be involved. Copyright © 2013. Published by Elsevier Ireland Ltd.

  12. Lymphotoxin organizes contributions to host defense and metabolic illness from innate lymphoid cells.

    Science.gov (United States)

    Upadhyay, Vaibhav; Fu, Yang-Xin

    2014-04-01

    The lymphotoxin (LT)-pathway is a unique constituent branch of the Tumor Necrosis Superfamily (TNFSF). Use of LT is a critical mechanism by which fetal innate lymphoid cells regulate lymphoid organogenesis. Within recent years, adult innate lymphoid cells have been discovered to utilize this same pathway to regulate IL-22 and IL-23 production for host defense. Notably, genetic studies have linked polymorphisms in the genes encoding LTα to several phenotypes contributing to metabolic syndrome. The role of the LT-pathway may lay the foundation for a bridge between host immune response, microbiota, and metabolic syndrome. The contribution of the LT-pathway to innate lymphoid cell function and metabolic syndrome will be visited in this review. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Y1 and Y5 Receptors Are Both Required for the Regulation of Food Intake and Energy Homeostasis in Mice

    Science.gov (United States)

    Mitchell, Natalie F.; Lin, Shu; Macia, Laurence; Yulyaningsih, Ernie; Baldock, Paul A.; Enriquez, Ronaldo F.; Zhang, Lei; Shi, Yan-Chuan; Zolotukhin, Serge

    2012-01-01

    Neuropeptide Y (NPY) acting in the hypothalamus is one of the most powerful orexigenic agents known. Of the five known Y receptors, hypothalamic Y1 and Y5 have been most strongly implicated in mediating hyperphagic effects. However, knockout of individual Y1 or Y5 receptors induces late-onset obesity – and Y5 receptor knockout also induces hyperphagia, possibly due to redundancy in functions of these genes. Here we show that food intake in mice requires the combined actions of both Y1 and Y5 receptors. Germline Y1Y5 ablation in Y1Y5−/− mice results in hypophagia, an effect that is at least partially mediated by the hypothalamus, since mice with adult-onset Y1Y5 receptor dual ablation targeted to the paraventricular nucleus (PVN) of the hypothalamus (Y1Y5Hyp/Hyp) also exhibit reduced spontaneous or fasting-induced food intake when fed a high fat diet. Interestingly, despite hypophagia, mice with germline or hypothalamus-specific Y1Y5 deficiency exhibited increased body weight and/or increased adiposity, possibly due to compensatory responses to gene deletion, such as the decreased energy expenditure observed in male Y1Y5−/− animals relative to wildtype values. While Y1 and Y5 receptors expressed in other hypothalamic areas besides the PVN – such as the dorsomedial nucleus and the ventromedial hypothalamus – cannot be excluded from having a role in the regulation of food intake, these studies demonstrate the pivotal, combined role of both Y1 and Y5 receptors in the mediation of food intake. PMID:22768253

  14. 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: potential role in the regulation of aging process.

    Science.gov (United States)

    Salminen, Antero; Kauppinen, Anu; Kaarniranta, Kai

    2015-10-01

    Recent studies have revealed that the members of an ancient family of nonheme Fe(2+)/2-oxoglutarate-dependent dioxygenases (2-OGDO) are involved in the functions associated with the aging process. 2-Oxoglutarate and O2 are the obligatory substrates and Fe(2+) a cofactor in the activation of 2-OGDO enzymes, which can induce the hydroxylation of distinct proteins and the demethylation of DNA and histones. For instance, ten-eleven translocation 1-3 (TET1-3) are the demethylases of DNA, whereas Jumonji C domain-containing histone lysine demethylases (KDM2-7) are the major epigenetic regulators of chromatin landscape, known to be altered with aging. The functions of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD1-3) as well as those of collagen hydroxylases are associated with age-related degeneration. Moreover, the ribosomal hydroxylase OGFOD1 controls mRNA translation, which is known to decline with aging. 2-OGDO enzymes are the sensors of energy metabolism, since the Krebs cycle intermediate 2-oxoglutarate is an activator whereas succinate and fumarate are the potent inhibitors of 2-OGDO enzymes. In addition, O2 availability and iron redox homeostasis control the activities of 2-OGDO enzymes in tissues. We will briefly elucidate the catalytic mechanisms of 2-OGDO enzymes and then review the potential functions of the above-mentioned 2-OGDO enzymes in the control of the aging process.

  15. Nrf2/Keap1 system regulates vascular smooth muscle cell apoptosis for vascular homeostasis: role in neointimal formation after vascular injury.

    Science.gov (United States)

    Ashino, Takashi; Yamamoto, Masayuki; Numazawa, Satoshi

    2016-05-20

    Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after a vascular injury is a key event in developing neointimal hyperplasia. To maintain vascular function, proliferation and apoptosis of VSMCs is tightly controlled during vascular remodeling. NF-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) system, a key component of the oxidative stress response that acts in maintaining homeostasis, plays an important role in neointimal hyperplasia after a vascular injury; however, the role of Nrf2/Keap1 in VSMC apoptosis has not been clarified. Here we report that 14 days after arterial injury in mice, TUNEL-positive VSMCs are detected in both the neointimal and medial layers. These layers contain cells expressing high levels of Nrf2 but low Keap1 expression. In VSMCs, Keap1 depletion induces features of apoptosis, such as positive TUNEL staining and annexin V binding. These changes are associated with an increased expression of nuclear Nrf2. Simultaneous Nrf2 depletion inhibits Keap1 depletion-induced apoptosis. At 14 days after the vascular injury, Nrf2-deficient mice demonstrated fewer TUNEL-positive cells and increased neointimal formation in the neointimal and medial areas. The results suggest that the Nrf2/Keap1 system regulates VSMC apoptosis during neointimal formation, thereby inhibiting neointimal hyperplasia after a vascular injury.

  16. BRD7 regulates XBP1s' activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K.

    Science.gov (United States)

    Park, Sang Won; Herrema, Hilde; Salazar, Mario; Cakir, Isin; Cabi, Serkan; Basibuyuk Sahin, Fatma; Chiu, Yu-Hsin; Cantley, Lewis C; Ozcan, Umut

    2014-07-01

    Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family that is known to play a role as tumor suppressors. Here, we show that BRD7 is a component of the unfolded protein response (UPR) signaling through its ability to regulate X-box binding protein 1 (XBP1) nuclear translocation. BRD7 interacts with the regulatory subunits of phosphatidylinositol 3-kinase (PI3K) and increases the nuclear translocation of both p85α and p85β and the spliced form of XBP1 (XBP1s). Deficiency of BRD7 blocks the nuclear translocation of XBP1s. Furthermore, our in vivo studies have shown that BRD7 protein levels are reduced in the liver of obese mice, and reinstating BRD7 levels in the liver restores XBP1s nuclear translocation, improves glucose homeostasis, and ultimately reduces the blood glucose levels in the obese and diabetic mouse models. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. The E-Id Protein Axis Specifies Adaptive Lymphoid Cell Identity and Suppresses Thymic Innate Lymphoid Cell Development.

    Science.gov (United States)

    Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Kenian; Jin, Yi; Turner, Jacob; Moore, Amanda J; Saito, Rintaro; Yoshida, Kenichi; Ogawa, Seishi; Rodewald, Hans-Reimer; Lin, Yin C; Kawamoto, Hiroshi; Murre, Cornelis

    2017-05-16

    Innate and adaptive lymphoid development is orchestrated by the activities of E proteins and their antagonist Id proteins, but how these factors regulate early T cell progenitor (ETP) and innate lymphoid cell (ILC) development remains unclear. Using multiple genetic strategies, we demonstrated that E proteins E2A and HEB acted in synergy in the thymus to establish T cell identity and to suppress the aberrant development of ILCs, including ILC2s and lymphoid-tissue-inducer-like cells. E2A and HEB orchestrated T cell fate and suppressed the ILC transcription signature by activating the expression of genes associated with Notch receptors, T cell receptor (TCR) assembly, and TCR-mediated signaling. E2A and HEB acted in ETPs to establish and maintain a T-cell-lineage-specific enhancer repertoire, including regulatory elements associated with the Notch1, Rag1, and Rag2 loci. On the basis of these and previous observations, we propose that the E-Id protein axis specifies innate and adaptive lymphoid cell fate. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Guards at the gate: physiological and pathological roles of tissue-resident innate lymphoid cells in the lung.

    Science.gov (United States)

    Cheng, Hang; Jin, Chengyan; Wu, Jing; Zhu, Shan; Liu, Yong-Jun; Chen, Jingtao

    2017-12-01

    The lung is an important open organ and the primary site of respiration. Many life-threatening diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases (COPDs), pulmonary fibrosis, and lung cancer. In the lung, innate immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role in containing these pulmonary diseases. Innate lymphoid cells (ILCs), characterized by their strict tissue residence and distinct function in the mucosa, are attracting increased attention in innate immunity. Upon sensing the danger signals from damaged epithelium, ILCs activate, proliferate, and release numerous cytokines with specific local functions; they also participate in mucosal immune-surveillance, immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and induce diseases. In this review, we discuss the physiological and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the function and plasticity of ILCs.

  19. Colonization and effector functions of innate lymphoid cells in mucosal tissues

    Science.gov (United States)

    Kim, Myunghoo; Kim, Chang H.

    2016-01-01

    Innate lymphoid cells (ILCs) protect mucosal barrier tissues to fight infection and maintain tissue integrity. ILCs and their progenitors are developmentally programmed to migrate, differentiate and populate various mucosal tissues and associated lymphoid tissues. Functionally mature ILC subsets respond to diverse pathogens such as bacteria, viruses, fungi and parasites in subset-specific manners. In this review, we will discuss how ILCs populate mucosal tissues and regulate immune responses to distinct pathogens to protect the host and maintain tissue integrity. PMID:27365193

  20. Overexpression of RING Domain E3 Ligase ZmXerico1 Confers Drought Tolerance through Regulation of ABA Homeostasis[OPEN

    Science.gov (United States)

    Zhang, Wenjing; Xu, Qingzhang; Scolaro, Eric J.; Kahsay, Robel Y.; Kise, Rie; Hakimi, Salim; Niu, Xiping; Habben, Jeffrey E.

    2017-01-01

    Drought stress is one of the main environmental problems encountered by crop growers. Reduction in arable land area and reduced water availability make it paramount to identify and develop strategies to allow crops to be more resilient in water-limiting environments. The plant hormone abscisic acid (ABA) plays an important role in the plants’ response to drought stress through its control of stomatal aperture and water transpiration, and transgenic modulation of ABA levels therefore represents an attractive avenue to improve the drought tolerance of crops. Several steps in the ABA-signaling pathway are controlled by ubiquitination involving really interesting new genes (RING) domain-containing proteins. We characterized the maize (Zea mays) RING protein family and identified two novel RING-H2 genes called ZmXerico1 and ZmXerico2. Expression of ZmXerico genes is induced by drought stress, and we show that overexpression of ZmXerico1 and ZmXerico2 in Arabidopsis and maize confers ABA hypersensitivity and improved water use efficiency, which can lead to enhanced maize yield performance in a controlled drought-stress environment. Overexpression of ZmXerico1 and ZmXerico2 in maize results in increased ABA levels and decreased levels of ABA degradation products diphaseic acid and phaseic acid. We show that ZmXerico1 is localized in the endoplasmic reticulum, where ABA 8′-hydroxylases have been shown to be localized, and that it functions as an E3 ubiquitin ligase. We demonstrate that ZmXerico1 plays a role in the control of ABA homeostasis through regulation of ABA 8′-hydroxylase protein stability, representing a novel control point in the regulation of the ABA pathway. PMID:28899960

  1. CCR10 regulates balanced maintenance and function of resident regulatory and effector T cells to promote immune homeostasis in the skin.

    Science.gov (United States)

    Xia, Mingcan; Hu, Shaomin; Fu, Yaoyao; Jin, Wensen; Yi, Qiyi; Matsui, Yurika; Yang, Jie; McDowell, Mary Ann; Sarkar, Surojit; Kalia, Vandana; Xiong, Na

    2014-09-01

    CCR10 and CCL27 make up the most skin-specific chemokine receptor/ligand pair implicated in skin allergy and inflammatory diseases, including atopic dermatitis and psoriasis. This pair is thought to regulate the migration, maintenance, or both of skin T cells and is suggested to be therapeutic targets for treatment of skin diseases. However, the functional importance of CCR10/CCL27 in vivo remains elusive. We sought to determine the expression and function of CCR10 in different subsets of skin T cells under both homeostatic and inflammatory conditions to gain a mechanistic insight into the potential roles of CCR10 during skin inflammation. Using heterozygous and homozygous CCR10 knockout/enhanced green fluorescent protein knockin mice, we assessed the expression of CCR10 on regulatory and effector T cells of healthy and inflamed skin induced by chemicals, pathogens, and autoreactive T cells. In addition, we assessed the effect of CCR10 knockout on the maintenance and functions of different T cells and inflammatory status in the skin during different phases of the immune response. CCR10 expression is preferentially induced on memory-like skin-resident T cells and their progenitors for their maintenance in homeostatic skin but not expressed on most skin-infiltrating effector T cells during inflammation. In CCR10 knockout mice the imbalanced presence and dysregulated function of resident regulatory and effector T cells result in over-reactive and prolonged innate and memory responses in the skin, leading to increased clearance of Leishmania species infection in the skin. CCR10 is a critical regulator of skin immune homeostasis. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  2. Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice.

    Science.gov (United States)

    Montaldo, Elisa; Juelke, Kerstin; Romagnani, Chiara

    2015-08-01

    Since their discovery, innate lymphoid cells (ILCs) have been the subject of intense research. As their name implies, ILCs are innate cells of lymphoid origin, and can be grouped into subsets based on their cytotoxic activity, cytokine profile, and the transcriptional requirements during ILC differentiation. The main ILC groups are "killer" ILCs, comprising NK cells, and "helper-like" ILCs (including ILC1s, ILC2s, and ILC3s). This review examines the origin, differentiation stages, and plasticity of murine and human ILC3s. ILC3s express the retinoic acid receptor (RAR) related orphan receptor RORγt and the signature cytokines IL-22 and IL-17. Fetal ILC3s or lymphoid tissue inducer cells are required for lymphoid organogenesis, while postnatally developing ILC3s are important for the generation of intestinal cryptopatches and isolated lymphoid follicles as well as for the defence against pathogens and epithelial homeostasis. Here, we discuss the transcription factors and exogenous signals (including cytokines, nutrients and cell-to-cell interaction) that drive ILC3 lineage commitment and acquisition of their distinctive effector program. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Shaping Innate Lymphoid Cell Diversity

    Directory of Open Access Journals (Sweden)

    Qiutong Huang

    2017-11-01

    Full Text Available Innate lymphoid cells (ILCs are a key cell type that are enriched at mucosal surfaces and within tissues. Our understanding of these cells is growing rapidly. Paradoxically, these cells play a role in maintaining tissue integrity but they also function as key drivers of allergy and inflammation. We present here the most recent understanding of how genomics has provided significant insight into how ILCs are generated and the enormous heterogeneity present within the canonical subsets. This has allowed the generation of a detailed blueprint for ILCs to become highly sensitive and adaptive sensors of environmental changes and therefore exquisitely equipped to protect immune surfaces.

  4. CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues.

    Science.gov (United States)

    Sisirak, Vanja; Vey, Nelly; Vanbervliet, Béatrice; Duhen, Thomas; Puisieux, Isabelle; Homey, Bernhard; Bowman, Edward P; Trinchieri, Giorgio; Dubois, Bertrand; Kaiserlian, Dominique; Lira, Sergio A; Puisieux, Alain; Blay, Jean-Yves; Caux, Christophe; Bendriss-Vermare, Nathalie

    2011-11-10

    Absent in peripheral tissues during homeostasis, human plasmacytoid dendritic cells (pDCs) are described in inflamed skin or mucosa. Here, we report that, unlike blood pDCs, a subset of tonsil pDCs express functional CCR6 and CCR10, and their respective ligands CCL20 and CCL27are detected in inflamed epithelia contacting blood dendritic cell antigen 2(+) pDCs. Moreover, pDCs are recruited to imiquimod-treated skin tumors in WT but not CCR6-deficient mice, and competitive adoptive transfers reveal that CCR6-deficient pDCs are impaired in homing to inflamed skin tumors after intravenous transfer. On IL-3 culture, CCR6 and CCR10 expression is induced on human blood pDCs that become responsive to CCL20 and CCL27/CCL28, respectively. Interestingly, unlike myeloid DC, blood pDCs initially up-regulate CCR7 expression and CCL19 responsiveness on IL-3 ± CpG-B and then acquire functional CCR6 and CCR10. Finally, IL-3-differentiated CCR6(+) CCR10(+) pDCs secrete high levels of IFN-α in response to virus. Overall, we propose an unexpected pDCs migratory model that may best apply for mucosal-associated lymphoid tissues. After CCR7-mediated extravasation into lymphoid tissues draining inflamed epithelia, blood pDCs may be instructed to up-regulate CCR6 and/or CCR10 allowing their homing into inflamed epithelia (in mucosae or skin). At this site, pDCs can then produce IFN-α contributing to pathogen clearance and/or local inflammation.

  5. Regulators of articular cartilage homeostasis

    NARCIS (Netherlands)

    Leijten, Jeroen Christianus Hermanus

    2012-01-01

    Prevention of hypertrophic differentiation is essential for successful cartilage repair strategies. Although this process is essential for longitudinal growth, it also is part of degenerative cartilage diseases such as osteoarthiritis. Moreover, it limits the use of cell types prone to this process

  6. Innate lymphoid cells in inflammation and immunity

    NARCIS (Netherlands)

    McKenzie, Andrew N. J.; Spits, Hergen; Eberl, Gerard

    2014-01-01

    Innate lymphoid cells (ILCs) were first described as playing important roles in the development of lymphoid tissues and more recently in the initiation of inflammation at barrier surfaces in response to infection or tissue damage. It has now become apparent that ILCs play more complex roles

  7. Lymphoid tissue inducer cells: architects of CD4 immune responses in mice and men.

    Science.gov (United States)

    Kim, M-Y; Kim, K-S; McConnell, F; Lane, P

    2009-07-01

    In this review, we summarize the current understanding of the multiple functions of the mouse lymphoid tissue inducer (LTi) cells in: (i) the development of organized lymphoid tissue, (ii) the generation and maintenance of CD4-dependent immunity in adult lymphoid tissues; and (iii) the regulation of central tolerance in thymus. By contrast with mouse LTi cells, which have been well described, the human equivalent is only just beginning to be characterized. Human LTi-like cells expressing interleukin (IL)-22 have been identified recently and found to differentiate into natural killer (NK) cells. The relationship of LTi cells to NK cells is discussed in the light of several studies reporting a close relationship in the mouse between LTi cells and transcription factor retinoid-related orphan receptor gammat-dependent IL-22 producing NK cells in the gut. We also outline our data suggesting that these cells are present in adult human lymphoid tissues.

  8. Hydrogen sulfide regulates salt tolerance in rice by maintaining Na+/K+ balance, mineral homeostasis and oxidative metabolism under excessive salt stress

    Directory of Open Access Journals (Sweden)

    Mohammad Golam Mostofa

    2015-12-01

    Full Text Available Being a salt sensitive crop, rice growth and development are frequently affected by soil salinity. Hydrogen sulfide (H2S has been recently explored as an important priming agent regulating diverse physiological processes of plant growth and development. Despite its enormous prospects in plant systems, the role of H2S in plant stress tolerance is still elusive. Here, a combined pharmacological, physiological and biochemical approach was executed aiming to examine the possible mechanism of H2S in enhancement of salt stress tolerance in rice. We show that pretreating rice plants with H2S donor sodium bisulfide (NaHS clearly improved, but application of H2S scavenger hypotaurine with NaHS decreased growth and biomass-related parameters under salt stress. NaHS-pretreated salt-stressed plants exhibited increased chlorophyll, carotenoid and soluble protein contents, as well as suppressed accumulation of reactive oxygen species (ROS, contributing to oxidative damage protection. The protective mechanism of H2S against oxidative stress was correlated with the elevated levels of ascorbic acid, glutathione, redox states, and the enhanced activities of ROS- and methylglyoxal-detoxifying enzymes. Notably, decreased uptake of Na+, decreased Na+/K+ ratio and balanced mineral contents indicated a role of H2S in ion homeostasis under salt stress. Altogether, our results highlight that modulation of the level of endogenous H2S genetically or exogenously could be employed to attain better growth and development of rice, and perhaps other crops, under salt stress. Furthermore, our study reveals the importance of the implication of gasotransmitter like H2S for the management of salt stress, thus assisting rice plants to adapt to adverse environmental changes.

  9. Iron homeostasis: An anthropocentric perspective.

    Science.gov (United States)

    Coffey, Richard; Ganz, Tomas

    2017-08-04

    The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Primary Pulmonary Lymphoid Lesions: Radiologic and Pathologic Findings.

    Science.gov (United States)

    Sirajuddin, Arlene; Raparia, Kirtee; Lewis, Vanessa A; Franks, Teri J; Dhand, Sabeen; Galvin, Jeffrey R; White, Charles S

    2016-01-01

    The pulmonary lymphoid system is complex and is composed of two compartments: the pulmonary lymphatics and the bronchus-associated lymphoid tissue (BALT). Additional important cells that function in the pulmonary lymphoid system include dendritic cells, Langherhans cells, macrophages, and plasma cells. An appreciation of the normal lymphoid anatomy of the lung as well as its immunology is helpful in understanding the radiologic and pathologic findings of the primary pulmonary lymphoid lesions. Primary lymphoid lesions of the lung arise from the BALT and are uncommon. However, they are increasingly recognized within the growing number of posttransplant patients as well as other patients who are receiving immunosuppressive therapies. Primary lymphoid lesions encompass a wide range of benign and malignant lesions. Benign lymphoid lesions of the lung include reactive lymphoid hyperplasia, follicular bronchiolitis, lymphoid interstitial pneumonia, and nodular lymphoid hyperplasia. Malignant lymphoid lesions of the lung include low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), other non-Hodgkin lymphomas, and Hodgkin lymphoma. Last, a miscellaneous group of primary lymphoid lesions includes lymphomatoid granulomatosis, posttransplant lymphoproliferative disorders, acquired immunodeficiency syndrome (AIDS)-related lymphoma, and intravascular lymphoma/lymphomatosis. These lesions are best evaluated with multidetector chest computed tomography. The radiologic findings of the primary lymphoid lesions are often nonspecific and are best interpreted in correlation with clinical data and pathologic findings. The purpose of this article is to review pulmonary lymphoid anatomy as well as the most common primary pulmonary lymphoid disorders. ©RSNA, 2016.

  11. Bronchus- and nasal-associated lymphoid tissues.

    Science.gov (United States)

    Bienenstock, John; McDermott, Mark R

    2005-08-01

    The bronchus-associated lymphoid tissue (BALT) and the nasal-associated lymphoid tissue (NALT) constitute organized lymphoid aggregates that are capable of T- and B-cell responses to inhaled antigens. BALT, located mostly at bifurcations of the bronchus in animals and humans, is present in the fetus and develops rapidly following birth, especially in the presence of antigens. Humoral immune responses elicited by BALT are primarily immunoglobulin A secretion both locally and by BALT-derived B cells that have trafficked to distant mucosal sites. Similarly located T-cell responses have been noted. On the basis of these findings, the BALT can be thought of as functionally analogous to mucosal lymphoid aggregates in the intestine and is deemed a member of the common mucosal immunologic system. NALT has been described principally in the rodent nasal passage as two separate lymphoid aggregates. It develops after birth, likely in response to antigen, and B- and T-cell responses parallel those that occur in BALT. It is not known whether NALT cells traffic to distant mucosal sites, although mucosal responses have been detected after nasal immunization. NALT appears from many studies to be a functionally distinct lymphoid aggregate when compared with BALT and Peyer's patches. It may exist, however, in humans as a diffuse collection of isolated lymphoid follicles.

  12. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology.

    Science.gov (United States)

    Eberl, Gérard; Colonna, Marco; Di Santo, James P; McKenzie, Andrew N J

    2015-05-22

    Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy. Copyright © 2015, American Association for the Advancement of Science.

  13. Innate Lymphoid Cells in Tumor Immunity.

    Science.gov (United States)

    van Beek, Jasper J P; Martens, Anne W J; Bakdash, Ghaith; de Vries, I Jolanda M

    2016-02-25

    Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring.

  14. Lymphoid cells in chicken intestinal epithelium

    DEFF Research Database (Denmark)

    Bjerregaard, P

    1975-01-01

    The intraepithelial lymphoid cells of chicken small intestine were studied by light microscopy using 1 mu Epon sections, and by electron microscopy. Three cell types were found: small lymphocytes, large lymphoid cells, and granular cells. These cells correspond to the theliolymphocytes and globule...... leucocytes of previous authors. The numbers of all cell types increased with age. Correlation was found between the number of small lymphocytes and large lymphoid cells, but not between granular cells and either of the other two. A hypothesis is proposed, assigning these cells with a function in mucosal...

  15. The Role of TOX in the Development of Innate Lymphoid Cells

    Directory of Open Access Journals (Sweden)

    Corey R. Seehus

    2015-01-01

    Full Text Available TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4+ T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.

  16. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

    Science.gov (United States)

    van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

    2014-04-01

    The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

  17. The Role of TOX in the Development of Innate Lymphoid Cells.

    Science.gov (United States)

    Seehus, Corey R; Kaye, Jonathan

    2015-01-01

    TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4(+) T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.

  18. Importance of the alternative oxidase (AOX) pathway in regulating cellular redox and ROS homeostasis to optimize photosynthesis during restriction of the cytochrome oxidase pathway in Arabidopsis thaliana.

    Science.gov (United States)

    Vishwakarma, Abhaypratap; Tetali, Sarada Devi; Selinski, Jennifer; Scheibe, Renate; Padmasree, Kollipara

    2015-09-01

    The importance of the alternative oxidase (AOX) pathway, particularly AOX1A, in optimizing photosynthesis during de-etiolation, under elevated CO2, low temperature, high light or combined light and drought stress is well documented. In the present study, the role of AOX1A in optimizing photosynthesis was investigated when electron transport through the cytochrome c oxidase (COX) pathway was restricted at complex III. Leaf discs of wild-type (WT) and aox1a knock-out mutants of Arabidopsis thaliana were treated with antimycin A (AA) under growth-light conditions. To identify the impact of AOX1A deficiency in optimizing photosynthesis, respiratory O2 uptake and photosynthesis-related parameters were measured along with changes in redox couples, reactive oxygen species (ROS), lipid peroxidation and expression levels of genes related to respiration, the malate valve and the antioxidative system. In the absence of AA, aox1a knock-out mutants did not show any difference in physiological, biochemical or molecular parameters compared with WT. However, after AA treatment, aox1a plants showed a significant reduction in both respiratory O2 uptake and NaHCO3-dependent O2 evolution. Chlorophyll fluorescence and P700 studies revealed that in contrast to WT, aox1a knock-out plants were incapable of maintaining electron flow in the chloroplastic electron transport chain, and thereby inefficient heat dissipation (low non-photochemical quenching) was observed. Furthermore, aox1a mutants exhibited significant disturbances in cellular redox couples of NAD(P)H and ascorbate (Asc) and consequently accumulation of ROS and malondialdehyde (MDA) content. By contrast, WT plants showed a significant increase in transcript levels of CSD1, CAT1, sAPX, COX15 and AOX1A in contrast to aox1a mutants. These results suggest that AOX1A plays a significant role in sustaining the chloroplastic redox state and energization to optimize photosynthesis by regulating cellular redox homeostasis and ROS

  19. Dysregulation of Innate Lymphoid Cells in Common Variable Immunodeficiency.

    Science.gov (United States)

    Maglione, Paul J; Cols, Montserrat; Cunningham-Rundles, Charlotte

    2017-10-05

    Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immune deficiency. With widespread use of immunoglobulin replacement therapy, non-infectious complications, such as autoimmunity, chronic intestinal inflammation, and lung disease, have replaced infections as the major cause of morbidity and mortality in this immune deficiency. The pathogenic mechanisms that underlie the development of these complications in CVID are not known; however, there have been numerous associated laboratory findings. Among the most intriguing of these associations is elevation of interferon signature genes in CVID patients with inflammatory/autoimmune complications, as a similar gene expression profile is found in systemic lupus erythematosus and other chronic inflammatory diseases. Linked with this heightened interferon signature in CVID is an expansion of circulating IFN-γ-producing innate lymphoid cells. Innate lymphoid cells are key regulators of both protective and pathogenic immune responses that have been extensively studied in recent years. Further exploration of innate lymphoid cell biology in CVID may uncover key mechanisms underlying the development of inflammatory complications in these patients and may inspire much needed novel therapeutic approaches.

  20. A thyroid hormone challenge in hypothyroid rats identifies t3 regulated genes in the hypothalamus and in models with altered energy balance and glucose homeostasis

    NARCIS (Netherlands)

    Herwig, Annika; Campbell, Gill; Mayer, Claus-Dieter; Boelen, Anita; Anderson, Richard A.; Ross, Alexander W.; Mercer, Julian G.; Barrett, Perry

    2014-01-01

    The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify

  1. PPAR alpha-dependent induction of the energy homeostasis-regulating nuclear receptor NR1i3 (CAR) in rat hepatocytes: Potential role in starvation adaptation

    NARCIS (Netherlands)

    Wieneke, N.; Hirsch-Ernst, K.I.; Kuna, M.; Kersten, A.H.; Pueschel, G.P.

    2007-01-01

    A tight hormonal control of energy homeostasis is of pivotal relevance for animals. Recent evidence suggests an involvement of the nuclear receptor NR1i3 (CAR). Fasting induces CAR by largely unknown mechanisms and CAR-deficient mice are defective in fasting adaptation. In rat hepatocytes CAR was

  2. Ectopic Tertiary Lymphoid Tissue in Inflammatory Bowel Disease: Protective or Provocateur?

    Directory of Open Access Journals (Sweden)

    Eoin Neil McNamee

    2016-08-01

    Full Text Available Organized lymphoid tissues like the thymus first appeared in jawed vertebrates around 500 million years ago and have evolved to equip the host with a network of specialized sites, strategically located to orchestrate strict immune-surveillance and efficient immune responses autonomously. The gut-associated lymphoid tissues (GALT maintain a mostly tolerant environment to dampen our responses to daily dietary and microbial products in the intestine. However, when this homeostasis is perturbed by chronic inflammation, the intestine is able to develop florid organized tertiary lymphoid tissues (TLT, which heralds the onset of regional immune dysregulation. While TLT are a pathologic hallmark of Crohn’s disease (CD, their role in the overall process remains largely enigmatic. A critical question remains; are intestinal TLT generated by the immune infiltrated intestine to modulate immune responses and rebuild tolerance to the microbiota or are they playing a more sinister role by generating dysregulated responses that perpetuate disease? Herein we discuss the main theories of intestinal tertiary lymphoid tissue neogenesis and focus on the most recent findings that open new perspectives to their role in inflammatory bowel disease.

  3. Neuronal control of energy homeostasis

    OpenAIRE

    Gao, Qian; Horvath, Tamas L.

    2007-01-01

    Neuronal control of body energy homeostasis is the key mechanism by which animals and humans regulate their long-term energy balance. Various hypothalamic neuronal circuits (which include the hypothalamic melanocortin, midbrain dopamine reward and caudal brainstem autonomic feeding systems) control energy intake and expenditure to maintain body weight within a narrow range for long periods of a life span. Numerous peripheral metabolic hormones and nutrients target these structures providing f...

  4. Total lymphoid irradiation in alloimmunity and autoimmunity

    Energy Technology Data Exchange (ETDEWEB)

    Strober, S.

    1987-12-01

    Total lymphoid irradiation has been used as an immunosuppressive regimen in autoimmune disease and organ transplantation. The rationale for its use originated from studies of patients with Hodgkin disease, in whom this radiotherapy regimen was noted to induce profound and long-lasting immune suppression and yet was well tolerated, with few long-term side effects. Total lymphoid irradiation is a unique immunosuppressive regimen that produces a selective (and long-lasting) reduction in the number and function of helper T cells and certain subsets of B cells. Conventional immunosuppressive drugs show little selectivity, and their effects are short-lived. The most important aspect of total lymphoid irradiation is the potential for achieving transplantation tolerance and permanent remissions in autoimmune disease in laboratory animals. Attempts are being made to achieve similar goals in humans given total lymphoid irradiation, so that immunosuppressive drugs can be ultimately withdrawn from transplant recipients and patients with lupus nephritis. 28 references.

  5. INTRACELLULAR Ca2+ HOMEOSTASIS

    Directory of Open Access Journals (Sweden)

    Shahdevi Nandar Kurniawan

    2015-01-01

    Full Text Available Ca2+ signaling functions to regulate many cellular processes. Dynamics of Ca2+ signaling or homeostasis is regulated by the interaction between ON and OFF reactions that control Ca2+ flux in both the plasma membrane and internal organelles such as the endoplasmic reticulum (ER and mitochondria. External stimuli activate the ON reactions, which include Ca2+ into the cytoplasm either through channels in the plasma membrane or from internal storage like in ER. Most of the cells utilize both channels/sources, butthere area few cells using an external or internal source to control certain processes. Most of the Ca2+ entering the cytoplasm adsorbed to the buffer, while a smaller part activate effect or to stimulate cellular processes. Reaction OFF is pumping of cytoplasmic Ca2+ using a combination mechanism of mitochondrial and others. Changes in Ca2+ signal has been detected in various tissues isolated from animals induced into diabetes as well as patients with diabetes. Ca2+ signal interference is also found in sensory neurons of experimental animals with diabetes. Ca2+ signaling is one of the main signaling systems in the cell.

  6. Iron homeostasis during pregnancy.

    Science.gov (United States)

    Fisher, Allison L; Nemeth, Elizabeta

    2017-12-01

    During pregnancy, iron needs to increase substantially to support fetoplacental development and maternal adaptation to pregnancy. To meet these iron requirements, both dietary iron absorption and the mobilization of iron from stores increase, a mechanism that is in large part dependent on the iron-regulatory hormone hepcidin. In healthy human pregnancies, maternal hepcidin concentrations are suppressed in the second and third trimesters, thereby facilitating an increased supply of iron into the circulation. The mechanism of maternal hepcidin suppression in pregnancy is unknown, but hepcidin regulation by the known stimuli (i.e., iron, erythropoietic activity, and inflammation) appears to be preserved during pregnancy. Inappropriately increased maternal hepcidin during pregnancy can compromise the iron availability for placental transfer and impair the efficacy of iron supplementation. The role of fetal hepcidin in the regulation of placental iron transfer still remains to be characterized. This review summarizes the current understanding and addresses the gaps in knowledge about gestational changes in hematologic and iron variables and regulatory aspects of maternal, fetal, and placental iron homeostasis. © 2017 American Society for Nutrition.

  7. The proteoglycan repertoire of lymphoid cells.

    Science.gov (United States)

    Fadnes, Bodil; Husebekk, Anne; Svineng, Gunbjørg; Rekdal, Øystein; Yanagishita, Masaki; Kolset, Svein O; Uhlin-Hansen, Lars

    2012-10-01

    Proteoglycans have been studied to a limited extent in lymphoid cells. In this study we have investigated the expression of proteoglycans in B-cells, CD4+ T-cells, CD8+ T-cells, natural killer cells, as well as in nine different cell lines established from patients with lymphoid malignancies. Serglycin was the major proteoglycan expressed at mRNA level by the primary lymphocytes. None of the syndecans or glycpicans was detected at mRNA level in the primary lymphocytes, except for syndecan-4 in CD4+ T-cells and CD8+ T-cells. All lymphoid cell lines expressed serglycin mRNA, as well as one or several members of the syndecan and glypican families. Further, increased synthesis of proteoglycans was found in the cell lines compared to the primary lymphocytes, as well as the presence of heparan sulfate on the cell surface of five of the cells lines. Western blot analysis showed a close correlation between serglycin mRNA level and expression of serglycin core protein. Our results show that serglycin is a major proteoglycan in all the normal lymphoid cells and that these cells carry little, or none, proteoglycans on the cell surface. Serglycin was also a major proteoglycan in the malignant lymphoid cells, but these also expressed one or more types of cell surface proteoglycans. Thus, malignant transformation of lymphoid cells may be followed by increased synthesis of proteoglycans and expression of cell surface proteoglycans.

  8. Total lymphoid irradiation and discordant cardiac xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Kaplan, E.; Dresdale, A.R.; Diehl, J.T.; Katzen, N.A.; Aronovitz, M.J.; Konstam, M.A.; Payne, D.D.; Cleveland, R.J. (Tufts Univ. School of Medicine, Boston, MA (USA))

    1990-01-01

    Total lymphoid irradiation can prolong concordant cardiac xenografts. The effects of total lymphoid irradiation in a discordant xenograft model (guinea pig to rat) were studied with and without adjuvant pharmacologic immunosuppression. Inbred Lewis rats were randomly allocated to one of four groups. Group 1 (n = 6) served as a control group and rats received no immunosuppression. Group 2 (n = 5) received triple-drug therapy that consisted of intraperitoneal azathioprine (2 mg/kg), cyclosporine (20 mg/kg), and methylprednisolone (1 mg/kg) for 1 week before transplantation. Group 3 animals (n = 5) received 15 Gy of total lymphoid irradiation in 12 divided doses over a 3-week period. Group 4 (n = 6) received both triple-drug therapy and total lymphoid irradiation as described for groups 2 and 3. Complement-dependent cytotoxicity assay was performed to determine if a correlation between complement-dependent cytotoxicity and rejection-free interval existed. Rejection was defined as cessation of graft pulsation and was confirmed by histologic test results. Only groups 1 and 2 showed a difference in survival (group 1, 6.9 +/- 1.0 minutes; group 2, 14.2 +/- 2.7 minutes, p = 0.02). Although total lymphoid irradiation did decrease complement-dependent cytotoxicity, linear regression revealed no correlation between complement-dependent cytotoxicity and graft survival (coefficient of correlation, 0.30). Unlike concordant cardiac xenografts, total lymphoid irradiation with or without triple-drug therapy does not prolong graft survival.

  9. HCV Virus and Lymphoid Neoplasms

    Directory of Open Access Journals (Sweden)

    Yutaka Tsutsumi

    2011-01-01

    Full Text Available Hepatitis C virus (HCV is one of the viruses known to cause hepatic cancer. HCV is also believed to be involved in malignant lymphoma. In this paper, we investigated characteristics of malignant lymphoma cases that were anti-HCV antibody (HCV-Ab positive. We were able to perform pathological examinations on 13 out of 14 HCV-positive cases. Of these, lymphoid tissues of 10 stained positive for HCV-Ab. There was no significant correlation between the degree of HCV staining and the rate of recurrence or resistance to treatment. However, there did appear to be a consistent decrease in the amount of HCV-RNA between pre- and posttreatment among HCV-Ab-positive cases; that is, treatment-resistant cases that exhibited resistance from the first treatment and recurrent cases more frequently had a higher HCV level at treatment termination compared to the pretreatment level. This suggests that the HCV virus either accelerates oncogenesis by direct interaction with B cells or indirectly affects lymphoma prognosis.

  10. Yeast Kch1 and Kch2 membrane proteins play a pleiotropic role in membrane potential establishment and monovalent cation homeostasis regulation

    Czech Academy of Sciences Publication Activity Database

    Felcmanová, Kristina; Nevečeřalová, Petra; Sychrová, Hana; Zimmermannová, Olga

    2017-01-01

    Roč. 17, č. 5 (2017), č. článku fox053. ISSN 1567-1356 R&D Projects: GA ČR(CZ) GA16-03398S; GA MŠk(CZ) LH14297 Institutional support: RVO:67985823 Keywords : Kch proteins * plasma-membrane potential * monovalent cation homeostasis * intracellular pH * Saccharomyces cerevisiae * Candida albicans Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.299, year: 2016

  11. Expression homeostasis during DNA replication.

    Science.gov (United States)

    Voichek, Yoav; Bar-Ziv, Raz; Barkai, Naama

    2016-03-04

    Genome replication introduces a stepwise increase in the DNA template available for transcription. Genes replicated early in S phase experience this increase before late-replicating genes, raising the question of how expression levels are affected by DNA replication. We show that in budding yeast, messenger RNA (mRNA) synthesis rate is buffered against changes in gene dosage during S phase. This expression homeostasis depends on acetylation of H3 on its internal K56 site by Rtt109/Asf1. Deleting these factors, mutating H3K56 or up-regulating its deacetylation, increases gene expression in S phase in proportion to gene replication timing. Therefore, H3K56 acetylation on newly deposited histones reduces transcription efficiency from replicated DNA, complementing its role in guarding genome stability. Our study provides molecular insight into the mechanism maintaining expression homeostasis during DNA replication. Copyright © 2016, American Association for the Advancement of Science.

  12. Cross-talk between type 3 innate lymphoid cells and the gut microbiota in inflammatory bowel disease.

    Science.gov (United States)

    Buela, Kristine-Ann G; Omenetti, Sara; Pizarro, Theresa T

    2015-11-01

    Innate lymphoid cells (ILCs) are a newly-identified population of immune cells prevalent in, but not limited to, mucosal tissues that not only play a significant role in immune homeostasis and host defense, but also in disease pathogenesis. This review highlights the importance of type 3 ILCs (ILC3s) and their interactions with the intestinal microflora, both in maintaining gut health and in the development of inflammatory bowel disease (IBD). Distinct lineages of ILCs are defined based on the presence of cell surface proteins, secretion of effector cytokines and expression of master transcription factors that determine their differentiation and inflammatory behavior. These ILC subgroups mirror corresponding CD4 T-cell subsets, with which they share many phenotypic, morphologic and functional attributes. ILC3s, in particular, through direct and indirect interactions with the gut microbiota, have been identified to promote protection and maintenance of epithelial integrity, as well as to regulate intestinal inflammation and fibrosis, such as that observed in IBD. Gut mucosal ILCs respond to environmental cues, such as diet and microflora composition, which can shape downstream immune function. As such, ILCs represent attractive targets for the development of therapeutic modalities to maintain gut health and to potentially treat IBD.

  13. Th1- and Th2-like subsets of innate lymphoid cells

    NARCIS (Netherlands)

    Bernink, Jochem; Mjösberg, Jenny; Spits, Hergen

    2013-01-01

    Innate lymphoid cells (ILCs) constitute a family of effectors in innate immunity and regulators of tissue remodeling that have a cytokine and transcription factor expression pattern that parallels that of the T-helper (Th) cell family. Here, we discuss how ILCs can be categorized and summarize the

  14. Atrial natriuretic peptide in the locus coeruleus and its possible role in the regulation of arterial blood pressure, fluid and electrolyte homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Geiger, H.; Sterzel, R.B. (Univ. of Erlangen-Nuernberg (West Germany)); Bahner, U.; Heidland, A. (Univ. of Wuerzburg (West Germany)); Palkovits, M. (Semmelweis Univ., Budapest (Hungary))

    1991-01-01

    Atrial natriuretic factor (ANP) is present in neuronal cells of the locus coeruleus and its vicinity in the pontine tegmentum and moderate amount of ANP is detectable in this area by radioimmunoassay. The ANP is known as a neuropeptide which may influence the body salt and water homeostasis and blood pressure by targeting both central and peripheral regulatory mechanisms. Whether this pontine ANP cell group is involved in any of these regulatory mechanisms, the effect of various types of hypertension and experimental alterations in the salt and water balance on ANP levels was measured by radioimmunoassay in the locus coeruleus of rats. Adrenalectomy, as well as aldosterone and dexamethasone treatments failed to alter ANP levels in the locus coeruleus. Reduced ANP levels were measured in spontaneously hypertensive rats, and in diabetes insipidus rats with vasopressin replacement. In contrast to these situations, elevated ANP levels were found in rats with DOCA-salt or 1-Kidney-1-clip hypertension. These data suggest a link between ANP levels in the locus coeruleus and fluid volume homeostasis. Whether this link is causal and connected with the major activity of locus coeruleus neurons needs further information.

  15. Loss of Mbd2 Protects Mice Against High-Fat Diet-Induced Obesity and Insulin Resistance by Regulating the Homeostasis of Energy Storage and Expenditure.

    Science.gov (United States)

    Cheng, Jia; Song, Jia; He, Xiaoyu; Zhang, Meng; Hu, Shuang; Zhang, Shu; Yu, Qilin; Yang, Ping; Xiong, Fei; Wang, Dao Wen; Zhou, Jianfeng; Ning, Qin; Chen, Zhishui; Eizirik, Decio L; Zhou, Zhiguang; Zhao, Chunxia; Wang, Cong-Yi

    2016-11-01

    Previous studies including ours demonstrated that methyl-CpG-binding domain 2 (MBD2) acts as a reader to decipher DNA methylome-encoded information. We thus in the current study used Mbd2(-/-) mice as a model to dissect the impact of high-fat diet (HFD) on DNA methylome relevant to the pathoetiology of obesity. It was interestingly noted that mice deficient in Mbd2 were protected from HFD-induced obesity and insulin resistance. Mechanistic study revealed that HFD rendered epididymal adipose tissues to undergo a DNA methylation turnover as evidenced by the changes of methylation levels and patterns. Specifically, HFD was noted with higher potency to induce DNA hypomethylation in genes relevant to energy storage than that in genes associated with energy expenditure. As a result, arrays of genes were subjected to expression changes, which led to an altered homeostasis for energy storage and expenditure in favor of obesity development. Loss of Mbd2 resulted in impaired implementation of above DNA methylation changes associated with altered energy homeostasis, which then protected mice from HFD-induced obesity and insulin resistance. Those data would provide novel insight into the understanding of the pathoetiology underlying obesity with potential for developing effective therapies against obesity in clinical settings. © 2016 by the American Diabetes Association.

  16. CbRCI35, a cold responsive peroxidase from Capsella bursa-pastoris regulates reactive oxygen species homeostasis and enhances cold tolerance in tobacco

    Directory of Open Access Journals (Sweden)

    Juan Lin

    2016-10-01

    Full Text Available Low temperature affects gene regulatory networks and alters cellular metabolism to inhibit plant growth. Peroxidases are widely distributed in plants and play a large role in adjusting and controlling reactive oxygen species (ROS homeostasis in response to abiotic stresses such as low temperature. The Rare Cold-Inducible 35 gene from Capsella bursa-pastoris (CbRCI35 belongs to the type III peroxidase family and has been reported to be a cold responsive gene in plants. Here we performed an expressional characterization of CbRCI35 under cold and ionic liquid treatments. The promoter of CbRCI35 was also cloned and its activity was examined using the GUS reporter system. CbRCI35 protein was localized in the cytoplasm according to sequence prediction and GFP fusion assay. Heterologous expression tests revealed that CbRCI35 conferred enhanced resistance to low temperature and activated endogenous cold responsive signaling in tobacco. Furthermore, in the normal condition the ROS accumulation was moderately enhanced while after chilling exposure superoxide dismutase (SOD activity was increased in CbRCI53 transgenic plants. The ROS metabolism related genes expression was altered accordingly. We conclude that CbRCI35 modulates ROS homeostasis and contributes to cold tolerance in plants.

  17. Effects of Cu(II) and cisplatin on the stability of Specific protein 1 (Sp1)-DNA binding: Insights into the regulation of copper homeostasis and platinum drug transport.

    Science.gov (United States)

    Yan, Dong; Aiba, Isamu; Chen, Helen H W; Kuo, Macus Tien

    2016-08-01

    The human high-affinity copper transporter 1 (hCtr1) transports both Cu(I) and cisplatin (cDDP). Because Cu deficiency is lethal yet Cu overload is poisonous, hCtr1 expression is transcriptionally upregulated in response to Cu deficiency but is downregulated under Cu replete conditions in controlling Cu homeostasis. The up- and down-regulation of hCtr1 is regulated by Specific protein 1 (Sp1), which itself is also correspondingly regulated under these Cu conditions. hCtr1 expression is also upregulated by cDDP via upregulation of Sp1. The underlying mechanisms of these regulations are unknown. Using gel-electrophoretic mobility shift assays, we demonstrated here that Sp1-DNA binding affinity is reduced under Cu replete conditions but increased under reduced Cu conditions. Similarly, Sp1-DNA binding affinity is increased by cDDP treatment. This in vitro system demonstrated, for the first time, that regulation of Sp1/hCtr1 expression by these agents is modulated by the stability of Sp1-DNA binding, the first step in the Sp1-mediated transcriptional regulation process. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Lymphoid neoplasia following connective tissue disease.

    Science.gov (United States)

    Banks, P M; Witrak, G A; Conn, D L

    1979-02-01

    A retrospective review was undertaken to ascertain whether there are distinctive histopathologic features of the lymphoid neoplasms that occur in patients with previous connective tissue disease. Of 29 patients studied, 12 had malignant lymphoma with diffuse large-cell cytomorphology. Only 1 of these 12 had an immunoblastic cell type. The remaining 17 patients had neoplasia of a widely diverse nature. Six had lymphocytic lymphoma (one nodular poorly differentiated, three diffuse poorly differentiated, and three diffuse well differentiated), two had Hodgkin's disease, three had plasma cell myeloma, and six had chronic lymphocytic leukemia. Data fail to confirm a relationship between lymphoid proliferations with immunoblastic morphology and connective tissue diseases.

  19. [Magnesium homeostasis and its disturbances].

    Science.gov (United States)

    Nakai, Kentaro

    2012-08-01

    Magnesium homeostasis is maintained through normal functions of the kidney, intestine, and bone. In the kidney, approximately 80% magnesium is filtered by the glomeruli. In general, 95% filtered magnesium is collectively reabsorbed in the proximal tubule (15%-20%) , thick ascending limb of Henle (TAL, 65%-75%) , and the distal convoluted tubule (DCT, 5%-10%) . In the TAL, magnesium reabsorption regulated by the paracellular pathway via claudin-16 is driven by electrochemical voltage. Chloride channel Kb and renal outer medullary potassium channels control this lumen-positive voltage. In the DCT, the transcellular pathway via transient receptor potential melastatin 6 (TRPM6) plays a fundamental role in the final 5%-10% magnesium reabsorption. The functions of TRPM6 depend on Na-Cl co-transporters and Na( + )-K( + )-ATPase. Defects in these regulatory proteins may cause inherited or drug-induced disorders of magnesium metabolism. Recently, some proteins have been confirmed to be responsible for magnesium homeostasis ; however, further research is required to elucidate the mechanisms underlying the maintenance of magnesium homeostasis.

  20. NFIL3 Orchestrates the Emergence of Common Helper Innate Lymphoid Cell Precursors

    Directory of Open Access Journals (Sweden)

    Wei Xu

    2015-03-01

    Full Text Available Innate lymphoid cells (ILCs are a family of effectors that originate from a common innate lymphoid cell progenitor. However, the transcriptional program that sets the identity of the ILC lineage remains elusive. Here, we show that NFIL3 is a critical regulator of the common helper-like innate lymphoid cell progenitor (CHILP. Cell-intrinsic Nfil3 ablation led to variably impaired development of fetal and adult ILC subsets. Conditional gene targeting demonstrated that NFIL3 exerted its function prior to ILC subset commitment. Accordingly, NFIL3 ablation resulted in loss of ID2+ CHILP and PLZF+ ILC progenitors. Nfil3 expression in lymphoid progenitors was under the control of the mesenchyme-derived hematopoietin IL-7, and NFIL3 exerted its function via direct Id2 regulation in the CHILP. Moreover, ectopic Id2 expression in Nfil3-null precursors rescued defective ILC lineage development in vivo. Our data establish NFIL3 as a key regulator of common helper-like ILC progenitors as they emerge during early lymphopoiesis.

  1. Iron homeostasis in the liver

    Science.gov (United States)

    Anderson, Erik R; Shah, Yatrik M

    2014-01-01

    Iron is an essential nutrient that is tightly regulated. A principal function of the liver is the regulation of iron homeostasis. The liver senses changes in systemic iron requirements and can regulate iron concentrations in a robust and rapid manner. The last 10 years have led to the discovery of several regulatory mechanisms in the liver which control the production of iron regulatory genes, storage capacity, and iron mobilization. Dysregulation of these functions leads to an imbalance of iron, which is the primary causes of iron-related disorders. Anemia and iron overload are two of the most prevalent disorders worldwide and affect over a billion people. Several mutations in liver-derived genes have been identified, demonstrating the central role of the liver in iron homeostasis. During conditions of excess iron, the liver increases iron storage and protects other tissues, namely the heart and pancreas from iron-induced cellular damage. However, a chronic increase in liver iron stores results in excess reactive oxygen species production and liver injury. Excess liver iron is one of the major mechanisms leading to increased steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. PMID:23720289

  2. Magnesium homeostasis in Mammalian cells.

    Science.gov (United States)

    Romani, Andrea M P

    2013-01-01

    Magnesium, the second most abundant cation within the cell, plays an important role in numerous biological functions. Experimental evidence indicates that mammalian cells tightly regulate cellular magnesium ion content through specific mechanisms controlling Mg(2+) entry and efflux across the cell membrane and the membrane of various cellular organelles as well as intracellular Mg(2+) buffering under resting conditions and following hormonal and metabolic stimuli. This chapter will provide an assessment of the various mechanisms controlling cellular Mg(2+) homeostasis and transport, and the implications changes in cellular Mg(2+) content play under physiological and pathological conditions.

  3. Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate

    DEFF Research Database (Denmark)

    Sørensen, Belinda Halling; Thorsteinsdottir, Unnur Arna; Lambert, Ian Henry

    2014-01-01

    Cisplatin resistance is a major challenge in the treatment of cancer and develops through reduced drug accumulation and an increased ability to avoid drug-induced cell damage, cell shrinkage, and hence initiation of apoptosis. Uptake and release of the semiessential amino acid taurine contribute...... to cell volume homeostasis, and taurine has been reported to have antiapoptotic effects. Here we find that volume-sensitive taurine release in cisplatin-sensitive [wild-type (WT)] human ovarian cancer A2780 cells is reduced in the presence of the phospholipase A2 inhibitor bromenol lactone, the 5......-lipoxygenase (5-LO) inhibitor ETH 615-139, and the cysteine leukotriene receptor 1 (CysLT1) antagonist zafirlukast and impaired by the anion channel blocker DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonate). Comparing WT and cisplatin-resistant (RES) A2780 cells we also find that evasion of cisplatin...

  4. Isolation and Flow Cytometry Analysis of Innate Lymphoid Cells from the Intestinal Lamina Propria.

    Science.gov (United States)

    Gronke, Konrad; Kofoed-Nielsen, Michael; Diefenbach, Andreas

    2017-01-01

    The intestinal mucosa constitutes the biggest surface area of the body. It is constantly challenged by bacteria, commensal and pathogenic, protozoa, and food-derived irritants. In order to maintain homeostasis, a complex network of signaling circuits has evolved that includes contributions of immune cells. In recent years a subset of lymphocytes, which belong to the innate immune system, has caught particular attention. These so-called innate lymphoid cells (ILC) reside within the lamina propria of the small and large intestines and rapidly respond to environmental challenges. They provide immunity to various types of infections but may also contribute to organ homeostasis as they produce factors acting on epithelial cells thereby enhancing barrier integrity. Here, we describe how these cells can be isolated from their environment and provide an in-depth protocol how to visualize the various ILC subsets by flow cytometry.

  5. The new WHO nomenclature: lymphoid neoplasms.

    Science.gov (United States)

    Leclair, Susan J; Rodak, Bernadette F

    2002-01-01

    The development of the WHO classification of lymphoid neoplasms is a remarkable example of cooperation and communication between pathologists and oncologists from around the world. Joint classification committees of the major hematopathology societies will periodically review and update this classification, facilitating further progress in the understanding and treatment of hematologic malignancies.

  6. Conjunctival lymphoma arising from reactive lymphoid hyperplasia

    Directory of Open Access Journals (Sweden)

    Fukuhara Junichi

    2012-09-01

    Full Text Available Abstract Extra nodal marginal zone B-cell lymphoma (EMZL of the conjunctiva typically arises in the marginal zone of mucosa-associated lymphoid tissue. The pathogenesis of conjunctival EMZL remains unknown. We describe an unusual case of EMZL arising from reactive lymphoid hyperplasia (RLH of the conjunctiva. A 35-year-old woman had fleshy salmon-pink conjunctival tumors in both eyes, oculus uterque (OU. Specimens from conjunctival tumors in the right eye, oculus dexter (OD, revealed a collection of small lymphoid cells in the stroma. Immunohistochemically, immunoglobulin (Ig light chain restriction was not detected. In contrast, diffuse atypical lymphoid cell infiltration was noted in the left eye, oculus sinister (OS, and positive for CD20, a marker for B cells OS. The tumors were histologically diagnosed as RLH OD, and EMZL OS. PCR analysis detected IgH gene rearrangement in the joining region (JH region OU. After 11 months, a re-biopsy specimen demonstrated EMZL based on compatible pathological and genetic findings OD, arising from RLH. This case suggests that even if the diagnosis of the conjunctival lymphoproliferative lesions is histologically benign, confirmation of the B-cell clonality by checking IgH gene rearrangement should be useful to predict the incidence of malignancy.

  7. Gene expression trees in lymphoid development

    Directory of Open Access Journals (Sweden)

    Schliep Alexander

    2007-10-01

    Full Text Available Abstract Background The regulatory processes that govern cell proliferation and differentiation are central to developmental biology. Particularly well studied in this respect is the lymphoid system due to its importance for basic biology and for clinical applications. Gene expression measured in lymphoid cells in several distinguishable developmental stages helps in the elucidation of underlying molecular processes, which change gradually over time and lock cells in either the B cell, T cell or Natural Killer cell lineages. Large-scale analysis of these gene expression trees requires computational support for tasks ranging from visualization, querying, and finding clusters of similar genes, to answering detailed questions about the functional roles of individual genes. Results We present the first statistical framework designed to analyze gene expression data as it is collected in the course of lymphoid development through clusters of co-expressed genes and additional heterogeneous data. We introduce dependence trees for continuous variates, which model the inherent dependencies during the differentiation process naturally as gene expression trees. Several trees are combined in a mixture model to allow inference of potentially overlapping clusters of co-expressed genes. Additionally, we predict microRNA targets. Conclusion Computational results for several data sets from the lymphoid system demonstrate the relevance of our framework. We recover well-known biological facts and identify promising novel regulatory elements of genes and their functional assignments. The implementation of our method (licensed under the GPL is available at http://algorithmics.molgen.mpg.de/Supplements/ExpLym/.

  8. Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation.

    Science.gov (United States)

    Wang, Shuo; Xia, Pengyan; Chen, Yi; Qu, Yuan; Xiong, Zhen; Ye, Buqing; Du, Ying; Tian, Yong; Yin, Zhinan; Xu, Zhiheng; Fan, Zusen

    2017-09-21

    An emerging family of innate lymphoid cells (termed ILCs) has an essential role in the initiation and regulation of inflammation. However, it is still unclear how ILCs are regulated in the duration of intestinal inflammation. Here, we identify a regulatory subpopulation of ILCs (called ILCregs) that exists in the gut and harbors a unique gene identity that is distinct from that of ILCs or regulatory T cells (Tregs). During inflammatory stimulation, ILCregs can be induced in the intestine and suppress the activation of ILC1s and ILC3s via secretion of IL-10, leading to protection against innate intestinal inflammation. Moreover, TGF-β1 is induced by ILCregs during the innate intestinal inflammation, and autocrine TGF-β1 sustains the maintenance and expansion of ILCregs. Therefore, ILCregs play an inhibitory role in the innate immune response, favoring the resolution of intestinal inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Cutting Edge: Skin CCR10+ CD8+ T Cells Support Resident Regulatory T Cells through the B7.2/Receptor Axis To Regulate Local Immune Homeostasis and Response.

    Science.gov (United States)

    Fu, Yaoyao; Yang, Jie; Xiong, Na

    2016-06-15

    Resident T cells in barrier tissues are important in protecting against foreign agents but can also contribute to inflammatory diseases if dysregulated. How T cell homeostasis is maintained in barrier tissues is still poorly understood. We report that resident CD8(+) T cells directly support maintenance of regulatory T cells (Tregs) in the skin to promote immune homeostasis. Impaired establishment of resident CD8(+) T cells caused by knockout of the skin-homing chemokine receptor CCR10 resulted in an altered balance of resident Tregs and CD4(+) effector T cells in the skin and overreactive inflammatory responses to cutaneous stimulations. Furthermore, B7.2 expressed on skin CD8(+) T cells supports the survival of Tregs, likely through interaction with its receptor CTLA-4, which is highly expressed on skin Tregs. Our findings provide novel insights into T cell homeostatic regulation in the skin and may improve our understanding of the pathobiology of tissue inflammatory diseases. Copyright © 2016 by The American Association of Immunologists, Inc.

  10. NK Cells and Other Innate Lymphoid Cells in Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Vacca, Paola; Montaldo, Elisa; Croxatto, Daniele; Moretta, Francesca; Bertaina, Alice; Vitale, Chiara; Locatelli, Franco; Mingari, Maria Cristina; Moretta, Lorenzo

    2016-01-01

    Natural killer (NK) cells play a major role in the T-cell depleted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILCs). At variance with NK cells, the other ILC populations (ILC1/2/3) are non-cytolytic, while they secrete different patterns of cytokines. ILCs provide host defenses against viruses, bacteria, and parasites, drive lymphoid organogenesis, and contribute to tissue remodeling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD) but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defenses that are reconstituted more rapidly than the adaptive ones. In this context, ILCs may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodeling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILCs. Of note, CD34(+) cells isolated from different sources of HSC may differentiate in vitro toward various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g., IL-1β) may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT.

  11. Mapping of NKp46+ cells in healthy human lymphoid and non-lymphoid tissues

    Directory of Open Access Journals (Sweden)

    Elena eTomasello

    2012-11-01

    Full Text Available Understanding Natural Killer (NK cell anatomical distribution is key to dissect the role of these unconventional lymphocytes in physiological and disease conditions. In mouse, NK cells have been detected in various lymphoid and non-lymphoid organs, while in humans the current knowledge of NK cell distribution at steady state is mainly restricted to lymphoid tissues. The translation to humans of findings obtained in mice is facilitated by the identification of NK cell markers conserved between these two species. The Natural Cytotoxicity Receptor (NCR NKp46 is a marker of the NK cell lineage evolutionary conserved in mammals. In mice, NKp46 is also present on rare T cell subsets and on a subset of gut Innate Lymphoid Cells (ILCs expressing the retinoic acid receptor-related orphan receptor t (RORt transcription factor. Here, we documented the distribution and the phenotype of human NKp46+ cells in lymphoid and non-lymphoid tissues isolated from healthy donors. Human NKp46+ cells were found in splenic red pulp, in lymph nodes, in lungs and gut lamina propria, thus mirroring mouse NKp46+ cell distribution. We also identified a novel cell subset of CD56dimNKp46low cells that includes RORt+ILCs with a lineage-CD94-CD117brightCD127bright phenotype. The use of NKp46 thus contributes to establish the basis for analyzing quantitative and qualitative changes of NK cell and ILC subsets in human diseases.

  12. AtLa1 protein initiates IRES-dependent translation of WUSCHEL mRNA and regulates the stem cell homeostasis of Arabidopsis in response to environmental hazards.

    Science.gov (United States)

    Cui, Yuchao; Rao, Shaofei; Chang, Beibei; Wang, Xiaoshuang; Zhang, Kaidian; Hou, Xueliang; Zhu, Xueyi; Wu, Haijun; Tian, Zhaoxia; Zhao, Zhong; Yang, Chengwei; Huang, Tao

    2015-10-01

    Plant stem cells are hypersensitive to environmental hazards throughout their life cycle, but the mechanism by which plants safeguard stem cell homeostasis in response to environmental hazards is largely unknown. The homeodomain transcription factor WUSCHEL (WUS) protein maintains the stem cell pool in the shoot apical meristem of Arabidopsis. Here, we demonstrate that the translation of WUS mRNA is directed by an internal ribosomal entry site (IRES) located in the 5'-untranslated region. The AtLa1 protein, an RNA-binding factor, binds to the 5'-untranslated region and initiates the IRES-dependent translation of WUS mRNA. Knockdown of AtLa1 expression represses the WUS IRES-dependent translation and leads to the arrest of growth and development. The AtLa1 protein is mainly located in the nucleoplasm. However, environmental hazards promote the nuclear-to-cytoplasmic translocation of the AtLa1 protein, which further enhances the IRES-dependent translation of WUS mRNA. Genetic evidence indicates that the WUS protein increases the tolerance of the shoot apical meristem to environmental hazards. Based on these results, we conclude that the stem cell niche in Arabidopsis copes with environmental hazards by enhancing the IRES-dependent translation of WUS mRNA under the control of the AtLa1 protein. © 2015 John Wiley & Sons Ltd.

  13. Deciphering alternative splicing and nonsense-mediated decay modulate expression in primary lymphoid tissues of birds infected with avian pathogenic E. coli (APEC).

    Science.gov (United States)

    Sun, Hongyan

    2017-03-07

    Avian pathogenic E. coli (APEC) can lead to a loss in millions of dollars in poultry annually because of mortality and produce contamination. Studies have verified that many immune-related genes undergo changes in alternative splicing (AS), along with nonsense mediated decay (NMD), to regulate the immune system under different conditions. Therefore, the splicing profiles of primary lymphoid tissues with systemic APEC infection need to be comprehensively examined. Gene expression in RNAseq data were obtained for three different immune tissues (bone marrow, thymus, and bursa) from three phenotype birds (non-challenged, resistant, and susceptible birds) at two time points. Alternative 5' splice sites and exon skipping/inclusion were identified as the major alternative splicing events in avian primary immune organs under systemic APEC infection. In this study, we detected hundreds of differentially-expressed-transcript-containing genes (DETs) between different phenotype birds at 5 days post-infection (dpi). DETs, PSAP and STT3A, with NMD have important functions under systemic APEC infection. DETs, CDC45, CDK1, RAG2, POLR1B, PSAP, and DNASE1L3, from the same transcription start sites (TSS) indicate that cell death, cell cycle, cellular function, and maintenance were predominant in host under systemic APEC. With the use of RNAseq technology and bioinformatics tools, this study provides a portrait of the AS event and NMD in primary lymphoid tissues, which play critical roles in host homeostasis under systemic APEC infection. According to this study, AS plays a pivotal regulatory role in the immune response in chicken under systemic APEC infection via either NMD or alternative TSSs. This study elucidates the regulatory role of AS for the immune complex under systemic APEC infection.

  14. Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity.

    Science.gov (United States)

    Everaere, Laetitia; Ait-Yahia, Saliha; Molendi-Coste, Olivier; Vorng, Han; Quemener, Sandrine; LeVu, Pauline; Fleury, Sebastien; Bouchaert, Emmanuel; Fan, Ying; Duez, Catherine; de Nadai, Patricia; Staels, Bart; Dombrowicz, David; Tsicopoulos, Anne

    2016-11-01

    Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and T H 2 and T H 17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1β levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including T H 2 and T H 17 infiltration. These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  15. The role of microRNA-126 in vascular homeostasis

    NARCIS (Netherlands)

    Solingen, Coen van

    2012-01-01

    This thesis details our studies assessing the role of the endothelial-enriched miRNA-126 in the regulation of vascular homeostasis. In Chapter 2 the current insight in the role of miRNA-126 in vascular homeostasis is reviewed. Chapter 3 focuses on the role of miRNA-126 in ischemia induced

  16. Subpopulations of lymphoid and non-lymphoid cells in bronchus-associated lymphoid tissue (BALT) of the mouse.

    Science.gov (United States)

    Breel, M; Van der Ende, M; Sminia, T; Kraal, G

    1988-01-01

    Lymphoid and non-lymphoid subpopulations were investigated in the lung of the mouse with immunocyto-, immunohisto- and enzyme-histochemical methods. Special attention was paid to the cell populations in bronchus-associated lymphoid tissue (BALT), which is positioned between a bronchus and an artery. In BALT, discrete T- and B-cell areas can be found. The majority of the T cells belong to the L3T4+ (T-helper) subpopulation. In the T-cell area interdigitating cells can be recognized by anti-class II antibodies as well as by specific monoclonal antibodies, NLDC-145 and MIDC-8. Macrophage subpopulations can be discriminated by location, enzyme reactivity and various macrophage-specific monoclonal antibody markers. On the outer rim of BALT macrophages are recognized by the MOMA-1 and ERTR9 antibody. Macrophages dispersed in BALT can only be discriminated with the MOMA-2 antibody. The macrophage markers F4/80 and Mac-1 show no reactivity in BALT. In lung, tissue macrophages around bronchi and blood vessels are predominantly recognized by the MOMA-1 and MOMA-2 antibody, and a minor population by the ERTR9 antibody. Alveolar macrophages show heterogeneity with the MOMA-1, MOMA-2 and NLDC-145 antibody. The relationship between alveolar macrophages and antigen-presenting cells is discussed here. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:3259206

  17. Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA.

    Science.gov (United States)

    Mowel, Walter K; McCright, Sam J; Kotzin, Jonathan J; Collet, Magalie A; Uyar, Asli; Chen, Xin; DeLaney, Alexandra; Spencer, Sean P; Virtue, Anthony T; Yang, EnJun; Villarino, Alejandro; Kurachi, Makoto; Dunagin, Margaret C; Pritchard, Gretchen Harms; Stein, Judith; Hughes, Cynthia; Fonseca-Pereira, Diogo; Veiga-Fernandes, Henrique; Raj, Arjun; Kambayashi, Taku; Brodsky, Igor E; O'Shea, John J; Wherry, E John; Goff, Loyal A; Rinn, John L; Williams, Adam; Flavell, Richard A; Henao-Mejia, Jorge

    2017-09-19

    Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs. Moreover, the Rroid locus, but not the lncRNA itself, controlled the identity and function of ILC1s by promoting chromatin accessibility and deposition of STAT5 at the promoter of Id2 in response to interleukin (IL)-15. Thus, non-coding elements responsive to extracellular cues unique to each ILC subset represent a key regulatory layer for controlling the identity and function of ILCs. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Transcription of DWARF4 plays a crucial role in auxin-regulated root elongation in addition to brassinosteroid homeostasis in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Yuya Yoshimitsu

    Full Text Available The expression of DWARF4 (DWF4, which encodes a C-22 hydroxylase, is crucial for brassinosteroid (BR biosynthesis and for the feedback control of endogenous BR levels. To advance our knowledge of BRs, we examined the effects of different plant hormones on DWF4 transcription in Arabidopsis thaliana. Semi-quantitative reverse-transcriptase PCR showed that the amount of the DWF4 mRNA precursor either decreased or increased, similarly with its mature form, in response to an exogenously applied bioactive BR, brassinolide (BL, and a BR biosynthesis inhibitor, brassinazole (Brz, respectively. The response to these chemicals in the levels of β-glucuronidase (GUS mRNA and its enzymatic activity is similar to the response of native DWF4 mRNA in DWF4::GUS plants. Contrary to the effects of BL, exogenous auxin induced GUS activity, but this enhancement was suppressed by anti-auxins, such as α-(phenylethyl-2-one-IAA and α-tert-butoxycarbonylaminohexyl-IAA, suggesting the involvement of SCF(TIR1-mediated auxin signaling in auxin-induced DWF4 transcription. Auxin-enhanced GUS activity was observed exclusively in roots; it was the most prominent in the elongation zones of both primary and lateral roots. Furthermore, auxin-induced lateral root elongation was suppressed by both Brz application and the dwf4 mutation, and this suppression was rescued by BL, suggesting that BRs act positively on root elongation under the control of auxin. Altogether, our results indicate that DWF4 transcription plays a novel role in the BR-auxin crosstalk associated with root elongation, in addition to its role in BR homeostasis.

  19. Long-term infusion of nesfatin-1 causes a sustained regulation of whole-body energy homeostasis of male Fischer 344 rats.

    Science.gov (United States)

    Mortazavi, Sima; Gonzalez, Ronald; Ceddia, Rolando; Unniappan, Suraj

    2015-01-01

    Nesfatin-1, the N-terminal fragment of nucleobindin 2 (NUCB2), is an 82 amino-acid peptide that inhibits food intake and exerts weight-reducing effects. Nesfatin-1 has been proposed as a potential anti-obesity peptide. However, studies to date have mainly focused on the acute satiety effects of centrally administered nesfatin-1. The main objective of our studies was to characterize the long-term/chronic effects of peripheral administration of nesfatin-1 on whole-body energy balance and metabolic partitioning in male Fischer 344 rats. Short-term (1 day) subcutaneous infusion of nesfatin-1 (50 μg/kg body weight/day) using osmotic mini-pumps increased spontaneous physical activity and whole-body fat oxidation during the dark phase. This was accompanied by decreased food intake and basal metabolic rate compared to saline infused controls. On the seventh day of nesfatin-1 infusion, cumulative food intake, and total spontaneous physical activity during the dark phase were significantly reduced and elevated, respectively. Meanwhile, intraperitoneal injection of nesfatin-1 only caused a dark phase specific reduction in food intake and an increase in physical activity. NUCB2 mRNA expression in the brain and stomach, as well as serum NUCB2 concentrations were significantly reduced after 24 h fasting, while a post-prandial increase in serum NUCB2 was found in ad libitum fed rats. Collectively, our results indicate that chronic peripheral administration of nesfatin-1 at the dose tested, results in a sustained reduction in food intake and modulation of whole body energy homeostasis.

  20. STUDIES ON TRANSMISSIBLE LYMPHOID LEUCEMIA OF MICE.

    Science.gov (United States)

    Furth, J; Strumia, M

    1931-04-30

    Lymphoid leucemia of the mouse is readily transmitted by intravenous inoculations. The majority of the mice inoculated successfully develop leucemic, a smaller number of them, aleucemic lymphadenosis. The data presented favor the view that leucemic and aleucemic lymphadenosis are essentially the same condition. Leucemia produced by transmission is preceded by an aleucemic stage, in which the lymph nodes and the spleen are uniformly enlarged, and the white blood count and the percentage of lymphocytes are within the normal range but immature lymphocytes are numerous in the circulating blood. Young as well as old mice may develop leucemia if leucotic material enters their circulation. Studies of transmissible leucemia favor the view that leucemia of mammals is a neoplastic disease. The basic problem of leucemia would seem to be determination of the factors that bring about a malignant transformation of lymphoid cells.

  1. Bronchus-associated lymphoid tissue lymphomas.

    Science.gov (United States)

    Arnaoutakis, Konstantinos; Oo, Thein H

    2009-12-01

    : Bronchus-associated Lymphoid Tissue (BALT) lymphomas are a rare type of extranodal marginal zone lymphomas. They comprise 1% of lymphomas and more than two-thirds of all primary non-Hodgkin lymphoma (NHL) of the lung. BALT lymphomas arise from the bronchus-associated lymphoid tissue. This report describes five cases of BALT lymphoma and discusses the pathogenesis, diagnosis, prognosis and treatment of BALT lymphomas. In our cohort of patients, patients were managed with surgery, watchful waiting, chemotherapy, immunotherapy, and chemoimmunotherapy. The outcomes are excellent and projected 5-year survival is 100%. BALT lymphomas are associated with chronic inflammation, and they are often asymptomatic. They have an indolent course and the survival outcome is excellent with different treatment modalities such as surgery, watchful waiting, radiotherapy, chemotherapy, immunotherapy or chemoimmunotherapy.

  2. 'Trained immunity': consequences for lymphoid malignancies.

    Science.gov (United States)

    Stevens, Wendy B C; Netea, Mihai G; Kater, Arnon P; van der Velden, Walter J F M

    2016-12-01

    In hematological malignancies complex interactions exist between the immune system, microorganisms and malignant cells. On one hand, microorganisms can induce cancer, as illustrated by specific infection-induced lymphoproliferative diseases such as Helicobacter pylori-associated gastric mucosa-associated lymphoid tissue lymphoma. On the other hand, malignant cells create an immunosuppressive environment for their own benefit, but this also results in an increased risk of infections. Disrupted innate immunity contributes to the neoplastic transformation of blood cells by several mechanisms, including the uncontrolled clearance of microbial and autoantigens resulting in chronic immune stimulation and proliferation, chronic inflammation, and defective immune surveillance and anti-cancer immunity. Restoring dysfunction or enhancing responsiveness of the innate immune system might therefore represent a new angle for the prevention and treatment of hematological malignancies, in particular lymphoid malignancies and associated infections. Recently, it has been shown that cells of the innate immune system, such as monocytes/macrophages and natural killer cells, harbor features of immunological memory and display enhanced functionality long-term after stimulation with certain microorganisms and vaccines. These functional changes rely on epigenetic reprogramming and have been termed 'trained immunity'. In this review the concept of 'trained immunity' is discussed in the setting of lymphoid malignancies. Amelioration of infectious complications and hematological disease progression can be envisioned to result from the induction of trained immunity, but future studies are required to prove this exciting new hypothesis. Copyright© Ferrata Storti Foundation.

  3. Innate Lymphoid Cells: a new paradigm in immunology

    Science.gov (United States)

    Eberl, Gérard; Colonna, Marco; Di Santo, James P.; McKenzie, Andrew N.J.

    2016-01-01

    Summary Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex crosstalk between microenvironment, ILCs and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed to regulate or enhance immune responses in disease prevention and therapy. PMID:25999512

  4. bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

    Energy Technology Data Exchange (ETDEWEB)

    Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Schulz, Robert A., E-mail: rschulz@nd.edu

    2014-10-24

    Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to lead to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche.

  5. Establishment and function of tissue-resident innate lymphoid cells in the skin

    Directory of Open Access Journals (Sweden)

    Jie Yang

    2017-03-01

    Full Text Available ABSTRACT Innate lymphoid cells (ILCs are a newly classified family of immune cells of the lymphoid lineage. While they could be found in both lymphoid organs and non-lymphoid tissues, ILCs are preferentially enriched in barrier tissues such as the skin, intestine, and lung where they could play important roles in maintenance of tissue integrity and function and protection against assaults of foreign agents. On the other hand, dysregulated activation of ILCs could contribute to tissue inflammatory diseases. In spite of recent progress towards understanding roles of ILCs in the health and disease, mechanisms regulating specific establishment, activation, and function of ILCs in barrier tissues are still poorly understood. We herein review the up-to-date understanding of tissue-specific relevance of ILCs. Particularly we will focus on resident ILCs of the skin, the outmost barrier tissue critical in protection against various foreign hazardous agents and maintenance of thermal and water balance. In addition, we will discuss remaining outstanding questions yet to be addressed.

  6. Establishment and function of tissue-resident innate lymphoid cells in the skin.

    Science.gov (United States)

    Yang, Jie; Zhao, Luming; Xu, Ming; Xiong, Na

    2017-07-01

    Innate lymphoid cells (ILCs) are a newly classified family of immune cells of the lymphoid lineage. While they could be found in both lymphoid organs and non-lymphoid tissues, ILCs are preferentially enriched in barrier tissues such as the skin, intestine, and lung where they could play important roles in maintenance of tissue integrity and function and protection against assaults of foreign agents. On the other hand, dysregulated activation of ILCs could contribute to tissue inflammatory diseases. In spite of recent progress towards understanding roles of ILCs in the health and disease, mechanisms regulating specific establishment, activation, and function of ILCs in barrier tissues are still poorly understood. We herein review the up-to-date understanding of tissue-specific relevance of ILCs. Particularly we will focus on resident ILCs of the skin, the outmost barrier tissue critical in protection against various foreign hazardous agents and maintenance of thermal and water balance. In addition, we will discuss remaining outstanding questions yet to be addressed.

  7. The interleukin-15 system suppresses T cell-mediated autoimmunity by regulating negative selection and nT(H)17 cell homeostasis in the thymus.

    Science.gov (United States)

    Hou, Mau-Sheng; Huang, Shih-Ting; Tsai, Ming-Han; Yen, Ching-Cheng; Lai, Yein-Gei; Liou, Yae-Huei; Lin, Chih-Kung; Liao, Nan-Shih

    2015-01-01

    The interleukin-15 (IL-15) system is important for regulating both innate and adaptive immune responses, however, its role in autoimmune disease remained unclear. Here we found that Il15(-/-) and Il15ra(-/-) mice spontaneously developed late-onset autoimmune phenotypes. CD4(+) T cells of the knockout mice showed elevated autoreactivity as demonstrated by the induction of lymphocyte infiltration in the lacrimal and salivary glands when transferred into nude mice. The antigen-presenting cells in the thymic medullary regions expressed IL-15 and IL-15Rα, whose deficiency resulted in insufficient negative selection and elevated number of natural IL-17A-producing CD4(+) thymocytes. These findings reveal previously unknown functions of the IL-15 system in thymocyte development, and thus a new layer of regulation in T cell-mediated autoimmunity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Multi-domain CGFS-type glutaredoxin Grx4 regulates iron homeostasis via direct interaction with a repressor Fep1 in fission yeast

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyoung-Dong; Kim, Hyo-Jin; Lee, Kyung-Chang [Laboratory of Molecular Microbiology, School of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul 151-742 (Korea, Republic of); Roe, Jung-Hye, E-mail: jhroe@snu.ac.kr [Laboratory of Molecular Microbiology, School of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul 151-742 (Korea, Republic of)

    2011-05-20

    Research highlights: {yields} Monothiol glutaredoxin Grx4 allows Fep1-mediated de-repression of iron uptake genes at low iron. {yields} Grx4 directly interacts with Fep1 in vivo and in vitro. {yields} The Cys172 in the CGFS motif of Grx4 is necessary for cell proliferation and iron regulation. {yields} The Cys172 of Grx4 is required for normal interaction with Fep1. -- Abstract: The fission yeast Schizosaccharomyces pombe contains two CGFS-type monothiol glutaredoxins, Grx4 and Grx5, which are localized primarily in the nucleus and mitochondria, respectively. We observed involvement of Grx4 in regulating iron-responsive gene expression, which is modulated by a repressor Fep1. Lack of Grx4 caused defects not only in growth but also in the expression of both iron-uptake and iron-utilizing genes regardless of iron availability. In order to unravel how Grx4 is involved in Fep1-mediated regulation, interaction between them was investigated. Co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) revealed that Grx4 physically interacts with Fep1 in vivo. BiFC revealed localized nuclear dots produced by interaction of Grx4 with Fep1. Mutation of cysteine-172 in the CGFS motif to serine (C172S) produced effects similarly observed under Grx4 depletion, such as the loss of iron-dependent gene regulation and the absence of nuclear dots in BiFC analysis. These results suggest that the ability of Grx4 to bind iron, most likely Fe-S cofactor, could be critical in interacting with and modulating the activity of Fep1.

  9. Tomato CRY1a plays a critical role in the regulation of phytohormone homeostasis, plant development, and carotenoid metabolism in fruits.

    Science.gov (United States)

    Liu, Chao-Chao; Ahammed, Golam Jalal; Wang, Guo-Ting; Xu, Chang-Jie; Chen, Kun-Song; Zhou, Yan-Hong; Yu, Jing-Quan

    2018-02-01

    Blue light photoreceptors, cryptochromes (CRYs), regulate multiple aspects of plant growth and development. However, our knowledge of CRYs is predominantly based on model plant Arabidopsis at early growth stage. In this study, we elucidated functions of CRY1a gene in mature tomato (Solanum lycopersicum) plants by using cry1a mutants and CRY1a-overexpressing lines (OE-CRY1a-1 and OE-CRY1a-2). In comparison with wild-type plants, cry1a mutants are relatively tall, accumulate low biomass, and bear more fruits, whereas OE-CRY1a plants are short stature, and they not only flower lately but also bear less fruits. RNA-seq, qRT-PCR, and LC-MS/MS analysis revealed that biosynthesis of gibberellin, cytokinin, and jasmonic acid was down-regulated by CRY1a. Furthermore, DNA replication was drastically inhibited in leaves of OE-CRY1a lines, but promoted in cry1a mutants with concomitant changes in the expression of cell cycle genes. However, CRY1a positively regulated levels of soluble sugars, phytofluene, phytoene, lycopene, and ß-carotene in the fruits. The results indicate the important role of CRY1a in plant growth and have implications for molecular interventions of CRY1a aimed at improving agronomic traits. © 2017 John Wiley & Sons Ltd.

  10. Suitability of stratagene reference RNA for analysis of lymphoid tissues

    DEFF Research Database (Denmark)

    Dybkaer, Karen; Zhou, Guimei; Iqbal, Javeed

    2004-01-01

    acceptable gene coverage to serve as a comprehensive standard for gene expression profiling of lymphoid tissues. Our lymphoid standard was prepared from thymus, spleen, tonsil, and cell lines representing immature B cells, plasma cells, and natural killer (NK) cells, thus covering the entire spectrum...... of lymphoid cells and most stromal elements present in specialized lymphoid tissues. The two standards were co-hybridized on oligonucleotide microarrays containing 17,260 genes, and both had fluorescence intensities above background for approximately 85% of the genes. Despite the limited representation......We evaluated a lymphoid RNA standard prepared in our laboratory for spotted microarrays against the Universal Human Reference standard from Stratagene. Our goal was to determine if the Stratagene standard, which contains only two lymphoid cell lines out of a pool of 10 human cancer cell lines, had...

  11. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Qiang; Chen, Xin-li; Wang, Chang-yuan; Liu, Qi; Sun, Hui-jun; Sun, Peng-yuan; Huo, Xiao-kui; Liu, Zhi-hao; Yao, Ji-hong; Liu, Ke-xin, E-mail: kexinliu@dlmedu.edu.cn

    2015-03-15

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. - Highlights: • AB23A has at least three roles in protection against ANIT-induced liver injury. • AB23A decreases Ntcp, and increases Bsep, Mrp2 and Mdr2 expression. • AB23A represses Cyp7a1 and Cyp8b1 through inducing Shp and Fgf15 expression. • AB23A increases bile acid metabolism through inducing Sult2a1 expression. • FXR activation is involved

  12. Alcohol disrupts sleep homeostasis.

    Science.gov (United States)

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  13. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels

    DEFF Research Database (Denmark)

    Reddy, I A; Pino, J A; Weikop, P

    2016-01-01

    Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine...... actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from...... the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within...

  14. Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons.

    Science.gov (United States)

    Llorente-Folch, Irene; Rueda, Carlos B; Amigo, Ignacio; del Arco, Araceli; Saheki, Takeyori; Pardo, Beatriz; Satrústegui, Jorgina

    2013-08-28

    Neuronal respiration is controlled by ATP demand and Ca2+ but the roles played by each are unknown, as any Ca2+ signal also impacts on ATP demand. Ca2+ can control mitochondrial function through Ca2+-regulated mitochondrial carriers, the aspartate-glutamate and ATP-Mg/Pi carriers, ARALAR/AGC1 and SCaMC-3, respectively, or in the matrix after Ca2+ transport through the Ca2+ uniporter. We have studied the role of Ca2+ signaling in the regulation of mitochondrial respiration in intact mouse cortical neurons in basal conditions and in response to increased workload caused by increases in [Na+]cyt (veratridine, high-K+ depolarization) and/or [Ca2+]cyt (carbachol). Respiration in nonstimulated neurons on 2.5-5 mm glucose depends on ARALAR-malate aspartate shuttle (MAS), with a 46% drop in aralar KO neurons. All stimulation conditions induced increased OCR (oxygen consumption rate) in the presence of Ca2+, which was prevented by BAPTA-AM loading (to preserve the workload), or in Ca2+-free medium (which also lowers cell workload). SCaMC-3 limits respiration only in response to high workloads and robust Ca2+ signals. In every condition tested Ca2+ activation of ARALAR-MAS was required to fully stimulate coupled respiration by promoting pyruvate entry into mitochondria. In aralar KO neurons, respiration was stimulated by veratridine, but not by KCl or carbachol, indicating that the Ca2+ uniporter pathway played a role in the first, but not in the second condition, even though KCl caused an increase in [Ca2+]mit. The results suggest a requirement for ARALAR-MAS in priming pyruvate entry in mitochondria as a step needed to activate respiration by Ca2+ in response to moderate workloads.

  15. Characterization of interactions between transcription factors and a regulatory region spanning nt-320 to-281 of the HIV-1 LTR in T-lymphoid and non-T-lymphoid cells

    NARCIS (Netherlands)

    Pereira, LA; Churchill, MJ; Elefanty, AG; Gouskos, T; Lambert, PF; Ramsay, RG; Deacon, NJ

    2002-01-01

    HIV-1 gene expression is regulated by the interplay of transcription factors with multiple binding motifs present within the U3, R and U5 regions of the long terminal repeat (LTR). Here we report novel DNA binding complexes (termed 9a, 9b and 9c) between nuclear proteins from T-lymphoid and

  16. File list: Unc.Bld.20.AllAg.Leukemia,_Lymphoid [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Bld.20.AllAg.Leukemia,_Lymphoid mm9 Unclassified Blood Leukemia, Lymphoid http:...//dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Unc.Bld.20.AllAg.Leukemia,_Lymphoid.bed ...

  17. File list: Pol.Bld.20.AllAg.Leukemia,_Lymphoid [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Bld.20.AllAg.Leukemia,_Lymphoid mm9 RNA polymerase Blood Leukemia, Lymphoid htt...p://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Pol.Bld.20.AllAg.Leukemia,_Lymphoid.bed ...

  18. File list: Pol.Bld.05.AllAg.Leukemia,_Lymphoid [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Bld.05.AllAg.Leukemia,_Lymphoid mm9 RNA polymerase Blood Leukemia, Lymphoid htt...p://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Pol.Bld.05.AllAg.Leukemia,_Lymphoid.bed ...

  19. File list: Unc.Bld.50.AllAg.Leukemia,_Lymphoid [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Bld.50.AllAg.Leukemia,_Lymphoid mm9 Unclassified Blood Leukemia, Lymphoid http:...//dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Unc.Bld.50.AllAg.Leukemia,_Lymphoid.bed ...

  20. Tolerance and lymphoid organ structure and function

    Directory of Open Access Journals (Sweden)

    Bryna Elizabeth Burrell

    2011-12-01

    Full Text Available This issue of Frontiers in Immunologic Tolerance explores barriers to tolerance from a variety of views of cells, molecules, and processes of the immune system. Our laboratory has spent over a decade focused on the migration of the cells of the immune system, and dissecting the signals that determine how and where effector and suppressive regulatory T cells traffic from one site to another in order to reject or protect allografts. These studies have led us to a greater appreciation of the anatomic structure of the immune system, and the realization that the path taken by lymphocytes during the course of the immune response to implanted organs determines the final outcome. In particular, the structures, microanatomic domains, and the cells and molecules that lymphocytes encounter during their transit through blood, tissues, lymphatics, and secondary lymphoid organs are powerful determinants for whether tolerance is achieved. Thus, the understanding of complex cellular and molecular processes of tolerance will not come from 96-well plate immunology, but from an integrated understanding of the temporal and spatial changes that occur during the response to the allograft. The study of the precise positioning and movement of cells in lymphoid organs has been difficult since it is hard to visualize cells within their 3-dimensional setting; instead techniques have tended to be dominated by 2-dimensional renderings, although advanced confocal and 2-photon systems are changing this view. It is difficult to precisely modify key molecules and events in lymphoid organs, so that existing knockouts, transgenics, inhibitors, and activators have global and pleiotropic effects, rather than precise anatomically restricted influences. Lastly, there are no well-defined postal codes or tracking systems for leukocytes, so that while we can usually track cells from point A to point B, it is exponentially more difficult or even impossible to track them to point C and

  1. Genetic dissection of sleep homeostasis.

    Science.gov (United States)

    Mang, Géraldine M; Franken, Paul

    2015-01-01

    Sleep is a complex behavior both in its manifestation and regulation, that is common to almost all animal species studied thus far. Sleep is not a unitary behavior and has many different aspects, each of which is tightly regulated and influenced by both genetic and environmental factors. Despite its essential role for performance, health, and well-being, genetic mechanisms underlying this complex behavior remain poorly understood. One important aspect of sleep concerns its homeostatic regulation, which ensures that levels of sleep need are kept within a range still allowing optimal functioning during wakefulness. Uncovering the genetic pathways underlying the homeostatic aspect of sleep is of particular importance because it could lead to insights concerning sleep's still elusive function and is therefore a main focus of current sleep research. In this chapter, we first give a definition of sleep homeostasis and describe the molecular genetics techniques that are used to examine it. We then provide a conceptual discussion on the problem of assessing a sleep homeostatic phenotype in various animal models. We finally highlight some of the studies with a focus on clock genes and adenosine signaling molecules.

  2. Innate lymphoid cells in inflammatory bowel diseases.

    Science.gov (United States)

    Peters, C P; Mjösberg, J M; Bernink, J H; Spits, H

    2016-04-01

    It is generally believed that inflammatory bowel diseases (IBD) are caused by an aberrant immune response to environmental triggers in genetically susceptible individuals. The exact contribution of the adaptive and innate immune system has not been elucidated. However, recent advances in treatments targeting key inflammatory mediators such as tumour necrosis factor highlight the crucial role of the innate immune system in IBD. Innate lymphoid cells (ILCs) have recently been identified to play an important role in immune mediated inflammatory diseases. In this review we recapitulate the current knowledge on ILCs in IBD. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  3. The Development of Adult Innate Lymphoid Cells

    Science.gov (United States)

    Yang, Qi; Bhandoola, Avinash

    2016-01-01

    Innate lymphoid cells (ILC) are a specialized family of effector lymphocytes that transcriptionally and functionally mirror effector subsets of T cells, but differ from T cells in that they lack clonally-distributed adaptive antigen receptors. Our understanding of this family of lymphocytes is still in its infancy. In this review, we summarize current understanding and discuss recent insights into the cellular and molecular events that occur during early ILC development in adult mice. We discuss how these events overlap and diverge with the early development of adaptive T cells, and how they may influence the molecular and functional properties of mature ILC. PMID:26871595

  4. Group 1 innate lymphoid cells in Toxoplasma gondii infection.

    Science.gov (United States)

    Dunay, I R; Diefenbach, A

    2018-02-01

    Innate lymphoid cells (ILCs) are a group of lymphocytes that carry out important functions in immunity to infections and in organ homeostasis at epithelial barrier surfaces. ILCs are innate immune cells that provide an early source of cytokines to initiate immune responses against pathogens. Cytotoxic ILCs (i.e. conventional (c)NK cells) and several subsets of helper-like ILCs are the major branches of the ILC family. Conventional NK cells and group 1 ILCs share several characteristics such as surface receptors and the ability to produce IFN-γ upon activation, but they differ in their developmental paths and in their dependence on specific transcription factors. Infection of mice with the intracellular parasite Toxoplasma gondii is followed by a strong Th1-mediated immune response. Previous studies indicate that NK1.1 + cells contribute to the production of IFN-γ and TNF and cytotoxicity during acute T. gondii infection. Upon oral infection, the parasite infects intestinal enterocytes, and within the lamina propria, innate immune responses lead to initial parasite control although the infection disseminates widely and persists long-term in immune privileged sites despite adaptive immunity. Upon parasite entry into the small intestine, during the acute stage, ILC1 produce high levels of IFN-γ and TNF protecting barrier surfaces, thus essentially contributing to early parasite control. We will discuss here the role of innate lymphocytes during T. gondii infection in the context of the only recently appreciated diversity of ILC subsets. © 2018 John Wiley & Sons Ltd.

  5. Regulation of Nutritional Metabolism in Transition Dairy Cows: Energy Homeostasis and Health in Response to Post-Ruminal Choline and Methionine.

    Science.gov (United States)

    Sun, Feifei; Cao, Yangchun; Cai, Chuanjiang; Li, Shengxiang; Yu, Chao; Yao, Junhu

    2016-01-01

    This study investigated the effects of rumen-protected methionine (RPM) and rumen-protected choline (RPC) on energy balance, postpartum lactation performance, antioxidant capacity and immune response in transition dairy cows. Forty-eight multiparous transition cows were matched and divided into four groups: control, 15 g/d RPC, 15 g/d RPM or 15 g/d RPC + 15 g/d RPM. Diet samples were collected daily before feeding, and blood samples were collected weekly from the jugular vein before morning feeding from 21 days prepartum to 21 days postpartum. Postpartum dry matter intake (DMI) was increased by both additives (P energy balance values in supplemented cows were improved after parturition (P ruminal choline and methionine elevated the blood antioxidant status, as indicated by total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px) activity and the vitamin E concentration (P energy balance by increasing postpartal DMI and regulating hepatic lipid metabolism, improved postpartum lactation performance and enhanced antioxidant capacity and immune function of transition dairy cows.

  6. Nesfatin-1-like peptide is a novel metabolic factor that suppresses feeding, and regulates whole-body energy homeostasis in male Wistar rats

    Science.gov (United States)

    Gawli, Kavishankar; Ramesh, Naresh

    2017-01-01

    Nucleobindin-1 has high sequence similarity to nucleobindin-2, which encodes the anorectic and metabolic peptide, nesfatin-1. We previously reported a nesfatin-1-like peptide (NLP), anorectic in fish and insulinotropic in mice islet beta-like cells. The main objective of this research was to determine whether NLP is a metabolic regulator in male Wistar rats. A single intraperitoneal (IP) injection of NLP (100 μg/kg BW) decreased food intake and increased ambulatory movement, without causing any change in total activity or energy expenditure when compared to saline-treated rats. Continuous subcutaneous infusion of NLP (100 μg/kg BW) using osmotic mini-pumps for 7 days caused a reduction in food intake on days 3 and 4. Similarly, water intake was also reduced for two days (days 3 and 4) with the effect being observed during the dark phase. This was accompanied by an increased RER and energy expenditure. However, decreased whole-body fat oxidation, and total activity were observed during the long-term treatment (7 days). Body weight gain was not significantly different between control and NLP infused rats. The expression of mRNAs encoding adiponectin, resistin, ghrelin, cholecystokinin and uncoupling protein 1 (UCP1) were significantly upregulated, while leptin and peptide YY mRNA expression was downregulated in NLP-treated rats. These findings indicate that administration of NLP at 100 μg/kg BW reduces food intake and modulates whole body energy balance. In summary, NLP is a novel metabolic peptide in rats. PMID:28542568

  7. The SlCBL10 Calcineurin B-Like Protein Ensures Plant Growth under Salt Stress by Regulating Na+and Ca2+Homeostasis.

    Science.gov (United States)

    Egea, Isabel; Pineda, Benito; Ortíz-Atienza, Ana; Plasencia, Félix A; Drevensek, Stéphanie; García-Sogo, Begoña; Yuste-Lisbona, Fernando J; Barrero-Gil, Javier; Atarés, Alejandro; Flores, Francisco B; Barneche, Fredy; Angosto, Trinidad; Capel, Carmen; Salinas, Julio; Vriezen, Wim; Esch, Elisabeth; Bowler, Chris; Bolarín, Maria C; Moreno, Vicente; Lozano, Rafael

    2018-02-01

    Characterization of a new tomato ( Solanum lycopersicum ) T-DNA mutant allowed for the isolation of the CALCINEURIN B-LIKE PROTEIN 10 ( SlCBL10 ) gene whose lack of function was responsible for the severe alterations observed in the shoot apex and reproductive organs under salinity conditions. Physiological studies proved that SlCBL10 gene is required to maintain a proper low Na + /Ca 2+ ratio in growing tissues allowing tomato growth under salt stress. Expression analysis of the main responsible genes for Na + compartmentalization (i.e. Na + /H + EXCHANGERs , SALT OVERLY SENSITIVE , HIGH-AFFINITY K+ TRANSPORTER 1;2 , H + -pyrophosphatase AVP1 [ SlAVP1 ] and V-ATPase [ SlVHA-A1 ]) supported a reduced capacity to accumulate Na + in Slcbl10 mutant leaves, which resulted in a lower uploading of Na + from xylem, allowing the toxic ion to reach apex and flowers. Likewise, the tomato CATION EXCHANGER 1 and TWO-PORE CHANNEL 1 ( SlTPC1 ), key genes for Ca 2+ fluxes to the vacuole, showed abnormal expression in Slcbl10 plants indicating an impaired Ca 2+ release from vacuole. Additionally, complementation assay revealed that SlCBL10 is a true ortholog of the Arabidopsis ( Arabidopsis thaliana ) CBL10 gene, supporting that the essential function of CBL10 is conserved in Arabidopsis and tomato. Together, the findings obtained in this study provide new insights into the function of SlCBL10 in salt stress tolerance. Thus, it is proposed that SlCBL10 mediates salt tolerance by regulating Na + and Ca 2+ fluxes in the vacuole, cooperating with the vacuolar cation channel SlTPC1 and the two vacuolar H + -pumps, SlAVP1 and SlVHA-A1 , which in turn are revealed as potential targets of SlCBL10 . © 2018 American Society of Plant Biologists. All Rights Reserved.

  8. Obesity- and gender-dependent role of endogenous somatostatin and cortistatin in the regulation of endocrine and metabolic homeostasis in mice.

    Science.gov (United States)

    Luque, Raúl M; Cordoba-Chacon, José; Pozo-Salas, Ana I; Porteiro, Begoña; de Lecea, Luis; Nogueiras, Rubén; Gahete, Manuel D; Castaño, Justo P

    2016-11-30

    Somatostatin (SST) and cortistatin (CORT) regulate numerous endocrine secretions and their absence [knockout (KO)-models] causes important endocrine-metabolic alterations, including pituitary dysregulations. We have demonstrated that the metabolic phenotype of single or combined SST/CORT KO-models is not drastically altered under normal conditions. However, the biological actions of SST/CORT are conditioned by the metabolic-status (e.g. obesity). Therefore, we used male/female SST- and CORT-KO mice fed low-fat (LF) or high-fat (HF) diet to explore the interplay between SST/CORT and obesity in the control of relevant pituitary-axes and whole-body metabolism. Our results showed that the SST/CORT role in the control of GH/prolactin secretions is maintained under LF- and HF-diet conditions as SST-KOs presented higher GH/prolactin-levels, while CORT-KOs displayed higher GH- and lower prolactin-levels than controls under both diets. Moreover, the impact of lack of SST/CORT on the metabolic-function was gender- and diet-dependent. Particularly, SST-KOs were more sensitive to HF-diet, exhibiting altered growth and body-composition (fat/lean percentage) and impaired glucose/insulin-metabolism, especially in males. Conversely, only males CORT-KO under LF-diet conditions exhibited significant alterations, displaying higher glucose-levels and insulin-resistance. Altogether, these data demonstrate a tight interplay between SST/CORT-axis and the metabolic status in the control of endocrine/metabolic functions and unveil a clear dissociation of SST/CORT roles.

  9. Overexpression of a tomato miR171 target gene SlGRAS24 impacts multiple agronomical traits via regulating gibberellin and auxin homeostasis.

    Science.gov (United States)

    Huang, Wei; Peng, Shiyuan; Xian, Zhiqiang; Lin, Dongbo; Hu, Guojian; Yang, Lu; Ren, Maozhi; Li, Zhengguo

    2017-04-01

    In Arabidopsis, the miR171-GRAS module has been clarified as key player in meristem maintenance. However, the knowledge about its role in fruit crops like tomato (Solanum lycopersicum) remains scarce. We previously identified tomato SlGRAS24 as a target gene of Sly-miR171. To study the role of this probable transcription factor, we generated transgenic tomato plants underexpressing SlGRAS24, overexpressing SlGRAS24, overexpressing Sly-miR171 and expressing β-glucuronidase (GUS) under the SlGRAS24 promoter (proSlGRAS24-GUS). Plants overexpressing SlGRAS24 (SlGRAS24-OE) had pleiotropic phenotypes associated with multiple agronomical traits including plant height, flowering time, leaf architecture, lateral branch number, root length, fruit set and development. Many GA/auxin-related genes were down-regulated and altered responsiveness to exogenous IAA/NAA or GA3 application was observed in SlGRAS24-OE seedlings. Moreover, compromised fruit set and development in SlGRAS24-OE was also observed. These newly identified phenotypes for SlGRAS24 homologs in tomato were later proved to be caused by impaired pollen sacs and fewer viable pollen grains. At anthesis, the comparative transcriptome results showed altered expression of genes involved in pollen development and hormone signalling. Taken together, our data demonstrate that SlGRAS24 participates in a series of developmental processes through modulating gibberellin and auxin signalling, which sheds new light on the involvement of hormone crosstalk in tomato development. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  10. Pregnancy Hyperglycemia in Prolactin Receptor Mutant, but Not Prolactin Mutant, Mice and Feeding-Responsive Regulation of Placental Lactogen Genes Implies Placental Control of Maternal Glucose Homeostasis.

    Science.gov (United States)

    Rawn, Saara M; Huang, Carol; Hughes, Martha; Shaykhutdinov, Rustem; Vogel, Hans J; Cross, James C

    2015-09-01

    Pregnancy is often viewed as a conflict between the fetus and mother over metabolic resources. Insulin resistance occurs in mothers during pregnancy but does not normally lead to diabetes because of an increase in the number of the mother's pancreatic beta cells. In mice, this increase is dependent on prolactin (Prl) receptor signaling but the source of the ligand has been unclear. Pituitary-derived Prl is produced during the first half of pregnancy in mice but the placenta produces Prl-like hormones from implantation to term. Twenty-two separate mouse genes encode the placenta Prl-related hormones, making it challenging to assess their roles in knockout models. However, because at least four of them are thought to signal through the Prl receptor, we analyzed Prlr mutant mice and compared their phenotypes with those of Prl mutants. We found that whereas Prlr mutants develop hyperglycemia during gestation, Prl mutants do not. Serum metabolome analysis showed that Prlr mutants showed other changes consistent with diabetes. Despite the metabolic changes, fetal growth was normal in Prlr mutants. Of the four placenta-specific, Prl-related hormones that have been shown to interact with the Prlr, their gene expression localizes to different endocrine cell types. The Prl3d1 gene is expressed by trophoblast giant cells both in the labyrinth layer, sitting on the arterial side where maternal blood is highest in oxygen and nutrients, and in the junctional zone as maternal blood leaves the placenta. Expression increases during the night, though the increase in the labyrinth is circadian whereas it occurs only after feeding in the junctional zone. These data suggest that the placenta has a sophisticated endocrine system that regulates maternal glucose metabolism during pregnancy. © 2015 by the Society for the Study of Reproduction, Inc.

  11. Induction of Barley Silicon Transporter HvLsi1 and HvLsi2, increased silicon concentration in the shoot and regulated Starch and ABA Homeostasis under Osmotic stress and Concomitant Potassium Deficiency

    Directory of Open Access Journals (Sweden)

    Seyed A. Hosseini

    2017-08-01

    Full Text Available Drought is one of the major stress factors reducing cereal production worldwide. There is ample evidence that the mineral nutrient status of plants plays a critical role in increasing plant tolerance to different biotic and abiotic stresses. In this regard, the important role of various nutrients e.g., potassium (K or silicon (Si in the mitigation of different stress factors, such as drought, heat or frost has been well documented. Si application has been reported to ameliorate plant nutrient deficiency. Here, we used K and Si either solely or in combination to investigate whether an additive positive effect on barley growth can be achieved under osmotic stress and which mechanisms contribute to a better tolerance to osmotic stress. To achieve this goal, barley plants were subjected to polyethylene glycol (PEG-induced osmotic stress under low or high K supply and two Si regimes. The results showed that barley silicon transporters HvLsi1 and HvLsi2 regulate the accumulation of Si in the shoot only when plant suffered from K deficiency. Si, in turn, increased the starch level under both osmotic stress and K deficiency and modulated the glycolytic and TCA pathways. Hormone profiling revealed that the beneficial effect of Si is most likely mediated also by ABA homeostasis and active cytokinin isopentenyl adenine (iP. We conclude that Si may effectively improve stress tolerance under K deficient condition in particular when additional stress like osmotic stress interferes.

  12. Deletion of apoptosis signal-regulating kinase 1 (ASK1 protects pancreatic beta-cells from stress-induced death but not from glucose homeostasis alterations under pro-inflammatory conditions.

    Directory of Open Access Journals (Sweden)

    Emilie Pepin

    Full Text Available Type 2 diabetes is characterized by pancreatic beta-cell dysfunction and is associated with low-grade inflammation. Recent observations suggest that apoptosis signal-regulating kinase 1 (ASK1 is involved in beta-cell death in response to different stressors. In this study, we tested whether ASK1 deficiency protects beta-cells from glucolipotoxic conditions and cytokines treatment or from glucose homeostasis alteration induced by endotoxemia.Insulin secretion was neither affected upon shRNA-mediated downregulation of ASK1 in MIN6 cells nor in islets from ASK1-deficient mice. ASK1 silencing in MIN6 cells and deletion in islets did not prevent the deleterious effect of glucolipotoxic conditions or cytokines on insulin secretion. However, it protected MIN6 cells from death induced by ER stress or palmitate and islets from short term caspase activation in response to cytokines. Moreover, endotoxemia induced by LPS infusion increased insulin secretion during hyperglycemic clamps but the response was similar in wild-type and ASK1-deficient mice. Finally, insulin sensitivity in the presence of LPS was not affected by ASK1-deficiency.Our study demonstrates that ASK1 is not involved in beta-cell function and dysfunction but controls stress-induced beta-cell death.

  13. Alcohol disrupts sleep homeostasis

    Science.gov (United States)

    Thakkar, Mahesh M.; Sharma, Rishi; Sahota, Pradeep

    2014-01-01

    Alcohol is a potent somnogen and one of the most commonly used “over the counter” sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to understand how and where alcohol acts to affect sleep. We have conducted a series of experiments using two different species, rats and mice, as animal models, and a combination of multi-disciplinary experimental methodologies to examine and understand anatomical and cellular substrates mediating the effects of acute and chronic alcohol exposure on sleep-wakefulness. The results of our studies suggest that the sleep-promoting effects of alcohol may be mediated via alcohol’s action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Lesions of the BF cholinergic neurons or blockade of AD A1 receptors results in attenuation of alcohol-induced sleep promotion, suggesting that AD and BF cholinergic neurons are critical for sleep-promoting effects of alcohol. Since binge alcohol consumption is a highly prevalent pattern

  14. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bergomas, Francesca [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Grizzi, Fabio [Laboratory of Molecular Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Doni, Andrea; Pesce, Samantha [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Laghi, Luigi [Laboratory of Molecular Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Department of Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Allavena, Paola [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Mantovani, Alberto [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Department of Translational Medicine, University of Milan, Milan 20089 (Italy); Marchesi, Federica, E-mail: federica.marchesi@humanitasresearch.it [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy)

    2011-12-28

    Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21{sup +} follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response.

  15. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    Directory of Open Access Journals (Sweden)

    Federica Marchesi

    2011-12-01

    Full Text Available Ectopic (or tertiary lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21+ follicular dendritic cells (FDC. We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS. B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV. Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response.

  16. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    Science.gov (United States)

    Bergomas, Francesca; Grizzi, Fabio; Doni, Andrea; Pesce, Samantha; Laghi, Luigi; Allavena, Paola; Mantovani, Alberto; Marchesi, Federica

    2011-01-01

    Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21+ follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response. PMID:24213222

  17. Regulation of Nutritional Metabolism in Transition Dairy Cows: Energy Homeostasis and Health in Response to Post-Ruminal Choline and Methionine.

    Directory of Open Access Journals (Sweden)

    Feifei Sun

    and regulating hepatic lipid metabolism, improved postpartum lactation performance and enhanced antioxidant capacity and immune function of transition dairy cows.

  18. Prion pathogenesis and secondary lymphoid organs (SLO)

    Science.gov (United States)

    Mabbott, Neil A.

    2012-01-01

    Prion diseases are subacute neurodegenerative diseases that affect humans and a range of domestic and free-ranging animal species. These diseases are characterized by the accumulation of PrPSc, an abnormally folded isoform of the cellular prion protein (PrPC), in affected tissues. The pathology during prion disease appears to occur almost exclusively within the central nervous system. The extensive neurodegeneration which occurs ultimately leads to the death of the host. An intriguing feature of the prion diseases, when compared with other protein-misfolding diseases, is their transmissibility. Following peripheral exposure, some prion diseases accumulate to high levels within lymphoid tissues. The replication of prions within lymphoid tissue has been shown to be important for the efficient spread of disease to the brain. This article describes recent progress in our understanding of the cellular mechanisms that influence the propagation of prions from peripheral sites of exposure (such as the lumen of the intestine) to the brain. A thorough understanding of these events will lead to the identification of important targets for therapeutic intervention, or alternatively, reveal additional processes that influence disease susceptibility to peripherally-acquired prion diseases. PMID:22895090

  19. Low fucose containing bacterial polysaccharide facilitate mitochondria-dependent ROS-induced apoptosis of human lung epithelial carcinoma via controlled regulation of MAPKs-mediated Nrf2/Keap1 homeostasis signaling.

    Science.gov (United States)

    Chowdhury, Sougata Roy; Sengupta, Suman; Biswas, Subir; Sen, Ramkrishna; Sinha, Tridib Kumar; Basak, Ratan Kumar; Adhikari, Basudam; Bhattacharyya, Arindam

    2015-12-01

    Reactive oxygen species (ROS), the key mediators of cellular oxidative stress and redox dysregulation involved in cancer initiation and progression, have recently emerged as promising targets for anticancer drug discovery. Continuous free radical assault upsets homeostasis in cellular redox system and regulates the associated signaling pathways to mediate stress-induced cell death. This study investigates the dose-specific pro-oxidative behavior of a bacterial fucose polysaccharide, which attenuated proliferation of different cancer cells. In the fermentation process, Bacillus megaterium RB-05 [GenBank Accession Number HM371417] was found to biosynthesize a polysaccharide with low-fucose content (4.9%), which conferred the maximum anti-proliferative activity (750 µg/mL) against human lung cancer epithelial cells (A549) during preliminary screening. Structural elucidation and morphological characterization of the duly purified polysaccharide was done using HPLC, GC-MS, (1)H/(13)C NMR, and microscopy. The polysaccharide exhibited concentration- and time-dependent anti-proliferative effects against A549 cells by inducing intracellular ROS level and regulating the mitochondrial membrane-permeability following the apoptotic pathway. This process encompasses activation of caspase-8/9/3/7, increase in the ratio of Bax/Bcl2 ratio, translocation of Bcl2-associated X protein (Bax) and cytochrome c, decrease in expression of anti-apoptotic members of Bcl2 family, and phosphorylation of mitogen activated protein kinases (MAPKs). Apoptosis was attenuated upon pretreatment with specific caspase-inhibitors. Simultaneously, during apoptosis, the ROS-mediated stress as well as activated MAPKs triggered nuclear translocation of transcription factors like nuclear factor (erythroid-derived)-like 2 (Nrf2) and promoted further transcription of downstream cytoprotective genes, which somehow perturbed the chemotherapeutic efficacy of the polysaccharide, although using CuPP, a chemical

  20. Relevance of the metabotropic glutamate receptor (mGluR5) in the regulation of NREM-REM sleep cycle and homeostasis: evidence from mGluR5 (-/-) mice.

    Science.gov (United States)

    Ahnaou, A; Raeymaekers, L; Steckler, T; Drinkenbrug, W H I M

    2015-04-01

    Sleep is a homeostatically regulated behavior and sleep loss evokes a proportional increase in sleep time and delta slow wave activity. Glutamate and pharmacological modulation of the metabotropic glutamate receptors (mGluR) signaling have been implicated in the organization of vigilance states. Here, the role of the mGluR5 on homeostatic regulation of sleep-wake cycle and electroencephalographic (EEG) activity was examined in mGluR5 (-/-) mice. We first characterized the sleep-wake EEG phenotype in mGluR5 (-/-) and wild-type (WT) littermates mice by continuous recording for 72h of EEG, body temperature (BT) and locomotor activity (LMA). Next, we investigated the influence of sleep deprivation on the recovery sleep and EEG slow wave activity (1-4Hz) during NREM sleep to assess whether mGluR5 deletion affects the sleep homeostasis process. Like the control animals, mGluR5 (-/-) mice exhibited a clear-cut circadian sleep-wake architecture, however they showed reduced REM sleep time during the light phase with shorter REM sleep bouts and reduced state transitions in the NREM sleep-REM sleep cycle during the first and last 24h of the spontaneous 72h recording period. In addition, mGluR5 (-/-) mice had decreased slow EEG delta power during NREM sleep and enhanced LMA associated with elevated BT during the dark phase. Moreover, mGluR5 (-/-) mice exhibited reduced slow wave activity and sleep drive after sleep deprivation, indicating altered sleep homeostatic processes. The findings strongly indicate that mGluR5 is involved in shaping the stability of NREM sleep-REM sleep state transitions, NREM slow wave activity and homeostatic response to sleep loss. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. NK cells and other innate lymphoid cells in haematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Paola eVacca

    2016-05-01

    Full Text Available Natural Killer (NK cells play a major role in the T-cell depleted haploidentical haematopoietic stem cell transplantation (haplo-HSCT to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILC. At variance with NK cells, the other ILC populations (ILC1/2/3 are non-cytolytic, while they secrete different patterns of cytokines. ILC provide host defences against viruses, bacteria and parasites, drive lymphoid organogenesis, and contribute to tissue remodelling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defences that are reconstituted more rapidly than the adaptive ones. In this context, ILC may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodelling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILC. Of note, CD34+ cells isolated from different sources of HSC, may differentiate in vitro towards various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g. IL-1β may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT.

  2. Amyloid and immune homeostasis.

    Science.gov (United States)

    Wang, Ying-Hui; Zhang, Yu-Gen

    2017-10-16

    Extracellular amyloid deposition defines a range of amyloidosis and amyloid-related disease. Addition to primary and secondary amyloidosis, amyloid-related disease can be observed in different tissue/organ that sharing the common pathogenesis based on the formation of amyloid deposition. Currently, both Alzheimer's disease and type 2 diabetes can be diagnosed with certainly only based on the autopsy results, by which amyloidosis of the associative tissue/organ is observed. Intriguingly, since it demonstrated that amyloid deposits trigger inflammatory reaction through the activation of cascaded immune response, wherein several lines of evidence implies a protective role of amyloid in preventing autoimmunity. Furthermore, attempts for preventing amyloid formation and/or removing amyloid deposits from the brain have caused meningoencephalitis and consequent deaths among the subjects. Hence, it is important to note that amyloid positively participates in maintaining immune homeostasis and contributes to irreversible inflammatory response. In this review, we will focus on the interactive relationship between amyloid and the immune system, discussing the potential functional roles of amyloid in immune tolerance and homeostasis. Copyright © 2017. Published by Elsevier GmbH.

  3. Ageing and water homeostasis

    Science.gov (United States)

    Robertson,