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Sample records for adult tissue homeostasis

  1. Debra-mediated Ci degradation controls tissue homeostasis in Drosophila adult midgut.

    PubMed

    Li, Zhouhua; Guo, Yueqin; Han, Lili; Zhang, Yan; Shi, Lai; Huang, Xudong; Lin, Xinhua

    2014-02-11

    Adult tissue homeostasis is maintained by resident stem cells and their progeny. However, the underlying mechanisms that control tissue homeostasis are not fully understood. Here, we demonstrate that Debra-mediated Ci degradation is important for intestinal stem cell (ISC) proliferation in Drosophila adult midgut. Debra inhibition leads to increased ISC activity and tissue homeostasis loss, phenocopying defects observed in aging flies. These defects can be suppressed by depleting Ci, suggesting that increased Hedgehog (Hh) signaling contributes to ISC proliferation and tissue homeostasis loss. Consistently, Hh signaling activation causes the same defects, whereas depletion of Hh signaling suppresses these defects. Furthermore, the Hh ligand from multiple sources is involved in ISC proliferation and tissue homeostasis. Finally, we show that the JNK pathway acts downstream of Hh signaling to regulate ISC proliferation. Together, our results provide insights into the mechanisms of stem cell proliferation and tissue homeostasis control.

  2. Embryonic origin of adult stem cells required for tissue homeostasis and regeneration.

    PubMed

    Davies, Erin L; Lei, Kai; Seidel, Christopher W; Kroesen, Amanda E; McKinney, Sean A; Guo, Longhua; Robb, Sofia Mc; Ross, Eric J; Gotting, Kirsten; Alvarado, Alejandro Sánchez

    2017-01-10

    Planarian neoblasts are pluripotent, adult somatic stem cells and lineage-primed progenitors that are required for the production and maintenance of all differentiated cell types, including the germline. Neoblasts, originally defined as undifferentiated cells residing in the adult parenchyma, are frequently compared to embryonic stem cells yet their developmental origin remains obscure. We investigated the provenance of neoblasts during Schmidtea mediterranea embryogenesis, and report that neoblasts arise from an anarchic, cycling piwi-1+ population wholly responsible for production of all temporary and definitive organs during embryogenesis. Early embryonic piwi-1+ cells are molecularly and functionally distinct from neoblasts: they express unique cohorts of early embryo enriched transcripts and behave differently than neoblasts in cell transplantation assays. Neoblast lineages arise as organogenesis begins and are required for construction of all major organ systems during embryogenesis. These subpopulations are continuously generated during adulthood, where they act as agents of tissue homeostasis and regeneration.

  3. Embryonic origin of adult stem cells required for tissue homeostasis and regeneration

    PubMed Central

    Davies, Erin L; Lei, Kai; Seidel, Christopher W; Kroesen, Amanda E; McKinney, Sean A; Guo, Longhua; Robb, Sofia MC; Ross, Eric J; Gotting, Kirsten; Alvarado, Alejandro Sánchez

    2017-01-01

    Planarian neoblasts are pluripotent, adult somatic stem cells and lineage-primed progenitors that are required for the production and maintenance of all differentiated cell types, including the germline. Neoblasts, originally defined as undifferentiated cells residing in the adult parenchyma, are frequently compared to embryonic stem cells yet their developmental origin remains obscure. We investigated the provenance of neoblasts during Schmidtea mediterranea embryogenesis, and report that neoblasts arise from an anarchic, cycling piwi-1+ population wholly responsible for production of all temporary and definitive organs during embryogenesis. Early embryonic piwi-1+ cells are molecularly and functionally distinct from neoblasts: they express unique cohorts of early embryo enriched transcripts and behave differently than neoblasts in cell transplantation assays. Neoblast lineages arise as organogenesis begins and are required for construction of all major organ systems during embryogenesis. These subpopulations are continuously generated during adulthood, where they act as agents of tissue homeostasis and regeneration. DOI: http://dx.doi.org/10.7554/eLife.21052.001 PMID:28072387

  4. Mechanics of epithelial tissue homeostasis and morphogenesis.

    PubMed

    Guillot, Charlène; Lecuit, Thomas

    2013-06-07

    Epithelia are robust tissues that support the structure of embryos and organs and serve as effective barriers against pathogens. Epithelia also chemically separate different physiological environments. These vital functions require tight association between cells through the assembly of junctions that mechanically stabilize the tissue. Remarkably, epithelia are also dynamic and can display a fluid behavior. Cells continuously die or divide, thereby allowing functional tissue homeostasis. Epithelial cells can change shape or intercalate as tissues deform during morphogenesis. We review the mechanical basis of tissue robustness and fluidity, with an emphasis on the pivotal role of junction dynamics. Tissue fluidity emerges from local active stresses acting at cell interfaces and allows the maintenance of epithelial organization during morphogenesis and tissue renewal.

  5. Origin, Development, and Homeostasis of Tissue-resident Macrophages

    PubMed Central

    Haldar, Malay; Murphy, Kenneth M.

    2014-01-01

    Summary Macrophages are versatile cells of the hematopoietic system that display remarkable functional diversity encompassing innate immune responses, tissue development, and tissue homeostasis. Macrophages are present in almost all tissues of the body and display distinct location-specific phenotypes and gene expression profiles. Recent studies also demonstrate distinct origins of tissue-resident macrophages. This emerging picture of ontological, functional, and phenotypic heterogeneity within tissue macrophages has altered our understanding of these cells, which play important roles in many human diseases. In this review, we discuss the different origins of tissue macrophages, the transcription factors regulating their development, and the mechanisms underlying their homeostasis at steady state. PMID:25319325

  6. Alcohol exposure in utero perturbs retinoid homeostasis in adult rats

    PubMed Central

    Kim, Youn-Kyung; Zuccaro, Michael V.; Zhang, Changqing; Sarkar, Dipak

    2015-01-01

    Background Maternal alcohol exposure and adult alcohol intake have been shown to perturb the metabolism of various micro- and macro-nutrients, including vitamin A and its derivatives (retinoids). Therefore, it has been hypothesized that the well-known detrimental consequences of alcohol consumption may be due to deregulations of the metabolism of such nutrients rather than to a direct effect of alcohol. Alcohol exposure in utero also has long-term harmful consequences on the health of the offspring with mechanisms that have not been fully clarified. Disruption of tissue retinoid homeostasis has been linked not only to abnormal embryonic development, but also to various adult pathological conditions, including cancer, metabolic disorders and abnormal lung function. We hypothesized that prenatal alcohol exposure may permanently perturb tissue retinoid metabolism, predisposing the offspring to adult chronic diseases. Methods Serum and tissues (liver, lung and prostate from males; liver and lung from females) were collected from 60-75 day-old sprague dawley rats born from dams that were: (I) fed a liquid diet containing 6.7% alcohol between gestational day 7 and 21; or (II) pair-fed with isocaloric liquid diet during the same gestational window; or (III) fed ad libitum with regular rat chow diet throughout pregnancy. Serum and tissue retinoid levels were analyzed by reverse-phase high-performance liquid chromatography (HPLC). Serum retinol-binding protein (RBP) levels were measured by western blot analysis, and liver, lung and prostate mRNA levels of lecithin-retinol acyltransferase (LRAT) were measured by qPCR. Results Retinyl ester levels were significantly reduced in the lung of both males and females, as well as in the liver and ventral prostate of males born from alcohol-fed dams. Tissue LRAT mRNA levels remained unchanged upon maternal alcohol treatment. Conclusions Prenatal alcohol exposure in rats affects retinoid metabolism in adult life, in a tissue- and sex

  7. Non-myogenic Contribution to Muscle Development and Homeostasis: The Role of Connective Tissues

    PubMed Central

    Nassari, Sonya; Duprez, Delphine; Fournier-Thibault, Claire

    2017-01-01

    Skeletal muscles belong to the musculoskeletal system, which is composed of bone, tendon, ligament and irregular connective tissue, and closely associated with motor nerves and blood vessels. The intrinsic molecular signals regulating myogenesis have been extensively investigated. However, muscle development, homeostasis and regeneration require interactions with surrounding tissues and the cellular and molecular aspects of this dialogue have not been completely elucidated. During development and adult life, myogenic cells are closely associated with the different types of connective tissue. Connective tissues are defined as specialized (bone and cartilage), dense regular (tendon and ligament) and dense irregular connective tissue. The role of connective tissue in muscle morphogenesis has been investigated, thanks to the identification of transcription factors that characterize the different types of connective tissues. Here, we review the development of the various connective tissues in the context of the musculoskeletal system and highlight their important role in delivering information necessary for correct muscle morphogenesis, from the early step of myoblast differentiation to the late stage of muscle maturation. Interactions between muscle and connective tissue are also critical in the adult during muscle regeneration, as impairment of the regenerative potential after injury or in neuromuscular diseases results in the progressive replacement of the muscle mass by fibrotic tissue. We conclude that bi-directional communication between muscle and connective tissue is critical for a correct assembly of the musculoskeletal system during development as well as to maintain its homeostasis in the adult. PMID:28386539

  8. Non-myogenic Contribution to Muscle Development and Homeostasis: The Role of Connective Tissues.

    PubMed

    Nassari, Sonya; Duprez, Delphine; Fournier-Thibault, Claire

    2017-01-01

    Skeletal muscles belong to the musculoskeletal system, which is composed of bone, tendon, ligament and irregular connective tissue, and closely associated with motor nerves and blood vessels. The intrinsic molecular signals regulating myogenesis have been extensively investigated. However, muscle development, homeostasis and regeneration require interactions with surrounding tissues and the cellular and molecular aspects of this dialogue have not been completely elucidated. During development and adult life, myogenic cells are closely associated with the different types of connective tissue. Connective tissues are defined as specialized (bone and cartilage), dense regular (tendon and ligament) and dense irregular connective tissue. The role of connective tissue in muscle morphogenesis has been investigated, thanks to the identification of transcription factors that characterize the different types of connective tissues. Here, we review the development of the various connective tissues in the context of the musculoskeletal system and highlight their important role in delivering information necessary for correct muscle morphogenesis, from the early step of myoblast differentiation to the late stage of muscle maturation. Interactions between muscle and connective tissue are also critical in the adult during muscle regeneration, as impairment of the regenerative potential after injury or in neuromuscular diseases results in the progressive replacement of the muscle mass by fibrotic tissue. We conclude that bi-directional communication between muscle and connective tissue is critical for a correct assembly of the musculoskeletal system during development as well as to maintain its homeostasis in the adult.

  9. Regulation of systemic energy homeostasis by serotonin in adipose tissues

    PubMed Central

    Oh, Chang-Myung; Namkung, Jun; Go, Younghoon; Shong, Ko Eun; Kim, Kyuho; Kim, Hyeongseok; Park, Bo-Yoon; Lee, Ho Won; Jeon, Yong Hyun; Song, Junghan; Shong, Minho; Yadav, Vijay K.; Karsenty, Gerard; Kajimura, Shingo; Lee, In-Kyu; Park, Sangkyu; Kim, Hail

    2015-01-01

    Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis. PMID:25864946

  10. Cell-size distribution in epithelial tissue formation and homeostasis.

    PubMed

    Puliafito, Alberto; Primo, Luca; Celani, Antonio

    2017-03-01

    How cell growth and proliferation are orchestrated in living tissues to achieve a given biological function is a central problem in biology. During development, tissue regeneration and homeostasis, cell proliferation must be coordinated by spatial cues in order for cells to attain the correct size and shape. Biological tissues also feature a notable homogeneity of cell size, which, in specific cases, represents a physiological need. Here, we study the temporal evolution of the cell-size distribution by applying the theory of kinetic fragmentation to tissue development and homeostasis. Our theory predicts self-similar probability density function (PDF) of cell size and explains how division times and redistribution ensure cell size homogeneity across the tissue. Theoretical predictions and numerical simulations of confluent non-homeostatic tissue cultures show that cell size distribution is self-similar. Our experimental data confirm predictions and reveal that, as assumed in the theory, cell division times scale like a power-law of the cell size. We find that in homeostatic conditions there is a stationary distribution with lognormal tails, consistently with our experimental data. Our theoretical predictions and numerical simulations show that the shape of the PDF depends on how the space inherited by apoptotic cells is redistributed and that apoptotic cell rates might also depend on size.

  11. Osteopontin: Relation between Adipose Tissue and Bone Homeostasis

    PubMed Central

    Messina, Antonietta; Monda, Vincenzo; Viggiano, Emanuela; Valenzano, Anna; Esposito, Teresa; Cibelli, Giuseppe

    2017-01-01

    Osteopontin (OPN) is a multifunctional protein mainly associated with bone metabolism and remodeling. Besides its physiological functions, OPN is implicated in the pathogenesis of a variety of disease states, such as obesity and osteoporosis. Importantly, during the last decades obesity and osteoporosis have become among the main threats to health worldwide. Because OPN is a protein principally expressed in cells with multifaceted effects on bone morphogenesis and remodeling and because it seems to be one of the most overexpressed genes in the adipose tissue of the obese contributing to osteoporosis, this mini review will highlight recent insights about relation between adipose tissue and bone homeostasis. PMID:28194185

  12. Concise review: The plasticity of stem cell niches: a general property behind tissue homeostasis and repair.

    PubMed

    Rojas-Ríos, Patricia; González-Reyes, Acaimo

    2014-04-01

    Stem cell activity is tightly regulated during development and in adult tissues through the combined action of local and systemic effectors. While stem cells and their microenvironments are capable of sustaining homeostasis in normal physiological circumstances, they also provide host tissues with a remarkable plasticity to respond to perturbations. Here, we review recent discoveries that shed light on the adaptive response of niches to systemic signals and aging, and on the ability of niches to modulate signaling upon local perturbations. These characteristics of stem cells and their niches give organs an essential advantage to deal with aging, injury or pathological conditions.

  13. Intermittent cold exposure improves glucose homeostasis associated with brown and white adipose tissues in mice

    PubMed Central

    Wang, Tse-Yao; Liu, Cuiqing; Wang, Aixia; Sun, Qinghua

    2015-01-01

    Aims The discovery of different shades of fat has been implicated in the pathogenesis of obesity-related metabolic disorders. However, the effects of early and intermittent exposure to cold temperature on systemic metabolic changes in adult life remain unclear. Main methods To elucidate the impact of cold temperature exposure on metabolic function of adipose tissues, we investigated the glucose homeostasis, activation of brown adipose tissue (BAT) and “browning” of white adipose tissue (WAT) in mice in response to intermittent cold exposure. Mice were exposed to 4 °C, 2 hours per day and 5 days per week, for 14 weeks. Glucose homeostasis was tested via intraperitoneal glucose tolerance test and insulin tolerance test; body fat mass was evaluated using in vivo magnetic resonance imaging; BAT activity was detected primarily by positron emission tomography/computed tomography; and WAT “browning” was evaluated using immunohistochemistry. Key findings Our results showed that 14-week cold exposure improved glucose tolerance and enhanced insulin sensitivity, reduced the relative weights of epididymal and retroperitoneal WAT, increased expressions of UCP1 and PGC1α in subcutaneous adipose tissue. Significance Intermittent exposure to cold temperature in early life may improve systemic glucose homeostasis and induce WAT “browning”, suggesting that ambient cold temperature exposure may serve as a promising intervention to metabolic disorders. PMID:26281919

  14. Mesenchymal to epithelial transition during tissue homeostasis and regeneration: Patching up the Drosophila midgut epithelium.

    PubMed

    Antonello, Zeus A; Reiff, Tobias; Dominguez, Maria

    2015-01-01

    Stem cells are responsible for preserving morphology and function of adult tissues. Stem cells divide to self-renew and to generate progenitor cells to sustain cell demand from the tissue throughout the organism's life. Unlike stem cells, the progenitor cells have limited proliferation potential but have the capacity to terminally differentiate and thereby to substitute older or damaged mature cells. Recent findings indicate that adult stem cells can adapt their division kinetics dynamically to match changes in tissue demand during homeostasis and regeneration. However, cell turnover not only requires stem cell division but also needs timed differentiation of the progenitor cells, which has been much less explored. In this Extra View article, we discuss the ability of progenitor cells to actively postpone terminal differentiation in the absence of a local demand and how tissue demand activates terminal differentiation via a conserved mesenchymal-epithelial transition program revealed in our recent EMBO J paper and other published and unpublished data. The extent of the significance of these results is discussed for models of tissue dynamics during both homeostasis and regeneration.

  15. Hs3st-A and Hs3st-B regulate intestinal homeostasis in Drosophila adult midgut.

    PubMed

    Guo, Yueqin; Li, Zhouhua; Lin, Xinhua

    2014-11-01

    Intrinsic and extrinsic signals as well as the extracellular matrix (ECM) tightly regulate stem cells for tissue homeostasis and regenerative capacity. Little is known about the regulation of tissue homeostasis by the ECM. Heparan sulfate proteoglycans (HSPGs), important components of the ECM, are involved in a variety of biological events. Two heparin sulfate 3-O sulfotransferase (Hs3st) genes, Hs3st-A and Hs3st-B, encode the modification enzymes in heparan sulfate (HS) biosynthesis. Here we demonstrate that Hs3st-A and Hs3st-B are required for adult midgut homeostasis. Depletion of Hs3st-A in enterocytes (ECs) results in increased intestinal stem cell (ISC) proliferation and tissue homeostasis loss. Moreover, increased ISC proliferation is also observed in Hs3st-B null mutant alone, or in combination with Hs3st-A RNAi. Hs3st-A depletion-induced ISC proliferation is effectively suppressed by simultaneous inhibition of the EGFR signaling pathway, suggesting that tissue homeostasis loss in Hs3st-A-deficient intestines is due to increased EGFR signaling. Furthermore, we find that Hs3st-A-depleted ECs are unhealthy and prone to death, while ectopic expression of the antiapoptotic p35 is able to greatly suppress tissue homeostasis loss in these intestines. Together, our data suggest that Drosophila Hs3st-A and Hs3st-B are involved in the regulation of ISC proliferation and midgut homeostasis maintenance.

  16. How Somatic Adult Tissues Develop Organizer Activity.

    PubMed

    Vogg, Matthias C; Wenger, Yvan; Galliot, Brigitte

    2016-01-01

    The growth and patterning of anatomical structures from specific cellular fields in developing organisms relies on organizing centers that instruct surrounding cells to modify their behavior, namely migration, proliferation, and differentiation. We discuss here how organizers can form in adult organisms, a process of utmost interest for regenerative medicine. Animals like Hydra and planarians, which maintain their shape and fitness thanks to a highly dynamic homeostasis, offer a useful paradigm to study adult organizers in steady-state conditions. Beside the homeostatic context, these model systems also offer the possibility to study how organizers form de novo from somatic adult tissues. Both extracellular matrix remodeling and caspase activation play a key role in this transition, acting as promoters of organizer formation in the vicinity of the wound. Their respective roles and the crosstalk between them just start to be deciphered.

  17. Interrogating the relevance of mitochondrial apoptosis for vertebrate development and postnatal tissue homeostasis

    PubMed Central

    Kaufmann, Thomas; Villunger, Andreas

    2016-01-01

    “Programmed cell death or ‘apoptosis’ is critical for organogenesis during embryonic development and tissue homeostasis in the adult. Its deregulation can contribute to a broad range of human pathologies, including neurodegeneration, cancer, or autoimmunity…” These or similar phrases have become generic opening statements in many reviews and textbooks describing the physiological relevance of apoptotic cell death. However, while the role in disease has been documented beyond doubt, facilitating innovative drug discovery, we wonder whether the former is really true. What goes wrong in vertebrate development or in adult tissue when the main route to apoptotic cell death, controlled by the BCL2 family, is impaired? Such scenarios have been mimicked by deletion of one or more prodeath genes within the BCL2 family, and gene targeting studies in mice exploring the consequences have been manifold. Many of these studies were geared toward understanding the role of BCL2 family proteins and mitochondrial apoptosis in disease, whereas fewer focused in detail on their role during normal development or tissue homeostasis, perhaps also due to an irritating lack of phenotype. Looking at these studies, the relevance of classical programmed cell death by apoptosis for development appears rather limited. Together, these many studies suggest either highly selective and context-dependent contributions of mitochondrial apoptosis or significant redundancy with alternative cell death mechanisms, as summarized and discussed here. PMID:27798841

  18. Tissues Use Resident Dendritic Cells and Macrophages to Maintain Homeostasis and to Regain Homeostasis upon Tissue Injury: The Immunoregulatory Role of Changing Tissue Environments

    PubMed Central

    Lech, Maciej; Gröbmayr, Regina; Weidenbusch, Marc; Anders, Hans-Joachim

    2012-01-01

    Most tissues harbor resident mononuclear phagocytes, that is, dendritic cells and macrophages. A classification that sufficiently covers their phenotypic heterogeneity and plasticity during homeostasis and disease does not yet exist because cell culture-based phenotypes often do not match those found in vivo. The plasticity of mononuclear phagocytes becomes obvious during dynamic or complex disease processes. Different data interpretation also originates from different conceptual perspectives. An immune-centric view assumes that a particular priming of phagocytes then causes a particular type of pathology in target tissues, conceptually similar to antigen-specific T-cell priming. A tissue-centric view assumes that changing tissue microenvironments shape the phenotypes of their resident and infiltrating mononuclear phagocytes to fulfill the tissue's need to maintain or regain homeostasis. Here we discuss the latter concept, for example, why different organs host different types of mononuclear phagocytes during homeostasis. We further discuss how injuries alter tissue environments and how this primes mononuclear phagocytes to enforce this particular environment, for example, to support host defense and pathogen clearance, to support the resolution of inflammation, to support epithelial and mesenchymal healing, and to support the resolution of fibrosis to the smallest possible scar. Thus, organ- and disease phase-specific microenvironments determine macrophage and dendritic cell heterogeneity in a temporal and spatial manner, which assures their support to maintain and regain homeostasis in whatever condition. Mononuclear phagocytes contributions to tissue pathologies relate to their central roles in orchestrating all stages of host defense and wound healing, which often become maladaptive processes, especially in sterile and/or diffuse tissue injuries. PMID:23251037

  19. Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism.

    PubMed

    Grgurevic, Lovorka; Christensen, Gitte Lund; Schulz, Tim J; Vukicevic, Slobodan

    2016-02-01

    Bore morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-β superfamily, a group of secreted proteins that regulate embryonic development. This review summarizes the effects of BMPs on physiological processes not exclusively linked to the musculoskeletal system. Specifically, we focus on the involvement of BMPs in inflammatory disorders, e.g. fibrosis, inflammatory bowel disease, anchylosing spondylitis, rheumatoid arthritis. Moreover, we discuss the role of BMPs in the context of vascular disorders, and explore the role of these signalling proteins in iron homeostasis (anaemia, hemochromatosis) and oxidative damage. The second and third parts of this review focus on BMPs in the development of metabolic pathologies such as type-2 diabetes mellitus and obesity. The pancreatic beta cells are the sole source of the hormone insulin and BMPs have recently been implicated in pancreas development as well as control of adult glucose homeostasis. Lastly, we review the recently recognized role of BMPs in brown adipose tissue formation and their consequences for energy expenditure and adiposity. In summary, BMPs play a pivotal role in metabolism beyond their role in skeletal homeostasis. However, increased understanding of these pleiotropic functions also highlights the necessity of tissue-specific strategies when harnessing BMP action as a therapeutic target.

  20. Adrenal cortex tissue homeostasis and zonation: A WNT perspective.

    PubMed

    Drelon, Coralie; Berthon, Annabel; Mathieu, Mickael; Martinez, Antoine; Val, Pierre

    2015-06-15

    The adrenal cortex plays essential roles in the control of sodium and water homeostasis, stress response, inflammation and metabolism, through secretion of glucocorticoids and mineralocorticoids. Coordinated production of these hormones relies on functional zonation of the cortex, characterised by expression of Cyp11b2 under the control of angiotensin II and plasma potassium level in zona glomerulosa (ZG) and Cyp11b1 under the control of ACTH in zona fasciculata (ZF). The mechanisms involved in the establishment of functional zonation and its maintenance during centripetal cortex cell renewal are still poorly understood. Here, we hypothesise that the hormonal and signalling pathways that control adrenal cortex function are also involved in cortical zonation. In particular, we summarise evidence on the role of WNT/β-catenin signalling in ZG differentiation and how tight control of its activity is required to shape the adult cortex. In this context, we discuss the potential role of known WNT regulators and the possibility of a reciprocal cross-talk between PKA and WNT signalling.

  1. Wnt Signaling and Its Contribution to Craniofacial Tissue Homeostasis.

    PubMed

    Yin, X; Li, J; Salmon, B; Huang, L; Lim, W H; Liu, B; Hunter, D J; Ransom, R C; Singh, G; Gillette, M; Zou, S; Helms, J A

    2015-11-01

    A new field of dental medicine seeks to exploit nature's solution for repairing damaged tissues, through the process of regeneration. Most adult mammalian tissues have limited regenerative capacities, but in lower vertebrates, the molecular machinery for regeneration is an elemental part of their genetic makeup. Accumulating data suggest that the molecular pathways responsible for the regenerative capacity of teleosts, amphibians, and reptiles have fallen into disuse in mammals but that they can be "jumpstarted" by the selective activation of key molecules. The Wnt family of secreted proteins constitutes one such critical pathway: Wnt proteins rank among the most potent and ubiquitous stem cell self-renewing factors, with tremendous potential for promoting human tissue regeneration. Wnt reporter and lineage-tracing strains of mice have been employed to create molecular maps of Wnt responsiveness in the craniofacial tissues, and these patterns of Wnt signaling colocalize with stem/progenitor populations in the rodent incisor apex, the dental pulp, the alveolar bone, the periodontal ligament, the cementum, and oral mucosa. The importance of Wnt signaling in both the maintenance and healing of these craniofacial tissues is summarized, and the therapeutic potential of Wnt-based strategies to accelerate healing through activation of endogenous stem cells is highlighted.

  2. Perinatal exercise improves glucose homeostasis in adult offspring

    PubMed Central

    Carter, Lindsay G.; Lewis, Kaitlyn N.; Wilkerson, Donald C.; Tobia, Christine M.; Ngo Tenlep, Sara Y.; Shridas, Preetha; Garcia-Cazarin, Mary L.; Wolff, Gretchen; Andrade, Francisco H.; Charnigo, Richard J.; Esser, Karyn A.; Egan, Josephine M.; de Cabo, Rafael

    2012-01-01

    Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P < 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P < 0.05 and P < 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P < 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring. PMID:22932781

  3. Perinatal exercise improves glucose homeostasis in adult offspring.

    PubMed

    Carter, Lindsay G; Lewis, Kaitlyn N; Wilkerson, Donald C; Tobia, Christine M; Ngo Tenlep, Sara Y; Shridas, Preetha; Garcia-Cazarin, Mary L; Wolff, Gretchen; Andrade, Francisco H; Charnigo, Richard J; Esser, Karyn A; Egan, Josephine M; de Cabo, Rafael; Pearson, Kevin J

    2012-10-15

    Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P < 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P < 0.05 and P < 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P < 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring.

  4. Requirement of matrix metalloproteinase-1 for intestinal homeostasis in the adult Drosophila midgut

    SciTech Connect

    Lee, Shin-Hae; Park, Joung-Sun; Kim, Young-Shin; Chung, Hae-Young; Yoo, Mi-Ae

    2012-03-10

    Stem cells are tightly regulated by both intrinsic and extrinsic signals as well as the extracellular matrix (ECM) for tissue homeostasis and regenerative capacity. Matrix metalloproteinases (MMPs), proteolytic enzymes, modulate the turnover of numerous substrates, including cytokine precursors, growth factors, and ECM molecules. However, the roles of MMPs in the regulation of adult stem cells are poorly understood. In the present study, we utilize the Drosophila midgut, which is an excellent model system for studying stem cell biology, to show that Mmp1 is involved in the regulation of intestinal stem cells (ISCs). The results showed that Mmp1 is expressed in the adult midgut and that its expression increases with age and with exposure to oxidative stress. Mmp1 knockdown or Timp-overexpressing flies and flies heterozygous for a viable, hypomorphic Mmp1 allele increased ISC proliferation in the gut, as shown by staining with an anti-phospho-histone H3 antibody and BrdU incorporation assays. Reduced Mmp1 levels induced intestinal hyperplasia, and the Mmp1depletion-induced ISC proliferation was rescued by the suppression of the EGFR signaling pathway, suggesting that Mmp1 regulates ISC proliferation through the EGFR signaling pathway. Furthermore, adult gut-specific knockdown and whole-animal heterozygotes of Mmp1 increased additively sensitivity to paraquat-induced oxidative stress and shortened lifespan. Our data suggest that Drosophila Mmp1 is involved in the regulation of ISC proliferation for maintenance of gut homeostasis. -- Highlights: Black-Right-Pointing-Pointer Mmp1 is expressed in the adult midgut. Black-Right-Pointing-Pointer Mmp1 is involved in the regulation of ISC proliferation activity. Black-Right-Pointing-Pointer Mmp1-related ISC proliferation is associated with EGFR signaling. Black-Right-Pointing-Pointer Mmp1 in the gut is required for the intestinal homeostasis and longevity.

  5. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis.

    PubMed

    Gao, Yan; Sartori, Daniel J; Li, Changhong; Yu, Qian-Chun; Kushner, Jake A; Simon, M Celeste; Diehl, J Alan

    2012-12-01

    Germ line PERK mutations are associated with diabetes mellitus and growth retardation in both rodents and humans. In contrast, late embryonic excision of PERK permits islet development and was found to prevent onset of diabetes, suggesting that PERK may be dispensable in the adult pancreas. To definitively establish the functional role of PERK in adult pancreata, we generated mice harboring a conditional PERK allele in which excision is regulated by tamoxifen administration. Deletion of PERK in either young adult or mature adult mice resulted in hyperglycemia associated with loss of islet and β cell architecture. PERK excision triggered intracellular accumulation of proinsulin and Glut2, massive endoplasmic reticulum (ER) expansion, and compensatory activation of the remaining unfolded-protein response (UPR) signaling pathways specifically in pancreatic tissue. Although PERK excision increased β cell death, this was not a result of decreased proliferation as previously reported. In contrast, a significant and specific increase in β cell proliferation was observed, a result reflecting increased cyclin D1 accumulation. This work demonstrates that contrary to expectations, PERK is required for secretory homeostasis and β cell survival in adult mice.

  6. Myosin Vb Mediated Plasma Membrane Homeostasis Regulates Peridermal Cell Size and Maintains Tissue Homeostasis in the Zebrafish Epidermis

    PubMed Central

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

    2014-01-01

    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. PMID:25233349

  7. Oestradiol and Diet Modulate Energy Homeostasis and Hypothalamic Neurogenesis in the Adult Female Mouse

    PubMed Central

    Bless, E. P.; Reddy, T.; Acharya, K. D.; Beltz, B. S.; Tetel, M. J.

    2014-01-01

    Leptin and oestradiol have overlapping functions in energy homeostasis and fertility, and receptors for these hormones are localised in the same hypothalamic regions. Although, historically, it was assumed that mammalian adult neurogenesis was confined to the olfactory bulbs and the hippocampus, recent research has found new neurones in the male rodent hypothalamus. Furthermore, some of these new neurones are leptin-sensitive and affected by diet. In the present study, we tested the hypothesis that diet and hormonal status modulate hypothalamic neurogenesis in the adult female mouse. Adult mice were ovariectomised and implanted with capsules containing oestradiol (E2) or oil. Within each group, mice were fed a high-fat diet (HFD) or maintained on standard chow (STND). All animals were administered i.c.v. 5-bromo-2′-deoxyuridine (BrdU) for 9 days and sacrificed 34 days later after an injection of leptin to induce phosphorylation of signal transducer of activation and transcription 3 (pSTAT3). Brain tissue was immunohistochemically labelled for BrdU (newly born cells), Hu (neuronal marker) and pSTAT3 (leptin sensitive). Although mice on a HFD became obese, oestradiol protected against obesity. There was a strong interaction between diet and hormone on new cells (BrdU+) in the arcuate, ventromedial hypothalamus and dorsomedial hypothalamus. HFD increased the number of new cells, whereas E2 inhibited this effect. Conversely, E2 increased the number of new cells in mice on a STND diet in all hypothalamic regions studied. Although the total number of new leptin-sensitive neurones (BrdU-Hu-pSTAT3) found in the hypothalamus was low, HFD increased these new cells in the arcuate, whereas E2 attenuated this induction. These results suggest that adult neurogenesis in the hypothalamic neurogenic niche is modulated by diet and hormonal status and is related to energy homeostasis in female mice. PMID:25182179

  8. Cell dynamics and gene expression control in tissue homeostasis and development.

    PubMed

    Rué, Pau; Martinez Arias, Alfonso

    2015-02-25

    During tissue and organ development and maintenance, the dynamic regulation of cellular proliferation and differentiation allows cells to build highly elaborate structures. The development of the vertebrate retina or the maintenance of adult intestinal crypts, for instance, involves the arrangement of newly created cells with different phenotypes, the proportions of which need to be tightly controlled. While some of the basic principles underlying these processes developing and maintaining these organs are known, much remains to be learnt from how cells encode the necessary information and use it to attain those complex but reproducible arrangements. Here, we review the current knowledge on the principles underlying cell population dynamics during tissue development and homeostasis. In particular, we discuss how stochastic fate assignment, cell division, feedback control and cellular transition states interact during organ and tissue development and maintenance in multicellular organisms. We propose a framework, involving the existence of a transition state in which cells are more susceptible to signals that can affect their gene expression state and influence their cell fate decisions. This framework, which also applies to systems much more amenable to quantitative analysis like differentiating embryonic stem cells, links gene expression programmes with cell population dynamics.

  9. Changes of gas metabolism, gas homeostasis and tissue respiration in rats during prolonged hypokinesia

    NASA Technical Reports Server (NTRS)

    Popkov, V. L.; Mailyan, E. S.; Galushko, Y. S.; Kovalenko, Y. A.; Zaytseva, Y. I.; Nitochkina, I. A.; Stulova, L. V.; Ryazhskiy, A. F.

    1979-01-01

    The oxygen uptake and tissue gas homeostasis of restrained albinic rats remained relatively constant during a 60 day experiment. The gas metabolism in some tissues changed, and O2 consumption increased in the liver and decreased in the myocardium. Capacity for physical work was reduced by five times. Hypokinesia for 60 days resulted in a delay in the animals growth.

  10. Planarian yorkie/YAP functions to integrate adult stem cell proliferation, organ homeostasis and maintenance of axial patterning.

    PubMed

    Lin, Alexander Y T; Pearson, Bret J

    2014-03-01

    During adult homeostasis and regeneration, the freshwater planarian must accomplish a constant balance between cell proliferation and cell death, while also maintaining proper tissue and organ size and patterning. How these ordered processes are precisely modulated remains relatively unknown. Here we show that planarians use the downstream effector of the Hippo signaling cascade, yorkie (yki; YAP in vertebrates) to control a diverse set of pleiotropic processes in organ homeostasis, stem cell regulation, regeneration and axial patterning. We show that yki functions to maintain the homeostasis of the planarian excretory (protonephridial) system and to limit stem cell proliferation, but does not affect the differentiation process or cell death. Finally, we show that Yki acts synergistically with WNT/β-catenin signaling to repress head determination by limiting the expression domains of posterior WNT genes and that of the WNT-inhibitor notum. Together, our data show that yki is a key gene in planarians that integrates stem cell proliferation control, organ homeostasis, and the spatial patterning of tissues.

  11. Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease.

    PubMed

    Gilbert, Penney M; Weaver, Valerie M

    2016-09-15

    Human tissues are remarkably adaptable and robust, harboring the collective ability to detect and respond to external stresses while maintaining tissue integrity. Following injury, many tissues have the capacity to repair the damage - and restore form and function - by deploying cellular and molecular mechanisms reminiscent of developmental programs. Indeed, it is increasingly clear that cancer and chronic conditions that develop with age arise as a result of cells and tissues re-implementing and deregulating a selection of developmental programs. Therefore, understanding the fundamental molecular mechanisms that drive cell and tissue responses is a necessity when designing therapies to treat human conditions. Extracellular matrix stiffness synergizes with chemical cues to drive single cell and collective cell behavior in culture and acts to establish and maintain tissue homeostasis in the body. This review will highlight recent advances that elucidate the impact of matrix mechanics on cell behavior and fate across these length scales during times of homeostasis and in disease states.

  12. Iron homeostasis: a new job for macrophages in adipose tissue?

    PubMed Central

    Hubler, Merla J.; Peterson, Kristin R.; Hasty, Alyssa H.

    2015-01-01

    Elevated serum ferritin and increased cellular iron concentrations are risk factors for diabetes; however, the etiology of this association is unclear. Metabolic tissues such as pancreas, liver, and adipose tissue (AT), as well as the immune cells resident in these tissues, may be involved. Recent studies demonstrate that the polarization status of macrophages has important relevance to their iron handling capabilities. Furthermore, a subset of macrophages in AT have elevated iron concentrations and a gene expression profile indicative of iron handling, a capacity diminished in obesity. Because iron overload in adipocytes increases systemic insulin resistance, iron handling by AT macrophages may have relevance not only to adipocyte iron stores but also to local and systemic insulin sensitivity. PMID:25600948

  13. Bim: guardian of tissue homeostasis and critical regulator of the immune system, tumorigenesis and bone biology.

    PubMed

    Akiyama, Toru; Tanaka, Sakae

    2011-08-01

    One of the most important roles of apoptosis is the maintenance of tissue homeostasis. Impairment of apoptosis leads to a number of pathological conditions. In response to apoptotic signals, various proteins are activated in a pathway and signal-specific manner. Recently, the pro-apoptotic molecule Bim has attracted increasing attention as a pivotal regulator of tissue homeostasis. The Bim expression level is strictly controlled in both transcriptional and post-transcriptional levels. This control is dependent on cell, tissue and apoptotic stimuli. The phenotype of Bim-deficient mice is a systemic lupus erythematosus-like autoimmune disease with an abnormal accumulation of hematopoietic cells. Bim is thus a critical regulator of hematopoietic cells and immune system. Further studies have revealed the critical roles of Bim in various normal and pathological conditions, including bone homeostasis and tumorigenesis. The current understanding of Bim signaling and roles in the maintenance of tissue homeostasis is reviewed in this paper, focusing on the immune system, bone biology and tumorigenesis to illustrate the diversified role of Bim.

  14. Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

    PubMed Central

    Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Porter, Craig; Annamalai, Palam; Enerbäck, Sven; Lidell, Martin E.; Saraf, Manish K.; Labbe, Sebastien M.; Hurren, Nicholas M.; Yfanti, Christina; Chao, Tony; Andersen, Clark R.; Cesani, Fernando; Hawkins, Hal

    2014-01-01

    Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans. PMID:25056438

  15. The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is “Inflammation” Always Inflammation?

    PubMed Central

    2016-01-01

    Inflammation is a response to infections or tissue injuries. Inflammation was once defined by clinical signs, later by the presence of leukocytes, and nowadays by expression of “proinflammatory” cytokines and chemokines. But leukocytes and cytokines often have rather anti-inflammatory, proregenerative, and homeostatic effects. Is there a need to redefine “inflammation”? In this review, we discuss the functions of “inflammatory” mediators/regulators of the innate immune system that determine tissue environments to fulfill the need of the tissue while regaining homeostasis after injury. PMID:27597803

  16. Genetic deletion of the EGFR ligand epigen does not affect mouse embryonic development and tissue homeostasis.

    PubMed

    Dahlhoff, Maik; Schäfer, Matthias; Wolf, Eckhard; Schneider, Marlon R

    2013-02-15

    The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor with manifold functions during development, tissue homeostasis and disease. EGFR activation, the formation of homodimers or heterodimers (with the related ERBB2-4 receptors) and downstream signaling is initiated by the binding of a family of structurally related growth factors, the EGFR ligands. Genetic deletion experiments clarified the biological function of all family members except for the last characterized ligand, epigen. We employed gene targeting in mouse embryonic stem cells to generate mice lacking epigen expression. Loss of epigen did not affect mouse development, fertility, or organ physiology. Quantitative RT-PCR analysis revealed increased expression of betacellulin and EGF in a few organs of epigen-deficient mice, suggesting a functional compensation by these ligands. In conclusion, we completed the genetic analysis of EGFR ligands and show that epigen has non-essential functions or functions that can be compensated by other EGFR ligands during growth and tissue homeostasis.

  17. Innate lymphoid cells promote lung tissue homeostasis following acute influenza virus infection

    PubMed Central

    Monticelli, Laurel A.; Sonnenberg, Gregory F.; Abt, Michael C.; Alenghat, Theresa; Ziegler, Carly G.K.; Doering, Travis A.; Angelosanto, Jill M.; Laidlaw, Brian J.; Yang, Cliff Y.; Sathaliyawala, Taheri; Kubota, Masaru; Turner, Damian; Diamond, Joshua M.; Goldrath, Ananda W.; Farber, Donna L.; Collman, Ronald G.; Wherry, E. John; Artis, David

    2012-01-01

    Innate lymphoid cells (ILCs), a recently identified heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine but whether ILCs can influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed CD90, CD25, CD127 and T1-ST2. Strikingly, mouse ILCs accumulated in the lung following influenza virus infection and depletion of ILCs resulted in loss of airway epithelial integrity, decreased lung function and impaired airway remodeling. These defects could be restored by administration of the lung ILC product amphiregulin. Collectively, these results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis following influenza virus infection. PMID:21946417

  18. Utility of Childhood Glucose Homeostasis Variables in Predicting Adult Diabetes and Related Cardiometabolic Risk Factors

    PubMed Central

    Nguyen, Quoc Manh; Srinivasan, Sathanur R.; Xu, Ji-Hua; Chen, Wei; Kieltyka, Lyn; Berenson, Gerald S.

    2010-01-01

    OBJECTIVE This study examines the usefulness of childhood glucose homeostasis variables (glucose, insulin, and insulin resistance index [homeostasis model assessment of insulin resistance {HOMA-IR}]) in predicting pre-diabetes and type 2 diabetes and related cardiometabolic risk factors in adulthood. RESEARCH DESIGN AND METHODS This retrospective cohort study consisted of normoglycemic (n = 1,058), pre-diabetic (n = 37), and type 2 diabetic (n = 25) adults aged 19–39 years who were followed on average for 17 years since childhood. RESULTS At least 50% of the individuals who ranked highest (top quintile) in childhood for glucose homeostasis variables maintained their high rank by being above the 60th percentile in adulthood. In a multivariate model, the best predictors of adulthood glucose homeostasis variables were the change in BMI Z score from childhood to adulthood and childhood BMI Z score, followed by the corresponding childhood levels of glucose, insulin, and HOMA-IR. Further, children in the top decile versus the rest for insulin and HOMA-IR were 2.85 and 2.55 times, respectively, more likely to develop pre-diabetes; children in the top decile versus the rest for glucose, insulin, and HOMA-IR were 3.28, 5.54, and 5.84 times, respectively, more likely to develop diabetes, independent of change in BMI Z score, baseline BMI Z score, and total-to-HDL cholesterol ratio. In addition, children with adverse levels (top quintile versus the rest) of glucose homeostasis variables displayed significantly higher prevalences of, among others, hyperglycemia, hypertriglyceridemia, and metabolic syndrome. CONCLUSIONS Adverse levels of glucose homeostasis variables in childhood not only persist into adulthood but also predict adult pre-diabetes and type 2 diabetes and relate to cardiometabolic risk factors. PMID:20009096

  19. Communicating Non-Targeted Effects of Ionizing Radiation to Achieve Adaptive Homeostasis in Tissues

    SciTech Connect

    Morgan, William F.

    2011-06-04

    Non-targeted effects, i.e., those responses in cells or tissues that were not subject to energy deposition events after localized exposure to ionizing radiaton, are well-established. While they are not universal phenotype, when they do occur they can be associated with subsequent tissue or whole body responses. Here it is argued that non-targeted effects are a tissue level response to restore equilibrium within an organ system, and thus restores tissue homeostasis. This "adaptive homeostasis" has evolved in response to a variety of environmental and other such stresses an individual is exposed to in their lifetime. These non-targeted effects are not likely to impact significantly on estimates of potential risks associated with radiation exposure because they are presumably "built into" current risk estimates. However, they could have implications for radiation carcinogenesis, by driving processes in targeted and non-targeted cells that could eliminate transformed cells or transform cells from a normal phenotype to a phenotype associated with malignancy within a tissue.

  20. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22.

    PubMed

    Sonnenberg, Gregory F; Fouser, Lynette A; Artis, David

    2011-05-01

    The maintenance of barrier function at exposed surfaces of the mammalian body is essential for limiting exposure to environmental stimuli, preventing systemic dissemination of commensal and pathogenic microbes and retaining normal homeostasis of the entire body. Indeed, dysregulated barrier function is associated with many infectious and inflammatory diseases, including psoriasis, influenza, inflammatory bowel disease and human immunodeficiency virus, which collectively afflict millions of people worldwide. Studies have shown that interleukin 22 (IL-22) is expressed at barrier surfaces and that its expression is dysregulated in certain human diseases, which suggests a critical role in the maintenance of normal barrier homeostasis. Consistent with that, studies of mouse model systems have identified a critical role for signaling by IL-22 through its receptor (IL-22R) in the promotion of antimicrobial immunity, inflammation and tissue repair at barrier surfaces. In this review we will discuss how the expression of IL-22 and IL-22R is regulated, the functions of the IL-22-IL-22R pathway in regulating immunity, inflammation and tissue homeostasis, and the therapeutic potential of targeting this pathway in human disease.

  1. Plasma 25-Hydroxyvitamin D Is Related to Protein Signaling Involved in Glucose Homeostasis in a Tissue-Specific Manner

    PubMed Central

    Parker, Lewan; Levinger, Itamar; Mousa, Aya; Howlett, Kirsten; de Courten, Barbora

    2016-01-01

    Vitamin D has been suggested to play a role in glucose metabolism. However, previous findings are contradictory and mechanistic pathways remain unclear. We examined the relationship between plasma 25-hydroxyvitamin D (25(OH)D), insulin sensitivity, and insulin signaling in skeletal muscle and adipose tissue. Seventeen healthy adults (Body mass index: 26 ± 4; Age: 30 ± 12 years) underwent a hyperinsulinemic-euglycemic clamp, and resting skeletal muscle and adipose tissue biopsies. In this cohort, the plasma 25(OH)D concentration was not associated with insulin sensitivity (r = 0.19, p = 0.56). However, higher plasma 25(OH)D concentrations correlated with lower phosphorylation of glycogen synthase kinase-3 (GSK-3) αSer21 and βSer9 in skeletal muscle (r = −0.66, p = 0.015 and r = −0.53, p = 0.06, respectively) and higher GSK-3 αSer21 and βSer9 phosphorylation in adipose tissue (r = 0.82, p < 0.01 and r = 0.62, p = 0.042, respectively). Furthermore, higher plasma 25(OH)D concentrations were associated with greater phosphorylation of both protein kinase-B (AktSer473) (r = 0.78, p < 0.001) and insulin receptor substrate-1 (IRS-1Ser312) (r = 0.71, p = 0.01) in adipose tissue. No associations were found between plasma 25(OH)D concentration and IRS-1Tyr612 phosphorylation in skeletal muscle and adipose tissue. The divergent findings between muscle and adipose tissue with regard to the association between 25(OH)D and insulin signaling proteins may suggest a tissue-specific interaction with varying effects on glucose homeostasis. Further research is required to elucidate the physiological relevance of 25(OH)D in each tissue. PMID:27754361

  2. Macrophage and adipocyte IGF1 maintain adipose tissue homeostasis during metabolic stresses

    PubMed Central

    Chang, Hye Rim; Kim, Hae Jin; Xu, Xiaoyuan; Ferrante, Anthony W.

    2015-01-01

    Objective IGF1 regulates differentiation and growth of tissues and reduces stress and injury. IGF1 also in a tissue specific manner modulates the differentiation and lipid storage capacity of adipocytes in vitro, but its roles in adipose tissue development and response to stress are not known. Methods To study IGF1 in vivo, we identified the cellular sources of adipose tissue Igf1 expression and generated mice with targeted deletion in adipocytes and macrophages. We studied the effects of adipocyte and macrophage deficiency of IGF1 on adipose tissue development, and the response to a chronic (high fat feeding) and acute (cold challenge) stress. Results The expression of Igf1 by adipose tissue is derived from multiple cell types including adipocytes and macrophages. In lean animals, adipocytes are the primary source of IGF1 but in obesity expression by adipocytes is reduced and by macrophages increased, so as to maintain overall adipose tissue Igf1 expression. Genetic deletion studies reveal that adipocyte-derived IGF1 regulates perigonadal but not subcutaneous adipose tissue mass during high fat feeding and the development of obesity. Conversely, macrophage-derived IGF1 acutely modulates PGAT (PGAT) mass during thermogenic challenges. Conclusions Local IGF1 is not required in lean adipose tissue development but required to maintain homeostasis during both chronic and acute metabolic stresses. PMID:26663512

  3. Transient adult microbiota, gut homeostasis and longevity: novel insights from the Drosophila model.

    PubMed

    Erkosar, Berra; Leulier, François

    2014-11-17

    In the last decade, Drosophila has emerged as a useful model to study host-microbiota interactions, creating an active research field with prolific publications. In the last 2 years, several studies contributed to a better understanding of the dynamic nature of microbiota composition and its impact on gut immunity and intestinal tissue homeostasis. These studies depicted the mechanisms by which microbiota regulates gut homeostasis to modulate host fitness and lifespan. Moreover, the latest findings demonstrating that the gut is a physiologically and histologically compartmentalized organ brought fresh perspectives to study the region-specific nature of the interactions between the commensal microbes and the intestinal tissue, and consequences of these interactions on overall host biology.

  4. Concise Review: Quiescence in Adult Stem Cells: Biological Significance and Relevance to Tissue Regeneration.

    PubMed

    Rumman, Mohammad; Dhawan, Jyotsna; Kassem, Moustapha

    2015-10-01

    Adult stem cells (ASCs) are tissue resident stem cells responsible for tissue homeostasis and regeneration following injury. In uninjured tissues, ASCs exist in a nonproliferating, reversibly cell cycle-arrested state known as quiescence or G0. A key function of the quiescent state is to preserve stemness in ASCs by preventing precocious differentiation, and thus maintaining a pool of undifferentiated ASCs. Recent evidences suggest that quiescence is an actively maintained state and that excessive or defective quiescence may lead to compromised tissue regeneration or tumorigenesis. The aim of this review is to provide an update regarding the biological mechanisms of ASC quiescence and their role in tissue regeneration.

  5. Identification of genes needed for regeneration, stem cell function, and tissue homeostasis by systematic gene perturbation in planaria.

    PubMed

    Reddien, Peter W; Bermange, Adam L; Murfitt, Kenneth J; Jennings, Joya R; Sánchez Alvarado, Alejandro

    2005-05-01

    Planarians have been a classic model system for the study of regeneration, tissue homeostasis, and stem cell biology for over a century, but they have not historically been accessible to extensive genetic manipulation. Here we utilize RNA-mediated genetic interference (RNAi) to introduce large-scale gene inhibition studies to the classic planarian system. 1065 genes were screened. Phenotypes associated with the RNAi of 240 genes identify many specific defects in the process of regeneration and define the major categories of defects planarians display following gene perturbations. We assessed the effects of inhibiting genes with RNAi on tissue homeostasis in intact animals and stem cell (neoblast) proliferation in amputated animals identifying candidate stem cell, regeneration, and homeostasis regulators. Our study demonstrates the great potential of RNAi for the systematic exploration of gene function in understudied organisms and establishes planarians as a powerful model for the molecular genetic study of stem cells, regeneration, and tissue homeostasis.

  6. Modular Design of Artificial Tissue Homeostasis: Robust Control through Synthetic Cellular Heterogeneity

    PubMed Central

    Sontag, Eduardo; Davidsohn, Noah; Subramanian, Sairam; Purnick, Priscilla E. M.; Lauffenburger, Douglas; Weiss, Ron

    2012-01-01

    Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of β-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation) are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for ‘synthetic cellular heterogeneity’ that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism), demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a ‘phenotypic sensitivity analysis’ method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in isolation

  7. Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity.

    PubMed

    Miller, Miles; Hafner, Marc; Sontag, Eduardo; Davidsohn, Noah; Subramanian, Sairam; Purnick, Priscilla E M; Lauffenburger, Douglas; Weiss, Ron

    2012-01-01

    Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of β-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation) are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for 'synthetic cellular heterogeneity' that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism), demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a 'phenotypic sensitivity analysis' method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in isolation, and

  8. A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis

    PubMed Central

    Köhn-Gaone, Julia; Chalupsky, Karel; Lüllmann-Rauch, Renate; Barikbin, Roja; Bergmann, Juri; Wöhner, Birte; Zbodakova, Olga; Leuschner, Ivo; Martin, Gregor; Tiegs, Gisa; Rose-John, Stefan; Sedlacek, Radislav; Tirnitz-Parker, Janina E.E.; Saftig, Paul; Schmidt-Arras, Dirk

    2016-01-01

    A Disintegrin And Metalloprotease (ADAM) 10 exerts essential roles during organ development and tissue integrity in different organs, mainly through activation of the Notch pathway. However, only little is known about its implication in liver tissue physiology. Here we show that in contrast to its role in other tissues, ADAM10 is dispensable for the Notch2-dependent biliary tree formation. However, we demonstrate that expression of bile acid transporters is dependent on ADAM10. Consequently, mice deficient for Adam10 in hepatocytes, cholangiocytes and liver progenitor cells develop spontaneous hepatocyte necrosis and concomitant liver fibrosis. We furthermore observed a strongly augmented ductular reaction in 15-week old ADAM10Δhep/Δch mice and demonstrate that c-Met dependent liver progenitor cell activation is enhanced. Additionally, liver progenitor cells are primed to hepatocyte differentiation in the absence of ADAM10. These findings show that ADAM10 is a novel central node controlling liver tissue homeostasis. Highlights: Loss of ADAM10 in murine liver results in hepatocyte necrosis and concomitant liver fibrosis. ADAM10 directly regulates expression of bile acid transporters but is dispensable for Notch2-dependent formation of the biliary system. Activation of liver progenitor cells is enhanced through increased c-Met signalling, in the absence of ADAM10. Differentiation of liver progenitor cells to hepatocytes is augmented in the absence of ADAM10. PMID:26942887

  9. DJ-1 maintains energy and glucose homeostasis by regulating the function of brown adipose tissue

    PubMed Central

    Wu, Rong; Liu, Xiao-meng; Sun, Jian-guang; Chen, Hong; Ma, Jun; Dong, Meng; Peng, Shengyi; Wang, Ji-qiu; Ding, Jian-qing; Li, Dong-hao; Speakman, John R; Ning, Guang; Jin, Wanzhu; Yuan, Zengqiang

    2017-01-01

    DJ-1 protein is involved in multiple physiological processes, including Parkinson’s disease. However, the role of DJ-1 in the metabolism is largely unknown. Here we found that DJ-1 maintained energy balance and glucose homeostasis via regulating brown adipose tissue (BAT) activity. DJ-1-deficient mice reduced body mass, increased energy expenditure and improved insulin sensitivity. DJ-1 deletion also resisted high-fat-diet (HFD) induced obesity and insulin resistance. Accordingly, DJ-1 transgene triggered autonomous obesity and glucose intolerance. Further BAT transplantation experiments clarified DJ-1 regulates energy and glucose homeostasis by modulating BAT function. Mechanistically, we found that DJ-1 promoted PTEN proteasomal degradation via an E3 ligase, mind bomb-2 (Mib2), which led to Akt activation and inhibited FoxO1-dependent Ucp1 (Uncoupling protein-1) expression in BAT. Consistently, ablation of Akt1 mitigated the obesity and BAT dysfunction induced by DJ-1 transgene. These findings define a new biological role of DJ-1 protein in regulating BAT function, with an implication of the therapeutic target in the treatment of metabolic disorders. PMID:28224045

  10. Heterozygous Vangl2(Looptail) mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair.

    PubMed

    Poobalasingam, Thanushiyan; Yates, Laura L; Walker, Simone A; Pereira, Miguel; Gross, Nina Y; Ali, Akmol; Kolatsi-Joannou, Maria; Jarvelin, Marjo-Riitta; Pekkanen, Juha; Papakrivopoulou, Eugenia; Long, David A; Griffiths, Mark; Wagner, Darcy; Königshoff, Melanie; Hind, Matthew; Minelli, Cosetta; Lloyd, Clare M; Dean, Charlotte H

    2017-02-24

    SCRIBBLE (SCRIB) are significantly downregulated in lung tissue from patients with emphysema.Our data reveals an important novel role for the PCP pathway in adult lung homeostasis and repair and sheds new light on the genetic factors which may modify destructive lung diseases such as emphysema.

  11. Peripheral effects of the endocannabinoid system in energy homeostasis: adipose tissue, liver and skeletal muscle.

    PubMed

    Silvestri, Cristoforo; Ligresti, Alessia; Di Marzo, Vincenzo

    2011-09-01

    The endocannabinoid system (ECS) is composed of lipid signalling ligands, their G-protein coupled receptors and the enzymes involved in ligand generation and metabolism. Increasingly, the ECS is emerging as a critical agent of energy metabolism regulation through its ability to modulate caloric intake centrally as well as nutrient transport, cellular metabolism and energy storage peripherally. Visceral obesity has been associated with an upregulation of ECS activity in several systems and inhibition of the ECS, either pharmacologically or genetically, results in decreased energy intake and increased metabolic output. This review aims to summarize the recent advances that have been made regarding our understanding of the role the ECS plays in crucial peripheral systems pertaining to energy homeostasis: adipose tissues, the liver and skeletal muscle.

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

    PubMed Central

    Laker, Rhianna C.; Taddeo, Evan P.; Akhtar, Yasir N.; Zhang, Mei; Hoehn, Kyle L.; Yan, Zhen

    2016-01-01

    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. PMID:28005946

  13. Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency.

    PubMed

    Müller, Julia; Mayerl, Steffen; Visser, Theo J; Darras, Veerle M; Boelen, Anita; Frappart, Lucien; Mariotta, Luca; Verrey, Francois; Heuer, Heike

    2014-01-01

    The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.

  14. Inflammatory Properties of Diet and Glucose-Insulin Homeostasis in a Cohort of Iranian Adults

    PubMed Central

    Moslehi, Nazanin; Ehsani, Behnaz; Mirmiran, Parvin; Shivappa, Nitin; Tohidi, Maryam; Hébert, James R.; Azizi, Fereidoun

    2016-01-01

    We aimed to investigate associations of the dietary inflammatory index (DII) with glucose-insulin homeostasis markers, and the risk of glucose intolerance. This cross-sectional study included 2975 adults from the Tehran Lipid and Glucose Study. Fasting plasma glucose (FPG), 2-h post-load glucose (2h-PG), and fasting serum insulin were measured. Homeostatic model assessment of insulin resistance index (HOMA-IR) and β-cell function (HOMA-B), and the quantitative insulin sensitivity check index (QUICKI) were calculated. Glucose tolerance abnormalities included impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM). DII scores were positively associated with 2h-PG (β = 0.04; p = 0.05). There was no significant linear trend across quartiles of DII for adjusted means of glucose-insulin homeostasis markers. Participants in the highest quartile of DII score tended to have higher FPG compared to those in the second quartile of DII score (5.46 vs. 5.38 mmol/L, p = 0.07) and higher fasting insulin and HOMA-IR compared to those in the lowest quartile (8.52 vs. 8.12 µU/mL for fasting insulin, p = 0.07; 2.06 vs. 1.96 for HOMA-IR, p = 0.08). No significant associations were observed between DII and risk of IFG, IGT, T2DM, and insulin resistance. Among glucose-insulin homeostasis markers, DII had a positive weak association only with 2h-PG. PMID:27869717

  15. Mutating RBF Can Enhance Its Pro-Apoptotic Activity and Uncovers a New Role in Tissue Homeostasis

    PubMed Central

    Milet, Cécile; Rincheval-Arnold, Aurore; Moriéras, Angéline; Clavier, Amandine; Garrigue, Alexandrine; Mignotte, Bernard; Guénal, Isabelle

    2014-01-01

    The tumor suppressor retinoblastoma protein (pRb) is inactivated in a wide variety of cancers. While its role during cell cycle is well characterized, little is known about its properties on apoptosis regulation and apoptosis-induced cell responses. pRb shorter forms that can modulate pRB apoptotic properties, resulting from cleavages at caspase specific sites are observed in several cellular contexts. A bioinformatics analysis showed that a putative caspase cleavage site (TELD) is found in the Drosophila homologue of pRb (RBF) at a position similar to the site generating the p76Rb form in mammals. Thus, we generated a punctual mutant form of RBF in which the aspartate of the TELD site is replaced by an alanine. This mutant form, RBFD253A, conserved the JNK-dependent pro-apoptotic properties of RBF but gained the ability of inducing overgrowth phenotypes in adult wings. We show that this overgrowth is a consequence of an abnormal proliferation in wing imaginal discs, which depends on the JNK pathway activation but not on wingless (wg) ectopic expression. These results show for the first time that the TELD site of RBF could be important to control the function of RBF in tissue homeostasis in vivo. PMID:25089524

  16. Connective tissue growth factor is required for skeletal development and postnatal skeletal homeostasis in male mice.

    PubMed

    Canalis, Ernesto; Zanotti, Stefano; Beamer, Wesley G; Economides, Aris N; Smerdel-Ramoya, Anna

    2010-08-01

    Connective tissue growth factor (CTGF), a member of the cysteine-rich 61 (Cyr 61), CTGF, nephroblastoma overexpressed (NOV) (CCN) family of proteins, is synthesized by osteoblasts, and its overexpression inhibits osteoblastogenesis and causes osteopenia. The global inactivation of Ctgf leads to defective endochondral bone formation and perinatal lethality; therefore, the consequences of Ctgf inactivation on the postnatal skeleton are not known. To study the function of CTGF, we generated Ctgf(+/LacZ) heterozygous null mice and tissue-specific null Ctgf mice by mating Ctgf conditional mice, where Ctgf is flanked by lox sequences with mice expressing the Cre recombinase under the control of the paired-related homeobox gene 1 (Prx1) enhancer (Prx1-Cre) or the osteocalcin promoter (Oc-Cre). Ctgf(+/LacZ) heterozygous mice exhibited transient osteopenia at 1 month of age secondary to decreased trabecular number. A similar osteopenic phenotype was observed in 1-month-old Ctgf conditional null male mice generated with Prx1-Cre, suggesting that the decreased trabecular number was secondary to impaired endochondral bone formation. In contrast, when the conditional deletion of Ctgf was achieved by Oc-Cre, an osteopenic phenotype was observed only in 6-month-old male mice. Osteoblast and osteoclast number, bone formation, and eroded surface were not affected in Ctgf heterozygous or conditional null mice. In conclusion, CTGF is necessary for normal skeletal development but to a lesser extent for postnatal skeletal homeostasis.

  17. PTEN is required to maintain luminal epithelial homeostasis and integrity in the adult mammary gland.

    PubMed

    Shore, Amy N; Chang, Chi-Hsuan; Kwon, Oh-Joon; Weston, Matthew C; Zhang, Mei; Xin, Li; Rosen, Jeffrey M

    2016-01-01

    In the mammary gland, PTEN loss in luminal and basal epithelial cells results in differentiation defects and enhanced proliferation, leading to the formation of tumors with basal epithelial characteristics. In breast cancer, PTEN loss is associated with a hormone receptor-negative, basal-like subtype that is thought to originate in a luminal epithelial cell. Here, we show that luminal-specific PTEN loss results in distinct effects on epithelial homeostasis and mammary tumor formation. Luminal PTEN loss increased proliferation of hormone receptor-negative cells, thereby decreasing the percentage of hormone receptor-positive cells. Moreover, luminal PTEN loss led to misoriented cell divisions and mislocalization of cells to the intraluminal space of mammary ducts. Despite their elevated levels of activated AKT, Pten-null intraluminal cells showed increased levels of apoptosis. One year after Pten deletion, the ducts had cleared and no palpable mammary tumors were detected. These data establish PTEN as a critical regulator of luminal epithelial homeostasis and integrity in the adult mammary gland, and further show that luminal PTEN loss alone is not sufficient to promote the progression of mammary tumorigenesis.

  18. Dopamine controls neurogenesis in the adult salamander midbrain in homeostasis and during regeneration of dopamine neurons.

    PubMed

    Berg, Daniel A; Kirkham, Matthew; Wang, Heng; Frisén, Jonas; Simon, András

    2011-04-08

    Appropriate termination of regenerative processes is critical for producing the correct number of cells in tissues. Here we provide evidence for an end-product inhibition of dopamine neuron regeneration that is mediated by dopamine. Ablation of midbrain dopamine neurons leads to complete regeneration in salamanders. Regeneration involves extensive neurogenesis and requires activation of quiescent ependymoglia cells, which express dopamine receptors. Pharmacological compensation for dopamine loss by L-dopa inhibits ependymoglia proliferation and regeneration in a dopamine receptor-signaling-dependent manner, specifically after ablation of dopamine neurons. Systemic administration of the dopamine receptor antagonist haloperidol alone causes ependymoglia proliferation and the appearance of excessive number of neurons. Our data show that stem cell quiescence is under dopamine control and provide a model for termination once normal homeostasis is restored. The findings establish a role for dopamine in the reversible suppression of neurogenesis in the midbrain and have implications for regenerative strategies in Parkinson's disease.

  19. DJ-1 maintains energy and glucose homeostasis by regulating the function of brown adipose tissue.

    PubMed

    Wu, Rong; Liu, Xiao-Meng; Sun, Jian-Guang; Chen, Hong; Ma, Jun; Dong, Meng; Peng, Shengyi; Wang, Ji-Qiu; Ding, Jian-Qing; Li, Dong-Hao; Speakman, John R; Ning, Guang; Jin, Wanzhu; Yuan, Zengqiang

    2017-01-01

    DJ-1 protein is involved in multiple physiological processes, including Parkinson's disease. However, the role of DJ-1 in the metabolism is largely unknown. Here we found that DJ-1 maintained energy balance and glucose homeostasisvia regulating brown adipose tissue (BAT) activity. DJ-1-deficient mice reduced body mass, increased energy expenditure and improved insulin sensitivity. DJ-1 deletion also resisted high-fat-diet (HFD) induced obesity and insulin resistance. Accordingly, DJ-1 transgene triggered autonomous obesity and glucose intolerance. Further BAT transplantation experiments clarified DJ-1 regulates energy and glucose homeostasis by modulating BAT function. Mechanistically, we found that DJ-1 promoted PTEN proteasomal degradation via an E3 ligase, mind bomb-2 (Mib2), which led to Akt activation and inhibited FoxO1-dependent Ucp1 (Uncoupling protein-1) expression in BAT. Consistently, ablation of Akt1 mitigated the obesity and BAT dysfunction induced by DJ-1 transgene. These findings define a new biological role of DJ-1 protein in regulating BAT function, with an implication of the therapeutic target in the treatment of metabolic disorders.

  20. Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

    PubMed

    Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

    2016-05-01

    GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1.

  1. A deregulated intestinal cell cycle program disrupts tissue homeostasis without affecting longevity in Drosophila.

    PubMed

    Petkau, Kristina; Parsons, Brendon D; Duggal, Aashna; Foley, Edan

    2014-10-10

    Recent studies illuminate a complex relationship between the control of stem cell division and intestinal tissue organization in the model system Drosophila melanogaster. Host and microbial signals drive intestinal proliferation to maintain an effective epithelial barrier. Although it is widely assumed that proliferation induces dysplasia and shortens the life span of the host, the phenotypic consequences of deregulated intestinal proliferation for an otherwise healthy host remain unexplored. To address this question, we genetically isolated and manipulated the cell cycle programs of adult stem cells and enterocytes. Our studies revealed that cell cycle alterations led to extensive cell death and morphological disruptions. Despite the extensive tissue damage, we did not observe an impact on longevity, suggesting a remarkable degree of plasticity in intestinal function.

  2. An aqueous extract of Curcuma longa (turmeric) rhizomes stimulates insulin release and mimics insulin action on tissues involved in glucose homeostasis in vitro.

    PubMed

    Mohankumar, Sureshkumar; McFarlane, James R

    2011-03-01

    Curcuma longa (turmeric) has been used widely as a spice, particularly in Asian countries. It is also used in the Ayurvedic system of medicine as an antiinflammatory and antimicrobial agent and for numerous other curative properties. The aim of this study was to investigate the effects of an aqueous extract of Curcuma longa (AEC) on tissues involved in glucose homeostasis. The extract was prepared by soaking 100 g of ground turmeric in 1 L of water, which was filtered and stored at -20°C prior to use. Pancreas and muscle tissues of adult mice were cultured in DMEM with 5 or 12 mmol/L glucose and varying doses of extract. The AEC stimulated insulin secretion from mouse pancreatic tissues under both basal and hyperglycaemic conditions, although the maximum effect was only 68% of that of tolbutamide. The AEC induced stepwise stimulation of glucose uptake from abdominal muscle tissues in the presence and absence of insulin, and the combination of AEC and insulin significantly potentiated the glucose uptake into abdominal muscle tissue. However, this effect was attenuated by wortmannin, suggesting that AEC possibly acts via the insulin-mediated glucose uptake pathway. In summary, water soluble compounds of turmeric exhibit insulin releasing and mimicking actions within in vitro tissue culture conditions.

  3. Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis.

    PubMed

    Lee, Jayhun; Kang, Sangjo; Lilja, Karin C; Colletier, Keegan J; Scheitz, Cornelia Johanna Franziska; Zhang, Ying V; Tumbar, Tudorita

    2016-04-15

    Mechanisms of plasticity to acquire different cell fates are critical for adult stem cell (SC) potential, yet are poorly understood. Reduced global histone methylation is an epigenetic state known to mediate plasticity in cultured embryonic SCs and T-cell progenitors. Here we find histone H3 K4/K9/K27me3 levels actively reduced in adult mouse skin and hair follicle stem cells (HFSCs) during G0 quiescence. The level of marks over specific gene promoters did not correlate to mRNA level changes in quiescent HFSCs. Skin hypomethylation during quiescence was necessary for subsequent progression of hair homeostasis (cycle). Inhibiting BMP signal, a known HFSC anti-proliferative factor, elevated HFSC methylation in vivo during quiescence prior to proliferation onset. Furthermore, removal of proliferation factors and addition of BMP4 reduced histone methylases and increased demethylases mRNAs in cultured skin epithelial cells. We conclude that signalling couples hair follicle stem cell quiescence with reduced H3 K4/K9/K27me3 levels for proper tissue homeostasis.

  4. Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis

    PubMed Central

    Lee, Jayhun; Kang, Sangjo; Lilja, Karin C.; Colletier, Keegan J.; Scheitz, Cornelia Johanna Franziska; Zhang, Ying V.; Tumbar, Tudorita

    2016-01-01

    Mechanisms of plasticity to acquire different cell fates are critical for adult stem cell (SC) potential, yet are poorly understood. Reduced global histone methylation is an epigenetic state known to mediate plasticity in cultured embryonic SCs and T-cell progenitors. Here we find histone H3 K4/K9/K27me3 levels actively reduced in adult mouse skin and hair follicle stem cells (HFSCs) during G0 quiescence. The level of marks over specific gene promoters did not correlate to mRNA level changes in quiescent HFSCs. Skin hypomethylation during quiescence was necessary for subsequent progression of hair homeostasis (cycle). Inhibiting BMP signal, a known HFSC anti-proliferative factor, elevated HFSC methylation in vivo during quiescence prior to proliferation onset. Furthermore, removal of proliferation factors and addition of BMP4 reduced histone methylases and increased demethylases mRNAs in cultured skin epithelial cells. We conclude that signalling couples hair follicle stem cell quiescence with reduced H3 K4/K9/K27me3 levels for proper tissue homeostasis. PMID:27080563

  5. Treatment Option Overview (Adult Soft Tissue Sarcoma)

    MedlinePlus

    ... superficial (in subcutaneous tissue with no spread into connective tissue or muscle below) or deep (in the muscle ... superficial (in subcutaneous tissue with no spread into connective tissue or muscle below) or deep (in the muscle ...

  6. Treatment Options for Adult Soft Tissue Sarcoma

    MedlinePlus

    ... superficial (in subcutaneous tissue with no spread into connective tissue or muscle below) or deep (in the muscle ... superficial (in subcutaneous tissue with no spread into connective tissue or muscle below) or deep (in the muscle ...

  7. General Information about Adult Soft Tissue Sarcoma

    MedlinePlus

    ... superficial (in subcutaneous tissue with no spread into connective tissue or muscle below) or deep (in the muscle ... superficial (in subcutaneous tissue with no spread into connective tissue or muscle below) or deep (in the muscle ...

  8. Stages of Adult Soft Tissue Sarcoma

    MedlinePlus

    ... superficial (in subcutaneous tissue with no spread into connective tissue or muscle below) or deep (in the muscle ... superficial (in subcutaneous tissue with no spread into connective tissue or muscle below) or deep (in the muscle ...

  9. Adult tissue sources for new β cells.

    PubMed

    Nichols, Robert J; New, Connie; Annes, Justin P

    2014-04-01

    The diabetes pandemic incurs extraordinary public health and financial costs that are projected to expand for the foreseeable future. Consequently, the development of definitive therapies for diabetes is a priority. Currently, a wide spectrum of therapeutic strategies-from implantable insulin delivery devices to transplantation-based cell replacement therapy, to β-cell regeneration-focus on replacing the lost insulin-producing capacity of individuals with diabetes. Among these, β-cell regeneration remains promising but heretofore unproved. Indeed, recent experimental work has uncovered surprising biology that underscores the potential therapeutic benefit of β-cell regeneration. These studies have elucidated a variety of sources for the endogenous production of new β cells from existing cells. First, β cells, long thought to be postmitotic, have demonstrated the potential for regenerative capacity. Second, the presence of pancreatic facultative endocrine progenitor cells has been established. Third, the malleability of cellular identity has availed the possibility of generating β cells from other differentiated cell types. Here, we review the exciting developments surrounding endogenous sources of β-cell production and consider the potential of realizing a regenerative therapy for diabetes from adult tissues.

  10. Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumourigenesis in murine mammary epithelium

    PubMed Central

    Daly, Carl S.; Shaw, Paul; Ordonez, Liliana D.; Williams, Geraint T.; Quist, Jelmar; Grigoriadis, Anita; Van Es, Johan H.; Clevers, Hans; Clarke, Alan R.; Reed, Karen R.

    2016-01-01

    Aberrant Wnt signaling within breast cancer is associated with poor prognosis, but regulation of this pathway in breast tissue remains poorly understood and the consequences of immediate or long-term dysregulation remain elusive. The exact contribution of the Wnt-regulating proteins APC and APC2 in the pathogenesis of human breast cancer are ill-defined, but our analysis of publically available array datasets indicates that tumors with concomitant low expression of both proteins occurs more frequently in the ‘triple negative’ phenotype, which is a subtype of breast cancer with particularly poor prognosis. We have used mouse transgenics to delete Apc and/or Apc2 from mouse mammary epithelium to elucidate the significance of these proteins in mammary homeostasis and delineate their influences on Wnt signaling and tumourigenesis. Loss of either protein alone failed to affect Wnt signaling levels or tissue homeostasis. Strikingly, concomitant loss led to local disruption of β-catenin status, disruption in epithelial integrity, cohesion and polarity, increased cell division and a distinctive form of ductal hyperplasia with ‘squamoid’ ghost cell nodules in young animals. Upon aging, the development of Wnt activated mammary carcinomas with squamous differentiation was accompanied by a significantly reduced survival. This novel Wnt driven mammary tumour model highlights the importance of functional redundancies existing between the Apc proteins both in normal homeostasis and in tumorigenesis. PMID:27694902

  11. Fibroblast growth factor 10-fibroblast growth factor receptor 2b mediated signaling is not required for adult glandular stomach homeostasis.

    PubMed

    Speer, Allison L; Al Alam, Denise; Sala, Frederic G; Ford, Henri R; Bellusci, Saverio; Grikscheit, Tracy C

    2012-01-01

    The signaling pathways that are essential for gastric organogenesis have been studied in some detail; however, those that regulate the maintenance of the gastric epithelium during adult homeostasis remain unclear. In this study, we investigated the role of Fibroblast growth factor 10 (FGF10) and its main receptor, Fibroblast growth factor receptor 2b (FGFR2b), in adult glandular stomach homeostasis. We first showed that mouse adult glandular stomach expressed Fgf10, its receptors, Fgfr1b and Fgfr2b, and most of the other FGFR2b ligands (Fgf1, Fgf7, Fgf22) except for Fgf3 and Fgf20. Fgf10 expression was mesenchymal whereas FGFR1 and FGFR2 expression were mostly epithelial. Studying double transgenic mice that allow inducible overexpression of Fgf10 in adult mice, we showed that Fgf10 overexpression in normal adult glandular stomach increased epithelial proliferation, drove mucous neck cell differentiation, and reduced parietal and chief cell differentiation. Although a similar phenotype can be associated with the development of metaplasia, we found that Fgf10 overexpression for a short duration does not cause metaplasia. Finally, investigating double transgenic mice that allow the expression of a soluble form of Fgfr2b, FGF10's main receptor, which acts as a dominant negative, we found no significant changes in gastric epithelial proliferation or differentiation in the mutants. Our work provides evidence, for the first time, that the FGF10-FGFR2b signaling pathway is not required for epithelial proliferation and differentiation during adult glandular stomach homeostasis.

  12. Generation of a conditional mouse model to target Acvr1b disruption in adult tissues.

    PubMed

    Ripoche, Doriane; Gout, Johann; Pommier, Roxane M; Jaafar, Rami; Zhang, Chang X; Bartholin, Laurent; Bertolino, Philippe

    2013-02-01

    Alk4 is a type I receptor that belongs to the transforming growth factor-beta (TGF-β) family. It takes part in the signaling of TGF-β ligands such as Activins, Gdfs, and Nodal that had been demonstrated to participate in numerous mechanisms ranging from early embryonic development to adult-tissue homeostasis. Evidences indicate that Alk4 is a key regulator of many embryonic processes, but little is known about its signaling in adult tissues and in pathological conditions where Alk4 mutations had been reported. Conventional deletion of Alk4 gene (Acvr1b) results in early embryonic lethality prior gastrulation, which has precluded study of Alk4 functions in postnatal and adult mice. To circumvent this problem, we have generated a conditional Acvr1b floxed-allele by flanking the fifth and sixth exons of the Acvr1b gene with loxP sites. Cre-mediated deletion of the floxed allele generates a deleted allele, which behaves as an Acvr1b null allele leading to embryonic lethality in homozygous mutant animals. A tamoxifen-inducible approach to target disruption of Acvr1b specifically in adult tissues was used and proved to be efficient for studying Alk4 functions in various organs. We report, therefore, a novel conditional model allowing investigation of biological role played by Alk4 in a variety of tissue-specific contexts.

  13. Alteration of local adipose tissue trace element homeostasis as a possible mechanism of obesity-related insulin resistance.

    PubMed

    Tinkov, Alexey A; Sinitskii, Anton I; Popova, Elizaveta V; Nemereshina, Olga N; Gatiatulina, Evgenia R; Skalnaya, Margarita G; Skalny, Anatoly V; Nikonorov, Alexandr A

    2015-09-01

    The mechanisms of association between obesity and the related metabolic disturbances in general and insulin resistance in particular are extensively studied. Taking into account a key role of adipose tissue insulin resistance in the development of systemic obesity-related insulin resistance, the estimation of mechanisms linking increased adiposity and impaired insulin signaling in adipocytes will allow to develop novel prophylactic and therapeutic approaches to treatment of these states. A number of trace elements like chromium, zinc, and vanadium have been shown to take part in insulin signaling via various mechanisms. Taking into account a key role of adipocyte in systemic carbohydrate homeostasis it can be asked if trace element homeostasis in adipose tissue may influence regulatory mechanisms of glucose metabolism. We hypothesize that caloric excess through currently unknown mechanisms results in decreased chromium, vanadium, and zinc content in adipocytes. Decreased content of trace elements in the adipose tissue causes impairment of intra-adipocyte insulin signaling subsequently leading to adipose tissue insulin resistance. The latter significantly contributes to systemic insulin resistance and further metabolic disruption in obesity. It is also possible that decreased adipose tissue trace element content is associated with dysregulation of insulin-sensitizing and proinflammatory adipokines also leading to insulin resistance. We hypothesize that insulin resistance and adipokine dysbalance increase the severity of obesity subsequently aggravating alteration of adipose tissue trace element balance. Single indications of high relative adipose tissue trace element content, decreased Cr, V, and Zn content in obese adipose tissue, and tight association between fat tissue chromium, vanadium, and zinc levels and metabolic parameters in obesity may be useful for hypothesis validation. If our hypothesis will be confirmed by later studies, adipose tissue chromium

  14. The coxsackie- and adenovirus receptor (CAR) is an in vivo marker for epithelial tight junctions, with a potential role in regulating permeability and tissue homeostasis.

    PubMed

    Raschperger, Elisabeth; Thyberg, Johan; Pettersson, Sven; Philipson, Lennart; Fuxe, Jonas; Pettersson, Ralf F

    2006-05-15

    The coxsackie- and adenovirus receptor (CAR) is a transmembrane protein belonging to the immunoglobulin superfamily. The function of CAR as a virus receptor has been extensively analyzed, while its physiological role and expression pattern in adult tissues have remained less clear. CAR associates with epithelial tight junctions in vitro and mediates cell-cell adhesion. Using a set of affinity-purified antibodies, we show that CAR is predominantly expressed in epithelial cells lining the body cavities in adult mice, where it specifically co-localizes with the tight junction components ZO-1 and occludin. Notably, CAR could not be detected in endothelial cells of the vasculature, including brain capillaries. CAR expression correlated positively with the maturity of tight junctions and inversely with permeability. With a few exceptions, the two known CAR isoforms were co-expressed in most epithelial cells analyzed. A CAR mutant lacking the intracellular tail over-expressed in transgenic mice was diffusely localized over the plasma membrane, showing the importance of this domain for correct subcellular localization in vivo. We conclude that CAR is localized to epithelial tight junctions in vivo where it may play a role in the regulation of epithelial permeability and tissue homeostasis.

  15. [Radiotherapy of adult soft tissue sarcoma].

    PubMed

    Le Péchoux, C; Moureau-Zabotto, L; Llacer, C; Ducassou, A; Sargos, P; Sunyach, M P; Thariat, J

    2016-09-01

    Incidence of soft tissue sarcoma is low and requires multidisciplinary treatment in specialized centers. The objective of this paper is to report the state of the art regarding indications and treatment techniques of main soft tissue sarcoma localisations.

  16. Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and CNS Homeostasis

    PubMed Central

    Tran, Khiem A.; Zhang, Xianming; Predescu, Dan; Huang, Xiaojia; Machado, Roberto F.; Göthert, Joachim R.; Malik, Asrar B.; Valyi-Nagy, Tibor; Zhao, You-Yang

    2015-01-01

    Background The blood-brain barrier (BBB) formed by brain endothelial cells (ECs) interconnected by tight junctions (TJs) is essential for the homeostasis of the central nervous system (CNS). Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Methods and Results Using a mouse model with tamoxifen-inducible EC-restricted disruption of ctnnb1 (iCKO), here we show that endothelial β-catenin signaling is essential for maintaining BBB integrity and CNS homeostasis in adult. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and CNS inflammation, and all died postictal. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of specific TJ proteins Claudin-1 and -3 in adult brain ECs. The clinical relevance of the data is indicated by the observation of decreased expression of Claudin-1 and nuclear β-catenin in brain ECs of hemorrhagic lesions of hemorrhagic stroke patients. Conclusion These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity and CNS inflammation. PMID:26538583

  17. Meeting current musculoskeletal health demand through deeper insights into tissue homeostasis and regeneration.

    PubMed

    Andia, Isabel; Maffulli, Nicola

    2015-06-01

    The burden of chronic musculoskeletal disorders is challenging and prompts therapeutic advancements. The notion that chronic conditions such as osteoarthritis and tendinopathy are linked to deficient healing by failure of one or several of the cellular/molecular processes involved is gaining ground. Alterations underpinning disruption of healing mechanisms that contribute to the development of chronic musculoskeletal pathologies include unresolved inflammation, abnormal angiogenic status, alterations in paracrine communication, decline in stem cell functioning and inability to maintain homeostasis in the extracellular matrix compartment. The complexity of failed healing may be challenged with interventions that target multiple biological processes such as cell therapies and/or platelet-rich plasma.

  18. Correction of Negative Effect of Antenatal Hypoxia on Liver Tissue Homeostasis in Newborn Albino Rats with Opioid Peptides.

    PubMed

    Pinaeva, O G; Sazonova, E N; Lebed'ko, O A; Timoshin, S S

    2016-12-01

    We studied the possibility of correction of the negative effects of antenatal hypoxia on the liver tissue homeostasis in 7-day-old albino rats by administration of opioid peptides in a dose of 100 μg/kg on postnatal days 2-6. Administration of mixed μ/δ-opioid receptor agonist Dalargin neutralized deviations of gravimetric indicators, parameters of proliferative activity, and activity of the nucleolar apparatus of hepatocytes. Administration of the non-opiate Leu-enkephalin analogue did not normalize gravimetric parameters and nucleolar apparatus parameters, however, it significantly increased the pool of proliferating hepatocytes. Both peptides significantly reduced the intensity of free radical oxidation, improved antioxidant antiradical defense and resistance to peroxidation in the liver tissue of animals subjected to antenatal hypoxia.

  19. Epimorphic regeneration approach to tissue replacement in adult mammals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor...

  20. Modulation of polyamine metabolic flux in adipose tissue alters the accumulation of body fat by affecting glucose homeostasis

    PubMed Central

    Liu, Chunli; Perez-Leal, Oscar; Barrero, Carlos; Zahedi, Kamyar; Soleimani, Manoocher; Porter, Carl

    2013-01-01

    The continued rise in obesity despite public education, awareness and policies indicates the need for mechanism-based therapeutic approaches to help control the disease. Our data, in conjunction with other studies, suggest an unexpected role for the polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT) in fat homeostasis. Our previous studies showed that deletion of SSAT greatly exaggerates weight gain and that the transgenic overexpression suppresses weight gain in mice on a high-fat diet. This discovery is substantial but the underlying molecular linkages are only vaguely understood. Here, we used a comprehensive systems biology approach, on white adipose tissue (WAT), to discover that the partition of acetyl-CoA towards polyamine catabolism alters glucose homeostasis and hence, fat accumulation. Comparative proteomics and antibody-based expression studies of WAT in SSAT knockout, wild type and transgenic mice identified nine proteins with an increasing gradient across the genotypes, all of which correlate with acetyl-CoA consumption in polyamine acetylation. Adipose-specific SSAT knockout mice and global SSAT knockout mice on a high-fat diet exhibited similar growth curves and proteomic patterns in their WAT, confirming that attenuated consumption of acetyl-CoA in acetylation of polyamines in adipose tissue drives the obese phenotype of these mice. Analysis of protein expression indicated that the identified changes in the levels of proteins regulating acetyl-CoA consumption occur via the AMP-activated protein kinase pathway. Together, our data suggest that differential expression of SSAT markedly alters acetyl-CoA levels, which in turn trigger a global shift in glucose metabolism in adipose tissue, thus affecting the accumulation of body fat. PMID:23881108

  1. The STRA6 receptor is essential for retinol-binding protein-induced insulin resistance but not for maintaining vitamin A homeostasis in tissues other than the eye.

    PubMed

    Berry, Daniel C; Jacobs, Hugues; Marwarha, Gurdeep; Gely-Pernot, Aurore; O'Byrne, Sheila M; DeSantis, David; Klopfenstein, Muriel; Feret, Betty; Dennefeld, Christine; Blaner, William S; Croniger, Colleen M; Mark, Manuel; Noy, Noa; Ghyselinck, Norbert B

    2013-08-23

    The plasma membrane protein STRA6 is thought to mediate uptake of retinol from its blood carrier retinol-binding protein (RBP) into cells and to function as a surface receptor that, upon binding of holo-RBP, activates a JAK/STAT cascade. It was suggested that STRA6 signaling underlies insulin resistance induced by elevated serum levels of RBP in obese animals. To investigate these activities in vivo, we generated and analyzed Stra6-null mice. We show that the contribution of STRA6 to retinol uptake by tissues in vivo is small and that, with the exception of the eye, ablation of Stra6 has only a modest effect on retinoid homeostasis and does not impair physiological functions that critically depend on retinoic acid in the embryo or in the adult. However, ablation of Stra6 effectively protects mice from RBP-induced suppression of insulin signaling. Thus one biological function of STRA6 in tissues other than the eye appears to be the coupling of circulating holo-RBP levels to cell signaling, in turn regulating key processes such as insulin response.

  2. Altered glucose and lipid homeostasis in liver and adipose tissue pre-dispose inducible NOS knockout mice to insulin resistance

    PubMed Central

    Kanuri, Babu Nageswararao; Kanshana, Jitendra S.; Rebello, Sanjay C.; Pathak, Priya; Gupta, Anand P.; Gayen, Jiaur R.; Jagavelu, Kumaravelu; Dikshit, Madhu

    2017-01-01

    On the basis of diet induced obesity and KO mice models, nitric oxide is implied to play an important role in the initiation of dyslipidemia induced insulin resistance. However, outcomes using iNOS KO mice have so far remained inconclusive. The present study aimed to assess IR in iNOS KO mice after 5 weeks of LFD feeding by monitoring body composition, energy homeostasis, insulin sensitivity/signaling, nitrite content and gene expressions changes in the tissues. We found that body weight and fat content in KO mice were significantly higher while the respiratory exchange ratio (RER), volume of carbon dioxide (VCO2), and heat production were lower as compared to WT mice. Furthermore, altered systemic glucose tolerance, tissue insulin signaling, hepatic gluconeogenesis, augmented hepatic lipids, adiposity, as well as gene expression regulating lipid synthesis, catabolism and efflux were evident in iNOS KO mice. Significant reduction in eNOS and nNOS gene expression, hepatic and adipose tissue nitrite content, circulatory nitrite was also observed. Oxygen consumption rate of mitochondrial respiration has remained unaltered in KO mice as measured using extracellular flux analyzer. Our findings establish a link between the NO status with systemic and tissue specific IR in iNOS KO mice at 5 weeks. PMID:28106120

  3. Adipose tissue α-linolenic acid is inversely associated with insulin resistance in adults1

    PubMed Central

    Sabaté, Joan

    2016-01-01

    Background: There is emerging evidence of the beneficial effects of n–3 (ω-3) fatty acids (FAs) on cardiometabolic risk factors. Nevertheless, not much is known about the association between adipose tissue α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and insulin resistance. Objective: We determined the association between adipose tissue n–3 FAs (total n–3 FAs, ALA, and EPA plus DHA) and insulin resistance in healthy adults. Design: In this cross-sectional study, multivariable analyses were used to assess the association between adipose tissue FAs (ALA, EPA plus DHA, and total n–3 FAs) and the homeostasis model assessment of insulin resistance (HOMA-IR) in a subset of adult participants (n = 716; mean age: 58 y) from the Adventist Health Study-2 (AHS-2) cohort. Results: Compared with the lowest tertile, the third tertile (β = −0.13; 95% CI: −0.24, −0.01) of adipose tissue ALA was inversely associated with the HOMA-IR. When stratified by waist circumference, ALA continued to be inversely associated [third tertile: β = −0.17 (95% CI: −0.31, −0.02)] with the HOMA-IR in subjects with a waist circumference ≤88 cm in women or ≤102 cm in men but not in those with a larger waist circumference. No significant association was noted between adipose tissue EPA plus DHA and HOMA-IR. Conclusions: Higher adipose tissue ALA was inversely associated with insulin resistance in this cohort of healthy adult men and women. This finding appears to be more pronounced in individuals with a normal waist circumference. PMID:26912497

  4. High-intensity-focused-ultrasound (HIFU) induced homeostasis and tissue ablation

    NASA Astrophysics Data System (ADS)

    Chauhan, Sunita; Michel, M. S.; Alken, Peter; Kohrmann, K. U.; Haecker, Axel

    2003-06-01

    At high intensity levels, ultrasound energy focused into remote tissue targets in human body has shown to produce thermal necrosis in circumscribed regions with sub-millimeter accuracy. The non-invasive modality known as HIFU has enormous potential for thermal ablation of cancers/tumors of the human body without any adverse effects in the surrounding normal tissue. In this paper, empirical results for parametric assessment and interdependence of several exposure variables are presented for producing thermal necrosis as well as hemostasis. Multiple HIFU transducers in selective spatial configuration have been deployed using a suitably designed experiemntal harness, with and without motorized jig scanning. The pre-planning and on-line procedure for treatment and specified instrumentation is described. Custom designed 25mm aperture HIFU probes resonating at 2 MHz focused at 64 and 80 mm are used. Results have been obtained in ex-vivo animal tissue and in vitro biological phantoms for hemostasis.

  5. Knockdown of the coenzyme Q synthesis gene Smed-dlp1 affects planarian regeneration and tissue homeostasis.

    PubMed

    Shiobara, Yumiko; Harada, Chiaki; Shiota, Takeshi; Sakamoto, Kimitoshi; Kita, Kiyoshi; Tanaka, Saeko; Tabata, Kenta; Sekie, Kiyoteru; Yamamoto, Yorihiro; Sugiyama, Tomoyasu

    2015-12-01

    The freshwater planarian is a model organism used to study tissue regeneration that occupies an important position among multicellular organisms. Planarian genomic databases have led to the identification of genes that are required for regeneration, with implications for their roles in its underlying mechanism. Coenzyme Q (CoQ) is a fundamental lipophilic molecule that is synthesized and expressed in every cell of every organism. Furthermore, CoQ levels affect development, life span, disease and aging in nematodes and mice. Because CoQ can be ingested in food, it has been used in preventive nutrition. In this study, we investigated the role of CoQ in planarian regeneration. Planarians synthesize both CoQ9 and rhodoquinone 9 (RQ9). Knockdown of Smed-dlp1, a trans-prenyltransferase gene that encodes an enzyme that synthesizes the CoQ side chain, led to a decrease in CoQ9 and RQ9 levels. However, ATP levels did not consistently decrease in these animals. Knockdown animals exhibited tissue regression and curling. The number of mitotic cells decreased in Smed-dlp1 (RNAi) animals. These results suggested a failure in physiological cell turnover and stem cell function. Accordingly, regenerating planarians died from lysis or exhibited delayed regeneration. Interestingly, the observed phenotypes were partially rescued by ingesting food supplemented with α-tocopherol. Taken together, our results suggest that oxidative stress induced by reduced CoQ9 levels affects planarian regeneration and tissue homeostasis.

  6. Knockdown of the coenzyme Q synthesis gene Smed-dlp1 affects planarian regeneration and tissue homeostasis

    PubMed Central

    Shiobara, Yumiko; Harada, Chiaki; Shiota, Takeshi; Sakamoto, Kimitoshi; Kita, Kiyoshi; Tanaka, Saeko; Tabata, Kenta; Sekie, Kiyoteru; Yamamoto, Yorihiro; Sugiyama, Tomoyasu

    2015-01-01

    The freshwater planarian is a model organism used to study tissue regeneration that occupies an important position among multicellular organisms. Planarian genomic databases have led to the identification of genes that are required for regeneration, with implications for their roles in its underlying mechanism. Coenzyme Q (CoQ) is a fundamental lipophilic molecule that is synthesized and expressed in every cell of every organism. Furthermore, CoQ levels affect development, life span, disease and aging in nematodes and mice. Because CoQ can be ingested in food, it has been used in preventive nutrition. In this study, we investigated the role of CoQ in planarian regeneration. Planarians synthesize both CoQ9 and rhodoquinone 9 (RQ9). Knockdown of Smed-dlp1, a trans-prenyltransferase gene that encodes an enzyme that synthesizes the CoQ side chain, led to a decrease in CoQ9 and RQ9 levels. However, ATP levels did not consistently decrease in these animals. Knockdown animals exhibited tissue regression and curling. The number of mitotic cells decreased in Smed-dlp1 (RNAi) animals. These results suggested a failure in physiological cell turnover and stem cell function. Accordingly, regenerating planarians died from lysis or exhibited delayed regeneration. Interestingly, the observed phenotypes were partially rescued by ingesting food supplemented with α-tocopherol. Taken together, our results suggest that oxidative stress induced by reduced CoQ9 levels affects planarian regeneration and tissue homeostasis. PMID:26516985

  7. Mitral valve leaflet remodelling during pregnancy: insights into cell-mediated recovery of tissue homeostasis.

    PubMed

    Rego, Bruno V; Wells, Sarah M; Lee, Chung-Hao; Sacks, Michael S

    2016-12-01

    Little is known about how valvular tissues grow and remodel in response to altered loading. In this work, we used the pregnancy state to represent a non-pathological cardiac volume overload that distends the mitral valve (MV), using both extant and new experimental data and a modified form of our MV structural constitutive model. We determined that there was an initial period of permanent set-like deformation where no remodelling occurs, followed by a remodelling phase that resulted in near-complete restoration of homeostatic tissue-level behaviour. In addition, we observed that changes in the underlying MV interstitial cell (MVIC) geometry closely paralleled the tissue-level remodelling events, undergoing an initial passive perturbation followed by a gradual recovery to the pre-pregnant state. Collectively, these results suggest that valvular remodelling is actively mediated by average MVIC deformations (i.e. not cycle to cycle, but over a period of weeks). Moreover, tissue-level remodelling is likely to be accomplished by serial and parallel additions of fibrillar material to restore the mean homeostatic fibre stress and MVIC geometries. This finding has significant implications in efforts to understand and predict MV growth and remodelling following such events as myocardial infarction and surgical repair, which also place the valve under altered loading conditions.

  8. Contribution of Fetal, but Not Adult, Pulmonary Mesothelium to Mesenchymal Lineages in Lung Homeostasis and Fibrosis.

    PubMed

    von Gise, Alexander; Stevens, Sean M; Honor, Leah B; Oh, Jin Hee; Gao, Chi; Zhou, Bin; Pu, William T

    2016-02-01

    The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease.

  9. Regulation of immunologic homeostasis in peripheral tissues by dendritic cells: the respiratory tract as a paradigm.

    PubMed

    Holt, P G; Stumbles, P A

    2000-03-01

    Dendritic cells are now recognized as the gatekeepers of the immune response, possessing a unique potential for acquisition of antigens at extremely low exposure levels and for efficient presentation of these in an immunogenic form to the naive T-cell system. Dendritic cell populations throughout the body exhibit a wide range of features in common that are associated with their primary functions, and these are considered in the initial section of this review. In addition, it is becoming evident that the properties and functions of these cells are refined by microenvironmental factors unique to their tissues of residence, a prime example being mucosal microenvironments such as those in respiratory tract tissues, and the latter represents the focus of the second section of this review.

  10. Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis.

    PubMed

    Zvonic, Sanjin; Floyd, Z Elizabeth; Mynatt, Randall L; Gimble, Jeffrey M

    2007-03-01

    Circadian oscillators play an indispensable role in the coordination of physiological processes with the cyclic changes in the physical environment. A significant number of recent clinical and molecular studies suggest that circadian biology may play an important role in the regulation of adipose and other metabolic tissue functions. In this discussion, we present the hypothesis that circadian dysfunction may be involved in the pathogenesis of obesity, type 2 diabetes, and the metabolic syndrome.

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

    PubMed

    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.

  12. Fisetin improves glucose homeostasis through the inhibition of gluconeogenic enzymes in hepatic tissues of streptozotocin induced diabetic rats.

    PubMed

    Prasath, Gopalan Sriram; Pillai, Subramanian Iyyam; Subramanian, Sorimuthu Pillai

    2014-10-05

    Liver plays a vital role in blood glucose homeostasis. Recent studies have provided considerable evidence that hepatic glucose production (HGP) plays an important role in the development of fasting hyperglycemia in diabetes. From this perspective, diminution of HGP has certainly been considered for the treatment of diabetes. In the present study, we have analyzed the modulatory effects of fisetin, a flavonoid of strawberries, on the expression of key enzymes of carbohydrate metabolism in STZ induced experimental diabetic rats. The physiological criterions such as food and fluid intake were regularly monitored. The levels of blood glucose, plasma insulin, hemoglobin and glycosylated hemoglobin were analyzed. The mRNA and protein expression levels of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were determined by immunoblot as well as PCR analysis. Diabetic group of rats showed significant increase in food and water intake when compared with control group of rats. Upon oral administration of fisetin as well as gliclazide to diabetic group of rats, the levels were found to be decreased. Oral administration of fisetin (10 mg/kg body weight) to diabetic rats for 30 days established a significant decline in blood glucose and glycosylated hemoglobin levels and a significant increase in plasma insulin level. The mRNA and protein expression levels of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), were decreased in liver tissues upon treatment with fisetin. The results of the present study suggest that fisetin improves glucose homeostasis by direct inhibition of gluconeogenesis in liver.

  13. Epidermal Homeostasis and Radiation Responses in a Multiscale Tissue Modeling Framework

    NASA Technical Reports Server (NTRS)

    Hu, Shaowen; Cucinotta, Francis A.

    2013-01-01

    The surface of skin is lined with several thin layers of epithelial cells that are maintained throughout life time by a small population of stem cells. High dose radiation exposures could injure and deplete the underlying proliferative cells and induce cutaneous radiation syndrome. In this work we propose a multiscale computational model for skin epidermal dynamics that links phenomena occurring at the subcellular, cellular, and tissue levels of organization, to simulate the experimental data of the radiation response of swine epidermis, which is closely similar to human epidermis. Incorporating experimentally measured histological and cell kinetic parameters, we obtain results of population kinetics and proliferation indexes comparable to observations in unirradiated and acutely irradiated swine experiments. At the sub-cellular level, several recently published Wnt signaling controlled cell-cycle models are applied and the roles of key components and parameters are analyzed. Based on our simulation results, we demonstrate that a moderate increase of proliferation rate for the survival proliferative cells is sufficient to fully repopulate the area denuded by high dose radiation, as long as the integrity of underlying basement membrane is maintained. Our work highlights the importance of considering proliferation kinetics as well as the spatial organization of tissues when conducting in vivo investigations of radiation responses. This integrated model allow us to test the validity of several basic biological rules at the cellular level and sub-cellular mechanisms by qualitatively comparing simulation results with published research, and enhance our understanding of the pathophysiological effects of ionizing radiation on skin.

  14. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis

    PubMed Central

    Yona, Simon; Kim, Ki-Wook; Wolf, Yochai; Mildner, Alexander; Varol, Diana; Breker, Michal; Strauss-Ayali, Dalit; Viukov, Sergey; Guilliams, Martin; Misharin, Alexander; Hume, David A.; Perlman, Harris; Malissen, Bernard; Zelzer, Elazar; Jung, Steffen

    2013-01-01

    SUMMARY Mononuclear phagocytes, including monocytes, macrophages and dendritic cells, contribute to tissue integrity, as well as innate and adaptive immune defense. Emerging evidence for labour division indicates that manipulation of these cells could bear therapeutic potential. However, specific ontogenies of individual populations and the overall functional organisation of the cellular network are not well-defined. Here we report a fate mapping study of the murine monocyte and macrophage compartment taking advantage of constitutive and conditional CX3CR1 promoter-driven Cre recombinase expression. We have demonstrated that major tissue resident macrophage populations, including liver Kupffer cells, lung alveolar, splenic and peritoneal macrophages, are established prior to birth and maintain themselves subsequently during adulthood independent of replenishment by blood monocytes. Furthermore, we have established that the short-lived Ly6C+ monocytes constitute obligatory steady state precursors of blood-resident Ly6C− cells and that the abundance of Ly6C+ blood monocytes dynamically controls the circulation life span of their progeny. PMID:23273845

  15. Ectopic Expression of WRINKLED1 Affects Fatty Acid Homeostasis in Brachypodium distachyon Vegetative Tissues1[OPEN

    PubMed Central

    Yang, Yang; Munz, Jacob; Cass, Cynthia; Zienkiewicz, Agnieszka; Kong, Que; Ma, Wei; Sedbrook, John; Benning, Christoph

    2015-01-01

    Triacylglycerol (TAG) is a storage lipid used for food purposes and as a renewable feedstock for biodiesel production. WRINKLED1 (WRI1) is a transcription factor that governs fatty acid (FA) synthesis and, indirectly, TAG accumulation in oil-storing plant tissues, and its ectopic expression has led to TAG accumulation in vegetative tissues of different dicotyledonous plants. The ectopic expression of BdWRI1 in the grass Brachypodium distachyon induced the transcription of predicted genes involved in glycolysis and FA biosynthesis, and TAG content was increased up to 32.5-fold in 8-week-old leaf blades. However, the ectopic expression of BdWRI1 also caused cell death in leaves, which has not been observed previously in dicotyledonous plants such as Arabidopsis (Arabidopsis thaliana). Lipid analysis indicated that the free FA content was 2-fold elevated in BdWRI1-expressing leaf blades of B. distachyon. The transcription of predicted genes involved in β-oxidation was induced. In addition, linoleic FA treatment caused cell death in B. distachyon leaf blades, an effect that was reversed by the addition of the FA biosynthesis inhibitor cerulenin. Taken together, ectopic expression of BdWRI1 in B. distachyon enhances FA biosynthesis and TAG accumulation in leaves, as expected, but also leads to increased free FA content, which has cytotoxic effects leading to cell death. Thus, while WRI appears to ubiquitously affect FA biosynthesis and TAG accumulation in diverse plants, its ectopic expression can lead to undesired side effects depending on the context of the specific lipid metabolism of the respective plant species. PMID:26419778

  16. Ectopic Expression of WRINKLED1 Affects Fatty Acid Homeostasis in Brachypodium distachyon Vegetative Tissues.

    PubMed

    Yang, Yang; Munz, Jacob; Cass, Cynthia; Zienkiewicz, Agnieszka; Kong, Que; Ma, Wei; Sedbrook, John; Benning, Christoph

    2015-11-01

    Triacylglycerol (TAG) is a storage lipid used for food purposes and as a renewable feedstock for biodiesel production. WRINKLED1 (WRI1) is a transcription factor that governs fatty acid (FA) synthesis and, indirectly, TAG accumulation in oil-storing plant tissues, and its ectopic expression has led to TAG accumulation in vegetative tissues of different dicotyledonous plants. The ectopic expression of BdWRI1 in the grass Brachypodium distachyon induced the transcription of predicted genes involved in glycolysis and FA biosynthesis, and TAG content was increased up to 32.5-fold in 8-week-old leaf blades. However, the ectopic expression of BdWRI1 also caused cell death in leaves, which has not been observed previously in dicotyledonous plants such as Arabidopsis (Arabidopsis thaliana). Lipid analysis indicated that the free FA content was 2-fold elevated in BdWRI1-expressing leaf blades of B. distachyon. The transcription of predicted genes involved in β-oxidation was induced. In addition, linoleic FA treatment caused cell death in B. distachyon leaf blades, an effect that was reversed by the addition of the FA biosynthesis inhibitor cerulenin. Taken together, ectopic expression of BdWRI1 in B. distachyon enhances FA biosynthesis and TAG accumulation in leaves, as expected, but also leads to increased free FA content, which has cytotoxic effects leading to cell death. Thus, while WRI appears to ubiquitously affect FA biosynthesis and TAG accumulation in diverse plants, its ectopic expression can lead to undesired side effects depending on the context of the specific lipid metabolism of the respective plant species.

  17. Tissue adaptations to gravitational stress - Newborn versus adult giraffes

    NASA Technical Reports Server (NTRS)

    Hargens, Alan R; Gershuni, David H.; Danzig, Larry A.; Millard, Ronald W.; Pettersson, Knut

    1988-01-01

    Preliminary results on developmental alterations in load-bearing tissues of newborn and adult giraffes are presented. Attention is focused on vascular wall thickness in relation to local blood pressure, and on meniscal adaptations to increased load bearing in the developing giraffe. It is believed that the developing giraffe provides an excellent model for investigations of adaptive mechanisms of increased weight bearing.

  18. Retinal pigment epithelium development, plasticity, and tissue homeostasis (Invited review for Experimental Eye Research)

    PubMed Central

    Fuhrmann, Sabine; Zou, ChangJiang; Levine, Edward M.

    2014-01-01

    The retinal pigment epithelium (RPE) is a simple epithelium interposed between the neural retina and the choroid. Although only 1 cell-layer in thickness, the RPE is a virtual workhorse, acting in several capacities that are essential for visual function and preserving the structural and physiological integrities of neighboring tissues. Defects in RPE function, whether through chronic dysfunction or age-related decline, are associated with retinal degenerative diseases including age-related macular degeneration. As such, investigations are focused on developing techniques to replace RPE through stem cell-based methods, motivated primarily because of the seemingly limited regeneration or self-repair properties of mature RPE. Despite this, RPE cells have an unusual capacity to transdifferentiate into various cell types, with the particular fate choices being highly context-dependent. In this review, we describe recent findings elucidating the mechanisms and steps of RPE development and propose a developmental framework for understanding the apparent contradiction in the capacity for low self-repair versus high transdifferentiation. PMID:24060344

  19. Tissue-Specific Apocarotenoid Glycosylation Contributes to Carotenoid Homeostasis in Arabidopsis Leaves1

    PubMed Central

    Hübner, Michaela; Matsubara, Shizue; Beyer, Peter

    2015-01-01

    Attaining defined steady-state carotenoid levels requires balancing of the rates governing their synthesis and metabolism. Phytoene formation mediated by phytoene synthase (PSY) is rate limiting in the biosynthesis of carotenoids, whereas carotenoid catabolism involves a multitude of nonenzymatic and enzymatic processes. We investigated carotenoid and apocarotenoid formation in Arabidopsis (Arabidopsis thaliana) in response to enhanced pathway flux upon PSY overexpression. This resulted in a dramatic accumulation of mainly β-carotene in roots and nongreen calli, whereas carotenoids remained unchanged in leaves. We show that, in chloroplasts, surplus PSY was partially soluble, localized in the stroma and, therefore, inactive, whereas the membrane-bound portion mediated a doubling of phytoene synthesis rates. Increased pathway flux was not compensated by enhanced generation of long-chain apocarotenals but resulted in higher levels of C13 apocarotenoid glycosides (AGs). Using mutant lines deficient in carotenoid cleavage dioxygenases (CCDs), we identified CCD4 as being mainly responsible for the majority of AGs formed. Moreover, changed AG patterns in the carotene hydroxylase mutants lutein deficient1 (lut1) and lut5 exhibiting altered leaf carotenoids allowed us to define specific xanthophyll species as precursors for the apocarotenoid aglycons detected. In contrast to leaves, carotenoid hyperaccumulating roots contained higher levels of β-carotene-derived apocarotenals, whereas AGs were absent. These contrasting responses are associated with tissue-specific capacities to synthesize xanthophylls, which thus determine the modes of carotenoid accumulation and apocarotenoid formation. PMID:26134165

  20. Tissue-Specific Apocarotenoid Glycosylation Contributes to Carotenoid Homeostasis in Arabidopsis Leaves.

    PubMed

    Lätari, Kira; Wüst, Florian; Hübner, Michaela; Schaub, Patrick; Beisel, Kim Gabriele; Matsubara, Shizue; Beyer, Peter; Welsch, Ralf

    2015-08-01

    Attaining defined steady-state carotenoid levels requires balancing of the rates governing their synthesis and metabolism. Phytoene formation mediated by phytoene synthase (PSY) is rate limiting in the biosynthesis of carotenoids, whereas carotenoid catabolism involves a multitude of nonenzymatic and enzymatic processes. We investigated carotenoid and apocarotenoid formation in Arabidopsis (Arabidopsis thaliana) in response to enhanced pathway flux upon PSY overexpression. This resulted in a dramatic accumulation of mainly β-carotene in roots and nongreen calli, whereas carotenoids remained unchanged in leaves. We show that, in chloroplasts, surplus PSY was partially soluble, localized in the stroma and, therefore, inactive, whereas the membrane-bound portion mediated a doubling of phytoene synthesis rates. Increased pathway flux was not compensated by enhanced generation of long-chain apocarotenals but resulted in higher levels of C13 apocarotenoid glycosides (AGs). Using mutant lines deficient in carotenoid cleavage dioxygenases (CCDs), we identified CCD4 as being mainly responsible for the majority of AGs formed. Moreover, changed AG patterns in the carotene hydroxylase mutants lutein deficient1 (lut1) and lut5 exhibiting altered leaf carotenoids allowed us to define specific xanthophyll species as precursors for the apocarotenoid aglycons detected. In contrast to leaves, carotenoid hyperaccumulating roots contained higher levels of β-carotene-derived apocarotenals, whereas AGs were absent. These contrasting responses are associated with tissue-specific capacities to synthesize xanthophylls, which thus determine the modes of carotenoid accumulation and apocarotenoid formation.

  1. Derailed B cell homeostasis in patients with mixed connective tissue disease.

    PubMed

    Hajas, A; Barath, S; Szodoray, P; Nakken, B; Gogolak, P; Szekanecz, Z; Zold, E; Zeher, M; Szegedi, G; Bodolay, E

    2013-07-01

    Mixed connective tissue disease (MCTD) is a systemic autoimmune disorder, characterized by the presence of antibodies to U1-RNP protein. We aimed to determine phenotypic abnormalities of peripheral B cell subsets in MCTD. Blood samples were obtained from 46 MCTD patients, and 20 controls. Using anti-CD19, anti-CD27, anti-IgD and anti-CD38 monoclonal antibodies, the following B cell subsets were identified by flow cytometry: (1) transitional B cells (CD19+CD27-IgD+CD38(high)); (2) naive B cells (CD19+CD27-IgD+CD38(low)); (3) non-switched memory B cells (CD19+CD27+IgD+); (4) switched memory B cells (CD19+CD27+IgD-); (5) double negative (DN) memory B cells (CD19+CD27-IgD-) and (6) plasma cells (CD19+CD27(high)IgD-). The proportion of transitional B cells, naive B cells and DN B lymphocytes was higher in MCTD than in controls. The DN B cells were positive for CD95 surface marker. This memory B cells population showed a close correlation with disease activity. The number of plasma cells was also increased, and there was an association between the number of plasma cells and the anti-U1RNP levels. Cyclophosphamide, methotrexate, and corticosteroid treatment decreased the number of DN and CD27(high) B cells. In conclusion, several abnormalities were found in the peripheral B-cell subsets in MCTD, which reinforces the role of derailed humoral autoimmune processes in the pathogenesis.

  2. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

    PubMed Central

    Mullenders, Jasper; Aranda-Orgilles, Beatriz; Lhoumaud, Priscillia; Keller, Matthew; Pae, Juhee; Wang, Kun; Kayembe, Clarisse; Rocha, Pedro P.; Raviram, Ramya; Gong, Yixiao; Premsrirut, Prem K.; Tsirigos, Aristotelis; Bonneau, Richard; Skok, Jane A.; Cimmino, Luisa; Hoehn, Daniela

    2015-01-01

    The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy. PMID:26438359

  3. Age-Dependent Netrin-1 Signaling Regulates NG2+ Glial Cell Spatial Homeostasis in Normal Adult Gray Matter.

    PubMed

    Birey, Fikri; Aguirre, Adan

    2015-04-29

    Neuron-glial antigen 2-positive (NG2(+)) glial cells are the most proliferative glia type in the adult CNS, and their tile-like arrangement in adult gray matter is under tight regulation. However, little is known about the cues that govern this unique distribution. To this end, using a NG2(+) glial cell ablation model in mice, we examined the repopulation dynamics of NG2(+) glial cells in the mature and aged mice gray matter. We found that some resident NG2(+) glial cells that escaped depletion rapidly enter the cell cycle to repopulate the cortex with altered spatial distribution. We reveal that netrin-1 signaling is involved in the NG2(+) glial cell early proliferative, late repopulation, and distribution response after ablation in the gray matter. However, ablation of NG2(+) glial cell in older animals failed to stimulate a similar repopulation response, possibly because of a decrease in the sensitivity to netrin-1. Our findings indicate that endogenous netrin-1 plays a role in NG2(+) glial cell homeostasis that is distinct from its role in myelination.

  4. In Vitro Spermatogenesis in Explanted Adult Mouse Testis Tissues.

    PubMed

    Sato, Takuya; Katagiri, Kumiko; Kojima, Kazuaki; Komeya, Mitsuru; Yao, Masahiro; Ogawa, Takehiko

    2015-01-01

    Research on in vitro spermatogenesis is important for elucidating the spermatogenic mechanism. We previously developed an organ culture method which can support spermatogenesis from spermatogonial stem cells up to sperm formation using immature mouse testis tissues. In this study, we examined whether it is also applicable to mature testis tissues of adult mice. We used two lines of transgenic mice, Acrosin-GFP and Gsg2-GFP, which carry the marker GFP gene specific for meiotic and haploid cells, respectively. Testis tissue fragments of adult GFP mice, aged from 4 to 29 weeks old, which express GFP at full extension, were cultured in medium supplemented with 10% KSR or AlbuMAX. GFP expression decreased rapidly and became the lowest at 7 to 14 days of culture, but then slightly increased during the following culture period. This increase reflected de novo spermatogenesis, confirmed by BrdU labeling in spermatocytes and spermatids. We also used vitamin A-deficient mice, whose testes contain only spermatogonia. The testes of those mice at 13-21 weeks old, showing no GFP expression at explantation, gained GFP expression during culturing, and spermatogenesis was confirmed histologically. In addition, the adult testis tissues of Sl/Sld mutant mice, which lack spermatogenesis due to Kit ligand mutation, were cultured with recombinant Kit ligand to induce spermatogenesis up to haploid formation. Although the efficiency of spermatogenesis was lower than that of pup, present results showed that the organ culture method is effective for the culturing of mature adult mouse testis tissue, demonstrated by the induction of spermatogenesis from spermatogonia to haploid cells.

  5. Asymptomatic and isolated accessory mitral valve tissue in an adult.

    PubMed

    Hisatomi, Kazuki; Hashizume, Koji; Tanigawa, Kazuyoshi; Miura, Takashi; Matsukuma, Seiji; Yokose, Shogo; Sumi, Mizuki; Eishi, Kiyoyuki

    2016-02-01

    Accessory mitral valve (AMV) tissue is a congenital anomaly that occurs in association with other congenital anomalies, and is an uncommon cause of left ventricular outflow tract obstruction. It is usually detected in early childhood when accompanied by symptoms of obstruction of the left ventricular outflow tract, and is rarely diagnosed in adults. We present a case of a 53-year-old man who was referred to our institution for evaluation of a systolic heart murmur. Echocardiography disclosed a diagnosis of AMV tissue. This case was uncommon because of the lack of severe obstruction of left ventricular outflow, cardiac symptoms, or other cardiac anomalies. We were able to carry out surgical resection of AMV tissue to avert possible progression of aortic insufficiency and the risk of a cerebrovascular embolization. The patient's postoperative course was uneventful, and postoperative echocardiography showed no residual accessory mitral tissue.

  6. Effects of Noise Exposure on Systemic and Tissue-Level Markers of Glucose Homeostasis and Insulin Resistance in Male Mice

    PubMed Central

    Liu, Lijie; Wang, Fanfan; Lu, Haiying; Cao, Shuangfeng; Du, Ziwei; Wang, Yongfang; Feng, Xian; Gao, Ye; Zha, Mingming; Guo, Min; Sun, Zilin; Wang, Jian

    2016-01-01

    Background: Epidemiological studies have indicated that noise exposure is associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the nature of the connection between noise exposure and T2DM remains to be explored. Objectives: We explored whether and how noise exposure affects glucose homeostasis in mice as the initial step toward T2DM development. Methods: Male ICR mice were randomly assigned to one of four groups: the control group and three noise groups (N20D, N10D, and N1D), in which the animals were exposed to white noise at 95 decibel sound pressure level (dB SPL) for 4 hr per day for 20 successive days, 10 successive days, or 1 day, respectively. Glucose tolerance and insulin sensitivity were evaluated 1 day, 1 week, and 1 month after the final noise exposure (1DPN, 1WPN, and 1MPN). Standard immunoblots, immunohistochemical methods, and enzyme-linked immunosorbent assays (ELISA) were performed to assess insulin signaling in skeletal muscle, the morphology of β cells, and plasma corticosterone levels. Results: Noise exposure for 1 day caused transient glucose intolerance and insulin resistance, whereas noise exposure for 10 and 20 days had no effect on glucose tolerance but did cause prolonged insulin resistance and an increased insulin response to glucose challenge. Akt phosphorylation and GLUT4 translocation in response to exogenous insulin were decreased in the skeletal muscle of noise-exposed animals. Conclusions: Noise exposure at 95 dB SPL caused insulin resistance in male ICR mice, which was prolonged with longer noise exposure and was likely related to the observed blunted insulin signaling in skeletal muscle. Citation: Liu L, Wang F, Lu H, Cao S, Du Z, Wang Y, Feng X, Gao Y, Zha M, Guo M, Sun Z, Wang J. 2016. Effects of noise exposure on systemic and tissue-level markers of glucose homeostasis and insulin resistance in male mice. Environ Health Perspect 124:1390–1398; http://dx.doi.org/10.1289/EHP162 PMID:27128844

  7. Growth hormone receptor antagonist (GHA) transgenic mice have increased subcutaneous adipose tissue mass, altered glucose homeostasis, and no change in white adipose tissue cellular senescence

    PubMed Central

    Comisford, Ross; Lubbers, Ellen R.; Householder, Lara; Suer, Ozan; Tchkonia, Tamara; Kirkland, James L.; List, Edward O.; Kopchick, John J.; Berryman, Darlene E.

    2015-01-01

    Background Growth hormone (GH) resistant/deficient mice experience improved glucose homeostasis and substantially increased lifespan. Recent evidence suggests long-lived GH resistant/deficient mice are protected from white adipose tissue (WAT) dysfunction, including WAT cellular senescence, impaired adipogenesis and loss of subcutaneous WAT in old age. This preservation of WAT function has been suggested to be a potential mechanism for the extended lifespan of these mice. OBJECTIVE The objective of this study was to examine white adipose tissue (WAT) senescence, WAT distribution, and glucose homeostasis in dwarf growth hormone receptor antagonist (GHA) transgenic mice, a unique mouse strain having decreased GH action but normal longevity. METHODS 18mo old female GHA mice and wild type (WT) littermate controls were used. Prior to dissection, body composition, fasting blood glucose, and glucose and insulin tolerance tests were performed. WAT distribution was determined by weighing four distinct WAT depots at the time of dissection. Cellular senescence in four WAT depots was assessed using senescence-associated β-galactosidase (SA-β-gal) staining to quantify the senescent cell burden and real time qPCR to quantify gene expression of senescence markers p16 and IL-6. RESULTS GHA mice had a 22% reduction in total body weight, 33% reduction in lean mass, and a 10% increase in body fat percentage compared to WT controls. GHA mice had normal fasting blood glucose and improved insulin sensitivity; however, they exhibited impaired glucose tolerance. Moreover, GHA mice displayed enhanced lipid storage in the inguinal subcutaneous WAT depot (p<.05) and a 1.7 fold increase in extra-/intraperitoneal WAT ratio compared to controls (p<.05). Measurements of WAT cellular senescence showed no difference between GHA mice and WT controls. CONCLUSIONS Similar to other mice with decreased GH action, female GHA mice display reduced age-related lipid redistribution and improved insulin

  8. Competition and Homeostasis of Excitatory and Inhibitory Connectivity in the Adult Mouse Visual Cortex.

    PubMed

    Saiepour, M Hadi; Chakravarthy, Sridhara; Min, Rogier; Levelt, Christiaan N

    2015-10-01

    During cortical development, synaptic competition regulates the formation and adjustment of neuronal connectivity. It is unknown whether synaptic competition remains active in the adult brain and how inhibitory neurons participate in this process. Using morphological and electrophysiological measurements, we show that expressing a dominant-negative form of the TrkB receptor (TrkB.T1) in the majority of pyramidal neurons in the adult visual cortex does not affect excitatory synapse densities. This is in stark contrast to the previously reported loss of excitatory input which occurs if the exact same transgene is expressed in sparse neurons at the same age. This indicates that synaptic competition remains active in adulthood. Additionally, we show that interneurons not expressing the TrkB.T1 transgene may have a competitive advantage and obtain more excitatory synapses when most neighboring pyramidal neurons do express the transgene. Finally, we demonstrate that inhibitory synapses onto pyramidal neurons are reduced when TrkB signaling is interfered with in most pyramidal neurons but not when few pyramidal neurons have this deficit. This adjustment of inhibitory innervation is therefore not a cell-autonomous consequence of decreased TrkB signaling but more likely a homeostatic mechanism compensating for activity changes at the population level.

  9. Homeostasis of Microglia in the Adult Brain: Review of Novel Microglia Depletion Systems.

    PubMed

    Waisman, Ari; Ginhoux, Florent; Greter, Melanie; Bruttger, Julia

    2015-10-01

    Microglia are brain macrophages that emerge from early erythro-myeloid precursors in the embryonic yolk sac and migrate to the brain mesenchyme before the blood brain barrier is formed. They seed the brain, and proliferate until they have formed a grid-like distribution in the central nervous system that is maintained throughout lifespan. The mechanisms through which these embryonic-derived cells contribute to microglia homoeostasis at steady state and upon inflammation are still not entirely clear. Here we review recent studies that provided insight into the contribution of embryonically-derived microglia and of adult 'microglia-like' cells derived from monocytes during inflammation. We examine different microglia depletion models, and discuss the origin of their rapid repopulation after depletion and outline important areas of future research.

  10. Tissue migration capability of larval and adult Brugia pahangi.

    PubMed

    Chirgwin, Sharon R; Coleman, Sharon U; Porthouse, Kristina H; Klei, Thomas R

    2006-02-01

    Infection with mosquito-born filarial nematodes occurs when hosts are bitten by a vector carrying the infective third stage larvae (L3) of the parasites. These larvae, deposited on the skin by the feeding mosquito, are presumed to enter the skin via the vector-induced puncture wound. Larvae of Brugia spp. must then migrate from the entry site, penetrate various skin layers, and locate a lymphatic vessel that leads to their lymphatic predilection site. We have recently established an intradermal (ID) infection model using B. pahangi and the Mongolian gerbil, allowing us to investigate the migratory capability ofB. pahangi. Larval and adult parasites recovered from the peritoneal cavities of gerbils were capable of establishing an infection following ID (larvae) or subcutaneous (adult) injection. Third and fourth stage larvae both migrated away from the injection site within hours, although data suggest they localize to different lymphatic tissues at 3 days postinfection (DPI). Immature adult (28 day) B. pahangi also migrated away from their SC inoculation site within 7 DPI. Mature (45 day) adult B. pahangi displayed little migration away from the SC infection site, suggesting tissue migration may be limited to developing stages of the parasite.

  11. Sex-specific associations of low birth weight with adult-onset diabetes and measures of glucose homeostasis: Brazilian Longitudinal Study of Adult Health

    PubMed Central

    Yarmolinsky, James; Mueller, Noel T; Duncan, Bruce B; Chor, Dóra; Bensenor, Isabela M; Griep, Rosane H; Appel, Lawrence J; Barreto, Sandhi M; Schmidt, Maria Inês

    2016-01-01

    Emerging evidence suggests sex differences in the early origins of adult metabolic disease, but this has been little investigated in developing countries. We investigated sex-specific associations between low birth weight (LBW; <2.5 kg) and adult-onset diabetes in 12,525 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Diabetes was defined by self-reported information and laboratory measurements. In confounder-adjusted analyses, LBW (vs. 2.5–4 kg) was associated with higher prevalence of diabetes in women (Prevalence Ratio (PR) 1.54, 95% CI: 1.32–1.79), not in men (PR 1.06, 95% CI: 0.91–1.25; Pheterogeneity = 0.003). The association was stronger among participants with maternal diabetes (PR 1.60, 95% CI: 1.35–1.91), than those without (PR 1.15, 95% CI: 0.99–1.32; Pheterogeneity = 0.03). When jointly stratified by sex and maternal diabetes, the association was observed for women with (PR 1.77, 95% CI: 1.37–2.29) and without (PR 1.45, 95% CI: 1.20–1.75) maternal diabetes. In contrast, in men, LBW was associated with diabetes in participants with maternal diabetes (PR 1.45, 95% CI: 1.15–1.83), but not in those without (PR 0.92, 95% CI: 0.74–1.14). These sex-specific findings extended to continuous measures of glucose homeostasis. LBW was associated with higher diabetes prevalence in Brazilian women, and in men with maternal diabetes, suggesting sex-specific intrauterine effects on adult metabolic health. PMID:27845438

  12. BAG3 regulates contractility and Ca2+ homeostasis in adult mouse ventricular myocytes

    PubMed Central

    Feldman, Arthur M.; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Myers, Valerie D.; Tilley, Douglas G.; Gao, Erhe; Hoffman, Nicholas E.; Tomar, Dhanendra; Madesh, Muniswamy; Rabinowitz, Joseph; Koch, Walter J.; Su, Feifei; Khalili, Kamel; Cheung, Joseph Y.

    2016-01-01

    Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na+-K+-ATPase and L-type Ca2+ channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with β1-adrenergic receptor, L-type Ca2+ channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca2+]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca2+ current (ICa) and sarcoplasmic reticulum (SR) Ca2+ content but not Na+/Ca2+ exchange current (INaCa) or SR Ca2+ uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyrl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca2+ entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the β1-adrenergic receptor and L-type Ca2+ channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure. PMID:26796036

  13. BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes.

    PubMed

    Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Myers, Valerie D; Tilley, Douglas G; Gao, Erhe; Hoffman, Nicholas E; Tomar, Dhanendra; Madesh, Muniswamy; Rabinowitz, Joseph; Koch, Walter J; Su, Feifei; Khalili, Kamel; Cheung, Joseph Y

    2016-03-01

    Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na(+)-K(+)-ATPase and L-type Ca(2+) channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with β1-adrenergic receptor, L-type Ca(2+) channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca(2+)]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca(2+) current (ICa) and sarcoplasmic reticulum (SR) Ca(2+) content but not Na(+)/Ca(2+) exchange current (INaCa) or SR Ca(2+) uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyryl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca(2+) entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the β1-adrenergic receptor and L-type Ca(2+) channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure.

  14. Ultrasonic assessment of facial soft tissue thicknesses in adult Egyptians.

    PubMed

    El-Mehallawi, I H; Soliman, E M

    2001-03-01

    The production of a three-dimensional plastic face on an unknown human skull has been practiced sporadically since the latter part of the last century. In recent years, the technique has been revived and applied to forensic science cases. The morphometric method of forensic facial reconstruction rests heavily on the use of facial soft tissue depth measurements. Moreover, it has been established that measurements made on the living are of more value than those made on the dead. In view of the well-known genetic complexities of the Egyptians, and the lack of knowledge of average facial soft tissue depths of the Egyptians that makes facial reconstruction questionable, it was decided to set up a table of norms for facial tissue thicknesses in 204 adult Egyptians aged 20-35 years. Tissue depths at 17 established landmarks (according to Aulsebrook et al. [Forensic Sci. Int. 79 (1996) 83]) were obtained using ultrasonic probing. The study revealed a unique spectrum of measurements for the Egyptians that might be useful for facial reconstruction purposes with obvious sexual dimorphism in facial soft tissue thickness. Additionally, the study provided evidence for the presence of interpopulation differences in average facial soft tissue thicknesses as evidenced from the comparison of the present data of Egyptians with those previously reported for some other populations.

  15. The PERK pathway independently triggers apoptosis and a Rac1/Slpr/JNK/Dilp8 signaling favoring tissue homeostasis in a chronic ER stress Drosophila model

    PubMed Central

    Demay, Y; Perochon, J; Szuplewski, S; Mignotte, B; Gaumer, S

    2014-01-01

    The endoplasmic reticulum (ER) has a major role in protein folding. The accumulation of unfolded proteins in the ER induces a stress, which can be resolved by the unfolded protein response (UPR). Chronicity of ER stress leads to UPR-induced apoptosis and in turn to an unbalance of tissue homeostasis. Although ER stress-dependent apoptosis is observed in a great number of devastating human diseases, how cells activate apoptosis and promote tissue homeostasis after chronic ER stress remains poorly understood. Here, using the Drosophila wing imaginal disc as a model system, we validated that Presenilin overexpression induces chronic ER stress in vivo. We observed, in this novel model of chronic ER-stress, a PERK/ATF4-dependent apoptosis requiring downregulation of the antiapoptotic diap1 gene. PERK/ATF4 also activated the JNK pathway through Rac1 and Slpr activation in apoptotic cells, leading to the expression of Dilp8. This insulin-like peptide caused a developmental delay, which partially allowed the replacement of apoptotic cells. Thanks to a novel chronic ER stress model, these results establish a new pathway that both participates in tissue homeostasis and triggers apoptosis through an original regulation. PMID:25299777

  16. Epimorphic regeneration approach to tissue replacement in adult mammals.

    PubMed

    Agrawal, Vineet; Johnson, Scott A; Reing, Janet; Zhang, Li; Tottey, Stephen; Wang, Gang; Hirschi, Karen K; Braunhut, Susan; Gudas, Lorraine J; Badylak, Stephen F

    2010-02-23

    Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor and stem cells to a site of injury. Bioactive molecules resulting from degradation of extracellular matrix (ECM) have been shown to recruit a variety of progenitor and stem cells in vitro in adult mammals. The ability to recruit multipotential cells to the site of injury by in vivo administration of chemotactic ECM degradation products in a mammalian model of digit amputation was investigated in the present study. Adult, 6- to 8-week-old C57/BL6 mice were subjected to midsecond phalanx amputation of the third digit of the right hind foot and either treated with chemotactic ECM degradation products or left untreated. At 14 days after amputation, mice treated with ECM degradation products showed an accumulation of heterogeneous cells that expressed markers of multipotency, including Sox2, Sca1, and Rex1 (Zfp42). Cells isolated from the site of amputation were capable of differentiation along neuroectodermal and mesodermal lineages, whereas cells isolated from control mice were capable of differentiation along only mesodermal lineages. The present findings demonstrate the recruitment of endogenous stem cells to a site of injury, and/or their generation/proliferation therein, in response to ECM degradation products.

  17. Strategies to Optimize Adult Stem Cell Therapy for Tissue Regeneration.

    PubMed

    Liu, Shan; Zhou, Jingli; Zhang, Xuan; Liu, Yang; Chen, Jin; Hu, Bo; Song, Jinlin; Zhang, Yuanyuan

    2016-06-21

    Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells) commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous). The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells), early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium), using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration), timing for cell therapy (immediate vs. a few days after injury), single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications.

  18. Strategies to Optimize Adult Stem Cell Therapy for Tissue Regeneration

    PubMed Central

    Liu, Shan; Zhou, Jingli; Zhang, Xuan; Liu, Yang; Chen, Jin; Hu, Bo; Song, Jinlin; Zhang, Yuanyuan

    2016-01-01

    Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells) commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous). The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells), early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium), using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration), timing for cell therapy (immediate vs. a few days after injury), single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications. PMID:27338364

  19. Cranial irradiation induces bone marrow-derived microglia in adult mouse brain tissue.

    PubMed

    Okonogi, Noriyuki; Nakamura, Kazuhiro; Suzuki, Yoshiyuki; Suto, Nana; Suzue, Kazutomo; Kaminuma, Takuya; Nakano, Takashi; Hirai, Hirokazu

    2014-07-01

    Postnatal hematopoietic progenitor cells do not contribute to microglial homeostasis in adult mice under normal conditions. However, previous studies using whole-body irradiation and bone marrow (BM) transplantation models have shown that adult BM cells migrate into the brain tissue and differentiate into microglia (BM-derived microglia; BMDM). Here, we investigated whether cranial irradiation alone was sufficient to induce the generation of BMDM in the adult mouse brain. Transgenic mice that express green fluorescent protein (GFP) under the control of a murine stem cell virus (MSCV) promoter (MSCV-GFP mice) were used. MSCV-GFP mice express GFP in BM cells but not in the resident microglia in the brain. Therefore, these mice allowed us to detect BM-derived cells in the brain without BM reconstitution. MSCV-GFP mice, aged 8-12 weeks, received 13.0 Gy irradiation only to the cranium, and BM-derived cells in the brain were quantified at 3 and 8 weeks after irradiation. No BM-derived cells were detected in control non-irradiated MSCV-GFP mouse brains, but numerous GFP-labeled BM-derived cells were present in the brain stem, basal ganglia and cerebral cortex of the irradiated MSCV-GFP mice. These BM-derived cells were positive for Iba1, a marker for microglia, indicating that GFP-positive BM-derived cells were microglial in nature. The population of BMDM was significantly greater at 8 weeks post-irradiation than at 3 weeks post-irradiation in all brain regions examined. Our results clearly show that cranial irradiation alone is sufficient to induce the generation of BMDM in the adult mouse.

  20. Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters retinoid homeostasis in maternal and perinatal tissues of the Holtzman rat

    SciTech Connect

    Kransler, Kevin M. Tonucci, David A. McGarrigle, Barbara P. Napoli, Joseph L. Olson, James R.

    2007-10-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the most widely studied environmental contaminants, causes a variety of adverse health effects including teratogenesis and altered development which may be related to disruptions in retinoid homeostasis. The purpose of this study was to determine the effect that gestational administration of TCDD has on retinoid homeostasis in both pregnant Holtzman rats and developing fetuses and neonates. A single oral dose of TCDD (0, 1.5, 3, or 6 {mu}g/kg) was administered to pregnant rats on gestation day 10, with fetuses analyzed on gestation days 17 and 20, and neonates analyzed on post natal day 7. Exposure to TCDD generally produced decreases in the concentrations of retinyl esters, such as retinyl palmitate, and retinol in maternal and perinatal liver and lung, while increasing levels in the maternal kidney. Additionally, perinatal hepatic retinol binding protein 1-dependent retinyl ester hydrolysis was also decrease by TCDD. Sensitivity of the developing perinates to TCDD appeared to have an age-related component demonstrated by an increased rate of mortality and significant alterations to body weight and length on post natal day 7 relative to that observed at gestation day 20. A unique observation made in this study was a significant decrease in lung weight observed in the perinates exposed to TCDD. Taken together, these data demonstrate that TCDD significantly alters retinoid homeostasis in tissues of the developing fetus and neonate, suggesting that their unique sensitivity to TCDD may at least be in part the result of altered retinoid homeostasis.

  1. Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue.

    PubMed

    Hu, Yaohua; Robichaux, William G; Mei, Fang C; Kim, Eun Ran; Wang, Hui; Tong, Qingchun; Jin, Jianping; Xu, Mingxuan; Chen, Ju; Cheng, Xiaodong

    2016-10-01

    Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates. In vivo and in vitro analyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT.

  2. New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains.

    PubMed

    Miyata, Seiji

    2015-01-01

    The blood-brain barrier (BBB) generally consists of endothelial tight junction barriers that prevent the free entry of blood-derived substances, thereby maintaining the extracellular environment of the brain. However, the circumventricular organs (CVOs), which are located along the midlines of the brain ventricles, lack these endothelial barriers and have fenestrated capillaries; therefore, they have a number of essential functions, including the transduction of information between the blood circulation and brain. Previous studies have demonstrated the extensive contribution of the CVOs to body fluid and thermal homeostasis, energy balance, the chemoreception of blood-derived substances, and neuroinflammation. In this review, recent advances have been discussed in fenestrated capillary characterization and dynamic tissue reconstruction accompanied by angiogenesis and neurogliogenesis in the sensory CVOs of adult brains. The sensory CVOs, including the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP), have size-selective and heterogeneous vascular permeabilities. Astrocyte-/tanycyte-like neural stem cells (NSCs) sense blood- and cerebrospinal fluid-derived information through the transient receptor potential vanilloid 1, a mechanical/osmotic receptor, Toll-like receptor 4, a lipopolysaccharide receptor, and Nax, a Na-sensing Na channel. They also express tight junction proteins and densely and tightly surround mature neurons to protect them from blood-derived neurotoxic substances, indicating that the NSCs of the CVOs perform BBB functions while maintaining the capacity to differentiate into new neurons and glial cells. In addition to neurogliogenesis, the density of fenestrated capillaries is regulated by angiogenesis, which is accompanied by the active proliferation and sprouting of endothelial cells. Vascular endothelial growth factor (VEGF) signaling may be involved in angiogenesis and neurogliogenesis, both of

  3. In vivo adeno-associated viral vector-mediated genetic engineering of white and brown adipose tissue in adult mice.

    PubMed

    Jimenez, Veronica; Muñoz, Sergio; Casana, Estefania; Mallol, Cristina; Elias, Ivet; Jambrina, Claudia; Ribera, Albert; Ferre, Tura; Franckhauser, Sylvie; Bosch, Fatima

    2013-12-01

    Adipose tissue is pivotal in the regulation of energy homeostasis through the balance of energy storage and expenditure and as an endocrine organ. An inadequate mass and/or alterations in the metabolic and endocrine functions of adipose tissue underlie the development of obesity, insulin resistance, and type 2 diabetes. To fully understand the metabolic and molecular mechanism(s) involved in adipose dysfunction, in vivo genetic modification of adipocytes holds great potential. Here, we demonstrate that adeno-associated viral (AAV) vectors, especially serotypes 8 and 9, mediated efficient transduction of white (WAT) and brown adipose tissue (BAT) in adult lean and obese diabetic mice. The use of short versions of the adipocyte protein 2 or uncoupling protein-1 promoters or micro-RNA target sequences enabled highly specific, long-term AAV-mediated transgene expression in white or brown adipocytes. As proof of concept, delivery of AAV vectors encoding for hexokinase or vascular endothelial growth factor to WAT or BAT resulted in increased glucose uptake or increased vessel density in targeted depots. This method of gene transfer also enabled the secretion of stable high levels of the alkaline phosphatase marker protein into the bloodstream by transduced WAT. Therefore, AAV-mediated genetic engineering of adipose tissue represents a useful tool for the study of adipose pathophysiology and, likely, for the future development of new therapeutic strategies for obesity and diabetes.

  4. Adult Tissue Sources for New β-cells

    PubMed Central

    Nichols, Robert J.; New, Connie; Annes, Justin P.

    2014-01-01

    The diabetes pandemic incurs extraordinary public health and financial costs that are projected to expand for the foreseeable future. Consequently, the development of definitive therapies for diabetes is a priority. Currently, a wide spectrum of therapeutic strategies, from implantable insulin-delivery devices to transplantation-based cell replacement therapy, to β-cell regeneration, focus on replacing the lost insulin-production capacity of diabetics. Among these, β-cell regeneration remains promising but heretofore unproven. Indeed, recent experimental work has uncovered surprising biology that underscores the potential therapeutic benefit of β-cell regeneration. These studies have elucidated a variety of sources for the endogenous production of new β-cells from existing cells. First, β-cells, long thought to be post-mitotic, have demonstrate potential for regenerative capacity. Second, the presence of pancreatic facultative endocrine progenitor cells has been established. Third, the malleability of cellular identity has availed the possibility of generating β-cells from other differentiated cell types. Here, we will review the exciting developments surrounding endogenous sources of β-cell production and consider the potential of realizing a regenerative therapy for diabetes from adult tissues. PMID:24345765

  5. The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia.

    PubMed

    Korde, Amit S; Pettigrew, L Creed; Craddock, Susan D; Maragos, William F

    2005-09-01

    Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable 'upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia-reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.

  6. Dietary α-linolenic acid-rich flaxseed oil prevents against alcoholic hepatic steatosis via ameliorating lipid homeostasis at adipose tissue-liver axis in mice

    PubMed Central

    Wang, Meng; Zhang, Xiao-Jing; Feng, Kun; He, Chengwei; Li, Peng; Hu, Yuan-Jia; Su, Huanxing; Wan, Jian-Bo

    2016-01-01

    Low levels of n-3 polyunsaturated fatty acids (PUFAs) in serum and liver tissue biopsies are the common characteristics in patients with alcoholic liver disease. The α-linolenic acid (ALA) is a plant-derived n-3 PUFA and is rich in flaxseed oil. However, the impact of ALA on alcoholic fatty liver is largely unknown. In this study, we assessed the potential protective effects of ALA-rich flaxseed oil (FO) on ethanol-induced hepatic steatosis and observed that dietary FO supplementation effectively attenuated the ethanol-induced hepatic lipid accumulation in mice. Ethanol exposure stimulated adipose lipolysis but reduced fatty acid/lipid uptake, which were normalized by FO. Our investigations into the corresponding mechanisms demonstrated that the ameliorating effect of FO might be associated with the lower endoplasmic reticulum stress and normalized lipid metabolism in adipose tissue. In the liver, alcohol exposure stimulated hepatic fatty acid uptake and triglyceride synthesis, which were attenuated by FO. Additionally, dietary FO upregulated plasma adiponectin concentration, hepatic adiponectin receptor 2 expression, and the activation of hepatic adenosine monophosphate-activated protein kinase. Collectively, dietary FO protects against alcoholic hepatic steatosis by improving lipid homeostasis at the adipose tissue-liver axis, suggesting that dietary ALA-rich flaxseed oil might be a promising approach for prevention of alcoholic fatty liver. PMID:27220557

  7. The metabolic syndrome of omega3-depleted rats. II. Body weight, adipose tissue mass and glycemic homeostasis.

    PubMed

    Sener, Abdullah; Zhang, Ying; Bulur, Nurdan; Louchami, Karim; Malaisse, Willy J; Carpentier, Yvon A

    2009-07-01

    Exposure of 7-week-old normal rats for 3-7 months to a diet deprived of long-chain polyunsaturated omega3 fatty acids was recently reported to induce changes in the fatty acid content and pattern of liver phospholipids and triglycerides similar to those otherwise found in second generation omega3-depleted rats. In the present study, the changes in body weight, parametrial adipose tissue mass, plasma glucose and insulin concentrations and insulin resistance index were investigated in the same control and omega3-depleted rats, which were then given access for 2 to 4-5 weeks to either a flaxseed oil-enriched diet (control and omega3-depleted rats) or a soybean oil-enriched diet (control rats). The body weight failed to differ between control and omega3-depleted rats. The latter rats, however, displayed increases in adipose tissue mass, plasma glucose and insulin concentrations, and insulin resistance index. In the control rats given access to the soybean or flaxseed oil-enriched diet, body weight and adipose tissue mass were little affected, but both the plasma glucose concentration and insulin resistance index decreased. In the omega3-depleted rats given access to the flaxseed oil-enriched diet, both body weight and adipose tissue mass underwent a rapid, pronounced and sustained increase, whilst the plasma glucose concentration and insulin resistance index decreased similarly to those in the control rats. The present design of omega3 fatty acid dietary deprivation thus reproduces the visceral obesity and insulin resistance otherwise observed in second-generation omega3-depleted rats. However, the supply of exogenous omega3 fatty acids to the omega3-depleted rats failed to oppose visceral obesity, possibly as a result of the orexigenic effects of these omega3 fatty acids.

  8. TSLP and immune homeostasis.

    PubMed

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

    2012-03-01

    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.

  9. Liver immunology and its role in inflammation and homeostasis

    PubMed Central

    Robinson, Mark W; Harmon, Cathal; O'Farrelly, Cliona

    2016-01-01

    The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the non-diseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear ‘dangerous' stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease. PMID:27063467

  10. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis.

    PubMed

    Qian, Shu-Wen; Tang, Yan; Li, Xi; Liu, Yuan; Zhang, You-You; Huang, Hai-Yan; Xue, Rui-Dan; Yu, Hao-Yong; Guo, Liang; Gao, Hui-Di; Liu, Yan; Sun, Xia; Li, Yi-Ming; Jia, Wei-Ping; Tang, Qi-Qun

    2013-02-26

    Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces "white adipocytes" with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4's role in altering insulin sensitivity by affecting WAT development.

  11. The cardiac stem cell compartment is indispensable for myocardial cell homeostasis, repair and regeneration in the adult.

    PubMed

    Nadal-Ginard, Bernardo; Ellison, Georgina M; Torella, Daniele

    2014-11-01

    Resident cardiac stem cells in embryonic, neonatal and adult mammalian heart have been identified by different membrane markers and transcription factors. However, despite a flurry of publications no consensus has been reached on the identity and actual regenerative effects of the adult cardiac stem cells. Intensive research on the adult mammalian heart's capacity for self-renewal of its muscle cell mass has led to a consensus that new cardiomyocytes (CMs) are indeed formed throughout adult mammalian life albeit at a disputed frequency. The physiological significance of this renewal, the origin of the new CMs, and the rate of adult CM turnover are still highly debated. Myocyte replacement, particularly after injury, was originally attributed to differentiation of a stem cell compartment. More recently, it has been reported that CMs are mainly replaced by the division of pre-existing post-mitotic CMs. These latter results, if confirmed, would shift the target of regenerative therapy toward boosting mature CM cell-cycle re-entry. Despite this controversy, it is documented that the adult endogenous c-kit(pos) cardiac stem cells (c-kit(pos) eCSCs) participate in adaptations to myocardial stress, and, when transplanted into the myocardium, regenerate most cardiomyocytes and microvasculature lost in an infarct. Nevertheless, the in situ myogenic potential of adult c-kit(pos) cardiac cells has been questioned. To revisit the regenerative potential of c-kit(pos) eCSCs, we have recently employed experimental protocols of severe diffuse myocardial damage in combination with several genetic murine models and cell transplantation approaches showing that eCSCs are necessary and sufficient for CM regeneration, leading to complete cellular, anatomical, and functional myocardial recovery. Here we will review the available data on adult eCSC biology and their regenerative potential placing it in the context of the different claimed mechanisms of CM replacement. These data are in

  12. Long term running biphasically improves methylglyoxal-related metabolism, redox homeostasis and neurotrophic support within adult mouse brain cortex.

    PubMed

    Falone, Stefano; D'Alessandro, Antonella; Mirabilio, Alessandro; Petruccelli, Giacomo; Cacchio, Marisa; Di Ilio, Carmine; Di Loreto, Silvia; Amicarelli, Fernanda

    2012-01-01

    Oxidative stress and neurotrophic support decline seem to be crucially involved in brain aging. Emerging evidences indicate the pro-oxidant methylglyoxal (MG) as a key player in the age-related dicarbonyl stress and molecular damage within the central nervous system. Although exercise promotes the overproduction of reactive oxygen species, habitual exercise may retard cellular aging and reduce the age-dependent cognitive decline through hormetic adaptations, yet molecular mechanisms underlying beneficial effects of exercise are still largely unclear. In particular, whereas adaptive responses induced by exercise initiated in youth have been broadly investigated, the effects of chronic and moderate exercise begun in adult age on biochemical hallmarks of very early senescence in mammal brains have not been extensively studied. This research investigated whether a long-term, forced and moderate running initiated in adult age may affect the interplay between the redox-related profile and the oxidative-/MG-dependent molecular damage patterns in CD1 female mice cortices; as well, we investigated possible exercise-induced effects on the activity of the brain derived neurotrophic factor (BDNF)-dependent pathway. Our findings suggested that after a transient imbalance in almost all parameters investigated, the lately-initiated exercise regimen strongly reduced molecular damage profiles in brains of adult mice, by enhancing activities of the main ROS- and MG-targeting scavenging systems, as well as by preserving the BDNF-dependent signaling through the transition from adult to middle age.

  13. The Resist Diabetes trial: Rationale, design, and methods of a hybrid efficacy/effectiveness intervention trial for resistance training maintenance to improve glucose homeostasis in older prediabetic adults

    PubMed Central

    Marinik, Elaina L.; Kelleher, Sarah; Savla, Jyoti; Winett, Richard A.; Davy, Brenda M.

    2014-01-01

    Advancing age is associated with reduced levels of physical activity, increased body weight and fat, decreased lean body mass, and a high prevalence of type 2 diabetes (T2D). Resistance training (RT) increases muscle strength and lean body mass, and reduces risk of T2D among older adults. The Resist Diabetes trial will determine if a social cognitive theory (SCT)-based intervention improves RT maintenance in older, prediabetic adults, using a hybrid efficacy/effectiveness approach. Sedentary, overweight/obese (BMI 25-39.9 kg/m2) adults aged 50-69 (N=170) with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) completed a supervised 3-month RT (2x/wk) Initiation Phase and were then randomly assigned (n=159; 94% retention) to one of two 6-month maintenance conditions: SCT or Standard care. The SCT intervention consisted of faded contacts compared to Standard care. Participants continue RT at an approved, self-selected community facility during maintenance. A subsequent 6-month period involves no contact for both conditions. Assessments occur at baseline and months 3 (post-initiation), 9 (post-intervention), and 15 (six months after no contact). Primary outcomes are prediabetes indices (i.e., impaired fasting and 2-hour glucose concentration) and strength. Secondary measures include insulin sensitivity, beta-cell responsiveness, and disposition index (oral glucose and C-peptide minimal model); adherence; body composition; and SCT measures. Resist Diabetes is the first trial to examine the effectiveness of a high fidelity SCT-based intervention for maintaining RT in older adults with prediabetes to improve glucose homeostasis. Successful application of SCT constructs for RT maintenance may support translation of our RT program for diabetes prevention into community settings. PMID:24252311

  14. Fructus xanthii improves lipid homeostasis in the epididymal adipose tissue of rats fed a high-fat diet

    PubMed Central

    LI, XIUMIN; YANG, MINGXING; LI, ZHIPENG; XUE, MEI; SHANGGUAN, ZHAOSHUI; OU, ZHIMIN; LIU, MING; LIU, SUHUAN; YANG, SHUYU; LI, XUEJUN

    2016-01-01

    High fat diet (HFD)-induced obesity triggers common features of human metabolic syndrome in rats. Our previous study showed that Fructus xanthii (FX) attenuates HFD-induced hepatic steatosis. The present study was designed to investigate the effects of FX on lipid metabolism in epididymal fat (EF), and examine its underlying mechanisms. Aqueous extraction fractions of FX or vehicle were orally administered by gavage for 6 weeks to rats fed either a HFD or a normal chow diet (NCD). The levels of circulating free fatty acid (FFA) were determined in plasma, and the expression levels of lipid metabolism- and inflammation-associated genes in the EF were measured using reverse transcription-quantitative polymerase chain reaction analysis. The general morphology, size and number of adipocytes in the EF, and the levels of macrophage infiltration were evaluated using hematoxylin and eosin staining or immunohistochemical staining. FX decreased circulating levels of FFA, increased the expression levels of sterol-regulatory-element-binding protein-1c, FAS, acetyl coenzyme A carboxylase, diacylglycerol acyltransferase and lipoprotein lipase lipogenic genes in the EF. FX increased the numbers of adipocytes in the EF, and featured a shift towards smaller adipocyte size. Compared with the vehicle-treated rats, positive staining of F4/80 was more dispersed in the FX-treated rats, and the percentage of F4/80 positive cells was significantly decreased. FX attenuated HFD-induced lipid dyshomeostasis in the epididymal adipose tissue. PMID:26648271

  15. Osmotic Homeostasis

    PubMed Central

    Zeidel, Mark L.

    2015-01-01

    Alterations in water homeostasis can disturb cell size and function. Although most cells can internally regulate cell volume in response to osmolar stress, neurons are particularly at risk given a combination of complex cell function and space restriction within the calvarium. Thus, regulating water balance is fundamental to survival. Through specialized neuronal “osmoreceptors” that sense changes in plasma osmolality, vasopressin release and thirst are titrated in order to achieve water balance. Fine-tuning of water absorption occurs along the collecting duct, and depends on unique structural modifications of renal tubular epithelium that confer a wide range of water permeability. In this article, we review the mechanisms that ensure water homeostasis as well as the fundamentals of disorders of water balance. PMID:25078421

  16. Facial soft-tissue thicknesses in the adult male Zulu.

    PubMed

    Aulsebrook, W A; Becker, P J; Işcan, M Y

    1996-05-31

    The morphometric method of forensic facial reconstruction rests heavily on the use of facial soft tissue depth measurements. In reconstructing the Negroid face, much use has been made of the tables of soft tissue thickness of American Negroid cadavers. However, the genetic complexities of American blacks are well known. In addition it is felt that measurements made on the living are of more value than those made on the dead. In view of this it was decided to set up a table of norms for facial soft tissue depths of the living Zulu, an African Negroid who has remained relatively free from genetic admixture with other populations. The tightly controlled sample consisted of 55 healthy male Zulus, aged 20 to 35. Tissue depths at established landmarks were measured from lateral and oblique cephalometric radiographs. These were then combined with ultrasonic readings at other landmarks on the subject's face to yield a comprehensive set of tissue depth data. This paper presents a set of average facial soft tissue depth measurements from the Zulu face that results in the development of a new profile. It also provides a method for linking two systems of measurement.

  17. Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

    PubMed Central

    Rantakari, Pia; Patten, Daniel A.; Valtonen, Joona; Karikoski, Marika; Gerke, Heidi; Dawes, Harriet; Laurila, Juha; Ohlmeier, Steffen; Elima, Kati; Hübscher, Stefan G.; Jalkanen, Sirpa; Adams, David H.; Salmi, Marko; Shetty, Shishir

    2016-01-01

    Macrophages are key regulators of fibrosis development and resolution. Elucidating the mechanisms by which they mediate this process is crucial for establishing their therapeutic potential. Here, we use experimental models of liver fibrosis to show that deficiency of the scavenger receptor, stabilin-1, exacerbates fibrosis and delays resolution during the recovery phase. We detected a subset of stabilin-1+ macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL (MDA-LDL) uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP+ fibrogenic cells. Stabilin-1−/− macrophages demonstrated a proinflammatory phenotype during liver injury and the normal induction of Ly6Clo monocytes during resolution was absent in stabilin-1 knockouts leading to persistence of fibrosis. Human stabilin-1+ monocytes efficiently internalized MDA-LDL and this suppressed their ability to secrete CCL3, suggesting that loss of stabilin-1 removes a brake to CCL3 secretion. Experiments with cell-lineage–specific knockouts revealed that stabilin-1 expression in myeloid cells is required for the induction of this subset of macrophages and that increased fibrosis occurs in their absence. This study demonstrates a previously unidentified regulatory pathway in fibrogenesis in which a macrophage scavenger receptor protects against organ fibrosis by removing fibrogenic products of lipid peroxidation. Thus, stabilin-1+ macrophages shape the tissue microenvironment during liver injury and healing. PMID:27474165

  18. Constitutive gene expression and specification of tissue identity in adult planarian biology

    PubMed Central

    Reddien, Peter W.

    2011-01-01

    Planarians are flatworms that constitutively maintain adult tissues through cell turnover and can regenerate entire organisms from tiny body fragments. In addition to requiring new cells (from neoblasts), these feats require mechanisms that specify tissue identity in the adult. Critical roles for Wnt and BMP signaling in regeneration and maintenance of the body axes have been uncovered, among other regulatory factors. Available data indicate that genes involved in positional identity regulation at key embryonic stages in other animals display persisting regionalized expression in adult planarians. These expression patterns suggest that a constitutively active gene expression map exists for maintenance of the planarian body. Planarians therefore present a fertile ground for identification of factors regulating regionalization of the metazoan body plan and for study of the attributes of these factors that can lead to maintenance and regeneration of adult tissues. PMID:21680047

  19. TGF-β Is Required for Vascular Barrier Function, Endothelial Survival and Homeostasis of the Adult Microvasculature

    PubMed Central

    Maharaj, Arindel S. R.; Sekiyama, Eiichi; Maldonado, Angel E.; D'Amore, Patricia A.

    2009-01-01

    Pericyte-endothelial cell (EC) interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-β signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-β signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-β signaling was inhibited by systemic expression of soluble endoglin (sEng) and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-β signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG). Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-β signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-β signaling. These results implicate constitutive TGF-β signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-β signaling in vasoproliferative and vascular degenerative retinal diseases. PMID:19340291

  20. The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis

    PubMed Central

    Gao, Jie; Buckley, Shannon M; Cimmino, Luisa; Guillamot, Maria; Strikoudis, Alexandros; Cang, Yong; Goff, Stephen P; Aifantis, Iannis

    2015-01-01

    Little is known on post-transcriptional regulation of adult and embryonic stem cell maintenance and differentiation. Here we characterize the role of Ddb1, a component of the CUL4-DDB1 ubiquitin ligase complex. Ddb1 is highly expressed in multipotent hematopoietic progenitors and its deletion leads to abrogation of both adult and fetal hematopoiesis, targeting specifically transiently amplifying progenitor subsets. However, Ddb1 deletion in non-dividing lymphocytes has no discernible phenotypes. Ddb1 silencing activates Trp53 pathway and leads to significant effects on cell cycle progression and rapid apoptosis. The abrogation of hematopoietic progenitor cells can be partially rescued by simultaneous deletion of Trp53. Conversely, depletion of DDB1 in embryonic stem cell (ESC) leads to differentiation albeit negative effects on cell cycle and apoptosis. Mass spectrometry reveals differing protein interactions between DDB1 and distinct DCAFs, the substrate recognizing components of the E3 complex, between cell types. Our studies identify CUL4-DDB1 complex as a novel post-translational regulator of stem and progenitor maintenance and differentiation. DOI: http://dx.doi.org/10.7554/eLife.07539.001 PMID:26613412

  1. Mechanotransduction and extracellular matrix homeostasis

    PubMed Central

    Humphrey, Jay D.; Dufresne, Eric R.; Schwartz, Martin A.

    2015-01-01

    Preface Soft connective tissues at steady state are yet dynamic; resident cells continually read environmental cues and respond to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the matrix by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechano-regulation process that includes the deposition, rearrangement, or removal of matrix to maintain overall form and function. Progress toward understanding the molecular, cellular, and tissue scale effects that promote mechanical homeostasis has helped identify key questions for future research. PMID:25355505

  2. Muscle regeneration by adipose tissue-derived adult stem cells attached to injectable PLGA spheres.

    PubMed

    Kim, MiJung; Choi, Yu Suk; Yang, Seung Hye; Hong, Hea-Nam; Cho, Sung-Woo; Cha, Sang Myun; Pak, Jhang Ho; Kim, Chan Wha; Kwon, Seog Woon; Park, Chan Jeoung

    2006-09-22

    The [corrected] use of adult stem cells for cell-based tissue engineering and regeneration strategies represents a promising approach for skeletal muscle repair. We have evaluated the combination of adipose tissue-derived adult stem cells (ADSCs) obtained from autologous liposuction and injectable poly(lactic-co-glycolic acid) (PLGA) spheres for muscle regeneration. ADSCs attached to PLGA spheres and PLGA spheres alone were cultured in myogenic medium for 21 days and injected subcutaneously into the necks of nude mice. After 30 and 60 days, the mice were sacrificed, and newly formed tissues were analyzed by immunostaining, H and E staining, and RT-PCR. We found that ADSCs attached to PLGA spheres, but not PLGA spheres alone, were able to generate muscle tissue. These findings suggest that ADSCs and PLGA spheres are useful materials for muscle tissue engineering and that their combination can be used in clinical settings for muscle regeneration.

  3. Quantitation of two endogenous lactose-inhibitable lectins in embryonic and adult chicken tissues

    SciTech Connect

    Beyer, E.C.; Barondes, S.H.

    1982-01-01

    Two lactose-binding lectins from chicken tissues, chicken-lactose-lectin-I (CLL-I) and chicken-lactose-lectin-II (CLL-II) were quantified with a radioimmunoassay in extracts of a number of developing and adult chicken tissues. Both lectins could be measured in the same extract without separation, because they showed no significant immunological cross- reactivity. Many embryonic and adult tissues, including brain, heart, intestine, kidney, liver, lung, muscle, pancreas, and spleen, contained one or both lectins, although their concentrations differed markedly. For example, embryonic muscle, the richest source of CLL-I contained only traces of CLL-II whereas embryonic kidney, a very rich source of CLL-II contained substantial CLL-I. In both muscle and kidney, lectin levels in adulthood were much lower than in the embryonic state. In contrast, CLL-I in liver and CLL-II in intestine were 10-fold to 30-fold more concentrated in the adult than in the 15-d embryo. CLL-I and CLL-II from several tissues were purified by affinity chromatography and their identity in the various tissues was confirmed by polyacrylamide gel electrophoresis, isoelectric focusing, and peptide mapping. The results suggest that these lectins might have different functions in the many developing and adult tissues in which they are found.

  4. Adipose tissue gene expression and metabolic health of obese adults

    PubMed Central

    Das, Swapan Kumar; Ma, Lijun; Sharma, Neeraj

    2014-01-01

    Obese subjects with a similar body mass index (BMI) exhibit substantial heterogeneity in gluco- and cardio-metabolic heath phenotypes. However, defining genes that underlie the heterogeneity of metabolic features among obese individuals and determining metabolically healthy and unhealthy phenotypes remain challenging. We conducted unsupervised hierarchical clustering analysis of subcutaneous adipose tissue transcripts from 30 obese men and women ≥40 years old. Despite similar BMIs in all subjects, we found two distinct subgroups, one metabolically healthy (Group 1) and one metabolically unhealthy (Group 2). Subjects in Group 2 showed significantly higher total cholesterol (p=0.005), LDL cholesterol (p=0.006), 2h-Insulin during OGTT (p=0.015) and lower insulin sensitivity (SI, p=0.029) compared to Group 1. We identified significant up-regulation of 141 genes (e.g. MMP9 and SPP1) and down-regulation of 17 genes (e.g. NDRG4 and GINS3) in group 2 subjects. Intriguingly, these differentially expressed transcripts were enriched for genes involved in cardiovascular disease-related processes (p=2.81×10−11–3.74×10−02) and pathways involved in immune and inflammatory response (p=8.32×10−5–0.04). Two down-regulated genes, NDRG4 and GINS3, have been located in a genomic interval associated with cardiac repolarization in published GWASs and zebra fish knockout models. Our study provides evidence that perturbations in the adipose tissue gene expression network are important in defining metabolic health in obese subjects. PMID:25520251

  5. Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice.

    PubMed

    Kodo, Kazuki; Sugimoto, Satoru; Nakajima, Hisakazu; Mori, Jun; Itoh, Ikuyo; Fukuhara, Shota; Shigehara, Keiichi; Nishikawa, Taichiro; Kosaka, Kitaro; Hosoi, Hajime

    2017-01-01

    Erythropoietin (EPO), clinically used as a hematopoietic drug, has received much attention due to its nonhematopoietic effects. EPO reportedly has beneficial effects on obesity and diabetes mellitus. We investigated whether interscapular brown adipose tissue (iBAT: main part of classical BAT) could play a role in EPO's anti-obesity and anti-diabetic effects in diet-induced obese mice. Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD-Con), and half were additionally given an intraperitoneal injection of recombinant human EPO (200 IU/kg) (HFD-EPO) thrice a week for four weeks. At 8 weeks, EPO-injected mice showed significantly reduced body weight with reduced epididymal and subcutaneous white fat mass and unchanged caloric intake and locomotor activity. HOMA-IR (insulin resistance index) and glucose levels during intraperitoneal glucose tolerance test (IPGTT) were significantly lower in HFD-EPO mice than in HFD-Con mice. EPO-injected mice also showed increased oxygen consumption, indicative of metabolic rate, and skin temperature around iBAT tissue masses. EPO significantly upregulated the PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16), a transcriptional factor with a crucial role in brown adipocyte differentiation. EPO significantly increased phosphorylated signal transducer and activator of transcription 3 (STAT3), which is downstream of erythropoietin receptor (EpoR) and known to stabilize PRDM16. EPO's suppression of myocyte enhancer factor 2c (Mef2c) and microRNA-133a (miR-133a) via β3-adrenergic receptor caused PRDM16 upregulation. EPO-mediated enhancement of EpoR/STAT3 and β-adrenergic receptor/Mef2c/miR-133 pathways dramatically increases total uncoupling protein 1 (UCP1), an essential enzyme for BAT thermogenesis. Furthermore, EPO activated BAT's endocrine functions. EPO facilitated fibroblast growth factor 21 (FGF21) production and excretion in iBAT, associated with reduction of liver gluconeogenesis-related genes. Thus, EPO

  6. Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice

    PubMed Central

    Kodo, Kazuki; Sugimoto, Satoru; Mori, Jun; Itoh, Ikuyo; Fukuhara, Shota; Shigehara, Keiichi; Nishikawa, Taichiro; Kosaka, Kitaro; Hosoi, Hajime

    2017-01-01

    Erythropoietin (EPO), clinically used as a hematopoietic drug, has received much attention due to its nonhematopoietic effects. EPO reportedly has beneficial effects on obesity and diabetes mellitus. We investigated whether interscapular brown adipose tissue (iBAT: main part of classical BAT) could play a role in EPO’s anti-obesity and anti-diabetic effects in diet-induced obese mice. Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD-Con), and half were additionally given an intraperitoneal injection of recombinant human EPO (200 IU/kg) (HFD-EPO) thrice a week for four weeks. At 8 weeks, EPO-injected mice showed significantly reduced body weight with reduced epididymal and subcutaneous white fat mass and unchanged caloric intake and locomotor activity. HOMA-IR (insulin resistance index) and glucose levels during intraperitoneal glucose tolerance test (IPGTT) were significantly lower in HFD-EPO mice than in HFD-Con mice. EPO-injected mice also showed increased oxygen consumption, indicative of metabolic rate, and skin temperature around iBAT tissue masses. EPO significantly upregulated the PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16), a transcriptional factor with a crucial role in brown adipocyte differentiation. EPO significantly increased phosphorylated signal transducer and activator of transcription 3 (STAT3), which is downstream of erythropoietin receptor (EpoR) and known to stabilize PRDM16. EPO’s suppression of myocyte enhancer factor 2c (Mef2c) and microRNA-133a (miR-133a) via β3-adrenergic receptor caused PRDM16 upregulation. EPO-mediated enhancement of EpoR/STAT3 and β-adrenergic receptor/Mef2c/miR-133 pathways dramatically increases total uncoupling protein 1 (UCP1), an essential enzyme for BAT thermogenesis. Furthermore, EPO activated BAT’s endocrine functions. EPO facilitated fibroblast growth factor 21 (FGF21) production and excretion in iBAT, associated with reduction of liver gluconeogenesis-related genes. Thus, EPO

  7. Brain tissue pressure measurements in perinatal and adult rabbits.

    PubMed

    Hornig, G W; Lorenzo, A V; Zavala, L M; Welch, K

    1987-12-01

    Brain tissue pressure (BTP) in pre- and post-natal anesthetized rabbits, held in a stereotactic head holder, was measured with a fluid filled 23 gauge open-ended cannula connected distally to a pressure transducer. By advancing the cannula step wise through a hole in the cranium it was possible to sequentially measure pressure from the cranial subarachnoid space, cortex, ventricle and basal ganglia. Separate cannulas and transducers were used to measure CSFP from the cisterna magna and arterial and/or venous pressure. Pressure recordings obtained when the tip of the BTP cannula was located in the cranial subarachnoid space or ventricle exhibited respiratory and blood pressure pulsations equivalent to and in phase with CSF pulsations recorded from the cisterna magna. When the tip was advanced into brain parenchymal sites such pulsations were suppressed or non-detectable unless communication with a CSF compartment had been established inadvertently. Although CSF pressures in the three spinal fluid compartments were equivalent, in most animals BTP was higher than CSFP. However, after momentary venting of the system BTP equilibrated at a pressure below that of CSFP. We speculate that venting of the low compliance system (1.20 x 10(-5) ml/mmHg) relieves the isometric pressure build-up due to insertion of the cannula into brain parenchyma. Under these conditions, and at all ages examined, BTP in the rabbit is consistently lower than CSFP and, as with CSFP, it increases as the animal matures.

  8. Great promise of tissue-resident adult stem/progenitor cells in transplantation and cancer therapies.

    PubMed

    Mimeault, Murielle; Batra, Surinder K

    2012-01-01

    Recent progress in tissue-resident adult stem/progenitor cell research has inspired great interest because these immature cells from your own body can act as potential, easily accessible cell sources for cell transplantation in regenerative medicine and cancer therapies. The use of adult stem/progenitor cells endowed with a high self-renewal ability and multilineage differentiation potential, which are able to regenerate all the mature cells in the tissues from their origin, offers great promise in replacing non-functioning or lost cells and regenerating diseased and damaged tissues. The presence of a small subpopulation of adult stem/progenitor cells in most tissues and organs provides the possibility of stimulating their in vivo differentiation, or of using their ex vivo expanded progenies for cell-replacement and gene therapies with multiple applications in humans without a high-risk of graft rejection and major side effects. Among the diseases that could be treated by adult stem cell-based therapies are hematopoietic and immune disorders, multiple degenerative disorders such as Parkinson's and Alzheimer's diseases, Types 1 and 2 diabetes mellitus as well as skin, eye, liver, lung, tooth and cardiovascular disorders. In addition, a combination of the current cancer treatments with an adjuvant treatment consisting of an autologous or allogeneic adult stem/progenitor cell transplantation also represents a promising strategy for treating and even curing diverse aggressive, metastatic, recurrent and lethal cancers. In this chapter, we reviewed the most recent advancements on the characterization of phenotypic and functional properties of adult stem/progenitor cell types found in bone marrow, heart, brain and other tissues and discussed their therapeutic implications in the stem cell-based transplantation therapy.

  9. JH Biosynthesis by Reproductive Tissues and Corpora Allata in Adult Longhorned Beetles, Apriona germari

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We report on juvenile hormone (JH) biosynthesis from long-chain intermediates by specific reproductive system tissues and the corpora allata (CA) prepared from adult longhorned beetles, Apriona germari. Testes, male accessory glands (MAGs), ovaries and CA contain the long-chain intermediates in the ...

  10. Neuroscience of glucose homeostasis.

    PubMed

    La Fleur, S E; Fliers, E; Kalsbeek, A

    2014-01-01

    Plasma glucose concentrations are homeostatically regulated and maintained within strict boundaries. Several mechanisms are in place to increase glucose output when glucose levels in the circulation drop as a result of glucose utilization, or to decrease glucose output and increase tissue glucose uptake to prevent hyperglycemia. Although the term homeostasis mostly refers to stable levels, the blood glucose concentrations fluctuate over the day/night cycle, with the highest concentrations occurring just prior to the activity period in anticipation of increased caloric need. In this chapter we describe how the brain, particularly the hypothalamus, is involved in both the daily rhythm of plasma glucose concentrations and acute glucose challenges.

  11. Exposure to Bisphenol-A during Pregnancy Partially Mimics the Effects of a High-Fat Diet Altering Glucose Homeostasis and Gene Expression in Adult Male Mice

    PubMed Central

    García-Arevalo, Marta; Alonso-Magdalena, Paloma; Rebelo Dos Santos, Junia; Quesada, Ivan; Carneiro, Everardo M.; Nadal, Angel

    2014-01-01

    Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group); BPA treated mice that also ate a normal chow diet (BPA); vehicle treated animals that had a high fat diet (HFD) and BPA treated animals that were fed HFD (HFD-BPA). The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA) in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity. PMID:24959901

  12. Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice.

    PubMed

    García-Arevalo, Marta; Alonso-Magdalena, Paloma; Rebelo Dos Santos, Junia; Quesada, Ivan; Carneiro, Everardo M; Nadal, Angel

    2014-01-01

    Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group); BPA treated mice that also ate a normal chow diet (BPA); vehicle treated animals that had a high fat diet (HFD) and BPA treated animals that were fed HFD (HFD-BPA). The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA) in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity.

  13. Wound healing in a fetal, adult, and scar tissue model: a comparative study.

    PubMed

    Coolen, Neeltje A; Schouten, Kelly C W M; Boekema, Bouke K H L; Middelkoop, Esther; Ulrich, Magda M W

    2010-01-01

    Early gestation fetal wounds heal without scar formation. Understanding the mechanism of this scarless healing may lead to new therapeutic strategies for improving adult wound healing. The aims of this study were to develop a human fetal wound model in which fetal healing can be studied and to compare this model with a human adult and scar tissue model. A burn wound (10 x 2 mm) was made in human ex vivo fetal, adult, and scar tissue under controlled and standardized conditions. Subsequently, the skin samples were cultured for 7, 14, and 21 days. Cells in the skin samples maintained their viability during the 21-day culture period. Already after 7 days, a significantly higher median percentage of wound closure was achieved in the fetal skin model vs. the adult and scar tissue model (74% vs. 28 and 29%, respectively, p<0.05). After 21 days of culture, only fetal wounds were completely reepithelialized. Fibroblasts migrated into the wounded dermis of all three wound models during culture, but more fibroblasts were present earlier in the wound area of the fetal skin model. The fast reepithelialization and prompt presence of many fibroblasts in the fetal model suggest that rapid healing might play a role in scarless healing.

  14. Spontaneous myogenic differentiation of Flk-1-positive cells from adult pancreas and other nonmuscle tissues.

    PubMed

    Di Rocco, Giuliana; Tritarelli, Alessandra; Toietta, Gabriele; Gatto, Ilaria; Iachininoto, Maria Grazia; Pagani, Francesca; Mangoni, Antonella; Straino, Stefania; Capogrossi, Maurizio C

    2008-02-01

    At the embryonic or fetal stages, autonomously myogenic cells (AMCs), i.e., cells able to spontaneously differentiate into skeletal myotubes, have been identified from several different sites other than skeletal muscle, including the vascular compartment. However, in the adult animal, AMCs from skeletal muscle-devoid tissues have been described in only two cases. One is represented by thymic myoid cells, a restricted population of committed myogenic progenitors of unknown derivation present in the thymic medulla; the other is represented by a small subset of adipose tissue-associated cells, which we recently identified. In the present study we report, for the first time, the presence of spontaneously differentiating myogenic precursors in the pancreas and in other skeletal muscle-devoid organs such as spleen and stomach, as well as in the periaortic tissue of adult mice. Immunomagnetic selection procedures indicate that AMCs derive from Flk-1(+) progenitors. Individual clones of myogenic cells from nonmuscle organs are morphologically and functionally indistinguishable from skeletal muscle-derived primary myoblasts. Moreover, they can be induced to proliferate in vitro and are able to participate in muscle regeneration in vivo. Thus, we provide evidence that fully competent myogenic progenitors can be derived from the Flk-1(+) compartment of several adult tissues that are embryologically unrelated to skeletal muscle.

  15. Postprandial Responses to Lipid and Carbohydrate Ingestion in Repeated Subcutaneous Adipose Tissue Biopsies in Healthy Adults.

    PubMed

    Dordevic, Aimee L; Pendergast, Felicity J; Morgan, Han; Villas-Boas, Silas; Caldow, Marissa K; Larsen, Amy E; Sinclair, Andrew J; Cameron-Smith, David

    2015-07-01

    Adipose tissue is a primary site of meta-inflammation. Diet composition influences adipose tissue metabolism and a single meal can drive an inflammatory response in postprandial period. This study aimed to examine the effect lipid and carbohydrate ingestion compared with a non-caloric placebo on adipose tissue response. Thirty-three healthy adults (age 24.5 ± 3.3 year (mean ± standard deviation (SD)); body mass index (BMI) 24.1 ± 3.2 kg/m2, were randomised into one of three parallel beverage groups; placebo (water), carbohydrate (maltodextrin) or lipid (dairy-cream). Subcutaneous, abdominal adipose tissue biopsies and serum samples were collected prior to (0 h), as well as 2 h and 4 h after consumption of the beverage. Adipose tissue gene expression levels of monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) increased in all three groups, without an increase in circulating TNF-α. Serum leptin (0.6-fold, p = 0.03) and adipose tissue leptin gene expression levels (0.6-fold, p = 0.001) decreased in the hours following the placebo beverage, but not the nutrient beverages. Despite increased inflammatory cytokine gene expression in adipose tissue with all beverages, suggesting a confounding effect of the repeated biopsy method, differences in metabolic responses of adipose tissue and circulating adipokines to ingestion of lipid and carbohydrate beverages were observed.

  16. Soft-tissue cephalometric norms in Chinese adults with esthetic facial profiles.

    PubMed

    Lew, K K; Ho, K K; Keng, S B; Ho, K H

    1992-11-01

    Using a double selection process comprised of professional and lay judges, the cephalometric tracings on a final sample of 48 Chinese adults with esthetically pleasing profiles were analyzed. The soft-tissue cephalometric norms and standard deviations of two widely accepted soft-tissue analyses, the Legan and Burstone analysis and the Holdaway analysis, were determined. In comparison with white norms, the Chinese nose was less prominent (P < .01), the nasolabial angle was less obtuse (P < .01), both the upper and lower lips were more protrusive (P < .05), the upper lip curvature was greater (P < .01), and the soft-tissue chin thickness was less (P < .05). This variance between racial types emphasizes the need to recognize that soft-tissue lateral cephalometric norms are specific for the racial group and cannot always be applied across different racial types.

  17. Distribution of bisphenol A into tissues of adult, neonatal, and fetal Sprague-Dawley rats

    SciTech Connect

    Doerge, Daniel R.; Twaddle, Nathan C.; Vanlandingham, Michelle; Brown, Ronald P.; Fisher, Jeffrey W.

    2011-09-15

    Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA metabolites in urine of > 90% of Americans aged 6-60 suggests ubiquitous and frequent exposure in the range of 0.02-0.2 {mu}g/kg bw/d (25th-95th percentiles). The current study used LC/MS/MS to measure placental transfer and concentrations of aglycone (receptor-active) and conjugated (inactive) BPA in tissues from Sprague-Dawley rats administered deuterated BPA (100 {mu}g/kg bw) by oral and IV routes. In adult female rat tissues, the tissue/serum concentration ratios for aglycone BPA ranged from 0.7 in liver to 5 in adipose tissue, reflecting differences in tissue perfusion, composition, and metabolic capacity. Following IV administration to dams, placental transfer was observed for aglycone BPA into fetuses at several gestational days (GD), with fetal/maternal serum ratios of 2.7 at GD 12, 1.2 at GD 16, and 0.4 at GD 20; the corresponding ratios for conjugated BPA were 0.43, 0.65, and 3.7. These ratios were within the ranges observed in adult tissues and were not indicative of preferential accumulation of aglycone BPA or hydrolysis of conjugates in fetal tissue in vivo. Concentrations of aglycone BPA in GD 20 fetal brain were higher than in liver or serum. Oral administration of the same dose did not produce measurable levels of aglycone BPA in fetal tissues. Amniotic fluid consistently contained levels of BPA at or below those in maternal serum. Concentrations of aglycone BPA in tissues of neonatal rats decreased with age in a manner consistent with the corresponding circulating levels. Phase II metabolism of BPA increased with fetal age such that near-term fetus was similar to early post-natal rats. These results show that concentrations of aglycone BPA in fetal tissues are similar to those in other maternal and neonatal tissues and that maternal Phase II metabolism, especially following oral

  18. Cholesterol metabolism and homeostasis in the brain.

    PubMed

    Zhang, Juan; Liu, Qiang

    2015-04-01

    Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.

  19. The connective tissue of the adductor canal--a morphological study in fetal and adult specimens.

    PubMed

    de Oliveira, Flavia; de Vasconcellos Fontes, Ricardo Bragança; da Silva Baptista, Josemberg; Mayer, William Paganini; de Campos Boldrini, Silvia; Liberti, Edson Aparecido

    2009-03-01

    The adductor canal is a conical or pyramid-shaped pathway that contains the femoral vessels, saphenous nerve and a varying amount of fibrous tissue. It is involved in adductor canal syndrome, a claudication syndrome involving young individuals. Our objective was to study modifications induced by aging on the connective tissue and to correlate them to the proposed pathophysiological mechanism. The bilateral adductor canals and femoral vessels of four adult and five fetal specimens were removed en bloc and analyzed. Sections 12 microm thick were obtained and the connective tissue studied with Sirius Red, Verhoeff, Weigert and Azo stains. Scanning electron microscopy (SEM) photomicrographs of the surfaces of each adductor canal were also analyzed. Findings were homogeneous inside each group. The connective tissue of the canal was continuous with the outer layer of the vessels in both groups. The pattern of concentric, thick collagen type I bundles in fetal specimens was replaced by a diffuse network of compact collagen bundles with several transversal fibers and an impressive content of collagen III fibers. Elastic fibers in adults were not concentrated in the thick bundles but dispersed in line with the transversal fiber system. A dynamic compression mechanism with or without an evident constricting fibrous band has been proposed previously for adductor canal syndrome, possibly involving the connective tissue inside the canal. The vessels may not slide freely during movement. These age-related modifications in normal individuals may represent necessary conditions for this syndrome to develop.

  20. The connective tissue of the adductor canal – a morphological study in fetal and adult specimens

    PubMed Central

    de Oliveira, Flavia; de Vasconcellos Fontes, Ricardo Bragança; da Silva Baptista, Josemberg; Mayer, William Paganini; de Campos Boldrini, Silvia; Liberti, Edson Aparecido

    2009-01-01

    The adductor canal is a conical or pyramid-shaped pathway that contains the femoral vessels, saphenous nerve and a varying amount of fibrous tissue. It is involved in adductor canal syndrome, a claudication syndrome involving young individuals. Our objective was to study modifications induced by aging on the connective tissue and to correlate them to the proposed pathophysiological mechanism. The bilateral adductor canals and femoral vessels of four adult and five fetal specimens were removed en bloc and analyzed. Sections 12 µm thick were obtained and the connective tissue studied with Sirius Red, Verhoeff, Weigert and Azo stains. Scanning electron microscopy (SEM) photomicrographs of the surfaces of each adductor canal were also analyzed. Findings were homogeneous inside each group. The connective tissue of the canal was continuous with the outer layer of the vessels in both groups. The pattern of concentric, thick collagen type I bundles in fetal specimens was replaced by a diffuse network of compact collagen bundles with several transversal fibers and an impressive content of collagen III fibers. Elastic fibers in adults were not concentrated in the thick bundles but dispersed in line with the transversal fiber system. A dynamic compression mechanism with or without an evident constricting fibrous band has been proposed previously for adductor canal syndrome, possibly involving the connective tissue inside the canal. The vessels may not slide freely during movement. These age-related modifications in normal individuals may represent necessary conditions for this syndrome to develop. PMID:19245505

  1. Head, Neck, Trunk and Pelvis Tissue Mass Predictions for Young Adults using Anthropometric Measures and DXA.

    PubMed

    Gyemi, Danielle L; Kahelin, Charles; George, Nicole C; Andrews, David M

    2017-03-24

    Accurate prediction of wobbling mass (WM), fat mass (FM), lean mass (LM) and bone mineral content (BMC) of living people using regression equations developed from anthropometric measures (lengths, circumferences, breadths, skinfolds) has previously been reported, but only for the extremities. Multiple linear stepwise regression was used to generate comparable equations for the head, neck, trunk and pelvis of young adults (38 males, 38 females). Equations were validated using actual tissue masses from an independent sample of 13 males and 13 females by manually segmenting full body Dual-energy X-ray Absorptiometry scans. Prediction equations exhibited adjusted R(2) values ranging from .249 to .940, with more explained variance for LM and WM than BMC and FM, especially for the head and neck. Mean relative errors between predicted and actual tissue masses ranged from -11.07% (trunk FM) to 7.61% (neck FM). Actual and predicted tissue masses from all equations were significantly correlated (R(2) = .329 to .937), except head BMC (R(2) = .046). These results show promise for obtaining in-vivo head, neck, trunk and pelvis tissue mass estimates in young adults. Further research is needed to improve head and neck FM and BMC predictions and develop tissue mass prediction equations for older populations.

  2. Hereditary Connective Tissue Diseases in Young Adult Stroke: A Comprehensive Synthesis

    PubMed Central

    Vanakker, Olivier M.; Hemelsoet, Dimitri; De Paepe, Anne

    2011-01-01

    Though the genetic background of ischaemic and haemorrhagic stroke is often polygenetic or multifactorial, it can in some cases result from a monogenic disease, particularly in young adults. Besides arteriopathies and metabolic disorders, several connective tissue diseases can present with stroke. While some of these diseases have been recognized for decades as causes of stroke, such as the vascular Ehlers-Danlos syndrome, others only recently came to attention as being involved in stroke pathogenesis, such as those related to Type IV collagen. This paper discusses each of these connective tissue disorders and their relation with stroke briefly, emphasizing the main clinical features which can lead to their diagnosis. PMID:21331163

  3. Identifying proteins in zebrafish embryos using spectral libraries generated from dissected adult organs and tissues.

    PubMed

    van der Plas-Duivesteijn, Suzanne J; Mohammed, Yassene; Dalebout, Hans; Meijer, Annemarie; Botermans, Anouk; Hoogendijk, Jordy L; Henneman, Alex A; Deelder, André M; Spaink, Herman P; Palmblad, Magnus

    2014-03-07

    Spectral libraries provide a sensitive and accurate method for identifying peptides from tandem mass spectra, complementary to searching genome-derived databases or sequencing de novo. Their application requires comprehensive libraries including peptides from low-abundant proteins. Here we describe a method for constructing such libraries using biological differentiation to "fractionate" the proteome by harvesting adult organs and tissues and build comprehensive libraries for identifying proteins in zebrafish (Danio rerio) embryos and larvae (an important and widely used model system). Hierarchical clustering using direct comparison of spectra was used to prioritize organ selection. The resulting and publicly available library covers 14,164 proteins, significantly improved the number of peptide-spectrum matches in zebrafish developmental stages, and can be used on data from different instruments and laboratories. The library contains information on tissue and organ expression of these proteins and is also applicable for adult experiments. The approach itself is not limited to zebrafish but would work for any model system.

  4. Limited Accuracy of Colour Doppler Ultrasound Dynamic Tissue Perfusion Measurement in Diabetic Adults

    PubMed Central

    Stoperka, Felix; Karger, Claudia

    2016-01-01

    Dynamic tissue perfusion measurement (DTPM) is a pre-described and available method in pediatric ultrasound to quantify tissue perfusion in renal Doppler ultrasound by particular video analysis software. This study evaluates DTPM during single and between repeated visits after 6 months, calibrates repeated DTPM within different region of interest (ROI) and compares DTPM with kidney function markers in adult patients with early diabetic nephropathy (n = 17). During repeated measurements, no association of readings at the same patients in the same (n = 3 readings) as well as repeated visit (n = 2 visits) could be retrieved. No association between DTPM, MDRD-GFR, albuminuria, age and duration of diabetes was observed. These negative results are presumably related to inconsistency of DTPM due to non-fixed ROI position as could be shown in calibrating series. Further development of the method should be performed to enable reproducible DTPM readings in adults. PMID:28033403

  5. An Overview of Notch Signaling in Adult Tissue Renewal and Maintenance

    PubMed Central

    Sato, Chihiro; Zhao, Guojun; Ilagan, Ma. Xenia G.

    2015-01-01

    The Notch pathway is a critical mediator of short-range cell-cell communication that is reiteratively used to regulate a diverse array of cellular processes during embryonic development and the renewal and maintenance of adult tissues. Most Notch-dependent processes utilize a core signaling mechanism that is dependent on regulated intramembrane proteolysis: Upon ligand binding, Notch receptors undergo ectodomain shedding by ADAM metalloproteases, followed by γ-secretase-mediated intramembrane proteolysis. This releases the Notch intracellular domain, which translocates to the nucleus to activate transcription. In this review, we highlight the roles of Notch signaling particularly in self-renewing tissues in adults and several human diseases and raise some key considerations when targeting ADAMs and γ-secretase as disease-modifying strategies for Alzheimer's Disease. PMID:21605032

  6. Soft Tissue Deformations Contribute to the Mechanics of Walking in Obese Adults

    PubMed Central

    Fu, Xiao-Yu; Zelik, Karl E.; Board, Wayne J.; Browning, Raymond C.; Kuo, Arthur D.

    2014-01-01

    Obesity not only adds to the mass that must be carried during walking, but also changes body composition. Although extra mass causes roughly proportional increases in musculoskeletal loading, less well understood is the effect of relatively soft and mechanically compliant adipose tissue. Purpose To estimate the work performed by soft tissue deformations during walking. The soft tissue would be expected to experience damped oscillations, particularly from high force transients following heel strike, and could potentially change the mechanical work demands for walking. Method We analyzed treadmill walking data at 1.25 m/s for 11 obese (BMI > 30 kg/m2) and 9 non-obese (BMI < 30 kg/m2) adults. The soft tissue work was quantified with a method that compares the work performed by lower extremity joints as derived using assumptions of rigid body segments, with that estimated without rigid body assumptions. Results Relative to body mass, obese and non-obese individuals perform similar amounts of mechanical work. But negative work performed by soft tissues was significantly greater in obese individuals (p= 0.0102), equivalent to about 0.36 J/kg vs. 0.27 J/kg in non-obese individuals. The negative (dissipative) work by soft tissues occurred mainly after heel strike, and for obese individuals was comparable in magnitude to the total negative work from all of the joints combined (0.34 J/kg vs. 0.33 J/kg for obese and non-obese adults, respectively). Although the joints performed a relatively similar amount of work overall, obese individuals performed less negative work actively at the knee. Conclusion The greater proportion of soft tissues in obese individuals results in substantial changes in the amount, location, and timing of work, and may also impact metabolic energy expenditure during walking. PMID:25380475

  7. Electric fish: new insights into conserved processes of adult tissue regeneration.

    PubMed

    Unguez, Graciela A

    2013-07-01

    Biology is replete with examples of regeneration, the process that allows animals to replace or repair cells, tissues and organs. As on land, vertebrates in aquatic environments experience the occurrence of injury with varying frequency and to different degrees. Studies demonstrate that ray-finned fishes possess a very high capacity to regenerate different tissues and organs when they are adults. Among fishes that exhibit robust regenerative capacities are the neotropical electric fishes of South America (Teleostei: Gymnotiformes). Specifically, adult gymnotiform electric fishes can regenerate injured brain and spinal cord tissues and restore amputated body parts repeatedly. We have begun to identify some aspects of the cellular and molecular mechanisms of tail regeneration in the weakly electric fish Sternopygus macrurus (long-tailed knifefish) with a focus on regeneration of skeletal muscle and the muscle-derived electric organ. Application of in vivo microinjection techniques and generation of myogenic stem cell markers are beginning to overcome some of the challenges owing to the limitations of working with non-genetic animal models with extensive regenerative capacity. This review highlights some aspects of tail regeneration in S. macrurus and discusses the advantages of using gymnotiform electric fishes to investigate the cellular and molecular mechanisms that produce new cells during regeneration in adult vertebrates.

  8. Electric fish: new insights into conserved processes of adult tissue regeneration

    PubMed Central

    Unguez, Graciela A.

    2013-01-01

    Summary Biology is replete with examples of regeneration, the process that allows animals to replace or repair cells, tissues and organs. As on land, vertebrates in aquatic environments experience the occurrence of injury with varying frequency and to different degrees. Studies demonstrate that ray-finned fishes possess a very high capacity to regenerate different tissues and organs when they are adults. Among fishes that exhibit robust regenerative capacities are the neotropical electric fishes of South America (Teleostei: Gymnotiformes). Specifically, adult gymnotiform electric fishes can regenerate injured brain and spinal cord tissues and restore amputated body parts repeatedly. We have begun to identify some aspects of the cellular and molecular mechanisms of tail regeneration in the weakly electric fish Sternopygus macrurus (long-tailed knifefish) with a focus on regeneration of skeletal muscle and the muscle-derived electric organ. Application of in vivo microinjection techniques and generation of myogenic stem cell markers are beginning to overcome some of the challenges owing to the limitations of working with non-genetic animal models with extensive regenerative capacity. This review highlights some aspects of tail regeneration in S. macrurus and discusses the advantages of using gymnotiform electric fishes to investigate the cellular and molecular mechanisms that produce new cells during regeneration in adult vertebrates. PMID:23761473

  9. Brain iron homeostasis.

    PubMed

    Moos, Torben

    2002-11-01

    [125I]transferrin in the brain. Some of the 59Fe was detected in CSF in a fraction less than 30 kDa (III). It was estimated that the iron-binding capacity of transferrin in CSF was exceeded, suggesting that iron is transported into the brain in a quantity that exceeds that of transferrin. Accordingly, it was concluded that the paramount iron transport across the BBB is the result of receptor-mediated endocytosis of iron-containing transferrin by capillary endothelial cells, followed by recycling of transferrin to the blood and transport of non-transferrin-bound iron into the brain. It was found that retrograde axonal transport in a cranial motor nerve is age-dependent, varying from almost negligible in the neonatal brain to high in the adult brain. The principle sources of extracellular transferrin in the brain are hepatocytes, oligodendrocytes, and the choroid plexus. As the passage of liver-derived transferrin into the brain is restricted due to the BBB, other candidates for binding iron in the interstitium should be considered. In vitro studies have revealed secretion of transferrin from the choroid plexus and oligodendrocytes. The second part of the thesis encompasses the circulation of iron in the extracellular fluids of the brain, i.e. the brain interstitial fluid and the CSF. As the latter receives drainage from the interstitial fluid, the CSF of the ventricles can be considered a mixture of these fluids, which may allow for analysis of CSF in matters that relate to the brain interstitial fluid. As the choroid plexus is known to synthesize transferrin, a key question is whether transferrin of the CSF might play a role for iron homeostasis by diffusing from the ventricles and subarachnoid space to the brain interstitium. Intracerebroventricular injection of [59Fe125I]transferrin led to a higher accumulation of 59Fe than of [125I]transferrin in the brain. Except for uptake and axonal transport by certain neurons with access to the ventricular CSF, both iron and

  10. Aberrant Synaptic Integration in Adult Lamina I Projection Neurons Following Neonatal Tissue Damage

    PubMed Central

    Li, Jie; Kritzer, Elizabeth; Craig, Paige E.

    2015-01-01

    Mounting evidence suggests that neonatal tissue damage evokes alterations in spinal pain reflexes which persist into adulthood. However, less is known about potential concomitant effects on the transmission of nociceptive information to the brain, as the degree to which early injury modulates synaptic integration and membrane excitability in mature spinal projection neurons remains unclear. Here we demonstrate that neonatal surgical injury leads to a significant shift in the balance between synaptic excitation and inhibition onto identified lamina I projection neurons of the adult mouse spinal cord. The strength of direct primary afferent input to mature spino-parabrachial neurons was enhanced following neonatal tissue damage, whereas the efficacy of both GABAergic and glycinergic inhibition onto the same population was compromised. This was accompanied by reorganization in the pattern of sensory input to adult projection neurons, which included a greater prevalence of monosynaptic input from low-threshold A-fibers when preceded by early tissue damage. In addition, neonatal incision resulted in greater primary afferent-evoked action potential discharge in mature projection neurons. Overall, these results demonstrate that tissue damage during early life causes a long-term increase in the gain of spinal nociceptive circuits, and suggest that the prolonged consequences of neonatal trauma may not be restricted to the spinal cord but rather include excessive ascending signaling to supraspinal pain centers. PMID:25673839

  11. Pathology, physiologic parameters, tissue contaminants, and tissue thiamine in morbid and healthy central Florida adult American alligators (Alligator mississippiensis)

    USGS Publications Warehouse

    Honeyfield, D.C.; Ross, J.P.; Carbonneau, D.A.; Terrell, S.P.; Woodward, A.R.; Schoeb, T.R.; Perceval, H.F.; Hinterkopf, J.P.

    2008-01-01

    An investigation of adult alligator (Alligator mississippiensis) mortalities in Lake Griffin, central Florida, was conducted from 1998-2004. Alligator mortality was highest in the months of April and May and annual death count peaked in 2000. Bacterial pathogens, heavy metals, and pesticides were not linked with the mortalities. Blood chemistry did not point to any clinical diagnosis, although differences between impaired and normal animals were noted. Captured alligators with signs of neurologic impairment displayed unresponsive and uncoordinated behavior. Three of 21 impaired Lake Griffin alligators were found to have neural lesions characteristic of thiamine deficiency in the telencephalon, particularly the dorsal ventricular ridge. In some cases, lesions were found in the thalamus, and parts of the midbrain. Liver and muscle tissue concentrations of thiamine (vitamin B"1) were lowest in impaired Lake Griffin alligators when compared to unimpaired alligators or to alligators from Lake Woodruff. The consumption of thiaminase-positive gizzard shad (Dorosoma cepedianum) is thought to have been the cause of the low tissue thiamine and resulting mortalities. ?? Wildlife Disease Association 2008.

  12. Pathology, physiologic parameters, tissue contaminants, and tissue thiamine in morbid and healthy central Florida adult American alligators (Alligator mississippiensis).

    PubMed

    Honeyfield, Dale C; Ross, J Perran; Carbonneau, Dwayne A; Terrell, Scott P; Woodward, Allan R; Schoeb, Trenton R; Perceval, H Franklin; Hinterkopf, Joy P

    2008-04-01

    An investigation of adult alligator (Alligator mississippiensis) mortalities in Lake Griffin, central Florida, was conducted from 1998-2004. Alligator mortality was highest in the months of April and May and annual death count peaked in 2000. Bacterial pathogens, heavy metals, and pesticides were not linked with the mortalities. Blood chemistry did not point to any clinical diagnosis, although differences between impaired and normal animals were noted. Captured alligators with signs of neurologic impairment displayed unresponsive and uncoordinated behavior. Three of 21 impaired Lake Griffin alligators were found to have neural lesions characteristic of thiamine deficiency in the telencephalon, particularly the dorsal ventricular ridge. In some cases, lesions were found in the thalamus, and parts of the midbrain. Liver and muscle tissue concentrations of thiamine (vitamin B(1)) were lowest in impaired Lake Griffin alligators when compared to unimpaired alligators or to alligators from Lake Woodruff. The consumption of thiaminase-positive gizzard shad (Dorosoma cepedianum) is thought to have been the cause of the low tissue thiamine and resulting mortalities.

  13. Calcium homeostasis and bone metabolic responses to high-protein diets during energy deficit in healthy young adults: a randomized control trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although consuming dietary protein above current recommendations during energy deficit enhances blood lipid profiles and preserves lean body mass, concerns have been raised regarding effects of high-protein diets on bone health. To determine whether calcium homeostasis and bone turnover are affected...

  14. Tissue-specific mutation accumulation in human adult stem cells during life

    NASA Astrophysics Data System (ADS)

    Blokzijl, Francis; de Ligt, Joep; Jager, Myrthe; Sasselli, Valentina; Roerink, Sophie; Sasaki, Nobuo; Huch, Meritxell; Boymans, Sander; Kuijk, Ewart; Prins, Pjotr; Nijman, Isaac J.; Martincorena, Inigo; Mokry, Michal; Wiegerinck, Caroline L.; Middendorp, Sabine; Sato, Toshiro; Schwank, Gerald; Nieuwenhuis, Edward E. S.; Verstegen, Monique M. A.; van der Laan, Luc J. W.; de Jonge, Jeroen; Ijzermans, Jan N. M.; Vries, Robert G.; van de Wetering, Marc; Stratton, Michael R.; Clevers, Hans; Cuppen, Edwin; van Boxtel, Ruben

    2016-10-01

    The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.

  15. Fetal and adult liver stem cells for liver regeneration and tissue engineering.

    PubMed

    Fiegel, H C; Lange, Claudia; Kneser, U; Lambrecht, W; Zander, A R; Rogiers, X; Kluth, D

    2006-01-01

    For the development of innovative cell-based liver directed therapies, e.g. liver tissue engineering, the use of stem cells might be very attractive to overcome the limitation of donor liver tissue. Liver specific differentiation of embryonic, fetal or adult stem cells is currently under investigation. Different types of fetal liver (stem) cells during development were identified, and their advantageous growth potential and bipotential differentiation capacity were shown. However, ethical and legal issues have to be addressed before using fetal cells. Use of adult stem cells is clinically established, e.g. transplantation of hematopoietic stem cells. Other bone marrow derived liver stem cells might be mesenchymal stem cells (MSC). However, the transdifferentiation potential is still in question due to the observation of cellular fusion in several in vivo experiments. In vitro experiments revealed a crucial role of the environment (e.g. growth factors and extracellular matrix) for specific differentiation of stem cells. Co-cultured liver cells also seemed to be important for hepatic gene expression of MSC. For successful liver cell transplantation, a novel approach of tissue engineering by orthotopic transplantation of gel-immobilized cells could be promising, providing optimal environment for the injected cells. Moreover, an orthotopic tissue engineering approach using bipotential stem cells could lead to a repopulation of the recipients liver with healthy liver and biliary cells, thus providing both hepatic functions and biliary excretion. Future studies have to investigate, which stem cell and environmental conditions would be most suitable for the use of stem cells for liver regeneration or tissue engineering approaches.

  16. Dedifferentiated fat cells: an alternative source of adult multipotent cells from the adipose tissues

    PubMed Central

    Shen, Jie-fei; Sugawara, Atsunori; Yamashita, Joe; Ogura, Hideo; Sato, Soh

    2011-01-01

    When adipose-derived stem cells (ASCs) are retrieved from the stromal vascular portion of adipose tissue, a large amount of mature adipocytes are often discarded. However, by modified ceiling culture technique based on their buoyancy, mature adipocytes can be easily isolated from the adipose cell suspension and dedifferentiated into lipid-free fibroblast-like cells, named dedifferentiated fat (DFAT) cells. DFAT cells re-establish active proliferation ability and undertake multipotent capacities. Compared with ASCs and other adult stem cells, DFAT cells showed unique advantages in their abundance, isolation and homogeneity. In this concise review, the establishment and culture methods of DFAT cells are introduced and the current profiles of their cellular nature are summarized. Under proper induction culture in vitro or environment in vivo, DFAT cells could demonstrate adipogenic, osteogenic, chondrogenic and myogenic potentials. In angiogenic conditions, DFAT cells could exhibit perivascular characteristics and elicit neovascularization. Our preliminary findings also suggested the pericyte phenotype underlying such cell lineage, which supported a novel interpretation about the common origin of mesenchymal stem cells and tissue-specific stem cells within blood vessel walls. Current research on DFAT cells indicated that this alternative source of adult multipotent cells has great potential in tissue engineering and regenerative medicine. PMID:21789960

  17. Dedifferentiated fat cells: an alternative source of adult multipotent cells from the adipose tissues.

    PubMed

    Shen, Jie-fei; Sugawara, Atsunori; Yamashita, Joe; Ogura, Hideo; Sato, Soh

    2011-07-01

    When adipose-derived stem cells (ASCs) are retrieved from the stromal vascular portion of adipose tissue, a large amount of mature adipocytes are often discarded. However, by modified ceiling culture technique based on their buoyancy, mature adipocytes can be easily isolated from the adipose cell suspension and dedifferentiated into lipid-free fibroblast-like cells, named dedifferentiated fat (DFAT) cells. DFAT cells re-establish active proliferation ability and undertake multipotent capacities. Compared with ASCs and other adult stem cells, DFAT cells showed unique advantages in their abundance, isolation and homogeneity. In this concise review, the establishment and culture methods of DFAT cells are introduced and the current profiles of their cellular nature are summarized. Under proper induction culture in vitro or environment in vivo, DFAT cells could demonstrate adipogenic, osteogenic, chondrogenic and myogenic potentials. In angiogenic conditions, DFAT cells could exhibit perivascular characteristics and elicit neovascularization. Our preliminary findings also suggested the pericyte phenotype underlying such cell lineage, which supported a novel interpretation about the common origin of mesenchymal stem cells and tissue-specific stem cells within blood vessel walls. Current research on DFAT cells indicated that this alternative source of adult multipotent cells has great potential in tissue engineering and regenerative medicine.

  18. Methylation of DNA in mouse early embryos, teratocarcinoma cells and adult tissues of mouse and rabbit.

    PubMed Central

    Singer, J; Roberts-Ems, J; Luthardt, F W; Riggs, A D

    1979-01-01

    The distribution and amount of 5-methylcytosine (5-MeCyt) in DNA was measured for early embryos of mouse strain CF1 (2 to 4 cell stage to blastocyst) and mouse teratocarcinoma cells. In each case, the pattern of methylation was examined by use of the restriction enzymes Hha I and HPA II HPA II, which cut DNA at the sites 5'GCGC and 5'CCGG respectively, when the cytosines at these sites are not methylated. Mouse embryo DNA was found to have the same level of methylation as adult mouse tissues, and no changes in methylation were seen during differentiation of the teratocarcinoma cells. The ratio of 5-MeCyt/Cyt in DNA was measured by high performance liquid chromatography for the differentiating teratocarcinoma cells and for several adult mouse and rabbit tissues. The variation between tissues or between teratocarcinoma cells at different stages of differentiation was less than 10 percent. These results are discussed in view of proposals that 5-MeCyt plays a role in differentiation. Images PMID:523320

  19. Localisation of embryonic prealbumin in formalin-fixed human fetal and adult tissue.

    PubMed Central

    Gallon, M E; Reid, W A; McHardie, G A; Hardman, R; Smith, G D; Horne, C H; Kalashnikov, V V; Tatarinov, Y S

    1981-01-01

    The presence of embryonic prealbumin (EPA) has been confirmed in fetal fibroblasts, chondrocytes, and distal tubular epithelial cells by an indirect immunoperoxidase technique. EPA has often been found also in the stromal cells of benign and malignant mesodermal tumours, but not in the epithelial cells of benign and malignant epithelial tumours. That EPA is not an exclusive product of neoplastic mesodermal cells is demonstrated by our finding of EPA in fibroblasts of granulation tissue, irradiated fibroblasts, and in distal tubular epithelial cells of miscellaneous adult kidneys. Images PMID:7021602

  20. Fourier analysis of human soft tissue facial shape: sex differences in normal adults.

    PubMed Central

    Ferrario, V F; Sforza, C; Schmitz, J H; Miani, A; Taroni, G

    1995-01-01

    Sexual dimorphism in human facial form involves both size and shape variations of the soft tissue structures. These variations are conventionally appreciated using linear and angular measurements, as well as ratios, taken from photographs or radiographs. Unfortunately this metric approach provides adequate quantitative information about size only, eluding the problems of shape definition. Mathematical methods such as the Fourier series allow a correct quantitative analysis of shape and of its changes. A method for the reconstruction of outlines starting from selected landmarks and for their Fourier analysis has been developed, and applied to analyse sex differences in shape of the soft tissue facial contour in a group of healthy young adults. When standardised for size, no sex differences were found between both cosine and sine coefficients of the Fourier series expansion. This shape similarity was largely overwhelmed by the very evident size differences and it could be measured only using the proper mathematical methods. PMID:8586558

  1. [Primitive neuroectodermal tumour of soft tissue of the index finger in an adult. A case report].

    PubMed

    Berrada, N; Bellarbi, S; El Mannouar, M; Errihani, H

    2012-12-01

    The primitive neuroectodermal tumours (PNET) of soft tissues belong to the Ewing's tumors family and affects particularly the child. The localization of the disease at the extremities is very rare within the adult population and raises the problem of differential diagnosis with others tumors of the soft tissues. We report the case of a 48-year-old patient with a localized tumor, at the level of the second right finger, of six months evolution. The biopsy showed the infiltrating nature of the tumour; and the diagnosis of (PNET) was confirmed after the histological and immunohistochemical study. The extension assessment was negative and the patient had an amputation of the second and third rays of the right hand. Four years afterwards, the patient showed no recurrence or metastases.

  2. On the nature of pre-freeze mortality in insects: water balance, ion homeostasis and energy charge in the adults of Pyrrhocoris apterus.

    PubMed

    Kostál, V; Vambera, J; Bastl, J

    2004-04-01

    Three acclimation groups [i.e. non-diapause (LD), diapause (SD) and diapause, cold-acclimated (SDA)] of the adult bugs Pyrrhocoris apterus differed markedly in their levels of chill tolerance. Survival time at a sub-zero, but non-freezing, temperature of -5 degrees C (Lt50) extended from 7.6 days, through 35.6 days, to >60 days in the LD, SD and SDA insects, respectively. The time necessary for recovery after chill-coma increased linearly with the increasing time of exposure to -5 degrees C, and the steepness of the slope of linear regression decreased in the order LD>SD>SDA. The capacity to prevent/counteract leakage of Na(+) down the electrochemical gradient (from haemolymph to tissues) during the exposure to -5 degrees C increased in the order LD

  3. Efficient Cargo Delivery into Adult Brain Tissue Using Short Cell-Penetrating Peptides.

    PubMed

    Kizil, Caghan; Iltzsche, Anne; Thomas, Alvin Kuriakose; Bhattarai, Prabesh; Zhang, Yixin; Brand, Michael

    2015-01-01

    Zebrafish brains can regenerate lost neurons upon neurogenic activity of the radial glial progenitor cells (RGCs) that reside at the ventricular region. Understanding the molecular events underlying this ability is of great interest for translational studies of regenerative medicine. Therefore, functional analyses of gene function in RGCs and neurons are essential. Using cerebroventricular microinjection (CVMI), RGCs can be targeted efficiently but the penetration capacity of the injected molecules reduces dramatically in deeper parts of the brain tissue, such as the parenchymal regions that contain the neurons. In this report, we tested the penetration efficiency of five known cell-penetrating peptides (CPPs) and identified two- polyR and Trans - that efficiently penetrate the brain tissue without overt toxicity in a dose-dependent manner as determined by TUNEL staining and L-Plastin immunohistochemistry. We also found that polyR peptide can help carry plasmid DNA several cell diameters into the brain tissue after a series of coupling reactions using DBCO-PEG4-maleimide-based Michael's addition and azide-mediated copper-free click reaction. Combined with the advantages of CVMI, such as rapidness, reproducibility, and ability to be used in adult animals, CPPs improve the applicability of the CVMI technique to deeper parts of the central nervous system tissues.

  4. Efficient Cargo Delivery into Adult Brain Tissue Using Short Cell-Penetrating Peptides

    PubMed Central

    Thomas, Alvin Kuriakose; Bhattarai, Prabesh; Zhang, Yixin; Brand, Michael

    2015-01-01

    Zebrafish brains can regenerate lost neurons upon neurogenic activity of the radial glial progenitor cells (RGCs) that reside at the ventricular region. Understanding the molecular events underlying this ability is of great interest for translational studies of regenerative medicine. Therefore, functional analyses of gene function in RGCs and neurons are essential. Using cerebroventricular microinjection (CVMI), RGCs can be targeted efficiently but the penetration capacity of the injected molecules reduces dramatically in deeper parts of the brain tissue, such as the parenchymal regions that contain the neurons. In this report, we tested the penetration efficiency of five known cell-penetrating peptides (CPPs) and identified two– polyR and Trans – that efficiently penetrate the brain tissue without overt toxicity in a dose-dependent manner as determined by TUNEL staining and L-Plastin immunohistochemistry. We also found that polyR peptide can help carry plasmid DNA several cell diameters into the brain tissue after a series of coupling reactions using DBCO-PEG4-maleimide-based Michael’s addition and azide-mediated copper-free click reaction. Combined with the advantages of CVMI, such as rapidness, reproducibility, and ability to be used in adult animals, CPPs improve the applicability of the CVMI technique to deeper parts of the central nervous system tissues. PMID:25894337

  5. A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues.

    PubMed

    Ratajczak, M Z; Machalinski, B; Wojakowski, W; Ratajczak, J; Kucia, M

    2007-05-01

    Accumulating evidence demonstrates that adult tissues contain a population of stem cells that express early developmental markers such as stage-specific embryonic antigen and transcription factors Oct-4 and Nanog. These are the markers characteristic for embryonic stem cells, epiblast stem cells and primordial germ cells. The presence of these stem cells in adult tissues including bone marrow, epidermis, bronchial epithelium, myocardium, pancreas and testes supports the concept that adult tissues contain some population of pluripotent stem cells that is deposited in embryogenesis during early gastrulation. In this review we will discuss these data and present a hypothesis that these cells could be direct descendants of the germ lineage. The germ lineage in order to pass genes on to the next generations creates soma and thus becomes a 'mother lineage' for all somatic cell lineages present in the adult body.

  6. Effect of Anti-Sclerostin Therapy and Osteogenesis Imperfecta on Tissue-level Properties in Growing and Adult Mice While Controlling for Tissue Age

    PubMed Central

    Sinder, Benjamin P.; Lloyd, William R.; Salemi, Joseph D.; Marini, Joan C.; Caird, Michelle S.; Morris, Michael D.; Kozloff, Kenneth M.

    2016-01-01

    Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as Osteogenesis Imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly→Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5 weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2–4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages >3wk) and rapidly growing Brtl/+ (at tissue ages > 4wk) mice compared to WT. At identical tissue ages defined by fluorescent labels adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age

  7. Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age.

    PubMed

    Sinder, Benjamin P; Lloyd, William R; Salemi, Joseph D; Marini, Joan C; Caird, Michelle S; Morris, Michael D; Kozloff, Kenneth M

    2016-03-01

    Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly➔Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and

  8. Variations of midline facial soft tissue thicknesses among three skeletal classes in Central Anatolian adults.

    PubMed

    Gungor, Kahraman; Bulut, Ozgur; Hizliol, Ismail; Hekimoglu, Baki; Gurcan, Safa

    2015-11-01

    Facial reconstruction is a technique employed in a forensic investigation as a last resort to recreate an individual's facial appearance from his/her skull. Forensic anthropologists or artists use facial soft tissue thickness (FSTT) measurements as a guide in facial reconstructions. The aim of this study was to develop FSTT values for Central Anatolian adults, taking into consideration sex and skeletal classes; first, to achieve better results obtaining the likenesses of deceased individuals in two or three-dimensional forensic facial reconstructions and, second, to compare these values to existing databases. Lateral cephalograms were used to determine FSTT values at 10 midline facial landmarks of 167 adults. Descriptive statistics were calculated for these facial soft tissue thickness values, and these values were compared to those reported in two other comparable databases. The majority of the landmarks showed sex-based differences. Males were found to have significantly larger landmark values than female subjects. These results point not only to the necessity to present data in accordance with sexual dimorphism, but also the need to consider that individuals from different geographical areas have unique facial features and that, as a result, geographical population-specific FSTT values are required.

  9. Differences in tissue distribution of HBCD alpha and gamma between adult and developing mice.

    PubMed

    Szabo, David T; Diliberto, Janet J; Huwe, Janice K; Birnbaum, Linda S

    2011-09-01

    Hexabromocyclododecane (HBCD) is a mixture of three stereoisomers alpha (α), beta (β), and gamma (γ). γ-HBCD dominates the mixture (∼70%), and despite α-HBCD's minor contribution to global HBCD production and usage (∼10%), it is the dominant congener found in most biotic samples worldwide. Evidence of toxicity and lack of stereoisomer studies drives the importance of understanding HBCD toxicokinetics in potentially susceptible populations. The majority of public health concern has focused on hazardous effects resulting from exposure of infants and young children to HBCD due to reports on adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to HBCD. This study was designed to investigate differences in the disposition of both γ-HBCD and α-HBCD in infantile mice reported to be susceptible to the HBCD commercial mixture. The tissue distribution of α-[(14)C]HBCD- and γ-[(14)C]HBCD-derived radioactivity was monitored in C57BL/6 mice following a single oral dose of either compound (3 mg/kg) after direct gavage at postnatal day 10. Mice were held up to 7 days in shoebox cages after which pups were sacrificed, tissue collected, and internal dosimetry was measured. Developing mice exposed to α-HBCD had an overall higher body burden than γ-HBCD at every time point measured; at 4 days postexposure, they retained 22% of the α-HBCD administered dose, whereas pups exposed to γ-HBCD retained 10%. Total body burden in infantile mice after exposure to γ-HBCD was increased 10-fold as compared with adults. Similarly, after exposure to α-HBCD, infantile mice contained 2.5-fold higher levels than adult. These differences lead to higher concentrations of the HBCD diastereomers at target tissues during critical windows of development. The results indicate that the toxicokinetics of the two HBCD diastereomers differ between developing and adult mice

  10. Organ and tissue donation: a survey of nurse's knowledge and educational needs in an adult ITU.

    PubMed

    Collins, Timothy J

    2005-08-01

    The aim of this paper is to present the results of a survey that was undertaken to assess nurses' knowledge and educational needs towards organ donation within one adult general intensive care unit. The survey consists of 31 registered nurses who completed a confidential questionnaire that aimed to assess their existing knowledge and deficits in organ and tissue donation. The survey highlights the sample lacked confidence in approaching relatives for donation consent, deficits in brain stem death testing and donor criteria. It was also apparent that a significant number of nurses could not identify which tissues can be donated and the contraindications for tissue donation. A majority of the sample stated their knowledge of donation issues would improve if an educational programme were developed on organ donation. This is further supported by previous work by [Bidigare S, Oermann M, 1991. Attitudes and knowledge of nurses regarding organ procurement. Heart & lung 1:20-3; Smith-Brew S, Yanai L, 1996. The organ donation process through a review of the literature. Part 1. Accident & emergency nursing 4:5-11; Roark D, 2000. Overhauling the organ donation system. Am J Nurs 6:44-9] who suggest that educational programmes covering donation issues should enhance nurses' knowledge and confidence in the organ donation process and ultimately increase the number of potential donors.

  11. SpSM30 gene family expression patterns in embryonic and adult biomineralized tissues of the sea urchin, Strongylocentrotus purpuratus.

    PubMed

    Killian, Christopher E; Croker, Lindsay; Wilt, Fred H

    2010-01-01

    The SpSM30 gene family of the sea urchin, Strongylocentrotus purpuratus, is comprised of six members, designated SpSM30A through SpSM30F (Livingston et al., 2006). The SpSM30 proteins are found uniquely in embryonic and adult mineralized tissues of the sea urchin. Previous studies have revealed that SpSM30 proteins are occluded within the embryonic endoskeleton and adult mineralized tissues (Killian and Wilt, 1996; Mann et al., 2008a,b; Urry et al., 2000). Furthermore, some of the SpSM30 proteins are among the most abundant of the approximately four-dozen integral matrix proteins of the larval spicule (Killian and Wilt, 1996). The amino acid sequence, protein domain architecture, and contiguity within the genome strongly support the supposition that the six genes constitute a gene family. Reverse transcription-polymerase chain reaction (RT-PCR) is used in the present study to describe the time course of expression of the family members during embryonic development, and their expression in adult tissues. SpSM30A, B, C and E are expressed, albeit at different levels, during overt spicule deposition in the embryo with some differences in the precise timing of expression. SpSM30D is not expressed in the embryo, and SpSM30F is expressed transiently and at low levels just prior to overt spicule formation. Whole mount in situ hybridization studies show that SpSM30A, B, C, and E are expressed exclusively in primary mesenchyme (PMC) cells and their descendants. In addition, tissue fractionation studies indicate that SpSM30F expression is highly enriched in PMCs. Each adult tissue examined expresses a different cohort of the SpSM30 family members at varying levels: SpSM30A mRNA is not expressed in adult tissues. Its expression is limited to the embryo. Conversely, SpSM30D mRNA is not expressed in the embryo, but is expressed in adult spines and teeth. SpSM30B and SpSM30C are expressed at modest levels in all mineralized adult tissues; SpSM30E is expressed highly in tooth and

  12. From the Cover: Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells

    NASA Astrophysics Data System (ADS)

    Sapir, Tamar; Shternhall, Keren; Meivar-Levy, Irit; Blumenfeld, Tamar; Cohen, Hamutal; Skutelsky, Ehud; Eventov-Friedman, Smadar; Barshack, Iris; Goldberg, Iris; Pri-Chen, Sarah; Ben-Dor, Lya; Polak-Charcon, Sylvie; Karasik, Avraham; Shimon, Ilan; Mor, Eytan; Ferber, Sarah

    2005-05-01

    Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue. pancreas | transdifferentiation

  13. Adult stem cells, scaffolds for in vivo and in vitro myocardial tissue engineering.

    PubMed

    Di Felice, Valentina; De Luca, Angela; Serradifalco, Claudia; Di Marco, Patrizia; Verin, Lucia; Motta, Antonella; Guercio, Annalisa; Zummo, Giovanni

    2010-01-01

    The main goal in the last few years in cardiac research has been to isolate cardiac potential stem cells from adult myocardium and to demonstrate their differentiation potential. We have previously demonstrated that c-Kit positive cardiac stem cells are able to organize themselves into a tissue-like cell mass. In this 3D mass, they can produce a high concentration of natural extracellular matrix, can create vessels, a capsule and, with the help of an Open-pore Polylactic Acid scaffold, many cells can organize an elementary myocardium. Drawing from this background, we decided to design and use poly-lactic scaffolds and the model of the athymic Nude-Foxn1(nu) mouse to evaluate the extent of the myogenic vs endothelial differentiation in vivo, and to evaluate the presence or the absence of a foreign body reaction.

  14. The sequential tissue distribution of duck Tembusu virus in adult ducks.

    PubMed

    Wu, Li; Liu, Jinxiong; Chen, Pucheng; Jiang, Yongping; Ding, Leilei; Lin, Yuan; Li, Qimeng; He, Xijun; Chen, Qiusheng; Chen, Hualan

    2014-01-01

    In 2010, a novel Tembusu virus (TMUV) that caused a severe decrease in the egg production of ducks was isolated in southeast China. Given the novelty of this duck pathogen, little information is available regarding its pathogenesis. Here, we systematically investigated the replication kinetics of TMUV PTD2010 in adult male and female ducks. We found that PTD2010 was detectable in most of the parenchymatous organs as well as the oviduct and intestinal tract from days 1 to 7 after inoculation. Viral titers were maintained at high levels for at least 9 days in the spleen, kidney, bursa of Fabricius, brain, and ovary. No virus was detected in any of these organs or tissues at 18 days after inoculation. PTD2010, thus, causes systemic infections in male and female ducks; its replication kinetics show similar patterns in most organs, with the exception of the ovaries and testes.

  15. Transcription levels of sirtuin family in neural stem cells and brain tissues of adult mice.

    PubMed

    Wang, H F; Li, Q; Feng, R L; Wen, T Q

    2012-09-10

    Neural stem cells (NSCs) has been used as a well-known model to investigate apoptosis, differentiation, maintenance of stem cells status, and therapy of neurological disease. The C17.2 NSCs line was produced after v-myc transformation of neural progenitor from mouse cerebellar cortex. Sirtuin family plays important roles involved in neuronal differentiation, genomic stability, lifespan, cell survival. However, little is known about gene expression variation of sirtuin family in C17.2 NSCs, primary NSCs, and different brain tissues in adult mice. Here, we confirmed that the mRNA expression levels of sirt2, 3, 4, 5, and 7 in E14.5 NSCs were significantly higher than in C17.2 NSCs, whereas that sirt 6 displayed an opposing mode. Moreover, a higher mRNA level of sirtuin family was observed in the adult mouse brain compared to C17.2 NSCs. In addition, histone deacetylase (HDAC) inhibitors nicotinamide and Trichostatin A (TSA) were used to explore differential changes at the transcriptional level of sirtuins. Results indicated that the expression of sirt1, sirt5 and sirt6 was significant downregulated by nicotinamide treatment. Whereas, a significant downregulation in sirt1 and sirt3 and a significant upregulation in sirt2, sirt4, sirt6, and sirt7 were observed in the treatment of TSA. Thus our studies indicate different sirtuin mRNA expression profiles between C17.2 NSCs, E14.5 NSCs and brain tissues, suggesting the transcriptional regulation of sirtuin family could be mediated by different histone acetylation.

  16. Microscopic comparative study of the exposure effects of testosterone cypionate and ethinylestradiol during prenatal life on the prostatic tissue of adult gerbils.

    PubMed

    Perez, Ana P S; Biancardi, Manoel F; Vilamaior, Patricia S L; Góes, Rejane M; Santos, Fernanda C A; Taboga, Sebastião R

    2012-08-01

    There is an increasing variety of endocrine disrupting chemicals (EDCs) either with (anti)estrogenic or (anti)androgenic potential widely present in the environment. These xenosteroids may mimic endogenous steroid hormones disrupting the homeostasis of physiological pathways and leading to several disturbances, especially in tissues highly dependent on steroid hormones such as the prostate. Taking this into account, this comparative study aimed to verify the potential of ethinylestradiol (EE) and testosterone acting as ECDs on the prostate of both male and female adult gerbils exposed to these agents during the embryonic phase. Consequently, pregnant gerbils were treated either with 10 μg/kg/day of EE or with a single dose of 1 mg of testosterone cypionate. The pups that were born 6-8 days after testosterone exposure and the pups that were born after 3 days of EE exposure were allowed to grow but were sacrificed within 4 months. Serological, morphological, stereological, and immunohistochemical analyses were used. Overall, the results showed that both sexes exposed to testosterone and EE during gestation had a prostatic gland with an increased stromal and epithelial and a reduced luminal compartment. Moreover, we observed that glands affected with prostatic intraepithelial neoplasia showed intense stromal reshuffling. In conclusion, although these alterations were observed in both sexes, more relevant to this study was the differential responsiveness of males and females exposed to these different drugs. Whereas the EE affected males more, the testosterone was more harmful to the females.

  17. Targeted therapy for soft tissue sarcomas in adolescents and young adults

    PubMed Central

    Steppan, Diana A; Pratilas, Christine A; Loeb, David M

    2017-01-01

    Soft tissue sarcomas (STSs) are a heterogeneous group of tumors originating from the mesenchyme. Even though they affect individuals in all age groups, the prevalence of subtypes of STSs changes significantly from childhood through adolescence into adulthood. The mainstay of therapy is surgery, with or without the addition of chemotherapy and/or radiation therapy. These treatment modalities are associated, in many cases, with significant morbidity and, given the heterogeneity of tumor histologies encompassed by the term “STS”, have not uniformly improved outcomes. Moreover, some subgroups of STSs appear to be more, and others less, responsive to conventional chemotherapy agents. Over the last two decades, our understanding of the biology of STSs is slowly increasing, allowing for the development of more targeted therapies. We review the new treatment modalities that have been tested on patients with STSs, with a special focus on adolescents and young adults, a group of patients that is often underrepresented in clinical trials and has not received the dedicated attention it deserves, given the significant differences in biology and treatment response in comparison to children and adults.

  18. Growth hormone (GH) differentially regulates NF-kB activity in preadipocytes and macrophages: implications for GH's role in adipose tissue homeostasis in obesity.

    PubMed

    Kumar, P Anil; Chitra, P Swathi; Lu, Chunxia; Sobhanaditya, J; Menon, Ram

    2014-06-01

    Adipose tissue remodeling in obesity involves macrophage infiltration and chronic inflammation. NF-kB-mediated chronic inflammation of the adipose tissue is directly implicated in obesity-associated insulin resistance. We have investigated the effect of growth hormone (GH) on NF-kB activity in preadipocytes (3T3-F442A) and macrophages (J774A.1). Our studies indicate that whereas GH increases NF-kB activity in preadipocytes, it decreases NF-kB activity in macrophages. This differential response of NF-kB activity to GH correlates with the GH-dependent expression of a cadre of NF-kB-activated cytokines in these two cell types. Activation of NF-kB by GH in preadipocytes heightens inflammatory response by stimulating production of multiple cytokines including TNF-α, IL-6, and MCP-1, the mediators of both local and systemic insulin resistance and chemokines that recruit macrophages. Our studies also suggest differential regulation of miR132 and SIRT1 expression as a mechanism underlying the observed variance in GH-dependent NF-kB activity and altered cytokine profile in preadipocytes and macrophages. These findings further our understanding of the complex actions of GH on adipocytes and insulin sensitivity.

  19. Isolation of pluripotent neural crest-derived stem cells from adult human tissues by connexin-43 enrichment.

    PubMed

    Pelaez, Daniel; Huang, Chun-Yuh Charles; Cheung, Herman S

    2013-11-01

    Identification and isolation of pluripotent stem cells in adult tissues represent an important advancement in the fields of stem cell biology and regenerative medicine. For several years, research has been performed on the identification of biomarkers that can isolate stem cells residing in neural crest (NC)-derived adult tissues. The NC is considered a good model in stem cell biology as cells from it migrate extensively and contribute to the formation of diverse tissues in the body during organogenesis. Migration of these cells is modulated, in part, by gap junction communication among the cell sheets. Here we present a study in which, selection of connexin 43 (Cx43) expressing cells from human adult periodontal ligament yields a novel pluripotent stem cell population. Cx43⁺ periodontal ligament stem cells express pluripotency-associated transcription factors OCT4, Nanog, and Sox2, as well as NC-specific markers Sox10, p75, and Nestin. When injected in vivo into an immunodeficient mouse model, these cells were capable of generating teratomas with tissues from the three embryological germ layers: endoderm, mesoderm, and ectoderm. Furthermore, the cells formed mature structures of tissues normally arising from the NC during embryogenesis such as eccrine sweat glands of the human skin, muscle, neuronal tissues, cartilage, and bone. Immunohistochemical analysis confirmed the human origin of the neoplastic cells as well as the ectodermal and endodermal nature of some of the structures found in the tumors. These results suggest that Cx43 may be used as a biomarker to select and isolate the remnant NC pluripotent stem cells from adult human tissues arising from this embryological structure. The isolation of these cells through routine medical procedures such as wisdom teeth extraction further enhances their applicability to the regenerative medicine field.

  20. Ex-Vivo Tissues Engineering Modeling for Reconstructive Surgery Using Human Adult Adipose Stem Cells and Polymeric Nanostructured Matrix

    PubMed Central

    Morena, Francesco; Argentati, Chiara; Calzoni, Eleonora; Cordellini, Marino; Emiliani, Carla; D’Angelo, Francesco; Martino, Sabata

    2016-01-01

    The major challenge for stem cell translation regenerative medicine is the regeneration of damaged tissues by creating biological substitutes capable of recapitulating the missing function in the recipient host. Therefore, the current paradigm of tissue engineering strategies is the combination of a selected stem cell type, based on their capability to differentiate toward committed cell lineages, and a biomaterial, that, due to own characteristics (e.g., chemical, electric, mechanical property, nano-topography, and nanostructured molecular components), could serve as active scaffold to generate a bio-hybrid tissue/organ. Thus, effort has been made on the generation of in vitro tissue engineering modeling. Here, we present an in vitro model where human adipose stem cells isolated from lipoaspirate adipose tissue and breast adipose tissue, cultured on polymeric INTEGRA® Meshed Bilayer Wound Matrix (selected based on conventional clinical applications) are evaluated for their potential application for reconstructive surgery toward bone and adipose tissue. We demonstrated that human adipose stem cells isolated from lipoaspirate and breast tissue have similar stemness properties and are suitable for tissue engineering applications. Finally, the overall results highlighted lipoaspirate adipose tissue as a good source for the generation of adult adipose stem cells.

  1. Negative elongation factor controls energy homeostasis in cardiomyocytes.

    PubMed

    Pan, Haihui; Qin, Kunhua; Guo, Zhanyong; Ma, Yonggang; April, Craig; Gao, Xiaoli; Andrews, Thomas G; Bokov, Alex; Zhang, Jianhua; Chen, Yidong; Weintraub, Susan T; Fan, Jian-Bing; Wang, Degeng; Hu, Yanfen; Aune, Gregory J; Lindsey, Merry L; Li, Rong

    2014-04-10

    Negative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptor α (PPARα), a master regulator of energy metabolism in the myocardium. Mechanistically, NELF helps stabilize the transcription initiation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPARα-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes.

  2. A Digital Gene Expression-Based Bovine Gene Atlas Evaluating 92 Adult, Juvenile and Fetal Cattle Tissues

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A comprehensive transcriptome survey, or “Gene Atlas,” provides information essential for a complete understanding of the genomic biology of an organism. Using a digital gene expression approach, we developed a Gene Atlas of RNA abundance in 92 adult, juvenile and fetal cattle tissues. The samples...

  3. Facial soft tissue thickness among various vertical facial patterns in adult Pakistani subjects.

    PubMed

    Jeelani, Waqar; Fida, Mubassar; Shaikh, Attiya

    2015-12-01

    Facial reconstruction techniques are used to obtain an approximation of an individual's appearance thus helping identification of unidentified decedents from their dried skeletal remains. Many of these techniques rely on the sets of average facial soft tissue thickness (FST) values at different anatomical landmarks provided by the previous studies. FST is influenced by the age, sex, ethnicity and the body mass index of the individual. Recent literature has shown that the anthropological variations of the skull may also affect FST at certain points. This study was designed to evaluate the effect of such variations in vertical skull morphology on FST as around one third of different population groups have either a long or short facial pattern as compared to the average facial pattern. Moreover, this study also provides a FST database for the adult Pakistani subjects that may have potential implications in the facial reconstruction of the local subjects. A retrospective analysis of 276 lateral cephalograms of adult subjects having normal sagittal facial pattern was performed. Subjects were categorized into three vertical facial patterns (long face=95, average face=102, short face=79) according to the vertical dimensions of the skull and the FST was measured at 11 midline points. To compare the FST between males and females Mann-Whitney U test was used. Kruskal-Wallis test was applied to compare FST among three vertical facial patterns. The results of our study revealed significant differences in FST at nine landmarks between males and females. These sex-based differences were more pronounced in the long and short facial patterns as compared to the average facial pattern. FST at stomion, pogonion, gnathion and menton was significantly greater in the short facial pattern as compared to the long facial pattern in both the sexes. The results of the present study highlight the importance of anthropological analysis of the skull and taking the vertical skeletal dimension

  4. THE PROS AND CONS OF APOPTOSIS ASSAYS FOR USE IN THE STUDY OF CELLS, TISSUES AND ORGANS

    EPA Science Inventory

    Abstract
    Programmed cell death or apoptosis occurs in many tissues during normal development and in the normal homeostasis of adult tissues. Apoptosis also plays a significant role in abnormal development and disease. Increased interest in apoptosis and cell death in general...

  5. Adjuvant Radiotherapy for Pediatric and Young Adult Nonrhabdomyosarcoma Soft-Tissue Sarcoma

    SciTech Connect

    Smith, Kristy B.; Indelicato, Daniel J.; Knapik, Jacquelyn A.; Lagmay, Joanne P.; Morris, Christopher; Kirwan, Jessica M.; Zlotecki, Robert A.; Scarborough, Mark T.; Gibbs, C. Parker; Marcus, Robert B.

    2011-09-01

    Purpose: To evaluate the prognostic factors, outcomes, and complications in patients aged {<=}30 years with resectable nonrhabdomyosarcoma soft-tissue sarcoma treated at the University of Florida with radiotherapy (RT) during a 34-year period. Methods and Materials: A total of 95 pediatric or young adult patients with nonrhabdomyosarcoma soft-tissue sarcoma were treated with curative intent with surgery and RT at the University of Florida between 1973 and 2007. The most common histologic tumor subtypes were synovial sarcoma in 22 patients, malignant fibrous histiocytoma in 19, and malignant peripheral nerve sheath tumor in 11 patients. The mean age at RT was 22 years (range, 6-30). Of the 95 patients, 73 had high-grade tumors; 45 had undergone preoperative RT and 50 postoperative RT. The prognostic factors for survival, local recurrence, and distant recurrence were analyzed. Results: The median follow-up was 7.2 years (range, 0.4-30.5). The actuarial 5-year local control rate was 88%. A microscopically negative margin was associated with superior local control. Although 83% of local recurrence cases initially developed in the absence of metastases, all patients with local failure ultimately died of their disease. The actuarial estimate of 5-year overall survival and disease-free survival was 65% and 63%, respectively. Of all the deaths, 92% were disease related. An early American Joint Committee on Cancer stage, tumor <8 cm, and the absence of neurovascular invasion were associated with superior disease-free survival. The National Cancer Institute Common Toxicity Criteria, version 3, Grade 3-4 treatment complication rate was 9%. No secondary malignancies were observed. Conclusion: In the present large single-institution study, we found positive margins and locally advanced features to be poor prognostic factors for both local progression and survival. The results from the present study have helped to characterize the therapeutic ratio of RT in pediatric and young

  6. Subcutaneous adipose tissue from obese and lean adults does not release hepcidin, in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hepcidin is a small peptide that functions as the both the main regulator of systemic iron homeostasis, and as the link between host defense and iron metabolism. Elevated hepcidin is associated with reduced iron bioavailability, while low hepcidin concentrations are associated with increased dietary...

  7. Metabolically distinct weight loss by 10,12 CLA and caloric restriction highlight the importance of subcutaneous white adipose tissue for glucose homeostasis in mice

    PubMed Central

    Wang, Shari; Goodspeed, Leela; Wietecha, Tomasz; Houston, Barbara; Omer, Mohamed; Ogimoto, Kayoko; Subramanian, Savitha; Gowda, G. A. Nagana; O’Brien, Kevin D.; Kaiyala, Karl J.; Morton, Gregory J.; Chait, Alan

    2017-01-01

    Background Widely used as a weight loss supplement, trans-10,cis-12 conjugated linoleic acid (10,12 CLA) promotes fat loss in obese mice and humans, but has also been associated with insulin resistance. Objective We therefore sought to directly compare weight loss by 10,12 CLA versus caloric restriction (CR, 15–25%), an acceptable healthy method of weight loss, to determine how 10,12 CLA-mediated weight loss fails to improve glucose metabolism. Methods Obese mice with characteristics of human metabolic syndrome were either supplemented with 10,12 CLA or subjected to CR to promote weight loss. Metabolic endpoints such as energy expenditure, glucose and insulin tolerance testing, and trunk fat distribution were measured. Results By design, 10,12 CLA and CR caused equivalent weight loss, with greater fat loss by 10,12 CLA accompanied by increased energy expenditure, reduced respiratory quotient, increased fat oxidation, accumulation of alternatively activated macrophages, and browning of subcutaneous white adipose tissue (WAT). Moreover, 10,12 CLA-supplemented mice better defended their body temperature against a cold challenge. However, 10,12 CLA concurrently induced the detrimental loss of subcutaneous WAT without reducing visceral WAT, promoted reduced plasma and WAT adipokine levels, worsened hepatic steatosis, and failed to improve glucose metabolism. Obese mice undergoing CR were protected from subcutaneous-specific fat loss, had improved hepatic steatosis, and subsequently showed the expected improvements in WAT adipokines, glucose metabolism and WAT inflammation. Conclusions These results suggest that 10,12 CLA mediates the preferential loss of subcutaneous fat that likely contributes to hepatic steatosis and maintained insulin resistance, despite significant weight loss and WAT browning in mice. Collectively, we have shown that weight loss due to 10,12 CLA supplementation or CR results in dramatically different metabolic phenotypes, with the latter

  8. Oxygen Sensing and Homeostasis

    PubMed Central

    Semenza, Gregg L.

    2015-01-01

    The discovery of carotid bodies as sensory receptors for detecting arterial blood oxygen levels, and the identification and elucidation of the roles of hypoxia-inducible factors (HIFs) in oxygen homeostasis have propelled the field of oxygen biology. This review highlights the gas-messenger signaling mechanisms associated with oxygen sensing, as well as transcriptional and non-transcriptional mechanisms underlying the maintenance of oxygen homeostasis by HIFs and their relevance to physiology and pathology. PMID:26328879

  9. A case of adult Langerhans cell histiocytosis showing successfully regenerated osseous tissue of the skull after chemotherapy.

    PubMed

    Suzuki, Takahiro; Izutsu, Koji; Kako, Shinichi; Ohta, Satoshi; Hangaishi, Akira; Kanda, Yoshinobu; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2008-04-01

    Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells and extremely rare in adults. Adult LCH is often associated with osteolytic bone lesions, but large bone-defective lesions have been rarely reported. We report an adult case of LCH accompanied by large osteolytic lesions in the skull that successfully responded to chemotherapy. A 47-year-old woman with LCH who had multiple, large osteolytic areas of more than 3 cm in diameter in the skull was admitted to our hospital. She was treated with systemic chemotherapy consisting of prednisolone, vinblastine, and 6-mercaptopurine. Twelve months later, when she completed the treatment, osteolytic areas were covered with hard osseous tissue, and X-ray examination confirmed regeneration of the bone. This case indicates that chemotherapy can be effective even for the treatment of large osteolytic lesions in adult LCH patients.

  10. A mystery unraveled: nontumorigenic pluripotent stem cells in human adult tissues

    PubMed Central

    Simerman, Ariel A; Perone, Marcelo J; Gimeno, María L; Dumesic, Daniel A; Chazenbalk, Gregorio D

    2014-01-01

    Introduction: Embryonic stem cells and induced pluripotent stem cells have emerged as the gold standard of pluripotent stem cells and the class of stem cell with the highest potential for contribution to regenerative and therapeutic application; however, their translational use is often impeded by teratoma formation, commonly associated with pluripotency. We discuss a population of nontumorigenic pluripotent stem cells, termed Multilineage Differentiating Stress Enduring (Muse) cells, which offer an innovative and exciting avenue of exploration for the potential treatment of various human diseases. Areas covered: This review discusses the origin of Muse cells, describes in detail their various unique characteristics, and considers future avenues of their application and investigation with respect to what is currently known of adult pluripotent stem cells in scientific literature. We begin by defining cell potency, then discuss both mesenchymal and various reported populations of pluripotent stem cells, and finally delve into Muse cells and the characteristics that set them apart from their contemporaries. Expert opinion: Muse cells derived from adipose tissue (Muse-AT) are efficiently, routinely and painlessly isolated from human lipoaspirate material, exhibit tripoblastic differentiation both spontaneously and under media-specific induction, and do not form teratomas. We describe qualities specific to Muse-AT cells and their potential impact on the field of regenerative medicine and cell therapy. PMID:24745973

  11. Cloning and study of adult-tissue-specific expression of Sox9 in Cyprinus carpio.

    PubMed

    Du, Qi-Yan; Wang, Feng-Yu; Hua, Hui-Ying; Chang, Zhong-Jie

    2007-08-01

    The Sox9 gene is one of the important transcription factors in the development of many tissues and organs, particularly in sex determination and chondrogenesis. We amplified the genomic DNA of Cyprinus carpio using degenerate primers, and found that there were two versions of Sox9 in this species: Sox9a and Sox9b, that differ in having an intron of different length (704 bp and 616 bp, respectively) in the conserved HMG box region that codes for identical amino acid sequences. We used a two-phase rapid amplification of cDNA ends (RACE) for the isolation of full-length cDNA of Sox9b. Sequence analyses revealed a 2447-bp cDNA containing 233-bp 5' untranslated region, a 927-bp 3' untranslated region, including poly(A), and a 1287 bp open reading frame (ORF) encoding a protein of 428 amino acids. The HMG box of 79 amino acid motif was confirmed from positions 96-174. Sequence alignment showed that the identity of amino acids of Sox9 among ten animal species, including C. carpio, is 75%, indicating that the Sox9 gene is evolutionarily quite conserved. The expression level of Sox9b gene varied among several organs of adult C. carpio, with the level of expression being highest in the brain and testis.

  12. Polyamines and Gut Mucosal Homeostasis

    PubMed Central

    Timmons, Jennifer; Chang, Elizabeth T.; Wang, Jian-Ying; Rao, Jaladanki N.

    2012-01-01

    The epithelium of gastrointestinal (GI) mucosa has the most rapid turnover rate of any tissue in the body and its integrity is preserved through the dynamic balance between cell migration, proliferation, growth arrest and apoptosis. To maintain tissue homeostasis of the GI mucosa, the rates of epithelial cell division and apoptosis must be highly regulated by various extracellular and intracellular factors including cellular polyamines. Natural polyamines spermidine, spermine and their precursor putrescine, are organic cations in eukaryotic cells and are implicated in the control of multiple signaling pathways and distinct cellular functions. Normal intestinal epithelial growth depends on the available supply of polyamines to the dividing cells in the crypts, and polyamines also regulate intestinal epithelial cell (IEC) apoptosis. Although the specific molecular processes controlled by polyamines remains to be fully defined, increasing evidence indicates that polyamines regulate intestinal epithelial integrity by modulating the expression of various growth-related genes. In this review, we will extrapolate the current state of scientific knowledge regarding the roles of polyamines in gut mucosal homeostasis and highlight progress in cellular and molecular mechanisms of polyamines and their potential clinical applications. PMID:25237589

  13. E-cadherin's role in development, tissue homeostasis and disease: Insights from mouse models: Tissue-specific inactivation of the adhesion protein E-cadherin in mice reveals its functions in health and disease.

    PubMed

    Schneider, Marlon R; Kolligs, Frank T

    2015-03-01

    Recent studies uncovered critical roles of the adhesion protein E-cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E-cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E-cadherin's functions beyond development, numerous mouse lines with tissue-specific disruption of Cdh1 have been generated. The consequences of E-cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of tissue structure and function. This review focuses on these studies and discusses how they provided important insights into E-cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial-to-mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research.

  14. The effect of type and amount of dietary carbohydrate on biomarkers of glucose homeostasis and C-reactive protein in overweight or obese adults: Results from the OmniCarb trial

    PubMed Central

    Juraschek, Stephen P; Miller, Edgar R; Selvin, Elizabeth; Carey, Vincent J; Appel, Lawrence J; Christenson, Robert H; Sacks, Frank M.

    2016-01-01

    OBJECTIVE The glycemic index (GI) of dietary carbohydrate is thought to affect glucose homeostasis. Recently, the OmniCarb Trial reported that a low GI diet did not improve insulin sensitivity. We conducted this ancillary study of the OmniCarb Trial to determine the effects of GI and carbohydrate content on glucose homeostasis and inflammation. RESEARCH DESIGN AND METHODS OmniCarb was a randomized crossover feeding study conducted in overweight or obese adults without diabetes (N=163). Participants were fed each of 4 diets for 5 weeks with 2-week washout periods. Weight was held constant. Diets were: high GI (GI≥65) with high carbohydrate (58% kcal), low GI (GI≤45) with low carbohydrate (40% kcal), low GI with high carbohydrate; and high GI with low carbohydrate. We measured glycated albumin (GA), fructosamine, and high sensitivity C-reactive protein (CRP) at baseline and following each dietary period. These biomarkers were compared within-person between diets. RESULTS The study population was 52% female and 50% black. Mean age was 53 (SD, 11) years; mean BMI was 32 (SD, 6) kg/m2. Reducing GI had no effect on GA or fructosamine, but increased fasting glucose in the setting of a high carbohydrate diet (+2.2 mg/dl; P=0.02). Reducing carbohydrate content decreased GA in the setting of a high GI diet (−0.2%; P=0.03) and decreased fructosamine in the setting of a low GI diet (−4 μmol/L; P=0.003). Reducing carbohydrate while simultaneously increasing GI significantly reduced both GA (−0.2%; P=0.04) and fructosamine (−4 μmol/L; P=0.009). Neither reducing GI nor amount of carbohydrate affected insulin or CRP. CONCLUSIONS Reducing carbohydrate, regardless of high or low GI, decreased GA and fructosamine. This suggests that reducing carbohydrate content, rather than GI, is a better strategy for lowering glycemia in adults at risk for diabetes. PMID:26636424

  15. Effect of type and amount of dietary carbohydrate on biomarkers of glucose homeostasis and C reactive protein in overweight or obese adults: results from the OmniCarb trial

    PubMed Central

    Juraschek, Stephen P; Miller, Edgar R; Selvin, Elizabeth; Carey, Vincent J; Appel, Lawrence J; Christenson, Robert H; Sacks, Frank M

    2016-01-01

    Objective The glycemic index (GI) of dietary carbohydrate is thought to affect glucose homeostasis. Recently, the Effect of Amount and Type of Dietary Carbohydrates on Risk for Cardiovascular Heart Disease and Diabetes Study (OmniCarb) trial reported that a low-GI diet did not improve insulin sensitivity. We conducted this ancillary study of the OmniCarb trial to determine the effects of GI and carbohydrate content on glucose homeostasis and inflammation. Research design and methods OmniCarb was a randomized cross-over feeding study conducted in overweight or obese adults without diabetes (N=163). Participants were fed each of 4 diets for 5 weeks with 2-week washout periods. Weight was held constant. Diets were: high GI (GI≥65) with high carbohydrate (58% kcal), low GI (GI≤45) with low carbohydrate (40% kcal), low GI with high carbohydrate, and high GI with low carbohydrate. We measured glycated albumin (GA), fructosamine, and high sensitivity C reactive protein (CRP) at baseline and following each dietary period. These biomarkers were compared within-person between diets. Results The study population was 52% female and 50% black. Mean age was 53 (SD, 11) years; mean body mass index was 32 (SD 6) kg/m2. Reducing GI had no effect on GA or fructosamine, but increased fasting glucose in the setting of a high-carbohydrate diet (+2.2 mg/dL; p=0.02). Reducing carbohydrate content decreased GA in the setting of a high-GI diet (−0.2%; p=0.03) and decreased fructosamine in the setting of a low-GI diet (−4 µmol/L; p=0.003). Reducing carbohydrate while simultaneously increasing GI significantly reduced both GA (−0.2%; p=0.04) and fructosamine (−4 µmol/L; p=0.009). Neither reducing GI nor amount of carbohydrate affected insulin or CRP. Conclusions Reducing carbohydrate, regardless of high or low GI, decreased GA and fructosamine. This suggests that reducing carbohydrate content, rather than GI, is a better strategy for lowering glycemia in adults at risk

  16. Blood spot-based measures of glucose homeostasis and diabetes prevalence in a nationally representative population of young U.S. adults

    PubMed Central

    Nguyen, Quynh C.; Whitsel, Eric A.; Tabor, Joyce W.; Cuthbertson, Carmen C.; Wener, Mark H.; Potter, Alan J.; Halpern, Carolyn T.; Killeya-Jones, Ley A; Hussey, Jon M.; Suchindran, Chirayath; Harris, Kathleen Mullan

    2014-01-01

    Purpose We investigated under-studied, biomarker-based diabetes among young U.S. adults, traditionally characterized by low cardiovascular disease risk. Methods We examined 15,701 participants aged 24–32 years at Wave IV of the National Longitudinal Study of Adolescent Health (Add Health, 2008). The study used innovative and relatively non-invasive methods to collect capillary whole blood via finger prick at in-home examinations in all fifty states. Results Assays of dried blood spots produced reliable and accurate values of HbA1c. Reliability was lower for fasting glucose and lowest for random glucose. Mean (standard deviation) HbA1c was 5.6% (0.8%). More than a quarter (27.4%) had HbA1c-defined pre-diabetes. HbA1c was highest in the black, non-Hispanic race/ethnic group; inversely associated with education; and more common among the overweight/obese, and physically inactive. The prevalence of diabetes defined by previous diagnosis or use of anti-diabetic medication was 2.9%. Further incorporating HbA1c and glucose values, the prevalence increased to 6.8%, and among these participants, 38.9% had a previous diagnosis of diabetes (i.e., aware). Among those aware, 37.6% were treated and 64.0% were controlled (i.e., HbA1c < 7%). Conclusions A contemporary cohort of young adults faces a historically high risk of diabetes but there is ample opportunity for early detection and intervention. PMID:25444890

  17. TRAF-4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissues.

    PubMed Central

    Krajewska, M.; Krajewski, S.; Zapata, J. M.; Van Arsdale, T.; Gascoyne, R. D.; Berern, K.; McFadden, D.; Shabaik, A.; Hugh, J.; Reynolds, A.; Clevenger, C. V.; Reed, J. C.

    1998-01-01

    TRAF-4 was discovered because of its expression in breast cancers and is a member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family of putative signal-transducing proteins. In vitro binding assays demonstrated that TRAF-4 interacts with the cytosolic domain of the lymphotoxin-beta receptor (LT beta R) and weakly with the p75 nerve growth factor receptor (NGFR) but not with TNFR1, TNFR2, Fas, or CD40. Immunofluorescence analysis of TRAF-4 in transfected cells demonstrated localization to cytosol but not nucleus. Immunohistochemical assays of normal human adult tissues revealed prominent cytosolic immunostaining in thymic epithelial cells and lymph node dendritic cells but not in lymphocytes or thymocytes, paralleling the reported patterns of LT beta R expression. The basal cell layer of most epithelia in the body was very strongly TRAF-4 immunopositive, including epidermis, nasopharynx, respiratory tract, salivary gland, and esophagus. Similar findings were obtained in 12- to 18-week human fetal tissue, indicating a highly restricted pattern of expression even during development in the mammary gland, epithelial cells of the terminal ducts were strongly TRAF-4 immunopositive whereas myoepithelial cells and most of the mammary epithelial cells lining the extralobular ducts were TRAF-4 immunonegative. Of 84 primary breast cancers evaluated, only 7 expressed TRAF-4. Ductal carcinoma in situ (DCIS) lesions were uniformly TRAF-4 immunonegative (n = 21). In the prostate, the basal cells were strongly immunostained for TRAF-4, whereas the secretory epithelial cells were TRAF-4 negative. Basal cells in prostate hypertrophy (n = 6) and prostatic intraepithelial neoplasia (PIN; n = 6) were strongly TRAF-4 positive, but none of the 32 primary and 16 metastatic prostate cancer specimens examined contained TRAF-4-positive malignant cells. Although also expressed in some types of mesenchymal cells, these findings suggest that TRAF-4 is a marker of normal

  18. The adult brain tissue response to hollow fiber membranes of varying surface architecture with or without cotransplanted cells

    NASA Astrophysics Data System (ADS)

    Zhang, Ning

    A variety of biomaterials have been chronically implanted into the central nervous system (CNS) for repair or therapeutic purposes. Regardless of the application, chronic implantation of materials into the CNS induces injury and elicits a wound healing response, eventually leading to the formation of a dense extracellular matrix (ECM)-rich scar tissue that is associated with the segregation of implanted materials from the surrounding normal tissue. Often this reaction results in impaired performance of indwelling CNS devices. In order to enhance the performance of biomaterial-based implantable devices in the CNS, this thesis investigated whether adult brain tissue response to implanted biomaterials could be manipulated by changing biomaterial surface properties or further by utilizing the biology of co-transplanted cells. Specifically, the adult rat brain tissue response to chronically implanted poly(acrylonitrile-vinylchloride) (PAN-PVC) hollow fiber membranes (HFMs) of varying surface architecture were examined temporally at 2, 4, and 12 weeks postimplantation. Significant differences were discovered in the brain tissue response to the PAN-PVC HFMs of varying surface architecture at 4 and 12 weeks. To extend this work, whether the soluble factors derived from a co-transplanted cellular component further affect the brain tissue response to an implanted HFM in a significant way was critically exploited. The cells used were astrocytes, whose ability to influence scar formation process following CNS injury by physical contact with the host tissue had been documented in the literature. Data indicated for the first time that astrocyte-derived soluble factors ameliorate the adult brain tissue reactivity toward HFM implants in an age-dependent manner. While immature astrocytes secreted soluble factors that suppressed the brain tissue reactivity around the implants, mature astrocytes secreted factors that enhanced the gliotic response. These findings prove the feasibility

  19. Sterol Regulation of Metabolism, Homeostasis and Development

    PubMed Central

    Wollam, Joshua; Antebi, Adam

    2014-01-01

    Sterol metabolites are critical signaling molecules that regulate metabolism, development, and homeostasis. Oxysterols, bile acids, and steroids work primarily through cognate sterol-responsive nuclear hormone receptors to control these processes through feed-forward and feedback mechanisms. These signaling pathways are conserved from simple invertebrates to mammals. Indeed, results from various model organisms have yielded fundamental insights into cholesterol and bile acid homeostasis, lipid and glucose metabolism, protective mechanisms, tissue differentiation, development, reproduction, and even aging. Here, we review how sterols act through evolutionarily ancient mechanisms to control these processes. PMID:21495846

  20. The Histone Methyltransferase Ash1l is Required for Epidermal Homeostasis in Mice

    PubMed Central

    Li, Gang; Ye, Zhisheng; Shi, Cheng; Sun, Ling; Han, Min; Zhuang, Yuan; Xu, Tian; Zhao, Shimin; Wu, Xiaohui

    2017-01-01

    Epidermal homeostasis under normal and healing conditions are critical for the physical and functional maintenance of the skin barrier. It requires a proper balance between keratinocyte proliferation and differentiation under genetic and epigenetic regulations. Here we show that mice carrying a hypomorphic mutation of the histone methyltransferase Ash1l [(absent, small, or homeotic)-like (Drosophila)] develop epidermal hyperplasia and impaired epidermal stratification upon aging. In adult mutants, loss of Ash1l leads to more proliferative keratinocytes in disturbed differentiation stages. After wounding, Ash1l mutation leads to delayed re-epithlialization but increased keratinocyte proliferation at the wound edge. Elevated c-Myc expression could be observed in both aged and wounded mutant tissues. Taken together, these observations revealed an important role of the epigenetic regulator Ash1l in epidermal homeostasis. PMID:28374742

  1. Phosphate homeostasis and disorders.

    PubMed

    Manghat, P; Sodi, R; Swaminathan, R

    2014-11-01

    Recent studies of inherited disorders of phosphate metabolism have shed new light on the understanding of phosphate metabolism. Phosphate has important functions in the body and several mechanisms have evolved to regulate phosphate balance including vitamin D, parathyroid hormone and phosphatonins such as fibroblast growth factor-23 (FGF23). Disorders of phosphate homeostasis leading to hypo- and hyperphosphataemia are common and have clinical and biochemical consequences. Notably, recent studies have linked hyperphosphataemia with an increased risk of cardiovascular disease. This review outlines the recent advances in the understanding of phosphate homeostasis and describes the causes, investigation and management of hypo- and hyperphosphataemia.

  2. Dietary fat and carbohydrate have different effects on body weight, energy expenditure, glucose homeostasis and behaviour in adult cats fed to energy requirement.

    PubMed

    Gooding, Margaret A; Atkinson, Jim L; Duncan, Ian J H; Niel, Lee; Shoveller, Anna K

    2015-01-01

    The effects of dietary carbohydrate and fat on feline health are not well understood. The effects of feeding diets moderately high in fat (HF; n 10; 30 % fat, 26 % carbohydrate as fed) or carbohydrate (HC; n 10; 11 % fat, 47 % carbohydrate), for 84 d, were investigated in healthy, adult cats (3·5 (sd 0·5) years). Data on indirect calorimetry, blood biomarkers, activity, play and cognition were collected at baseline, and at intervals throughout the study. Body composition was measured by dual-energy X-ray absorptiometry at baseline and on day 85. There were no significant main effects of diet on body weight and composition. When data were analysed over study day within diet, cats fed HF diets experienced a significant increase in body fat (P = 0·001) and body weight (P = 0·043) in contrast to cats consuming the HC diet that experienced no change in body fat or body weight (P = 0·762) throughout the study. Overall, energy expenditure was similar between diets (P = 0·356 (fasted), P = 0·086 (postprandial)) and respiratory quotient declined with exposure to the HF diet and increased with exposure to the HC diet (P < 0·001; fasted and postprandial). There was no difference in insulin sensitivity as an overall effect of diet (P = 0·266). Activity declined from baseline with exposure to both diets (HC: P = 0·002; HF: P = 0·01) but was not different between diets (P = 0·247). There was no effect of diet on play (P = 0·387) and cats consuming either the HF or HC diet did not successfully learn the cognitive test. Overall, cats adapt to dietary macronutrient content, and the implications of feeding HC and HF diets on risk for adiposity as driven by metabolic and behavioural mechanisms are discussed.

  3. Iron homeostasis: new players, newer insights.

    PubMed

    Edison, Eunice S; Bajel, Ashish; Chandy, Mammen

    2008-12-01

    Although iron is a relatively abundant element in the universe, it is estimated that more than 2 billion people worldwide suffer from iron deficiency anemia. Iron deficiency results in impaired production of iron-containing proteins, the most prominent of which is hemoglobin. Cellular iron deficiency inhibits cell growth and subsequently leads to cell death. Hemochromatosis, an inherited disorder results in disproportionate absorption of iron and the extra iron builds up in tissues resulting in organ damage. As both iron deficiency and iron overload have adverse effects, cellular and systemic iron homeostasis is critically important. Recent advances in the field of iron metabolism have led to newer understanding of the pathways involved in iron homeostasis and the diseases which arise from alteration in the regulators. Although insight into this complex regulation of the proteins involved in iron homeostasis has been obtained mainly through animal studies, it is most likely that this knowledge can be directly extrapolated to humans.

  4. Association between subcutaneous white adipose tissue and serum 25-hydroxyvitamin D in overweight and obese adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Cholecalciferol is known to be deposited in human adipose tissue, but the distribution of 25-hydroxyvitamin D (25(OH)D) in adipose tissue is not known. Objectives: To determine whether 25(OH)D is detectable in subcutaneous white adipose tissue (SWAT) in overweight and obese persons an...

  5. Homeostasis, Inflammation, and Disease Susceptibility

    PubMed Central

    Kotas, Maya E.; Medzhitov, Ruslan

    2015-01-01

    While modernization has dramatically increased lifespan, it has also witnessed the increasing prevalence of diseases such as obesity, hypertension and type 2 diabetes. Such chronic, acquired diseases result when normal physiologic control goes awry and may thus be viewed as failures of homeostasis. However, while nearly every process in human physiology relies on homeostatic mechanisms for stability, only some have demonstrated vulnerability to dysregulation. Additionally, chronic inflammation is a common accomplice of the diseases of homeostasis, yet the basis for this connection is not fully understood. Here we review the design of homeostatic systems and discuss universal features of control circuits that operate at the cellular, tissue and organismal levels. We suggest a framework for classification of homeostatic signals that is based on different classes of homeostatic variables they report on. Finally, we discuss how adaptability of homeostatic systems with adjustable set points creates vulnerability to dysregulation and disease. This framework highlights the fundamental parallels between homeostatic and inflammatory control mechanisms and provides a new perspective on the physiological origin of inflammation. PMID:25723161

  6. Bone marrow stromal cell-mediated tissue sparing enhances functional repair after spinal cord contusion in adult rats.

    PubMed

    Ritfeld, Gaby J; Nandoe Tewarie, Rishi D S; Vajn, Katarina; Rahiem, Sahar T; Hurtado, Andres; Wendell, Dane F; Roos, Raymund A C; Oudega, Martin

    2012-01-01

    Bone marrow stromal cell (BMSC) transplantation has shown promise for repair of the spinal cord. We showed earlier that a BMSC transplant limits the loss of spinal nervous tissue after a contusive injury. Here, we addressed the premise that BMSC-mediated tissue sparing underlies functional recovery in adult rats after a contusion of the thoracic spinal cord. Our results reveal that after 2 months BMSCs had elicited a significant increase in spared tissue volumes and in blood vessel density in the contusion epicenter. A strong functional relationship existed between spared tissue volumes and blood vessel density. BMSC-transplanted rats exhibited significant improvements in motor, sensorimotor, and sensory functions, which were strongly correlated with spared tissue volumes. Retrograde tracing revealed that rats with BMSCs had twice as many descending brainstem neurons with an axon projecting beyond the contused spinal cord segment and these correlated strongly with the improved motor/sensorimotor functions but not sensory functions. Together, our data indicate that tissue sparing greatly contributes to BMSC-mediated functional repair after spinal cord contusion. The preservation/formation of blood vessels and sparing/regeneration of descending brainstem axons may be important mediators of the BMSC-mediated anatomical and functional improvements.

  7. Epigenetic regulation of cholesterol homeostasis

    PubMed Central

    Meaney, Steve

    2014-01-01

    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. PMID:25309573

  8. Farnesoid X receptor immunolocalization in reproductive tissues of adult female rabbits.

    PubMed

    Anaya-Hernández, Arely; Méndez-Tepepa, Maribel; Hernández-Aragón, Laura G; Pacheco, Pablo; Martínez-Gómez, Margarita; Castelán, Francisco; Cuevas, Estela

    2014-07-01

    Farnesoid X receptor (FXR) has been involved in lipid metabolism, cell proliferation, apoptosis, and aromatase expression, as well as in the steroid synthesis and signaling. Considering that these events occur in reproductive tissues in females, the aim of the present study was to determine the immunolocalization of FXR in the ovary, oviduct, uterus, and vagina of rabbits. Rabbits were sacrificed and their reproductive tissues were excised and histologically processed. Immunohistochemistry for FXR was done and reproductive tissues were photographed. FXR immunoreactivity was found in all types of ovarian follicles, ovarian stroma, and corpus luteum of virgin and pregnant rabbits. Also, oviductal and vaginal epithelium of virgins, as well as the oviductal smooth muscle, showed anti-FXR immunoreactivity. The uterine epithelium and musculature of virgins had scarce anti-FXR immunoreactivity. Although the role of FXR in female reproductive tissues is still not known, it is possible to consider various functions related to the reproductive tissue.

  9. Immunobiotic Lactobacillus strains augment NLRP3 expression in newborn and adult porcine gut-associated lymphoid tissues.

    PubMed

    Tohno, Masanori; Shimosato, Takeshi; Aso, Hisashi; Kitazawa, Haruki

    2011-12-15

    We isolated cDNA encoding porcine nucleotide-binding domain-like receptor family, pryin domain containing 3 (NLRP3) from Peyer's patches. The complete nucleotide open reading frame of porcine NLRP3 contains 3108-bp encoding a deduced polypeptide of 1036-amino acid residues. The porcine NLRP3 amino acid sequence is more similar to the longest isoform of human than the mouse counterpart. The predicted amino acid sequence of porcine NLRP3 presented nine C-terminal leucine-rich repeat domains. In newborn swine, the expression of NLRP3 was detected at higher levels in spleen and mesenteric lymph nodes, while lower levels were observed in intestinal tissues. In adult swine, NLRP3 was strongly expressed in Peyer's patches and the mesenteric lymph nodes, and the expression level in the lower intestinal tissues was comparable to that in spleen. Toll-like receptor and nucleotide-binding domain ligands, as well as Lactobacillus delbrueckii subsp. bulgaricus and Lactobacillus gasseri, enhanced NLRP3 expression in gut-associated lymphoid tissues (GALT) of newborn and adult swine. Our results should aid in understanding the intestinal immunoregulatory mechanisms underlying NLRP3 activation and the priming ability of immunobiotic lactic acid bacteria in porcine GALT.

  10. Alcohol disrupts sleep homeostasis.

    PubMed

    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

  11. A distinct regulatory region of the Bmp5 locus activates gene expression following adult bone fracture or soft tissue injury.

    PubMed

    Guenther, Catherine A; Wang, Zhen; Li, Emma; Tran, Misha C; Logan, Catriona Y; Nusse, Roel; Pantalena-Filho, Luiz; Yang, George P; Kingsley, David M

    2015-08-01

    Bone morphogenetic proteins (BMPs) are key signaling molecules required for normal development of bones and other tissues. Previous studies have shown that null mutations in the mouse Bmp5 gene alter the size, shape and number of multiple bone and cartilage structures during development. Bmp5 mutations also delay healing of rib fractures in adult mutants, suggesting that the same signals used to pattern embryonic bone and cartilage are also reused during skeletal regeneration and repair. Despite intense interest in BMPs as agents for stimulating bone formation in clinical applications, little is known about the regulatory elements that control developmental or injury-induced BMP expression. To compare the DNA sequences that activate gene expression during embryonic bone formation and following acute injuries in adult animals, we assayed regions surrounding the Bmp5 gene for their ability to stimulate lacZ reporter gene expression in transgenic mice. Multiple genomic fragments, distributed across the Bmp5 locus, collectively coordinate expression in discrete anatomic domains during normal development, including in embryonic ribs. In contrast, a distinct regulatory region activated expression following rib fracture in adult animals. The same injury control region triggered gene expression in mesenchymal cells following tibia fracture, in migrating keratinocytes following dorsal skin wounding, and in regenerating epithelial cells following lung injury. The Bmp5 gene thus contains an "injury response" control region that is distinct from embryonic enhancers, and that is activated by multiple types of injury in adult animals.

  12. Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb (14)C.

    PubMed

    Heinemeier, Katja Maria; Schjerling, Peter; Heinemeier, Jan; Magnusson, Stig Peter; Kjaer, Michael

    2013-05-01

    Tendons are often injured and heal poorly. Whether this is caused by a slow tissue turnover is unknown, since existing data provide diverging estimates of tendon protein half-life that range from 2 mo to 200 yr. With the purpose of determining life-long turnover of human tendon tissue, we used the (14)C bomb-pulse method. This method takes advantage of the dramatic increase in atmospheric levels of (14)C, produced by nuclear bomb tests in 1955-1963, which is reflected in all living organisms. Levels of (14)C were measured in 28 forensic samples of Achilles tendon core and 4 skeletal muscle samples (donor birth years 1945-1983) with accelerator mass spectrometry (AMS) and compared to known atmospheric levels to estimate tissue turnover. We found that Achilles tendon tissue retained levels of (14)C corresponding to atmospheric levels several decades before tissue sampling, demonstrating a very limited tissue turnover. The tendon concentrations of (14)C approximately reflected the atmospheric levels present during the first 17 yr of life, indicating that the tendon core is formed during height growth and is essentially not renewed thereafter. In contrast, (14)C levels in muscle indicated continuous turnover. Our observation provides a fundamental premise for understanding tendon function and pathology, and likely explains the poor regenerative capacity of tendon tissue.

  13. Histological image data of limb skeletal tissue from larval and adult Ambystoma mexicanum.

    PubMed

    McCusker, Catherine D; Diaz-Castillo, Carlos; Sosnik, Julian; Phan, Anne; Gardiner, David M

    2016-09-01

    The data presented in this article are related to the article entitled "Cartilage and bone cells do not participate in skeletal regeneration in Ambystoma mexicanum limbs" [1]. Here we present image data of the post-embryonic development of the forelimb skeletal tissue of Ambystoma Mexicanum. Histological staining was performed on sections from the intact limbs of young (6.5 cm) and old (25 cm) animals, and on dissected skeletal tissues (cartilage, bone, and periosteum) from these animals.

  14. Facial soft tissue thickness in a sample of Sudanese adults with different occlusions.

    PubMed

    Hamid, Sama; Abuaffan, Amal H

    2016-09-01

    Facial soft tissue thickness is essential to orthodontists and plastic surgeons for treatment planning, and to forensic anthropologists for facial reconstruction, a process combining science and art to recreate a recognizable face from an unidentified skull. The facial profile, together with the age and sex of a person, is related to facial soft tissue thickness, which is required for accurate facial reconstruction and recognition. Skeletal occlusions in orthodontics are classified according to the basic human facial profiles: straight, convex, and concave or skeletal class I, II, and III, respectively. In the present study, the facial soft tissue thickness of 233 Sudanese subjects (105 men and 128 women), ranging in age from 18 to 35 years, with different facial profiles at 20 landmarks was measured (10 soft tissue and 10 dentoskeletal). Sexual dimorphism was noted, with males having thicker facial soft tissue at all measured points. The facial soft tissue thickness varied among different occlusions. Individuals with skeletal class II occlusion had the thickest lower lip, and class III individuals had the thickest upper lip. In general, the Sudanese sample had a unique spectrum of measurements, with thick upper and lower lips, compared with African and Caucasoid subjects, pointing to the need for ethnic-specific data.

  15. Neonatal Tissue Damage Promotes Spike Timing-Dependent Synaptic Long-Term Potentiation in Adult Spinal Projection Neurons

    PubMed Central

    Li, Jie

    2016-01-01

    Mounting evidence from both humans and rodents suggests that tissue damage during the neonatal period can “prime” developing nociceptive pathways such that a subsequent injury during adulthood causes an exacerbated degree of pain hypersensitivity. However, the cellular and molecular mechanisms that underlie this priming effect remain poorly understood. Here, we demonstrate that neonatal surgical injury relaxes the timing rules governing long-term potentiation (LTP) at mouse primary afferent synapses onto mature lamina I projection neurons, which serve as a major output of the spinal nociceptive network and are essential for pain perception. In addition, whereas LTP in naive mice was only observed if the presynaptic input preceded postsynaptic firing, early tissue injury removed this temporal requirement and LTP was observed regardless of the order in which the inputs were activated. Neonatal tissue damage also reduced the dependence of spike-timing-dependent LTP on NMDAR activation and unmasked a novel contribution of Ca2+-permeable AMPARs. These results suggest for the first time that transient tissue damage during early life creates a more permissive environment for the production of LTP within adult spinal nociceptive circuits. This persistent metaplasticity may promote the excessive amplification of ascending nociceptive transmission to the mature brain and thereby facilitate the generation of chronic pain after injury, thus representing a novel potential mechanism by which early trauma can prime adult pain pathways in the CNS. SIGNIFICANCE STATEMENT Tissue damage during early life can “prime” developing nociceptive pathways in the CNS, leading to greater pain severity after repeat injury via mechanisms that remain poorly understood. Here, we demonstrate that neonatal surgical injury widens the timing window during which correlated presynaptic and postsynaptic activity can evoke long-term potentiation (LTP) at sensory synapses onto adult lamina I

  16. Pancreatic regulation of glucose homeostasis

    PubMed Central

    Röder, Pia V; Wu, Bingbing; Liu, Yixian; Han, Weiping

    2016-01-01

    In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed. PMID:26964835

  17. Pharmacokinetics of bisphenol A in serum and adipose tissue following intravenous administration to adult female CD-1 mice.

    PubMed

    Doerge, Daniel R; Twaddle, Nathan C; Vanlandingham, Michelle; Fisher, Jeffrey W

    2012-06-01

    Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for use in food can liners. Worldwide biomonitoring studies consistently find high prevalence of BPA conjugates in urine consistent with pervasive exposure at levels typically below 1 μg/kg bw/day. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult female CD-1 mice following intravenous (IV) injection, which produces higher serum levels by circumventing the processes of absorption from the GI tract and presystemic metabolism that occur after oral administration. Deuterated BPA (100 μg/kg bw) was used to avoid interference by background contamination from trace amounts of native BPA. Additionally, the pharmacokinetics of unconjugated BPA were determined in adipose tissue, a proposed site of action and "depot" for BPA. After IV injection, unconjugated BPA rapidly distributed out of the circulation (t(1/2)=0.2 h) and terminal elimination also proceeded rapidly (t(1/2)=0.8 h). Consistent with the degree of aqueous solubility, lipid/water solubility ratio, and partitioning from blood into adipose tissue in vivo, the levels of unconjugated BPA in mouse adipose tissue rapidly reached a maximal level (0.25 h) that did not exceed the serum maximum at the initial sampling time (0.08 h). Terminal elimination of unconjugated BPA from adipose tissue (t(1/2)=7.0 h) was similar to that for conjugated BPA in serum (t(1/2)=6.6 h) and <0.01% of the administered dose remained in adipose tissue after 24 h. These plasma and tissue kinetics are consistent with rapid equilibria and underscore the non-persistent nature of BPA, particularly when compared with slowly metabolized lipophilic organic pollutants like halogenated dibenzodioxins.

  18. Liver Progenitors Isolated from Adult Healthy Mouse Liver Efficiently Differentiate to Functional Hepatocytes In Vitro and Repopulate Liver Tissue.

    PubMed

    Tanimizu, Naoki; Ichinohe, Norihisa; Ishii, Masayuki; Kino, Junichi; Mizuguchi, Toru; Hirata, Koichi; Mitaka, Toshihiro

    2016-12-01

    It has been proposed that tissue stem cells supply multiple epithelial cells in mature tissues and organs. However, it is unclear whether tissue stem cells generally contribute to cellular turnover in normal healthy organs. Here, we show that liver progenitors distinct from bipotent liver stem/progenitor cells (LPCs) persistently exist in mouse livers and potentially contribute to tissue maintenance. We found that, in addition to LPCs isolated as EpCAM(+) cells, liver progenitors were enriched in CD45(-) TER119(-) CD31(-) EpCAM(-) ICAM-1(+) fraction isolated from late-fetal and postnatal livers. ICAM-1(+) liver progenitors were abundant by 4 weeks (4W) after birth. Although their number decreased with age, ICAM-1(+) liver progenitors existed in livers beyond that stage. We established liver progenitor clones derived from ICAM-1(+) cells between 1 and 20W and found that those clones efficiently differentiated into mature hepatocytes (MHs), which secreted albumin, eliminated ammonium ion, stored glycogen, and showed cytochrome P450 activity. Even after long-term culture, those clones kept potential to differentiate to MHs. When ICAM-1(+) clones were transplanted into nude mice after retrorsine treatment and 70% partial hepatectomy, donor cells were incorporated into liver plates and expressed hepatocyte nuclear factor 4α, CCAAT/enhancer binding protein α, and carbamoylphosphate synthetase I. Moreover, after short-term treatment with oncostatin M, ICAM-1(+) clones could efficiently repopulate the recipient liver tissues. Our results indicate that liver progenitors that can efficiently differentiate to MHs exist in normal adult livers. Those liver progenitors could be an important source of new MHs for tissue maintenance and repair in vivo, and for regenerative medicine ex vivo. Stem Cells 2016;34:2889-2901.

  19. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms.

    PubMed

    Prockop, Darwin J

    2009-06-01

    Research on stem cells has progressed at a rapid pace and, as might be anticipated, the results have generated several controversies, a few myths and a change in a major paradigm. Some of these issues will be reviewed in this study with special emphasis on how they can be applied to the adult stem/progenitor cells from bone marrow, referred to as MSCs.

  20. Mass spectral determination of phenylacetonitrile (PAN) levels in body tissues of adult desert locust, Schistocerca gregaria

    Technology Transfer Automated Retrieval System (TEKTRAN)

    : Wings and legs of the gregarious desert locust, Schistocerca gregaria have been shown to be release sites of phenylacetonitrile (PAN), the major adult male-produced pheromone. However, there is limited information on the distribution of PAN within the locust. Here we show, using gas chromatograph...

  1. Incidence and Survival of Pediatric Soft Tissue Sarcomas: Comparison between Adults and Children

    PubMed Central

    Lim, Sun Min; Yoo, Cheol Joo; Han, Jung Woo; Cho, Yong Jin; Kim, Soo Hee; Ahn, Joong Bae; Rha, Sun Young; Shin, Sang Joon; Chung, Hyun Cheol; Yang, Woo Ick; Shin, Kyoo-Ho; Rho, Jae Kyung; Kim, Hyo Song

    2015-01-01

    Purpose Pediatric-type sarcomas such as rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), primitive neuroectodermal tumor (PNET), and desmoplastic small round-cell tumor (DSRCT) are rare in adults, with limited studies on their prognosis and optimal treatment strategies. We aimed to examine the outcome of children and adult patients with RMS, EWS, PNET, and DSRCT and relevant prognostic factors. Materials and Methods We retrospectively reviewed 220 pediatric-type sarcoma patients at a single institution between 1985 and 2011. Comparisons were made in order to examine differences in demographics, disease characteristics, and survival. Survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models. Results A total of 220 consecutive patients were identified at our institute. Median age was 15.6 years (range, 0 to 81 years) and there were 108 children (49%) and 112 adult patients (51%). According to histological classification, 106 patients (48.2%) had RMS, 60 (27.3%) had EWS, 50 (22.7%) had PNET, and 4 (1.8%) had DSRCT. With a median follow-up period of 6.6 years, the estimated median overall survival (OS) of all patients was 75 months (95% confidence interval [CI], 27.2 to 122.8 months) and median event-free survival (EFS) for all patients was 11 months (95% CI, 8.8 to 13.2 months). No significant difference in OS and EFS was observed between adults and children. In multivariate analysis, distant metastasis (hazard ratio [HR], 1.617; 95% CI, 1.022 to 2.557; p=0.040) and no debulking surgery (HR, 1.443; 95% CI, 1.104 to 1.812; p=0.012) showed independent association with worse OS. Conclusion Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children. PMID:25143049

  2. Assessment of the relationships among posture, maxillomandibular denture complex, and soft-tissue profile of aesthetic adult Korean women.

    PubMed

    Choi, B; Baek, S H; Yang, W S; Kim, S

    2000-11-01

    The objective of this study was to assess the relationships among the posture, the maxillomandibular denture complex, and the soft-tissue profile of aesthetic adult Korean women. From an initial group of 346 women, the authors examined 28 beautiful adult Korean women who had normal vertical and sagittal skeletal relationships and normal occlusion. There were no differences in the inclinations of the incisors to the occlusal planes in the maxilla and the mandible in the data for Korean women vs. Arnett's data for white women. However, the overbite and overjet in Korean women were slightly smaller than in white women. AB to maxillary occlusal plane angle (MxOP) represented the anteroposterior denture base discrepancy to the occlusal plane. Angulation of the maxillary occlusal plane to the Frankfurt (FH) plane and the true vertical line at submasale (TVL) (Sn) was a little steeper in Korean women than in white women. The FH plane was almost parallel to the true horizontal line in Korean women who had normal vertical and sagittal skeletal relationships and normal occlusion. With regard to soft-tissue variables, the upper lip length (Sn-Stms), interlabial gap, upper incisor exposure, nasolabial angle, lip and nose tip projection value, and TVL (Sn)-to-upper lip line (UL) angle showed interracial differences. The results of this study can assist in the diagnosis and treatment planning of orthognathic surgery.

  3. Novel Functions of Renin Precursors in Homeostasis and Disease

    PubMed Central

    2015-01-01

    Renin progenitors appear early and are found in multiple tissues throughout the embryo. Besides their well known role in blood pressure and fluid homeostasis, renin progenitors participate in tissue morphogenesis, repair, and regeneration, and may integrate immune and endocrine responses. In the bone marrow, renin cells offer clues to understand normal and neoplastic hematopoiesis. PMID:26661526

  4. Mouse matriptase-2: identification, characterization and comparative mRNA expression analysis with mouse hepsin in adult and embryonic tissues.

    PubMed Central

    Hooper, John D; Campagnolo, Luisa; Goodarzi, Goodarz; Truong, Tony N; Stuhlmann, Heidi; Quigley, James P

    2003-01-01

    We report the identification and characterization of mouse matriptase-2 (m-matriptase-2), an 811-amino-acid protein composed of an N-terminal cytoplasmic domain, a membrane-spanning domain, two CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domains, three LDLR (low-density-lipoprotein receptor class A) domains and a C-terminal serine-protease domain. All m-matriptase-2 protein domain boundaries corresponded with intron/exon junctions of the encoding gene, which spans approx. 29 kb and comprises 18 exons. Matriptase-2 is highly conserved in human, mouse and rat, with the rat matriptase-2 gene ( r-maltriptase-2 ) predicted to encode transmembrane and soluble isoforms. Western-blot analysis indicated that m-matriptase-2 migrates close to its theoretical molecular mass of 91 kDa, and immunofluorescence analysis was consistent with the proposed surface membrane localization of this protein. Reverse-transcription PCR and in-situ -hybridization analysis indicated that m-matriptase-2 expression overlaps with the distribution of mouse hepsin (m-hepsin, a cell-surface serine protease identified in hepatoma cells) in adult tissues and during embryonic development. In adult tissues both are expressed at highest levels in liver, kidney and uterus. During embryogenesis m-matriptase-2 expression peaked between days 12.5 and 15.5. m-hepsin expression was biphasic, with peaks at day 7.5 to 8.5 and again between days 12.5 and 15.5. In situ hybridization of embryonic tissues indicated abundant expression of both m-matriptase-2 and m-hepsin in the developing liver and at lower levels in developing pharyngo-tympanic tubes. While m-hepsin was detected in the residual embryonic yolk sac and with lower intensity in lung, heart, gastrointestinal tract, developing kidney tubules and epithelium of the oral cavity, m-matriptase-2 was absent in these tissues, but strongly expressed within the nasal cavity by olfactory epithelial

  5. Ageing and water homeostasis

    NASA Technical Reports Server (NTRS)

    Robertson, David; Jordan, Jens; Jacob, Giris; Ketch, Terry; Shannon, John R.; Biaggioni, Italo

    2002-01-01

    This review outlines current knowledge concerning fluid intake and volume homeostasis in ageing. The physiology of vasopressin is summarized. Studies have been carried out to determine orthostatic changes in plasma volume and to assess the effect of water ingestion in normal subjects, elderly subjects, and patients with dysautonomias. About 14% of plasma volume shifts out of the vasculature within 30 minutes of upright posture. Oral ingestion of water raises blood pressure in individuals with impaired autonomic reflexes and is an important source of noise in blood pressure trials in the elderly. On the average, oral ingestion of 16 ounces (473ml) of water raises blood pressure 11 mmHg in elderly normal subjects. In patients with autonomic impairment, such as multiple system atrophy, strikingly exaggerated pressor effects of water have been seen with blood pressure elevations greater than 75 mmHg not at all uncommon. Ingestion of water is a major determinant of blood pressure in the elderly population. Volume homeostasis is importantly affected by posture and large changes in plasma volume may occur within 30 minutes when upright posture is assumed.

  6. Metal homeostasis in dementia.

    PubMed

    Sensi, Stefano

    2014-10-01

    The molecular determinants of dementia of Alzheimer's tipe (DAT) are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor is represented by the unbalanced homeostasis of two cations: calcium (Ca(2) ) and zinc (Zn(2)). The two ions serve a critical role in the physiological signalling of the central nervous system. However, Alzheimer's disease-related neurodegeneration, deregulation of brain levels of Ca(2) and Zn(2) is instrumental in promoting amyloid-β (Aβ) dysmetabolism and tau phosphorylation as well as interference with additional pathogenic factors like energy production failure, hyperexcitabilty, excitotoxicity, and oxidative stress. Hyperexcitabilty and excitotoxicity are key mechanisms in the disease development and progression as an altered glutamatergic activation can further promote both Ca(2) and Zn(2) dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further increase intracellular Ca(2) and Zn(2) rises and set the stage for a self-perpetuating injurious loop. In the talk, we will review mechanisms of AD-related Ca(2) and Zn(2) dyshomeostasis in a preclinical model of DAT and discuss opportunity for disease-modifying strategies based on interventions aimed at restoring brain metal homeostasis.

  7. Anterior eye tissue morphology: Scleral and conjunctival thickness in children and young adults

    PubMed Central

    Read, Scott A.; Alonso-Caneiro, David; Vincent, Stephen J.; Bremner, Alexander; Fothergill, Annabel; Ismail, Brittney; McGraw, Rebecca; Quirk, Charlotte J.; Wrigley, Elspeth

    2016-01-01

    The sclera and conjunctiva form part of the eye’s tough, protective outer coat, and play important roles in the eye’s mechanical protection and immune defence, as well as in determining the size and shape of the eye globe. Advances in ocular imaging technology now allow these tissues in the anterior eye to be imaged non-invasively and with high resolution, however there is a paucity of data examining the dimensions of these tissues in paediatric populations. In this study, we have used optical coherence tomography (OCT) imaging to examine the normal in vivo thickness profile of the anterior sclera and overlying conjunctiva in 111 healthy young participants, including a large proportion of paediatric subjects. We demonstrate that the thickness of the anterior sclera varies significantly with measurement location and meridian. Tissue thickness also varied significantly with age, with younger subjects exhibiting significantly thinner scleras and significantly greater conjunctival thickness. Males were also found to exhibit significantly greater scleral thickness. Refractive error however was not significantly associated with either scleral or conjunctival thickness in this population. These findings provide new data describing the normative dimensions of anterior eye tissues in children and the factors that can influence these dimensions in young populations. PMID:27646956

  8. Planarians as a Model to Assess In Vivo the Role of Matrix Metalloproteinase Genes during Homeostasis and Regeneration

    PubMed Central

    Isolani, Maria Emilia; Abril, Josep F.; Saló, Emili; Deri, Paolo; Bianucci, Anna Maria; Batistoni, Renata

    2013-01-01

    Matrix metalloproteinases (MMPs) are major executors of extracellular matrix remodeling and, consequently, play key roles in the response of cells to their microenvironment. The experimentally accessible stem cell population and the robust regenerative capabilities of planarians offer an ideal model to study how modulation of the proteolytic system in the extracellular environment affects cell behavior in vivo. Genome-wide identification of Schmidtea mediterranea MMPs reveals that planarians possess four mmp-like genes. Two of them (mmp1 and mmp2) are strongly expressed in a subset of secretory cells and encode putative matrilysins. The other genes (mt-mmpA and mt-mmpB) are widely expressed in postmitotic cells and appear structurally related to membrane-type MMPs. These genes are conserved in the planarian Dugesia japonica. Here we explore the role of the planarian mmp genes by RNA interference (RNAi) during tissue homeostasis and regeneration. Our analyses identify essential functions for two of them. Following inhibition of mmp1 planarians display dramatic disruption of tissues architecture and significant decrease in cell death. These results suggest that mmp1 controls tissue turnover, modulating survival of postmitotic cells. Unexpectedly, the ability to regenerate is unaffected by mmp1(RNAi). Silencing of mt-mmpA alters tissue integrity and delays blastema growth, without affecting proliferation of stem cells. Our data support the possibility that the activity of this protease modulates cell migration and regulates anoikis, with a consequent pivotal role in tissue homeostasis and regeneration. Our data provide evidence of the involvement of specific MMPs in tissue homeostasis and regeneration and demonstrate that the behavior of planarian stem cells is critically dependent on the microenvironment surrounding these cells. Studying MMPs function in the planarian model provides evidence on how individual proteases work in vivo in adult tissues. These results

  9. Planarians as a model to assess in vivo the role of matrix metalloproteinase genes during homeostasis and regeneration.

    PubMed

    Isolani, Maria Emilia; Abril, Josep F; Saló, Emili; Deri, Paolo; Bianucci, Anna Maria; Batistoni, Renata

    2013-01-01

    Matrix metalloproteinases (MMPs) are major executors of extracellular matrix remodeling and, consequently, play key roles in the response of cells to their microenvironment. The experimentally accessible stem cell population and the robust regenerative capabilities of planarians offer an ideal model to study how modulation of the proteolytic system in the extracellular environment affects cell behavior in vivo. Genome-wide identification of Schmidtea mediterranea MMPs reveals that planarians possess four mmp-like genes. Two of them (mmp1 and mmp2) are strongly expressed in a subset of secretory cells and encode putative matrilysins. The other genes (mt-mmpA and mt-mmpB) are widely expressed in postmitotic cells and appear structurally related to membrane-type MMPs. These genes are conserved in the planarian Dugesia japonica. Here we explore the role of the planarian mmp genes by RNA interference (RNAi) during tissue homeostasis and regeneration. Our analyses identify essential functions for two of them. Following inhibition of mmp1 planarians display dramatic disruption of tissues architecture and significant decrease in cell death. These results suggest that mmp1 controls tissue turnover, modulating survival of postmitotic cells. Unexpectedly, the ability to regenerate is unaffected by mmp1(RNAi). Silencing of mt-mmpA alters tissue integrity and delays blastema growth, without affecting proliferation of stem cells. Our data support the possibility that the activity of this protease modulates cell migration and regulates anoikis, with a consequent pivotal role in tissue homeostasis and regeneration. Our data provide evidence of the involvement of specific MMPs in tissue homeostasis and regeneration and demonstrate that the behavior of planarian stem cells is critically dependent on the microenvironment surrounding these cells. Studying MMPs function in the planarian model provides evidence on how individual proteases work in vivo in adult tissues. These results

  10. Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish.

    PubMed

    Michel, Maximilian; Page-McCaw, Patrick S; Chen, Wenbiao; Cone, Roger D

    2016-03-15

    Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals.

  11. Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish

    PubMed Central

    Michel, Maximilian; Page-McCaw, Patrick S.; Chen, Wenbiao; Cone, Roger D.

    2016-01-01

    Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals. PMID:26903647

  12. Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches.

    PubMed

    Kaur, Simranpreet; Raggatt, Liza Jane; Batoon, Lena; Hume, David Arthur; Levesque, Jean-Pierre; Pettit, Allison Robyn

    2017-01-01

    Macrophages, named for their phagocytic ability, participate in homeostasis, tissue regeneration and inflammatory responses. Bone and adjacent marrow contain multiple functionally unique resident tissue macrophage subsets which maintain and regulate anatomically distinct niche environments within these interconnected tissues. Three subsets of bone-bone marrow resident tissue macrophages have been characterised; erythroblastic island macrophages, haematopoietic stem cell niche macrophages and osteal macrophages. The role of these macrophages in controlling homeostasis and repair in bone and bone marrow niches is reviewed in detail.

  13. The Drosophila CD36 Homologue croquemort Is Required to Maintain Immune and Gut Homeostasis during Development and Aging

    PubMed Central

    Guillou, Aurélien; Wang, Hui

    2016-01-01

    Phagocytosis is an ancient mechanism central to both tissue homeostasis and immune defense. Both the identity of the receptors that mediate bacterial phagocytosis and the nature of the interactions between phagocytosis and other defense mechanisms remain elusive. Here, we report that Croquemort (Crq), a Drosophila member of the CD36 family of scavenger receptors, is required for microbial phagocytosis and efficient bacterial clearance. Flies mutant for crq are susceptible to environmental microbes during development and succumb to a variety of microbial infections as adults. Crq acts parallel to the Toll and Imd pathways to eliminate bacteria via phagocytosis. crq mutant flies exhibit enhanced and prolonged immune and cytokine induction accompanied by premature gut dysplasia and decreased lifespan. The chronic state of immune activation in crq mutant flies is further regulated by negative regulators of the Imd pathway. Altogether, our data demonstrate that Crq plays a key role in maintaining immune and organismal homeostasis. PMID:27780230

  14. Apela Regulates Fluid Homeostasis by Binding to the APJ Receptor to Activate Gi Signaling.

    PubMed

    Deng, Cheng; Chen, Haidi; Yang, Na; Feng, Yi; Hsueh, Aaron J W

    2015-07-24

    Apela (APJ early endogenous ligand, also known as elabela or toddler) is a recently discovered peptide hormone. Based on genetic studies in zebrafish, apela was found to be important for endoderm differentiation and heart development during embryogenesis. Although common phenotypes of apela and APJ-null zebrafish during embryonic development suggested that apela interacts with the APJ receptor, kinetics of apela binding to APJ and intracellular signaling pathways for apela remain unknown. The role of apela in adults is also uncertain. Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (Kd = 0.51 nm) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding. Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. In adult rats, apela is expressed exclusively in the kidney, unlike the wide tissue distribution of apelin. In vivo studies demonstrated the ability of apela to regulate fluid homeostasis by increasing diuresis and water intake. Dose-response studies further indicated that apela induces 2- and 5-fold higher maximal responses than apelin in ERK1/2 phosphorylation and diuresis/water intake, respectively. After designing an apela antagonist, we further demonstrated the role of endogenous ligand(s) in regulating APJ-mediated fluid homeostasis. Our results identified apela as a potent peptide hormone capable of regulating fluid homeostasis in adult kidney through coupling to the APJ-mediated Gi signaling pathway.

  15. A CT-scan database for the facial soft tissue thickness of Taiwan adults.

    PubMed

    Chung, Ju-Hui; Chen, Hsiao-Ting; Hsu, Wan-Yi; Huang, Guo-Shu; Shaw, Kai-Ping

    2015-08-01

    Facial reconstruction is a branch of forensic anthropology used to assist in the identification of skeletal remains. The majority of facial reconstruction techniques use facial soft tissue depth chart data to recreate facial tissue on a skull or a model of a skull through the use of modeling clay. This study relied on 193 subjects selected from the Taiwanese population on the basis of age and gender to determine the average values of 32 landmarks, include midline and bilateral measures, by means of CT scans. The mean age of the subjects was 46.9±16.4 years, with a mean age of 43.8±16.6 for males and 49.9±15.8 for females respectively. There were 16 landmarks with statistically significant differences between male and female subjects, namely S, G, N, Na, Ph, Sd and Id in the midline portion, FE, LO, ZA and Sub M2 in the bilateral-right and left portion, and IM point in the bilateral-left portion (abbreviations adapted from Karen T. Taylor's work). The mean soft tissue depth was greater in males than in females, and there was significant difference between the right and left sides of the face in Za point. This study's findings were compared with those of Bulut et al.

  16. Asymmetric cell division of stem and progenitor cells during homeostasis and cancer.

    PubMed

    Gómez-López, Sandra; Lerner, Robin G; Petritsch, Claudia

    2014-02-01

    Stem and progenitor cells are characterized by their ability to self-renew and produce differentiated progeny. A fine balance between these processes is achieved through controlled asymmetric divisions and is necessary to generate cellular diversity during development and to maintain adult tissue homeostasis. Disruption of this balance may result in premature depletion of the stem/progenitor cell pool, or abnormal growth. In many tissues, including the brain, dysregulated asymmetric divisions are associated with cancer. Whether there is a causal relationship between asymmetric cell division defects and cancer initiation is as yet not known. Here, we review the cellular and molecular mechanisms that regulate asymmetric cell divisions in the neural lineage and discuss the potential connections between this regulatory machinery and cancer.

  17. Association between subcutaneous white adipose tissue and serum 25-hydroxyvitamin D in overweight and obese adults.

    PubMed

    Piccolo, Brian D; Dolnikowski, Gregory; Seyoum, Elias; Thomas, Anthony P; Gertz, Erik R; Souza, Elaine C; Woodhouse, Leslie R; Newman, John W; Keim, Nancy L; Adams, Sean H; Van Loan, Marta D

    2013-08-26

    Cholecalciferol is known to be deposited in human adipose tissue, but it is not known whether 25-hydroxyvitamin D (25(OH)D) is found in detectable concentrations. Therefore, our objective was to determine whether 25(OH)D is detectable in subcutaneous white adipose tissue (SWAT) in overweight and obese persons enrolled in a twelve week energy restricted diet. Baseline and post-intervention gluteal SWAT biopsies were collected from 20 subjects participating in a larger clinical weight loss intervention. LC-MS/MS was utilized to determine SWAT 25(OH)D concentrations. Serum 25(OH)D and 1,25(OH)2D were measured by RIA. Body composition was assessed by dual energy x-ray absorptiometry. SWAT 25(OH)D concentrations were 5.8 ± 2.6 nmol/kg tissue and 6.2 ± 2.7 nmol/kg tissue pre- and post-intervention SWAT, respectively. There was a significant positive association between SWAT 25(OH)D concentration and serum 25(OH)D concentration (r = 0.52, P < 0.01). Both SWAT and serum 25(OH)D concentrations did not significantly change after a twelve-week period of energy restriction with approximately 5 kg of fat loss. In conclusion, we have demonstrated our LC-MS/MS method can detect 25(OH)D3 in human subcutaneous fat tissue from overweight and obese individuals and is consistent with previously reported concentrations in swine. Additionally, our findings of no significant changes in SWAT 25(OH)D3 or serum 25(OH)D after a 6% loss of total body weight and 13% reduction in total fat provides the first human evidence that adipose 25(OH)D does not likely contribute to serum 25(OH)D with moderate weight loss; whether this is also the case with larger amounts of weight loss is unknown. Weight loss alone is not sufficient to increase serum 25(OH)D and increases in dietary or dermal biosynthesis of vitamin D appear to be the most critical contributors to in vitamin D status.

  18. Functional significance of mononuclear phagocyte populations generated through adult hematopoiesis

    PubMed Central

    Gutknecht, Michael F.; Bouton, Amy H.

    2014-01-01

    Tissue homeostasis requires a complete repertoire of functional macrophages in peripheral tissues. Recent evidence indicates that many resident tissue macrophages are seeded during embryonic development and persist through adulthood as a consequence of localized proliferation. Mononuclear phagocytes are also produced during adult hematopoiesis; these cells are then recruited to sites throughout the body, where they function in tissue repair and remodeling, resolution of inflammation, maintenance of homeostasis, and disease progression. The focus of this review is on mononuclear phagocytes that comprise the nonresident monocyte/macrophage populations in the body. Key features of monocyte differentiation are presented, focusing primarily on the developmental hierarchy that is established through this process, the markers used to identify discrete cell populations, and novel, functional attributes of these cells. These features are then explored in the context of the tumor microenvironment, where mononuclear phagocytes exhibit extensive plasticity in phenotype and function. PMID:25225678

  19. Regulation of cholesterol homeostasis.

    PubMed

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

    2013-04-10

    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 non-coding RNA's. The last two decades insight into underlying mechanisms has increased vastly but there are still a lot of unknowns, particularly regarding intracellular cholesterol transport. After decades of concentration on the liver, in recent years the intestine has come into focus as an important control point in cholesterol homeostasis. This review will discuss current knowledge of cholesterol physiology, with emphasis on cholesterol absorption, cholesterol synthesis and fecal excretion, and new (possible) therapeutic options for hypercholesterolemia.

  20. Neuronal ubiquitin homeostasis

    PubMed Central

    Hallengren, Jada; Chen, Ping-Chung; Wilson, Scott M.

    2013-01-01

    Neurons have highly specialized intracellular compartments that facilitate the development and activity of the nervous system. Ubiquitination is a post-translational modification that controls many aspects of neuronal function by regulating protein abundance. Disruption of this signaling pathway has been demonstrated in neurological disorders such as Parkinson’s disease, Amyotrophic Lateral Sclerosis and Angleman Syndrome. Since many neurological disorders exhibit ubiquitinated protein aggregates, the loss of neuronal ubiquitin homeostasis may be an important contributor of disease. This review discusses the mechanisms utilized by neurons to control the free pool of ubiquitin necessary for normal nervous system development and function as well as new roles of protein ubiquitination in regulating synaptic activity. PMID:23686613

  1. Pain emotion and homeostasis.

    PubMed

    Panerai, Alberto E

    2011-05-01

    Pain has always been considered as part of a defensive strategy, whose specific role is to signal an immediate, active danger. This definition partially fits acute pain, but certainly not chronic pain, that is maintained also in the absence of an active noxa or danger and that nowadays is considered a disease by itself. Moreover, acute pain is not only an automatic alerting system, but its severity and characteristics can change depending on the surrounding environment. The affective, emotional components of pain have been and are the object of extensive attention and research by psychologists, philosophers, physiologists and also pharmacologists. Pain itself can be considered to share the same genesis as emotions and as a specific emotion in contributing to the maintenance of the homeostasis of each unique subject. Interestingly, this role of pain reaches its maximal development in the human; some even argue that it is specific for the human primate.

  2. [Glucose homeostasis in children. I. Regulation of blood glucose].

    PubMed

    Otto Buczkowska, E; Szirer, G; Jarosz-Chobot, P

    2001-01-01

    The amount of glucose in the circulation depends on its absorption from the intestine, uptake by and release from the liver and uptake by peripheral tissues. Insulin and glucagon together control the metabolities required by peripheral tissues and both are involved in maintaining glucose homeostasis. Insulin is considered to be an anabolic hormone in that it promotes the synthesis of protein, lipid and glycogen. The key target tissues for insulin are liver, muscles and adipose tissue. Glucagon acts largely to increase catabolic processes. Between meals or during fast, the most tightly regulated process is the release of glucose from the liver. During fasting glucose is produced from glycogen and is formed by enzymes on the gluconeogenic pathway. Fetal metabolism is directed to ensure anabolism with formation of glycogen, fat and protein. Glucogen is stored in the liver and serves as the immediate source of new glucose during first few hours after birth. Glucose is the most important substrate for brain metabolism. Due to the large size of neonatal brain in relation to body weight cerebral glucose consumption is particularly high. Postnatal hormonal changes have a central role in regulating glucose mobilization through glycogenolysis and gluconeogenesis. The initial glucagon surge is the key adaptive change which triggers the switch to glucose production. The control of insulin and glucagon secretion is of fundamental importance during first hours after birth. Children have a decreased tolerance to starvation when compared with adults, they are more prone to develop hypoglycaemia after short fasting. The faster rate in the fall of blood glucose and gluconeogenic substrates and rapid rate of ketogenesis are characteristic features of fasting adaptation in children.

  3. Adult marrow-derived very small embryonic-like stem cells and tissue engineering.

    PubMed

    Kucia, Magda; Zuba-Surma, Ewa K; Wysoczynski, Marcin; Wu, Wan; Ratajczak, Janina; Machalinski, Boguslaw; Ratajczak, Mariusz Z

    2007-10-01

    A population of CXCR4(+) lin(-) CD45(-) cells that express SSEA, Oct-4 and Nanog has been identified in adult bone marrow. These cells are very small and display several features typical for primary embryonic stem cells such as: i) a large nuclei surrounded by a narrow rim of cytoplasm; ii) open-type chromatin (euchromatin); and iii) high telomerase activity. These cells were named very small embryonic-like stem cells (VSEL-SC). The authors hypothesized that they are direct descendants of the germ lineage. Germ lineage, in order to pass genes on to the next generation, has to create soma and thus becomes a 'mother lineage' for all somatic cell lineages present in the adult body. Germ potential is established after conception in a totipotent zygote and retained subsequently during development in blastomers of morula, cells form the inner cell mass of blastocyst, epiblast and population of primordial germ cells. The authors envision that VSEL-SC are epiblast-derived pluripotent stem cells and could potentially become a less-controversial source of stem cells for regeneration.

  4. Testosterone perturbs epidermal permeability barrier homeostasis.

    PubMed

    Kao, J S; Garg, A; Mao-Qiang, M; Crumrine, D; Ghadially, R; Feingold, K R; Elias, P M

    2001-03-01

    Although there are no known gender-related differences in permeability barrier function in adults, estrogens accelerate whereas testosterone retards barrier development in fetal skin, and male fetuses demonstrate slower barrier development than female littermates. Moreover, prenatal administration of the androgen receptor antagonist, flutamide, equalizes developmental rates in male and female fetuses. Therefore, we evaluated the effects of changes in testosterone on barrier homeostasis in adult murine and human skin. Hypogonadal mice (whether by castration or by treatment with systemic flutamide) displayed significantly faster barrier recovery at 3, 6, and 12 h than did controls, and testosterone replacement slowed barrier recovery in castrated mice. Moreover, testosterone directly effects the skin, as topical flutamide also accelerated barrier recovery in normal male mice. These findings appear to be of physiologic significance, since prepubertal male mice (age 5 wk) displayed accelerated barrier recovery in comparison with adult postpubertal (11 wk) males. These studies also appear to be relevant for humans, as a hypopituitary human subject demonstrated repeated changes in barrier recovery in parallel with peaks and nadirs in serum testosterone levels during intermittent testosterone replacement. Mechanistic studies showed that differences in epidermal lipid synthesis do not account for the testosterone-induced functional alterations. Instead, epidermal lamellar body (LB) formation and secretion both decrease, resulting in decreased extracellular lamellar bilayers in testosterone-replete animals. These studies demonstrate that fluctuations in testosterone modulate barrier function, and that testosterone repletion can have negative consequences for permeability barrier homeostasis.

  5. Ionic homeostasis in brain conditioning

    PubMed Central

    Cuomo, Ornella; Vinciguerra, Antonio; Cerullo, Pierpaolo; Anzilotti, Serenella; Brancaccio, Paola; Bilo, Leonilda; Scorziello, Antonella; Molinaro, Pasquale; Di Renzo, Gianfranco; Pignataro, Giuseppe

    2015-01-01

    Most of the current focus on developing neuroprotective therapies is aimed at preventing neuronal death. However, these approaches have not been successful despite many years of clinical trials mainly because the numerous side effects observed in humans and absent in animals used at preclinical level. Recently, the research in this field aims to overcome this problem by developing strategies which induce, mimic, or boost endogenous protective responses and thus do not interfere with physiological neurotransmission. Preconditioning is a protective strategy in which a subliminal stimulus is applied before a subsequent harmful stimulus, thus inducing a state of tolerance in which the injury inflicted by the challenge is mitigated. Tolerance may be observed in ischemia, seizure, and infection. Since it requires protein synthesis, it confers delayed and temporary neuroprotection, taking hours to develop, with a pick at 1–3 days. A new promising approach for neuroprotection derives from post-conditioning, in which neuroprotection is achieved by a modified reperfusion subsequent to a prolonged ischemic episode. Many pathways have been proposed as plausible mechanisms to explain the neuroprotection offered by preconditioning and post-conditioning. Although the mechanisms through which these two endogenous protective strategies exert their effects are not yet fully understood, recent evidence highlights that the maintenance of ionic homeostasis plays a key role in propagating these neuroprotective phenomena. The present article will review the role of protein transporters and ionic channels involved in the control of ionic homeostasis in the neuroprotective effect of ischemic preconditioning and post-conditioning in adult brain, with particular regards to the Na+/Ca2+ exchangers (NCX), the plasma membrane Ca2+-ATPase (PMCA), the Na+/H+ exchange (NHE), the Na+/K+/2Cl− cotransport (NKCC) and the acid-sensing cation channels (ASIC). Ischemic stroke is the third leading

  6. The circadian clock in skin: implications for adult stem cells, tissue regeneration, cancer, aging, and immunity

    PubMed Central

    Plikus, Maksim V.; Van Spyk, Elyse Noelani; Pham, Kim; Geyfman, Mikhail; Kumar, Vivek; Takahashi, Joseph S.; Andersen, Bogi

    2015-01-01

    Historically work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as liver, fat and muscle. In recent years, skin is emerging as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging and carcinogenesis. Morphologically skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable and exhibit prominent daily cell proliferation cycles. Hair follicle stem cells also participate in recurrent, long-lasting cycles of regeneration -- the hair growth cycles. Among other advantages of skin is a broad repertoire of available genetic tools enabling the creation of cell-type specific circadian mutants. Also, due to the accessibility of the skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar UV radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it represents a promising model system to further explore the role of the clock in the regulation of the body's immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. The skin also provides opportunities to interrogate clock regulation of tissue metabolism in the context of stem cells and regeneration. Furthermore, many animal species feature prominent seasonal hair molt cycles, offering an attractive model for investigating the

  7. The circadian clock in skin: implications for adult stem cells, tissue regeneration, cancer, aging, and immunity.

    PubMed

    Plikus, Maksim V; Van Spyk, Elyse N; Pham, Kim; Geyfman, Mikhail; Kumar, Vivek; Takahashi, Joseph S; Andersen, Bogi

    2015-06-01

    Historically, work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as the liver, fat, and muscle. In recent years, skin has emerged as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging, and carcinogenesis. Morphologically, skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable, and exhibit prominent daily cell proliferation cycles. Hair follicle stem cells also participate in recurrent, long-lasting cycles of regeneration: the hair growth cycles. Among other advantages of skin is a broad repertoire of available genetic tools enabling the creation of cell type-specific circadian mutants. Also, due to the accessibility of skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar ultraviolet (UV) radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it also represents a promising model system to further explore the role of the clock in the regulation of the body's immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. Skin also provides opportunities to interrogate the clock regulation of tissue metabolism in the context of stem cells and regeneration. Furthermore, many animal species feature prominent seasonal hair molt cycles, offering an attractive model

  8. "The preadipocyte factor" DLK1 marks adult mouse adipose tissue residing vascular cells that lack in vitro adipogenic differentiation potential.

    PubMed

    Andersen, Ditte Caroline; Jensen, Line; Schrøder, Henrik Daa; Jensen, Charlotte Harken

    2009-09-03

    Delta-like 1 (Dlk1) is expressed in 3T3-L1 preadipocytes and has frequently been referred to as "the" preadipocyte marker, yet the phenotype of DLK1(+) cells in adipose tissue remains undetermined. Herein, we demonstrate that DLK1(+) cells encompass around 1-2% of the adult mouse adipose stromal vascular fraction (SVF). Unexpectedly, the DLK1(+)SVF population was enriched for cells expressing genes generally ascribed to the vascular lineage and did not possess any adipogenic differentiation potential in vitro. Instead, DLK1(+) cells comprised an immediate ability for cobblestone formation, generation of tube-like structures on matrigel, and uptake of Acetylated Low Density-Lipoprotein, all characteristics of endothelial cells. We therefore suggest that DLK1(+)SVF cells are of a vascular origin and not them-selves committed preadipocytes as assumed hitherto.

  9. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging.

    PubMed

    Kang, S; Louboutin, J-P; Datta, P; Landel, C P; Martinez, D; Zervos, A S; Strayer, D S; Fernandes-Alnemri, T; Alnemri, E S

    2013-02-01

    mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals.

  10. Correction of Class II malocclusion and soft tissue profile in an adult patient

    PubMed Central

    Gaur, Aditi; Maheshwari, Sandhya; Verma, Sanjeev Kumar

    2016-01-01

    Treatment of Class II malocclusion in nongrowing individuals is a challenging situation for the clinician. Class II malocclusion with bialveolar protrusion often dictates premolar extractions with maximum anchorage. The present article describes the case of an adult female with skeletal Class II malocclusion, bimaxillary protrusion, increased overjet, deep bite, lip protrusion, everted lower lip, deep mentolabial sulcus, and lip incompetence. To correct the malocclusion, all four first premolars were extracted. Direct anchorage from miniscrews was used for retraction of the anterior segment. The mandibular buccal segment was protracted into the extraction space using Class II mechanics. Ideal Class I canine and molar relation were achieved in 24 months. There was a significant improvement in facial profile and smile esthetics of the patient. PMID:27630505

  11. Group B streptococcus infections of soft tissue and bone in California adults, 1995-2012.

    PubMed

    Smith, E M; Khan, M A; Reingold, A; Watt, J P

    2015-11-01

    Group B streptococcus (GBS) is an increasing cause of disease in adults. We present long-term trends in incidence of overall infections and identify characteristics of patients with GBS cellulitis, bone and joint infections. Active, population-based surveillance was conducted from 1995-2012 in three California counties and the data were analysed retrospectively. All cases had isolation of GBS from a normally sterile site. Cases of cellulitis were classified based on clinical diagnosis. GBS bone or joint infection was defined as isolation of GBS from a bone or joint or a diagnosis of osteomyelitis or septic arthritis. Medical charts were reviewed for demographic and clinical information. There were 3917 cases of GBS; the incidence of disease increased from 5·8 to 8·3 cases/100 000 persons (P < 0·001) from 1995 to 2012. In adults aged ⩾40 years, the overall incidence of GBS increased from 8·5 to 14·2 cases/100 000 (P < 0·001) persons during the study period. The incidence of cellulitis increased from 1·6 to 3·8 cases/100 000 (P < 0·001), bone infection increased from 0·7 to 2·6 cases/100 000 (P < 0·001), and the incidence of joint infection remained approximately constant at an average rate of 1·0 case/100 000. The highest incidence rates were observed in men, persons aged ⩾80 years, non-Hispanic blacks and Hispanics. Diabetes was the most common underlying condition (51·2% cellulitis cases, 76·3% bone infections, 29·8% joint infections).

  12. A Physiologist's View of Homeostasis

    ERIC Educational Resources Information Center

    Modell, Harold; Cliff, William; Michael, Joel; McFarland, Jenny; Wenderoth, Mary Pat; Wright, Ann

    2015-01-01

    Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of…

  13. Studies on renal adaptation to altered dietary amino acid intake: tissue taurine responses in nursing and adult rats.

    PubMed

    Chesney, R W; Lippincott, S; Gusowski, N; Padilla, M; Zelikovic, I

    1986-10-01

    This study examines the effect of a low sulfur amino acid diet (LTD) and a high taurine diet (HTD), compared with a normal diet, on the plasma, urine, muscle, brain and renal cortex levels of taurine in immature and adult rats. Milk taurine from lactating dams reflected the taurine content of the diet, being low in LTD-fed and high in HTD-fed animals. Nursing pups (7, 14 and 21 d old) often had plasma, urine and tissue--renal cortex, heart, skeletal muscle--levels of taurine related to dietary exposure, a situation also found in adult animals. These diets did not influence the urinary excretion of the sulfur-containing alpha-amino acids methionine and cystine but a sulfur aminoaciduria of immaturity was evident. By contrast, the content of taurine in brain was constant regardless of dietary intake of sulfur amino acids. An age-related decline in brain taurine content was found--as noted by others--but this too was influenced by diet. This dual finding of brain taurine constancy despite wide differences in sulfur amino acid intake and changes in the renal handling of taurine as influenced by diet suggest that the renal adaptive response serves to maintain the stability of brain taurine content.

  14. Expression of putative markers of pluripotency in equine embryonic and adult tissues.

    PubMed

    Esteves, Cristina L; Sharma, Ruchi; Dawson, Lucy; Taylor, Sarah E; Pearson, Gemma; Keen, John A; McDonald, Kieran; Aurich, Christine; Donadeu, F Xavier

    2014-12-01

    Expression of several putative markers of pluripotency (OCT4, SOX2, NANOG, LIN28A, REX1, DNMT3B and TERT) was examined in a range of equine tissues, including early embryos, induced pluripotent stem cells (iPSCs), testis, adipose- and bone marrow-derived mesenchymal stromal cells (MSCs), and keratinocytes. Transcript levels of all markers were highest in embryos and iPSCs and, except for SOX2, were very low or undetectable in keratinocytes. Mean expression levels of all markers were lower in testis than in embryos or iPSCs and, except for DNMT3B, were higher in testis than in MSCs. Expression of OCT4, NANOG and DNMT3B, but not the other markers, was detected in MSCs. Of all markers analysed, only LIN28A, REX1 and TERT were associated exclusively with pluripotent cells in the horse.

  15. Excessive energy intake does not modify fed-state tissue protein synthesis rates in adult rats.

    PubMed

    Adéchian, Solange; Giardina, Silvana; Rémond, Didier; Papet, Isabelle; Buonocore, Daniela; Gaudichon, Claire; Dardevet, Dominique; Marzatico, Fulvio; Mosoni, Laurent

    2009-07-01

    The impact of chronic excessive energy intake on protein metabolism is still controversial. Male Wistar rats were fed ad libitum during 5 weeks with either a high-fat high-sucrose diet (HF: n = 9) containing 45% of total energy as lipids (protein 14%; carbohydrate 40% with 83.5% sucrose) or a standard diet (controls: n = 10). Energy intake and body weight were recorded. At the end of the experiment, we measured body composition, metabolic parameters (plasma amino acid, lipid, insulin, and glucose levels), inflammatory parameter (plasma alpha2-macroglobulin), oxidative stress parameters (antioxidant enzyme activities, lipoperoxidation (LPO), protein carbonyl content in liver and muscle), and in vivo fed-state fractional protein synthesis rates (FSRs) in muscle and liver. Energy intake was significantly higher in HF compared with control rats (+28%). There were significant increases in body weight (+8%), body fat (+21%), renal (+41%), and epidydimal (+28%) fat pads in HF compared with control rats. No effect was observed in other tissue weights (liver, muscle, spleen, kidneys, intestine). Liver and muscle FSRs, plasma levels of lipids, glucose, insulin and alpha2-macroglobulin, soleus and liver glutathione reductase and peroxidase activities, MnSOD activity, LPO, and protein carbonyl content were not altered by the HF diet. Only soleus muscle and liver Cu/ZnSOD activity and soleus muscle catalase activities were reduced in HF rats compared with control rats. Thus, chronic excessive energy intake and increased adiposity, in the absence of other metabolic alterations, do not stimulate fed-state tissue protein synthesis rates.

  16. Expression of spicule matrix protein gene SM30 in embryonic and adult mineralized tissues of sea urchin Hemicentrotus pulcherrimus

    NASA Technical Reports Server (NTRS)

    Kitajima, T.; Tomita, M.; Killian, C. E.; Akasaka, K.; Wilt, F. H.

    1996-01-01

    We have isolated a cDNA clone for spicule matrix protein, SM30, from sea urchin Hemicentrotus pulcherrimus and have studied the expression of this gene in comparison with that of another spicule matrix protein gene, SM50. In cultured micromeres as well as in intact embryos transcripts of SM30 were first detectable around the onset of spicule formation and rapidly increased with the growth of spicules, which accompanied accumulation of glycosylated SM30 protein(s). When micromeres were cultured in the presence of Zn2+, spicule formation and SM30 expression were suppressed, while both events resumed concurrently after the removal of Zn2+ from the culture medium. Expression of SM50, in contrast, started before the appearance of spicules and was not sensitive to Zn2+. Differences were also observed in adult tissues; SM30 mRNA was detected in spines and tube feet but not in the test, while SM50 mRNA was apparent in all of these mineralized tissues at similar levels. These results strongly suggest that the SM30 gene is regulated by a different mechanism to that of the SM50 gene and that the products of these two genes are differently involved in sea urchin biomineralization. A possible role of SM30 protein in skeleton formation is discussed.

  17. Three-dimensional hard tissue palatal size and shape: a 10-year longitudinal evaluation in healthy adults.

    PubMed

    Ferrario, Virgilio F; Sforza, Chiarella; Dellavia, Claudia; Colombo, Anna; Ferrari, Raffaella P

    2002-01-01

    A 10-year longitudinal evaluation of the morphology (size and shape) of hard tissue palate was performed in 6 female and 6 male healthy adults (mean age at the second evaluation was 33 years, SD = 2.2). All subjects had a complete permanent dentition, including the second molars, and were free from respiratory problems. Palatal landmarks were digitized with a computerized 3D instrument, and their coordinates were used to derive a mathematical model of palatal form. Palatal shape (size-independent) was assessed by a fourth-grade polynomial in the sagittal and frontal plane projections. Palatal dimensions in the frontal and sagittal planes were computed and compared between the 2 evaluations by paired Student t tests. A great variability was observed, and no significant modifications in size were found (P > .05 for all variables). No variations in shape were observed. Sex had no significant effect for any variable (Student t for independent samples, P > .05). This study showed that in healthy subjects, hard tissue palatal morphology does not seem to change between the third and the fourth decades of life.

  18. Apoptosis, stem cells, and tissue regeneration.

    PubMed

    Bergmann, Andreas; Steller, Hermann

    2010-10-26

    Most metazoans have at least some ability to regenerate damaged cells and tissues, although the regenerative capacity varies depending on the species, organ, or developmental stage. Cell replacement and regeneration occur in two contexts: renewal of spent cells during tissue homeostasis (homeostatic growth), and in response to external injury, wounding, or amputation (epimorphic regeneration). Model organisms that display remarkable regenerative capacity include amphibians, planarians, Hydra, and the vertebrate liver. In addition, several mammalian organs--including the skin, gut, kidney, muscle, and even the human nervous system--have some ability to replace spent or damaged cells. Although the regenerative response is complex, it typically involves the induction of new cell proliferation through formation of a blastema, followed by cell specification, differentiation, and patterning. Stem cells and undifferentiated progenitor cells play an important role in both tissue homeostasis and tissue regeneration. Stem cells are typically quiescent or passing slowly through the cell cycle in adult tissues, but they can be activated in response to cell loss and wounding. A series of studies, mostly performed in Drosophila as well as in Hydra, Xenopus, and mouse, has revealed an unexpected role of apoptotic caspases in the production of mitogenic signals that stimulate the proliferation of stem and progenitor cells to aid in tissue regeneration. This Review summarizes some of the key findings and discusses links to stem cell biology and cancer.

  19. Water Homeostasis: Evolutionary Medicine

    PubMed Central

    Zeidel, Mark L.

    2012-01-01

    As a major component of homeostasis, all organisms regulate the water composition of various compartments. Through the selective use of barrier membranes and surface glycoproteins, as well as aquaporin water channels, organisms ranging from Archaebacteria to humans can vary water permeabilities across their cell membranes by 4 to 5 orders of magnitude. In barrier epithelia the outer, or exofacial, leaflet acts as the main resistor to water flow; this leaflet restricts water flow by minimizing the surface area of lipid molecules which is not covered by phosphate headgroups and by packing hydrocarbon chains at maximal density. Cells may enhance the barrier by expressing glycoproteins that augment the “thickness” of unstirred layers at their surfaces, reducing osmotic gradients at the lipid bilayer surface. Aquaporins markedly and highly selectively accelerate water flux and are “switched on” either by deployment into membranes or gating. This review summarizes these mechanisms in many species, and indicates potential roles for manipulating water permeabilities in treating disease. PMID:23303973

  20. Epigenetic regulation of iron homeostasis in Arabidopsis

    PubMed Central

    Xing, Jiewen; Wang, Tianya; Ni, Zhongfu

    2015-01-01

    Iron (Fe) is one of the most important microelement required for plant growth and development because of its unique property of catalyzing oxidation/reduction reactions. Iron deficiency impairs fundamental processes which could lead to a decrease in chlorophyll production and pollen fertility, thus influencing crop productivity and quality. However, iron in excess is toxic to the cell and is harmful to the plant. To exactly control the iron content in all tissues, plants have evolved many strategies to regulate iron homeostasis, which refers to 2 successive steps: iron uptake at the root surface, and iron distribution in vivo. In the last decades, a number of transporters and regulatory factors involved in this process have been isolated and identified. To cope with the complicated flexible environmental conditions, plants apply diverse mechanisms to regulate the expression and activity of these components. One of the most important mechanisms is epigenetic regulation of iron homeostasis. This review has been presented to provide an update on the information supporting the involvement of histone modifications in iron homeostasis and possible future course of the field. PMID:26313698

  1. Endocannabinoids and energy homeostasis: an update.

    PubMed

    Cristino, Luigia; Becker, Thorsten; Di Marzo, Vincenzo

    2014-01-01

    The endocannabinoid system (ECS) is a widespread intercellular signaling system that plays a critical role in energy homeostasis, meant as the precise matching of caloric intake with energy expenditure which normally keeps body weight stable over time. Complex interactions between environmental and neurohormonal systems directly contribute to the balance of energy homeostasis. This review highlights established and more recent data on the brain circuits in which the ECS plays an important regulatory role, with focus on the hypothalamus, a region where numerous interacting systems regulating feeding, satiety, stress, and other motivational states coexist. Although not meant as an exhaustive review of the field, this article will discuss how endocannabinoid tone, in addition to reinforcing reward circuitries and modulating food intake and the salience of food, controls lipid and glucose metabolism in several peripheral organs, particularly the liver and adipose tissue. Direct actions in the skeletal muscle and pancreas are also emerging and are briefly discussed. This review provides new perspectives into endocannabinoid control of the neurochemical causes and consequences of energy homeostasis imbalance, a knowledge that might lead to new potential treatments for obesity and related morbidities.

  2. Depleted uranium induces sex- and tissue-specific methylation patterns in adult zebrafish.

    PubMed

    Gombeau, Kewin; Pereira, Sandrine; Ravanat, Jean-Luc; Camilleri, Virginie; Cavalie, Isabelle; Bourdineaud, Jean-Paul; Adam-Guillermin, Christelle

    2016-04-01

    We examined the effects of chronic exposure to different concentrations (2 and 20 μg L(-)(1)) of environmentally relevant waterborne depleted uranium (DU) on the DNA methylation patterns both at HpaII restriction sites (5'-CCGG-3') and across the whole genome in the zebrafish brain, gonads, and eyes. We first identified sex-dependent differences in the methylation level of HpaII sites after exposure. In males, these effects were present as early as 7 days after exposure to 20 μg L(-)(1) DU, and were even more pronounced in the brain, gonads, and eyes after 24 days. However, in females, hypomethylation was only observed in the gonads after exposure to 20 μg L(-)(1) DU for 24 days. Sex-specific effects of DU were also apparent at the whole-genome level, because in males, exposure to 20 μg L(-)(1) DU for 24 days resulted in cytosine hypermethylation in the brain and eyes and hypomethylation in the gonads. In contrast, in females, hypermethylation was observed in the brain after exposure to both concentrations of DU for 7 days. Based on our current knowledge of uranium toxicity, several hypotheses are proposed to explain these findings, including the involvement of oxidative stress, alteration of demethylation enzymes and the calcium signaling pathway. This study reports, for the first time, the sex- and tissue-specific epigenetic changes that occur in a nonhuman organism after exposure to environmentally relevant concentrations of uranium, which could induce transgenerational epigenetic effects.

  3. ASICs and cardiovascular homeostasis.

    PubMed

    Abboud, François M; Benson, Christopher J

    2015-07-01

    In this review we address primarily the role of ASICs in determining sensory signals from arterial baroreceptors, peripheral chemoreceptors, and cardiopulmonary and somatic afferents. Alterations in these sensory signals during acute cardiovascular stresses result in changes in sympathetic and parasympathetic activities that restore cardiovascular homeostasis. In pathological states, however, chronic dysfunctions of these afferents result in serious sympatho-vagal imbalances with significant increases in mortality and morbidity. We identified a role for ASIC2 in the mechano-sensitivity of aortic baroreceptors and of ASIC3 in the pH sensitivity of carotid bodies. In spontaneously hypertensive rats, we reported decreased expression of ASIC2 in nodose ganglia neurons and overexpression of ASIC3 in carotid bodies. This reciprocal expression of ASIC2 and ASIC3 results in reciprocal changes in sensory sensitivity of baro- and chemoreceptors and a consequential synergistic exaggeration sympathetic nerve activity. A similar reciprocal sensory dysautonomia prevails in heart failure and increases the risk of mortality. There is also evidence that ASIC heteromers in skeletal muscle afferents contribute significantly to the exercise pressor reflex. In cardiac muscle afferents of the dorsal root ganglia, they contribute to nociception and to the detrimental sympathetic activation during ischemia. Finally, we report that an inhibitory influence of ASIC2-mediated baroreceptor activity suppresses the sympatho-excitatory reflexes of the chemoreceptors and skeletal muscle afferents, as well as the ASIC1a-mediated excitation of central neurons during fear, threat, or panic. The translational potential of activation of ASIC2 in cardiovascular disease states may be a beneficial sympatho-inhibition and parasympathetic activation. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.

  4. CCI-779 in Treating Patients With Soft Tissue Sarcoma or Gastrointestinal Stromal Tumor

    ClinicalTrials.gov

    2013-06-03

    Gastrointestinal Stromal Tumor; Recurrent Adult Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  5. Calcium homeostasis in barley aleurone

    SciTech Connect

    Jones, R.L.

    1990-02-21

    Under the auspices of the Department of Energy we investigated calcium homeostasis in aleurone cells of barley. This investigation was initiated to explore the role played by extracellular Ca{sup 2+} in gibberellic acid (GA)-induced synthesis and secretion of hydrolases in the aleurone layer. We have focused our attention on four topics that relate to the role of Ca{sup 2+} in regulating the synthesis of {alpha}-amylase. First, we determined the stoichiometry of Ca{sup 2+} binding to the two principal classes of barley {alpha}-amylase and examined some of the biochemical and physical properties of the native and Ca{sup 2+}-depleted forms of the enzyme. Second, since {alpha}-amylase is a Ca{sup 2+} containing metalloenzyme that binds one atom of Ca{sup 2+} per molecule, we developed methods to determine the concentration of Ca{sup 2+} in the cytosol of the aleurone cell. We developed a technique for introducing Ca{sup 2+}-sensitive dyes into aleurone protoplasts that allows the measurement of Ca{sup 2+} in both cytosol and endoplasmic reticulum (ER). Third, because the results of our Ca{sup 2+} measurements showed higher levels of Ca{sup 2+} in the ER than in the cytosol, we examined Ca{sup 2+} transport into the ER of control and GA-treated aleurone tissue. And fourth, we applied the technique of patch-clamping to the barley aleurone protoplast to examine ion transport at the plasma membrane. Our results with the patch-clamp technique established the presence of K{sup +} channels in the plasma membrane of the aleurone protoplast, and they showed that this cell is ideally suited for the application of this methodology for studying ion transport. 34 refs.

  6. Effects of FGF-2 on human adipose tissue derived adult stem cells morphology and chondrogenesis enhancement in Transwell culture

    SciTech Connect

    Kabiri, Azadeh; Esfandiari, Ebrahim; Hashemibeni, Batool; Kazemi, Mohammad; Mardani, Mohammad; Esmaeili, Abolghasem

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We investigated effects of FGF-2 on hADSCs. Black-Right-Pointing-Pointer We examine changes in the level of gene expressions of SOX-9, aggrecan and collagen type II and type X. Black-Right-Pointing-Pointer FGF-2 induces chondrogenesis in hADSCs, which Bullet Increasing information will decrease quality if hospital costs are very different. Black-Right-Pointing-Pointer The result of this study may be beneficial in cartilage tissue engineering. -- Abstract: Injured cartilage is difficult to repair due to its poor vascularisation. Cell based therapies may serve as tools to more effectively regenerate defective cartilage. Both adult mesenchymal stem cells (MSCs) and human adipose derived stem cells (hADSCs) are regarded as potential stem cell sources able to generate functional cartilage for cell transplantation. Growth factors, in particular the TGF-b superfamily, influence many processes during cartilage formation, including cell proliferation, extracellular matrix synthesis, maintenance of the differentiated phenotype, and induction of MSCs towards chondrogenesis. In the current study, we investigated the effects of FGF-2 on hADSC morphology and chondrogenesis in Transwell culture. hADSCs were obtained from patients undergoing elective surgery, and then cultured in expansion medium alone or in the presence of FGF-2 (10 ng/ml). mRNA expression levels of SOX-9, aggrecan and collagen type II and type X were quantified by real-time polymerase chain reaction. The morphology, doubling time, trypsinization time and chondrogenesis of hADSCs were also studied. Expression levels of SOX-9, collagen type II, and aggrecan were all significantly increased in hADSCs expanded in presence of FGF-2. Furthermore FGF-2 induced a slender morphology, whereas doubling time and trypsinization time decreased. Our results suggest that FGF-2 induces hADSCs chondrogenesis in Transwell culture, which may be beneficial in cartilage tissue engineering.

  7. Age-Dependent Changes in Geometry, Tissue Composition and Mechanical Properties of Fetal to Adult Cryopreserved Human Heart Valves.

    PubMed

    van Geemen, Daphne; Soares, Ana L F; Oomen, Pim J A; Driessen-Mol, Anita; Janssen-van den Broek, Marloes W J T; van den Bogaerdt, Antoon J; Bogers, Ad J J C; Goumans, Marie-José T H; Baaijens, Frank P T; Bouten, Carlijn V C

    2016-01-01

    There is limited information about age-specific structural and functional properties of human heart valves, while this information is key to the development and evaluation of living valve replacements for pediatric and adolescent patients. Here, we present an extended data set of structure-function properties of cryopreserved human pulmonary and aortic heart valves, providing age-specific information for living valve replacements. Tissue composition, morphology, mechanical properties, and maturation of leaflets from 16 pairs of structurally unaffected aortic and pulmonary valves of human donors (fetal-53 years) were analyzed. Interestingly, no major differences were observed between the aortic and pulmonary valves. Valve annulus and leaflet dimensions increase throughout life. The typical three-layered leaflet structure is present before birth, but becomes more distinct with age. After birth, cell numbers decrease rapidly, while remaining cells obtain a quiescent phenotype and reside in the ventricularis and spongiosa. With age and maturation-but more pronounced in aortic valves-the matrix shows an increasing amount of collagen and collagen cross-links and a reduction in glycosaminoglycans. These matrix changes correlate with increasing leaflet stiffness with age. Our data provide a new and comprehensive overview of the changes of structure-function properties of fetal to adult human semilunar heart valves that can be used to evaluate and optimize future therapies, such as tissue engineering of heart valves. Changing hemodynamic conditions with age can explain initial changes in matrix composition and consequent mechanical properties, but cannot explain the ongoing changes in valve dimensions and matrix composition at older age.

  8. Biodegradation of the ZnO:Eu nanoparticles in the tissues of adult mouse after alimentary application.

    PubMed

    Kielbik, Paula; Kaszewski, Jaroslaw; Rosowska, Julita; Wolska, Ewelina; Witkowski, Bartłomiej S; Gralak, Mikolaj A; Gajewski, Zdzisław; Godlewski, Marek; Godlewski, Michal M

    2016-11-21

    Biodegradable zinc oxide nanoparticles (ZnO NPs) are considered promising materials for future biomedical applications. To fulfil this potential, biodistribution and elimination patterns of ZnO NPs in the living organism need to be resolved. In order to investigate gastrointestinal absorption of ZnO NPs and their intra-organism distribution, water suspension of ZnO or fluorescent ZnO:Eu (Europium-doped zinc oxide) NPs (10mg/ml; 0.3ml/mouse) was alimentary-administered (IG: intra-gastric) to adult mice. Internal organs collected at key time-points after IG were evaluated by AAS for Zn concentration and analysed by cytometric techniques. We found that Zn-based NPs were readily absorbed and distributed (3 h post IG) in the nanoparticle form throughout the organism. Results suggest, that liver and kidneys were key organs responsible for NPs elimination, while accumulation was observed in the spleen and adipose tissues. We also showed that ZnO/ZnO:Eu NPs were able to cross majority of biological barriers in the organism (including blood-brain-barrier).

  9. A new method of infrared thermography for quantification of brown adipose tissue activation in healthy adults (TACTICAL): a randomized trial.

    PubMed

    Ang, Qi Yan; Goh, Hui Jen; Cao, Yanpeng; Li, Yiqun; Chan, Siew-Pang; Swain, Judith L; Henry, Christiani Jeyakumar; Leow, Melvin Khee-Shing

    2017-05-01

    The ability to alter the amount and activity of brown adipose tissue (BAT) in human adults is a potential strategy to manage obesity and related metabolic disorders associated with food, drug, and environmental stimuli with BAT activating/recruiting capacity. Infrared thermography (IRT) provides a non-invasive and inexpensive alternative to the current methods (e.g. (18)F-FDG PET) used to assess BAT. We have quantified BAT activation in the cervical-supraclavicular (C-SCV) region using IRT video imaging and a novel image computational algorithm by studying C-SCV heat production in healthy young men after cold stimulation and the ingestion of capsinoids in a prospective double-blind placebo-controlled randomized trial. Subjects were divided into low-BAT and high-BAT groups based on changes in IR emissions in the C-SCV region induced by cold. The high-BAT group showed significant increases in energy expenditure, fat oxidation, and heat output in the C-SCV region post-capsinoid ingestion compared to post-placebo ingestion, but the low-BAT group did not. Based on these results, we conclude that IRT is a promising tool for quantifying BAT activity.

  10. Stage- and tissue-specific expression of two homeo box genes in sea urchin embryos and adults.

    PubMed

    Dolecki, G J; Wang, G; Humphreys, T

    1988-12-23

    We report the isolation of two different homeo box genes, HB3 and HB4, from the Hawaiian sea urchin Tripneustes gratilla. DNA sequencing revealed a definitive Antennapedia (Antp) class homeo box in each gene. Southern transfer hybridizations showed the genes to be single-copy. A 5.7-kb transcript of the HB3 gene was found in ovary, testis, small intestine and gastrula poly(A)+ RNA. The HB4 gene produces three transcripts. A 3.7-kb and a 4.4-kb transcript are expressed during embryogenesis. A 3.5-kb transcript appears in each of the adult tissues studied. The HB4 gene appears to be the sea urchin cognate of the Drosophila infrabdominal-7 (iab-7) gene, the mouse Hox 1.7 and Hox 3.2 genes and the Xenopus X1Hbox 6 gene. An examination of Antp class homeo box genes in deuterostomes indicates that a chromosomal duplication has taken place in the evolutionary line leading to the vertebrates after the divergence of the echinoderms. Thus, the sea urchin represents the primitive condition.

  11. Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma

    ClinicalTrials.gov

    2016-11-14

    Adult Alveolar Soft Part Sarcoma; Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Hemangioendothelioma; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Undifferentiated Pleomorphic Sarcoma; Malignant Adult Hemangiopericytoma; Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  12. Building Epithelial Tissues from Skin Stem Cells

    PubMed Central

    Fuchs, E.; Nowak, J.A.

    2009-01-01

    The skin epidermis and its appendages provide a protective barrier that guards against loss of fluids, physical trauma, and invasion by harmful microbes. To perform these functions while confronting the harsh environs of the outside world, our body surface undergoes constant rejuvenation through homeostasis. In addition, it must be primed to repair wounds in response to injury. The adult skin maintains epidermal homeostasis, hair regeneration, and wound repair through the use of its stem cells. What are the properties of skin stem cells, when do they become established during embryogenesis, and how are they able to build tissues with such remarkably distinct architectures? How do stem cells maintain tissue homeostasis and repair wounds and how do they regulate the delicate balance between proliferation and differentiation? What is the relationship between skin cancer and mutations that perturbs the regulation of stem cells? In the past 5 years, the field of skin stem cells has bloomed as we and others have been able to purify and dissect the molecular properties of these tiny reservoirs of goliath potential. We report here progress on these fronts, with emphasis on our laboratory’s contributions to the fascinating world of skin stem cells. PMID:19022769

  13. Wnt signaling regulates homeostasis of the periodontal ligament

    PubMed Central

    Lim, W.H.; Liu, B.; Cheng, D.; Williams, B.O.; Mah, S.J.; Helms, J.A.

    2014-01-01

    Background and Objective In health, the periodontal ligament maintains a constant width throughout an organism’s lifetime. The molecular signals responsible for maintaining homeostatic control over the periodontal ligament are unknown. The purpose of this study was to investigate the role of Wnt signaling in this process by removing an essential chaperone protein, Wntless (Wls) from odontoblasts and cementoblasts, and observing the effects of Wnt depletion on cells of the periodontal complex. Material and Methods The Wnt responsive status of the periodontal complex was assessed using two strains of Wnt reporter mice, Axin2LacZ/+ mice and Lgr5LacZ/+. The function of this endogenous Wnt signal was evaluated by conditionally eliminating the Wntless (Wls) gene using an Osteocalcin Cre driver. The resulting OCN-Cre;Wlsfl/fl mice were examined using micro-CT and histology, immunohistochemical analyses for Osteopontin, Runx2 and Fibromodulin, in situ hybridization for Osterix, and alkaline phosphatase activity. Results The adult periodontal ligament is Wnt responsive. Elimination of Wnt signaling in the periodontal complex of OCN-Cre;Wlsfl/fl mice results in a wider periodontal ligament space. This pathologically increased periodontal width is due to a reduction in the expression of osteogenic genes and proteins, which results in thinner alveolar bone. A concomitant increase in fibrous tissue occupying the periodontal space was observed along with a disruption in the orientation of the periodontal ligament. Conclusion The periodontal ligament is a Wnt dependent tissue. Cells in the periodontal complex are Wnt responsive and eliminating an essential component of the Wnt signaling network leads to a pathological widening of the periodontal ligament space. Osteogenic stimuli are reduced and a disorganized fibrillary matrix results from depletion of Wnt signaling. Collectively, these data underscore the importance of Wnt signaling in homeostasis of the periodontal ligament

  14. Neurohypophyseal Hormones: Novel Actors of Striated Muscle Development and Homeostasis

    PubMed Central

    Costa, Alessandra; Rossi, Eleonora; Scicchitano, Bianca Maria; Coletti, Dario; Moresi, Viviana

    2014-01-01

    Since the 1980’s, novel functional roles of the neurohypophyseal hormones vasopressin and oxytocin have emerged. Several studies have investigated the effects of these two neurohormones on striated muscle tissues, both in vitro and in vivo. The effects of vasopressin on skeletal myogenic cells, developing muscle and muscle homeostasis have been documented. Oxytocin appears to have a greater influence on cardiomyocite differentiation and heart homeostasis. This review summarizes the studies on these novel roles of the two neurohypophyseal hormones, and open the possibility of new therapeutic approaches for diseases affecting striated muscle. PMID:26913138

  15. Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease.

    PubMed

    Puri, Sapna; Folias, Alexandra E; Hebrok, Matthias

    2015-01-08

    Cellular identity is established by genetic, epigenetic, and environmental factors that regulate organogenesis and tissue homeostasis. Although some flexibility in fate potential is beneficial to overall organ health, dramatic changes in cellular identity can have disastrous consequences. Emerging data within the field of pancreas biology are revising current beliefs about how cellular identity is shaped by developmental and environmental cues under homeostasis and stress conditions. Here, we discuss the changes occurring in cellular states upon fate modulation and address how our understanding of the nature of this fluidity is shaping therapeutic approaches to pancreatic disorders such as diabetes and cancer.

  16. Lifespan Extension by Preserving Proliferative Homeostasis in Drosophila

    PubMed Central

    Supoyo, Stephen; DeGennaro, Matthew; Lehmann, Ruth; Jasper, Heinrich

    2010-01-01

    Regenerative processes are critical to maintain tissue homeostasis in high-turnover tissues. At the same time, proliferation of stem and progenitor cells has to be carefully controlled to prevent hyper-proliferative diseases. Mechanisms that ensure this balance, thus promoting proliferative homeostasis, are expected to be critical for longevity in metazoans. The intestinal epithelium of Drosophila provides an accessible model in which to test this prediction. In aging flies, the intestinal epithelium degenerates due to over-proliferation of intestinal stem cells (ISCs) and mis-differentiation of ISC daughter cells, resulting in intestinal dysplasia. Here we show that conditions that impair tissue renewal lead to lifespan shortening, whereas genetic manipulations that improve proliferative homeostasis extend lifespan. These include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK) signaling activities, as well as over-expression of stress-protective genes in somatic stem cell lineages. Interestingly, proliferative activity in aging intestinal epithelia correlates with longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited. Our results highlight the importance of the balance between regenerative processes and strategies to prevent hyperproliferative disorders and demonstrate that promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan. PMID:20976250

  17. Calcium and vitamin D supplementation is associated with decreased abdominal visceral adipose tissue in overweight and obese adults1234

    PubMed Central

    Rosenblum, Jennifer L; Castro, Victor M; Moore, Carolyn E; Kaplan, Lee M

    2012-01-01

    Background: Several studies suggest that calcium and vitamin D (CaD) may play a role in the regulation of abdominal fat mass. Objective: This study investigated the effect of CaD-supplemented orange juice (OJ) on weight loss and reduction of visceral adipose tissue (VAT) in overweight and obese adults (mean ± SD age: 40.0 ± 12.9 y). Design: Two parallel, double-blind, placebo-controlled trials were conducted with either regular or reduced-energy (lite) orange juice. For each 16-wk trial, 171 participants were randomly assigned to 1 of 2 groups. The treatment groups consumed three 240-mL glasses of OJ (regular or lite) fortified with 350 mg Ca and 100 IU vitamin D per serving, and the control groups consumed either unfortified regular or lite OJ. Computed tomography scans of VAT and subcutaneous adipose tissue were performed by imaging a single cut at the lumbar 4 level. Results: After 16 wk, the average weight loss (∼2.45 kg) did not differ significantly between groups. In the regular OJ trial, the reduction of VAT was significantly greater (P = 0.024) in the CaD group (−12.7 ± 25.0 cm2) than in the control group (−1.3 ± 13.6 cm2). In the lite OJ trial, the reduction of VAT was significantly greater (P = 0.039) in the CaD group (−13.1 ± 18.4 cm2) than in the control group (−6.4 ± 17.5 cm2) after control for baseline VAT. The effect of calcium and vitamin D on VAT remained highly significant when the results of the 2 trials were combined (P = 0.007). Conclusions: The findings suggest that calcium and/or vitamin D supplementation contributes to a beneficial reduction of VAT. This trial is registered at clinicaltrial.gov as NCT00386672, NCT01363115. PMID:22170363

  18. Diseases of Pulmonary Surfactant Homeostasis

    PubMed Central

    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

  19. Maternal dietary restriction alters offspring's sleep homeostasis.

    PubMed

    Shimizu, Noriyuki; Chikahisa, Sachiko; Nishi, Yuina; Harada, Saki; Iwaki, Yohei; Fujihara, Hiroaki; Kitaoka, Kazuyoshi; Shiuchi, Tetsuya; Séi, Hiroyoshi

    2013-01-01

    Nutritional state in the gestation period influences fetal growth and development. We hypothesized that undernutrition during gestation would affect offspring sleep architecture and/or homeostasis. Pregnant female mice were assigned to either control (fed ad libitum; AD) or 50% dietary restriction (DR) groups from gestation day 12 to parturition. After parturition, dams were fed AD chow. After weaning, the pups were also fed AD into adulthood. At adulthood (aged 8-9 weeks), we carried out sleep recordings. Although offspring mice displayed a significantly reduced body weight at birth, their weights recovered three days after birth. Enhancement of electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (NREM) sleep was observed in the DR mice over a 24-hour period without changing the diurnal pattern or amounts of wake, NREM, or rapid eye movement (REM) sleep. In addition, DR mice also displayed an enhancement of EEG-SWA rebound after a 6-hour sleep deprivation and a higher threshold for waking in the face of external stimuli. DR adult offspring mice exhibited small but significant increases in the expression of hypothalamic peroxisome proliferator-activated receptor α (Pparα) and brain-specific carnitine palmitoyltransferase 1 (Cpt1c) mRNA, two genes involved in lipid metabolism. Undernutrition during pregnancy may influence sleep homeostasis, with offspring exhibiting greater sleep pressure.

  20. Cellular Cholesterol Homeostasis in Alzheimer's Disease.

    PubMed

    Chang, Ta Yuan; Yamauchi, Yoshio; Hasan, Mazahir; Chang, Catherine Cy

    2017-03-15

    Alzheimer's disease [AD] is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid beta peptides [Abeta; especially Abeta1-42], and neurofibrillary tangles, composed of hyper-phosphorylated tau, accompanied with chronic neuroinflammation. Abeta are derived from the amyloid precursor protein APP. The oligomeric form of Abeta is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques. ApoE is the major cholesterol transport protein in the CNS that has three alleles, of which the Apoe4 allele constitutes the major risk factor for late onset AD [LOAD]. In this review we describe the complex relationship between ApoE4, oligomeric Abeta peptides, and cholesterol homeostasis. The review consists of four parts: 1. Key elements involved in cellular cholesterol metabolism and regulation; II. Key elements involved in intracellular cholesterol trafficking; III. Links between ApoE4, Abeta, and disturbance of cholesterol homeostasis in the CNS; IV. Potential lipid based therapeutic targets to treat AD. At the end, we recommend several research topics that we believe would help in better understanding the connection between cholesterol and AD for further investigations.

  1. Primary intracranial soft tissue sarcomas in children, adolescents, and young adults: single institution experience and review of the literature.

    PubMed

    Maher, Ossama M; Khatua, Soumen; Mukherjee, Devashis; Olar, Adriana; Lazar, Alexander; Luthra, Raja; Liu, Diane; Wu, Jimin; Ketonen, Leena; Zaky, Wafik

    2016-03-01

    There is a paucity of literature reporting the outcome of intracranial sarcomas (IS) in children, adolescents, and young adults (CAYA). A multimodal therapeutic approach is commonly used, with no well-established treatment consensus. We conducted a retrospective review of CAYA with IS, treated at our institution, to determine their clinical findings, treatments, and outcomes. Immunohistochemistry (PDGFRA and EGFR) and DNA sequencing were performed on 5 tumor samples. A literature review of IS was also conducted. We reviewed 13 patients (median age, 7 years) with a primary diagnosis of IS between 1990 and 2015. Diagnoses included unclassified sarcoma (n = 9), chondrosarcoma (n = 2), and rhabdomyosarcoma (n = 2). Five patients underwent upfront gross total resection (GTR) of the tumor. The 5-drug regimen (vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide) was the most common treatment used. Nine patients died due to progression or recurrence (n = 8) or secondary malignancy (n = 1). The median follow-up period of the 4 surviving patients was 1.69 years (range 1.44-5.17 years). The 5-year progression-free survival and overall survival rates were 21 and 44 %, respectively. BRAF, TP53, KRAS, KIT, ERBB2, MET, RET, ATM, and EGFR mutations were detected in 4 of the 5 tissue samples. All 5 samples were immunopositive for PDGFRA, and only 2 were positive for EGFR. IS remain a therapeutic challenge due to high progression and recurrence rates. Collaborative multi-institutional studies are warranted to delineate a treatment consensus and investigate tumor biology to improve the disease outcome.

  2. Sensorimotor experience influences recovery of forelimb abilities but not tissue loss after focal cortical compression in adult rats.

    PubMed

    Martinez, Marina; Brezun, Jean-Michel; Xerri, Christian

    2011-02-16

    Sensorimotor activity has been shown to play a key role in functional outcome after extensive brain damage. This study was aimed at assessing the influence of sensorimotor experience through subject-environment interactions on the time course of both lesion and gliosis volumes as well as on the recovery of forelimb sensorimotor abilities following focal cortical injury. The lesion consisted of a cortical compression targeting the forepaw representational area within the primary somatosensory cortex of adult rats. After the cortical lesion, rats were randomly subjected to various postlesion conditions: unilateral C5-C6 dorsal root transection depriving the contralateral cortex from forepaw somatosensory inputs, standard housing or an enriched environment promoting sensorimotor experience and social interactions. Behavioral tests were used to assess forelimb placement during locomotion, forelimb-use asymmetry, and forepaw tactile sensitivity. For each group, the time course of tissue loss was described and the gliosis volume over the first postoperative month was evaluated using an unbiased stereological method. Consistent with previous studies, recovery of behavioral abilities was found to depend on post-injury experience. Indeed, increased sensorimotor activity initiated early in an enriched environment induced a rapid and more complete behavioral recovery compared with standard housing. In contrast, severe deprivation of peripheral sensory inputs led to a delayed and only partial sensorimotor recovery. The dorsal rhizotomy was found to increase the perilesional gliosis in comparison to standard or enriched environments. These findings provide further evidence that early sensory experience has a beneficial influence on the onset and time course of functional recovery after focal brain injury.

  3. Disorders of erythrocyte volume homeostasis.

    PubMed

    Glogowska, E; Gallagher, P G

    2015-05-01

    Inherited disorders of erythrocyte volume homeostasis are a heterogeneous group of rare disorders with phenotypes ranging from dehydrated to overhydrated erythrocytes. Clinical, laboratory, physiologic, and genetic heterogeneities characterize this group of disorders. A series of recent reports have provided novel insights into our understanding of the genetic bases underlying some of these disorders of red cell volume regulation. This report reviews this progress in understanding determinants that influence erythrocyte hydration and how they have yielded a better understanding of the pathways that influence cellular water and solute homeostasis.

  4. Origins and Hallmarks of Macrophages: Development, Homeostasis, and Disease

    PubMed Central

    Wynn, Thomas A.; Chawla, Ajay; Pollard, Jeffrey W.

    2013-01-01

    Preface Macrophages the most plastic cells of the hematopoietic system are found in all tissues and exhibit great functional diversity. They have roles in development, homeostasis, tissue repair, and immunity. While anatomically distinct, resident tissue macrophages exhibit different transcriptional profiles, and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this review, we discuss how macrophages regulate normal physiology and development and provide several examples of their pathophysiologic roles in disease. We define the “hallmarks” of macrophages performing particular functions, taking into account novel insights into the diversity of their lineages, identity, and regulation. This diversity is essential to understand because macrophages have emerged as important therapeutic targets in many important human diseases. PMID:23619691

  5. The alteration of copper homeostasis in inflammation induced by lipopolysaccharides.

    PubMed

    Han, Ming; Lin, Zhexuan; Zhang, Yuan

    2013-08-01

    Significant changes of copper homeostasis were triggered by lipopolysaccharides, which result in systemic inflammatory response and contribute to hepatic injury. Administration of lipopolysaccharides resulted in the increase of plasma "free" copper and total copper concentrations, whereas, the decrease of "free" copper and total copper contents in liver tissue. Copper-associated proteins were detected and showed a down-regulation of X-linked inhibitor of apoptosis protein, and up-regulation of copper metabolism domain containing 1 and copper transporter 1. The alteration of these proteins would lower the apoptotic threshold. Meanwhile, the increasing of circulation copper might cause oxidative injury through Fenton reaction and contribute to tissue injury. Our findings underscored the possibility that these changes in systemic copper homeostasis might provide a novel insight of the characteristic of the acute phase of inflammatory response and the underlying influence on tissue injury.

  6. Immune regulation of metabolic homeostasis in health and disease

    PubMed Central

    Brestoff, Jonathan R.; Artis, David

    2015-01-01

    Obesity is an increasingly prevalent disease worldwide. While genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases, emerging studies indicate that innate and adaptive immune cell responses in adipose tissue have critical roles in the regulation of metabolic homeostasis. In the lean state, type 2 cytokine-associated immune cell responses predominate in white adipose tissue and protect against weight gain and insulin resistance through direct effects on adipocytes and elicitation of beige adipose. In obesity, these metabolically beneficial immunologic pathways become dysregulated, and adipocytes and other factors initiate metabolically deleterious type 1 inflammation that impairs glucose metabolism. This review discusses our current understanding of the functions of different types of adipose tissue, how immune cells regulate adipocyte function and metabolic homeostasis in the context of health and disease, and highlights the potential of targeting immuno-metabolic pathways as a therapeutic strategy to treat obesity and associated diseases. PMID:25815992

  7. Promoting longevity by maintaining metabolic and proliferative homeostasis

    PubMed Central

    Wang, Lifen; Karpac, Jason; Jasper, Heinrich

    2014-01-01

    Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster. The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality. Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine. PMID:24353210

  8. Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice

    PubMed Central

    Moresi, Viviana; Carrer, Michele; Grueter, Chad E.; Rifki, Oktay F.; Shelton, John M.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

    2012-01-01

    Maintenance of skeletal muscle structure and function requires efficient and precise metabolic control. Autophagy plays a key role in metabolic homeostasis of diverse tissues by recycling cellular constituents, particularly under conditions of caloric restriction, thereby normalizing cellular metabolism. Here we show that histone deacetylases (HDACs) 1 and 2 control skeletal muscle homeostasis and autophagy flux in mice. Skeletal muscle-specific deletion of both HDAC1 and HDAC2 results in perinatal lethality of a subset of mice, accompanied by mitochondrial abnormalities and sarcomere degeneration. Mutant mice that survive the first day of life develop a progressive myopathy characterized by muscle degeneration and regeneration, and abnormal metabolism resulting from a blockade to autophagy. HDAC1 and HDAC2 regulate skeletal muscle autophagy by mediating the induction of autophagic gene expression and the formation of autophagosomes, such that myofibers of mice lacking these HDACs accumulate toxic autophagic intermediates. Strikingly, feeding HDAC1/2 mutant mice a high-fat diet from the weaning age releases the block in autophagy and prevents myopathy in adult mice. These findings reveal an unprecedented and essential role for HDAC1 and HDAC2 in maintenance of skeletal muscle structure and function and show that, at least in some pathological conditions, myopathy may be mitigated by dietary modifications. PMID:22307625

  9. Compound- and sex-specific effects on programming of energy and immune homeostasis in adult C57BL/6JxFVB mice after perinatal TCDD and PCB 153.

    PubMed

    van Esterik, J C J; Verharen, H W; Hodemaekers, H M; Gremmer, E R; Nagarajah, B; Kamstra, J H; Dollé, M E T; Legler, J; van der Ven, L T M

    2015-12-01

    Early life exposure to endocrine disrupting compounds has been linked to chronic diseases later in life, like obesity and related metabolic disorders. We exposed C57BL/6JxFVB hybrid mice to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the constitutive androstane receptor/pregnane X receptor agonist polychlorinated biphenyl 153 (PCB 153) in an experimental design relevant for human exposure. Exposure occurred during gestation and lactation via maternal feed to a wide dose range (TCDD: 10-10,000 pg/kg body weight/day; PCB 153: 0.09-1406 μg/kg body weight/d). Then exposure was ceased and offspring were followed up to 1 year of age. Metabolic parameters like body weight, fat pad weights, glucose tolerance, endocrine serum profile, and neurobehavioral and immunological parameters were determined. Body weight was transiently affected by both compounds throughout the follow-up. TCDD-exposed males showed decreased fat pad and spleen weights and an increase in IL-4 production of splenic immune cells. In contrast, females showed increased fat pad weights and production of IFNγ. PCB 153-exposed males showed an increase in glucose, whereas females showed an increase in glucagon, a decrease in pancreas weight, and an increase in thymus weight. In conclusion, early life exposure to TCDD appears to affect programming of energy and immune homeostasis in offspring, whereas the effects of perinatal PCB 153 were mainly on programming of glucose homeostasis. Both compounds act sex-specifically. Lowest derived BMDLs (lower bounds of the (two sided) 90%-confidence interval for the benchmark dose) for both compounds are not lower than current tolerable daily intakes.

  10. Air pollution particles and iron homeostasis | Science ...

    EPA Pesticide Factsheets

    Background: The mechanism underlying biological effects of particles deposited in the lung has not been defined. Major Conclusions: A disruption in iron homeostasis follows exposure of cells to all particulate matter including air pollution particles. Following endocytosis, functional groups at the surface of retained particle complex iron available in the cell. In response to a reduction in concentrations of requisite iron, a functional deficiency can result intracellularly. Superoxide production by the cell exposed to a particle increases ferrireduction which facilitates import of iron with the objective being the reversal of the metal deficiency. Failure to resolve the functional iron deficiency following cell exposure to particles activates kinases and transcription factors resulting in a release of inflammatory mediators and inflammation. Tissue injury is the end product of this disruption in iron homeostasis initiated by the particle exposure. Elevation of available iron to the cell precludes deficiency of the metal and either diminishes or eliminates biological effects.General Significance: Recognition of the pathway for biological effects after particle exposure to involve a functional deficiency of iron suggests novel therapies such as metal supplementation (e.g. inhaled and oral). In addition, the demonstration of a shared mechanism of biological effects allows understanding the common clinical, physiological, and pathological presentation fol

  11. Vitamin D, calcium homeostasis and aging

    PubMed Central

    Veldurthy, Vaishali; Wei, Ran; Oz, Leyla; Dhawan, Puneet; Jeon, Yong Heui; Christakos, Sylvia

    2016-01-01

    Osteoporosis is characterized by low bone mass and microarchitecture deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk. Evidence is accumulating for an important role of calcium deficiency as the process of aging is associated with disturbed calcium balance. Vitamin D is the principal factor that maintains calcium homeostasis. Increasing evidence indicates that the reason for disturbed calcium balance with age is inadequate vitamin D levels in the elderly. In this article, an overview of our current understanding of vitamin D, its metabolism, and mechanisms involved in vitamin D-mediated maintenance of calcium homeostasis is presented. In addition, mechanisms involved in age-related dysregulation of 1,25(OH)2D3 action, recommended daily doses of vitamin D and calcium, and the use of vitamin D analogs for the treatment of osteoporosis (which remains controversial) are reviewed. Elucidation of the molecular pathways of vitamin D action and modifications that occur with aging will be an active area of future research that has the potential to reveal new therapeutic strategies to maintain calcium balance. PMID:27790378

  12. A method for high purity intestinal epithelial cell culture from adult human and murine tissues for the investigation of innate immune function.

    PubMed

    Graves, Christina L; Harden, Scott W; LaPato, Melissa; Nelson, Michael; Amador, Byron; Sorenson, Heather; Frazier, Charles J; Wallet, Shannon M

    2014-12-01

    Intestinal epithelial cells (IECs) serve as an important physiologic barrier between environmental antigens and the host intestinal immune system. Thus, IECs serve as a first line of defense and may act as sentinel cells during inflammatory insults. Despite recent renewed interest in IEC contributions to host immune function, the study of primary IEC has been hindered by lack of a robust culture technique, particularly for small intestinal and adult tissues. Here, a novel adaptation for culture of primary IEC is described for human duodenal organ donor tissue as well as duodenum and colon of adult mice. These epithelial cell cultures display characteristic phenotypes and are of high purity. In addition, the innate immune function of human primary IEC, specifically with regard to Toll-like receptor (TLR) expression and microbial ligand responsiveness, is contrasted with a commonly used intestinal epithelial cell line (HT-29). Specifically, TLR expression at the mRNA level and production of cytokine (IFNγ and TNFα) in response to TLR agonist stimulation is assessed. Differential expression of TLRs as well as innate immune responses to ligand stimulation is observed in human-derived cultures compared to that of HT-29. Thus, use of this adapted method to culture primary epithelial cells from adult human donors and from adult mice will allow for more appropriate studies of IECs as innate immune effectors.

  13. Detection and quantification of a very high density lipoprotein in different tissues of Triatoma infestans during the last nymphal and adult stages.

    PubMed

    Rimoldi, O J; Córsico, B; González, M S; Brenner, R R

    1996-07-01

    The presence of a very high density lipoprotein (VHDL), an hexameric protein, was explored in different tissues of Triatoma infestans throughout the last nymphal and adult stages, and in egg extracts by Western blot assays. The VHDL was always detected in both, hemolymph and fat body, during the above mentioned stages and it was also observed in the buffer soluble fraction of testis and egg homogenates. An enzyme-linked immunosorbent assay (ELISA) was used to measure the VHDL titer in these tissues. Hemolymph VHDL reaches a maximum value before the last molt, then it abruptly declines in males and females just after emergence, but during adult life it increases again. Fat body VHDL decreases slowly and continuously during the nymph growth reaching a minimum value prior to molting, and in the first week of adult life the values were even two-fold lower; then, it shows a different cycle of accumulation and depletion in males and females. In adult testis the VHDL undergoes a cycle similar to the one observed in male fat body. This protein increases progressively during embryonic development and, at the time of larval hatching it reaches its maximum value. The hexameric protein presents homologies in its N-terminal sequence with storage hexamerins of Diptera, Lepidoptera and Hymenoptera.

  14. Two distinct roles of the yorkie/yap gene during homeostasis in the planarian Dugesia japonica.

    PubMed

    Hwang, Byulnim; An, Yang; Agata, Kiyokazu; Umesono, Yoshihiko

    2015-04-01

    Adult planarians possess somatic pluripotent stem cells called neoblasts that give rise to all missing cell types during regeneration and homeostasis. Recent studies revealed that the Yorkie (Yki)/Yes-associated protein (YAP) transcriptional coactivator family plays an important role in the regulation of tissue growth during development and regeneration, and therefore we investigated the role of a planarian yki-related gene (termed Djyki) during regeneration and homeostasis of the freshwater planarian Dugesia japonica. We found that knockdown of the function of Djyki by RNA interference (RNAi) downregulated neoblast proliferation and caused regeneration defects after amputation. In addition, Djyki RNAi caused edema during homeostasis. These seemingly distinct defects induced by Djyki RNAi were rescued by simultaneous RNAi of a planarian mats-related gene (termed Djmats), suggesting an important role of Djmats in the negative regulation of Djyki, in accordance with the conservation of the functional relationship of these two genes during the course of evolution. Interestingly, Djyki RNAi did not prevent normal protonephridial structure, suggesting that Djyki RNAi induced the edema phenotype without affecting the excretory system. Further analyses revealed that increased expression of the D. japonica gene DjaquaporinA (DjaqpA), which belongs to a large gene family that encodes a water channel protein for the regulation of transcellular water flow, promoted the induction of edema, but not defects in neoblast dynamics, in Djyki(RNAi) animals. Thus, we conclude that Djyki plays two distinct roles in the regulation of active proliferation of stem cells and in osmotic water transport across the body surface in D. japonica.

  15. Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma

    ClinicalTrials.gov

    2016-11-03

    Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  16. Integrin α1β1 is involved in the differentiation into myofibroblasts in adult reactive tissues in vivo

    PubMed Central

    Rodriguez, Alejandro; Karen, Jakob; Gardner, Humphrey; Gerdin, Bengt; Rubin, Kristofer; Sundberg, Christian

    2009-01-01

    Connective tissue cell activation is of importance during reactive conditions such as solid tumour growth, wound healing and pannus formation in rheumatoid arthritis. Here, we have compared connective tissue cells of mesenchymal origin in human tissues from these conditions and their normal counterparts using a panel of cell-type-specific markers. In particular, we investigated variations of integrin expression among connective tissue cell phenotypes. Connective tissue cell populations were defined based on their association with the microvasculature and their expression of activation markers. The phenotype of these cells varied according to the type of pathological connective tissue examined. Our morphological data from human tissues suggested that the α1β1 integrin, a collagen/laminin receptor, is involved in the differentiation of precursor cells into myofibroblasts. To mechanistically investigate this hypothesis, we employed experimental models for carcinoma growth and wound healing utilizing α1 integrin-deficient mice. The data confirmed that the α1β1 integrin is of importance not only for the differentiation of mesenchymal cells into myofibroblasts but also for the neovascularization and connective tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of tissue repair, inflammation and tumour growth. PMID:19397781

  17. Reflex Principles of Immunological Homeostasis

    PubMed Central

    Andersson, Ulf; Tracey, Kevin J.

    2015-01-01

    The reasoning that neural reflexes maintain homeostasis in other body organs, and that the immune system is innervated, prompted a search for neural circuits that regulate innate and adaptive immunity. This elucidated the inflammatory reflex, a prototypical reflex circuit that maintains immunological homeostasis. Molecular products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors (α7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. Herein is reviewed the neurophysiological basis of reflexes that provide stability to the immune system, the neural- and receptor-dependent mechanisms, and the potential opportunities for developing novel therapeutic devices and drugs that target neural pathways to treat inflammatory diseases. PMID:22224768

  18. Three-component homeostasis control

    NASA Astrophysics Data System (ADS)

    Xu, Jin; Hong, Hyunsuk; Jo, Junghyo

    2014-03-01

    Two reciprocal components seem to be sufficient to maintain a control variable constant. However, pancreatic islets adapt three components to control glucose homeostasis. They are α (secreting glucagon), β (insulin), and δ (somatostatin) cells. Glucagon and insulin are the reciprocal hormones for increasing and decreasing blood glucose levels, while the role of somatostatin is unknown. However, it has been known how each hormone affects other cell types. Based on the pulsatile hormone secretion and the cellular interactions, this system can be described as coupled oscillators. In particular, we used the Landau-Stuart model to consider both amplitudes and phases of hormone oscillations. We found that the presence of the third component, δ cell, was effective to resist under glucose perturbations, and to quickly return to the normal glucose level once perturbed. Our analysis suggested that three components are necessary for advanced homeostasis control.

  19. Peripheral Serotonin: a New Player in Systemic Energy Homeostasis.

    PubMed

    Namkung, Jun; Kim, Hail; Park, Sangkyu

    2015-12-01

    Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment.

  20. ROS homeostasis and metabolism: a critical liaison for cancer therapy

    PubMed Central

    Kim, Jongdoo; Kim, Jaehong; Bae, Jong-Sup

    2016-01-01

    Evidence indicates that hypoxia and oxidative stress can control metabolic reprogramming of cancer cells and other cells in tumor microenvironments and that the reprogrammed metabolic pathways in cancer tissue can also alter the redox balance. Thus, important steps toward developing novel cancer therapy approaches would be to identify and modulate critical biochemical nodes that are deregulated in cancer metabolism and determine if the therapeutic efficiency can be influenced by changes in redox homeostasis in cancer tissues. In this review, we will explore the molecular mechanisms responsible for the metabolic reprogramming of tumor microenvironments, the functional modulation of which may disrupt the effects of or may be disrupted by redox homeostasis modulating cancer therapy. PMID:27811934

  1. A multistep procedure to prepare pre-vascularized cardiac tissue constructs using adult stem sells, dynamic cell cultures, and porous scaffolds

    PubMed Central

    Pagliari, Stefania; Tirella, Annalisa; Ahluwalia, Arti; Duim, Sjoerd; Goumans, Marie-Josè; Aoyagi, Takao; Forte, Giancarlo

    2014-01-01

    The vascularization of tissue engineered products represents a key issue in regenerative medicine which needs to be addressed before the translation of these protocols to the bedside can be foreseen. Here we propose a multistep procedure to prepare pre-vascularized three-dimensional (3D) cardiac bio-substitutes using dynamic cell cultures and highly porous biocompatible gelatin scaffolds. The strategy adopted exploits the peculiar differentiation potential of two distinct subsets of adult stem cells to obtain human vascularized 3D cardiac tissues. In the first step of the procedure, human mesenchymal stem cells (hMSCs) are seeded onto gelatin scaffolds to provide interconnected vessel-like structures, while human cardiomyocyte progenitor cells (hCMPCs) are stimulated in vitro to obtain their commitment toward the cardiac phenotype. The use of a modular bioreactor allows the perfusion of the whole scaffold, providing superior performance in terms of cardiac tissue maturation and cell survival. Both the cell culture on natural-derived polymers and the continuous medium perfusion of the scaffold led to the formation of a densely packaged proto-tissue composed of vascular-like and cardiac-like cells, which might complete maturation process and interconnect with native tissue upon in vivo implantation. In conclusion, the data obtained through the approach here proposed highlight the importance to provide stem cells with complementary signals in vitro able to resemble the complexity of cardiac microenvironment. PMID:24917827

  2. Association between vitamin D metabolites in fat tissue and serum 25-hydroxy vitamin D in overweight and obese adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cholecalciferol has been measured in human white adipose tissue (WAT), but little is known about the relationship between the other circulating vitamin D metabolites and WAT. We measured concentrations of 25(OH)D and 1,25(OH)2D in subcutaneous fat tissue from 20 overweight and obese subjects partic...

  3. Lack of an association of depression with n-3 polyunsaturated fatty acids in adipose tissue and serum phospholipids in healthy adults.

    PubMed

    Mamalakis, George; Kiriakakis, Michael; Tsibinos, George; Jansen, Eugene; Cremers, Hans; Strien, Carlo; Hatzis, Christos; Moschandreas, Joanna; Linardakis, Manolis; Kromhout, Daan; Kafatos, Anthony

    2008-03-01

    Studies have shown that depression relates to biomarkers of both short-term and long-term polyunsaturated fatty acid intake. However, it is not known which of these two biomarkers is more closely related to depression. The aim of this study was to examine the relationship of depression with both adipose tissue and serum phospholipid polyunsaturated fatty acids and to assess the importance of each of these two biomarkers in relating to depression. This is a cross-sectional study of healthy adults from the island of Crete. Subjects were examined by the Preventive Medicine and Nutrition Clinic of the University of Crete. Subjects were 394 healthy adults (175 males, 219 females) aged 18-60. The sample consisted of farmers from a number of rural communities of Crete. Fatty acids were determined by gas chromatography in adipose tissue and serum phospholipids. Information about depression was obtained through the Beck Depression Inventory (BDI) and Zung Self-rating Depression Scale (ZSRDS). Adipose tissue alpha-linolenic acid (ALA) (C18:3n-3) was inversely correlated to BDI (r=-0.17, p<0.02). Multiple linear regression analysis taking into account the possible confounding effect of age, gender, body mass index (BMI), smoking and educational level did not confirm this association. The other polyunsaturated fatty acids in adipose tissue were not related to depression. Serum phospholipid polyunsaturated fatty acids did not correlate with depression. This study did not show that the polyunsaturated fatty acids in the adipose tissue are better predictors of depression than those in serum phospholipids.

  4. Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver.

    PubMed

    Harmon, Cathal; Robinson, Mark W; Fahey, Ronan; Whelan, Sarah; Houlihan, Diarmaid D; Geoghegan, Justin; O'Farrelly, Cliona

    2016-09-01

    The adult human liver is enriched with natural killer (NK) cells, accounting for 30-50% of hepatic lymphocytes, which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells have altered expression of the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes). Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations. Hepatic NK cells were isolated from donor liver perfusates and biopsies obtained during orthotopic liver transplantation (N = 28). Hepatic CD56(bright) NK cells were Eomes(hi) T-bet(lo) , a phenotype virtually absent from peripheral blood. These NK cells express the chemokine receptor CXCR6 (chemokine (C-X-C motif) receptor 6), a marker of tissue residency, which is absent from hepatic CD56(dim) and blood NK cells. Compared to blood populations, these hepatic CD56(bright) NK cells have increased expression of activatory receptors (NKp44, NKp46, and NKG2D). They show reduced ability to produce IFN-γ but enhanced degranulation in response to challenge with target cells. This functionally distinct population of hepatic NK cells constitutes 20-30% of the total hepatic lymphocyte repertoire and represents a tissue-resident immune cell population adapted to the tolerogenic liver microenvironment.

  5. The effect of in vivo hydrocortisone administration on the labelling index and size of chromaffin tissue in the postnatal and adult mouse.

    PubMed Central

    Monkhouse, W S

    1986-01-01

    Hydrocortisone administration in vivo to neonatal mice for seven days led to a significant increase in both the size and the labelling index of extra-adrenal chromaffin tissue (as represented by the para-aortic body) of 8 days old mice. In untreated animals at this age, the para-aortic body was in most cases too small to obtain a valid labelling index. In the para-aortic bodies of 14 days old, 21 days old and adult mice, the extra-adrenal chromaffin tissue was too dispersed to obtain values for either volumetric analysis or labelling indices, and hydrocortisone was without significant effect in promoting a hyperplastic response. In the postnatal adrenal medulla at all ages studied, hydrocortisone had no effect on the medullary size or on the labelling indices of either adrenaline- or noradrenaline-storing cells, although it led to a marked diminution of adrenocortical volume. The relative proportion of adrenaline-storing cells increased between the values for 8 days old animals and those for adults; this was unaffected by hydrocortisone. The cortico-medullary ratio remained unchanged from the eighth postnatal day onwards. The results are discussed and related to those of other workers. It is suggested that factors as yet unknown might modulate the response to corticosteroids of developing intra- and extra-adrenal chromaffin tissue. Images Fig. 1 Fig. 2 PMID:3693040

  6. Pathogen recognition or homeostasis? APC receptor functions in innate immunity.

    PubMed

    Gordon, Siamon

    2004-06-01

    Myeloid cells (macrophages, neutrophils, dendritic cells) express a repertoire of plasma membrane receptors able to recognize all classes of macromolecules. The concept of pattern recognition has emphasized microbial ligands and host defence. However, these receptors play a broader role in tissue homeostasis within multicellular hosts, clearing the extracellular environment of potential undesirable ligands arising endogenously as well as from without. This article will evaluate one of the paradigms that underlie innate immunity.

  7. Comparison of gene-specific DNA methylation patterns in equine induced pluripotent stem cell lines with cells derived from equine adult and fetal tissues.

    PubMed

    Hackett, Catherine H; Greve, Line; Novakofski, Kira D; Fortier, Lisa A

    2012-07-01

    Cellular pluripotency is associated with expression of the homeobox transcription factor genes NANOG, SOX2, and POU5F1 (OCT3/4 protein). Some reports suggest that mesenchymal progenitor cells (MPCs) may express increased quantities of these genes, creating the possibility that MPCs are more "pluripotent" than other adult cell types. The objective of this study was to determine whether equine bone marrow-derived MPCs had gene expression or DNA methylation patterns that differed from either early fetal-derived or terminally differentiated adult cells. Specifically, this study compared DNA methylation of the NANOG and SOX2 promoter regions and concurrent gene expression of NANOG, SOX2, and POU5F1 in equine induced pluripotent stem (iPS) cells, fetal fibroblasts, fetal brain cells, adult chondrocytes, and MPCs. Results indicate that NANOG and POU5F1 were not detectable in appreciable quantities in tissues other than the equine iPS cell lines. Equine iPS cells expressed large quantities of all three genes examined. Significantly increased quantities of SOX2 were noted in iPS cells and both fetal-derived cell types compared with adult cells. MPCs and adult chondrocytes expressed equivalent, low quantities of SOX2. Further, NANOG and SOX2 expression inversely correlated with the DNA methylation pattern in the promoter region, such that as gene expression increased, DNA methylation decreased. The equine iPS cell lines examined demonstrated DNA methylation and gene expression patterns that were consistent with pluripotency features described in other species. Results do not support previous reports that NANOG, SOX2, and POU5F1 are poised for increased activity in MPCs compared with other adult cells.

  8. Improved adipose tissue metabolism after 5-year growth hormone replacement therapy in growth hormone deficient adults: The role of zinc-α2-glycoprotein

    PubMed Central

    Balaž, Miroslav; Ukropcova, Barbara; Kurdiova, Timea; Vlcek, Miroslav; Surova, Martina; Krumpolec, Patrik; Vanuga, Peter; Gašperíková, Daniela; Klimeš, Iwar; Payer, Juraj; Wolfrum, Christian; Ukropec, Jozef

    2014-01-01

    Growth hormone (GH) supplementation therapy to adults with GH deficiency has beneficial effects on adipose tissue lipid metabolism, improving thus adipocyte functional morphology and insulin sensitivity. However, molecular nature of these effects remains unclear. We therefore tested the hypothesis that lipid-mobilizing adipokine zinc-α2-glycoprotein is causally linked to GH effects on adipose tissue lipid metabolism. Seventeen patients with severe GH deficiency examined before and after the 5-year GH replacement therapy were compared with age-, gender- and BMI-matched healthy controls. Euglycemic hyperinsulinemic clamp was used to assess whole-body and adipose tissue-specific insulin sensitivity. Glucose tolerance was determined by oGTT, visceral and subcutaneous abdominal adiposity by MRI, adipocyte size morphometrically after collagenase digestion, lipid accumulation and release was studied in differentiated human primary adipocytes in association with GH treatment and zinc-α2-glycoprotein gene silencing. Five-year GH replacement therapy improved glucose tolerance, adipose tissue insulin sensitivity and reduced adipocyte size without affecting adiposity and whole-body insulin sensitivity. Adipose tissue zinc-α2-glycoprotein expression was positively associated with whole-body and adipose tissue insulin sensitivity and negatively with adipocyte size. GH treatment to adipocytes in vitro increased zinc-α2-glycoprotein expression (>50%) and was paralleled by enhanced lipolysis and decreased triglyceride accumulation (>35%). Moreover, GH treatment improved antilipolytic action of insulin in cultured adipocytes. Most importantly, silencing zinc-α2-glycoprotein eliminated all of the GH effects on adipocyte lipid metabolism. Effects of 5-year GH supplementation therapy on adipose tissue lipid metabolism and insulin sensitivity are associated with zinc-α2-glycoprotein. Presence of this adipokine is required for the GH action on adipocyte lipid metabolism in vitro

  9. Disruption of iron homeostasis in mesothelial cells after talc pleurodesis.

    PubMed

    Ghio, Andrew J; Soukup, Joleen M; Dailey, Lisa A; Richards, Judy H; Turi, Jennifer L; Pavlisko, Elizabeth N; Roggli, Victor L

    2012-01-01

    The mechanism for biological effects after exposure to particles is incompletely understood. One postulate proposed to explain biological effects after exposure to particles involves altered iron homeostasis in the host. The fibro-inflammatory properties of mineral oxide particles are exploited therapeutically with the instillation of massive quantities of talc into the pleural space, to provide sclerosis. We tested the postulates that (1) in vitro exposure to talc induces a disruption in iron homeostasis, oxidative stress, and a biological effect, and (2) talc pleurodesis in humans alters iron homeostasis. In vitro exposures of both mesothelial and airway epithelial cells to 100 μg/ml talc significantly increased iron importation and concentrations of the storage protein ferritin. Using dichlorodihydrofluorescein, exposure to talc was associated with a time-dependent and concentration-dependent generation of oxidants in both cell types. The expression of proinflammatory mediators was also increased after in vitro exposures of mesothelial and airway epithelial cells to talc. Relative to control lung tissue, lung tissue from patients treated with sclerodesis demonstrated an accumulation of iron and increased expression of iron-related proteins, including ferritin, the importer divalent metal transport-1 and the exporter ferroportin-1. Talc was also observed to translocate to the parenchyma, and changes in iron homeostasis were focally distributed to sites of retention. We conclude that exposure to talc disrupts iron homeostasis, is associated with oxidative stress, and results in a biological effect (i.e., a fibro-inflammatory response). Talc pleurodesis can function as a model of the human response to mineral oxide particle exposure, albeit a massive one.

  10. Adamts5, the gene encoding a proteoglycan-degrading metalloprotease, is expressed by specific cell lineages during mouse embryonic development and in adult tissues.

    PubMed

    McCulloch, Daniel R; Le Goff, Carine; Bhatt, Sumantha; Dixon, Laura J; Sandy, John D; Apte, Suneel S

    2009-06-01

    The secreted metalloprotease ADAMTS5 is implicated in destruction of the cartilage proteoglycan aggrecan in arthritis, but its physiological functions are unknown. Its expression profile during embryogenesis and in adult tissues is therefore of considerable interest. beta-Galactosidase (beta-gal) histochemistry, enabled by a LacZ cassette inserted in the Adamts5 locus, and validated by in situ hybridization with an Adamts5 cRNA probe and ADAMTS5 immunohistochemistry, was used to profile Adamts5 expression during mouse embryogenesis and in adult mouse tissues. Embryonic expression was scarce prior to 11.5 days of gestation (E11.5) and noted only in the floor plate of the developing brain at E 9.5. After E11.5 there was continued expression in brain, especially in the choroid plexus, peripheral nerves, dorsal root ganglia, cranial nerve ganglia, spinal and cranial nerves, and neural plexuses of the gut. In addition to nerves, developing limbs have Adamts5 expression in skeletal muscle (from E13.5), tendons (from E16.5), and inter-digital mesenchyme of the developing autopod (E13.5-15.5). In adult tissues, there is constitutive Adamts5 expression in arterial smooth muscle cells, mesothelium lining the peritoneal, pericardial and pleural cavities, smooth muscle cells in bronchi and pancreatic ducts, glomerular mesangial cells in the kidney, dorsal root ganglia, and in Schwann cells of the peripheral and autonomic nervous system. Expression of Adamts5 during neuromuscular development and in smooth muscle cells coincides with the broadly distributed proteoglycan versican, an ADAMTS5 substrate. These observations suggest the major contexts in which developmental and physiological roles could be sought for this protease.

  11. Thrombospondin-1 Silencing Down-Regulates Integrin Expression Levels in Human Anaplastic Thyroid Cancer Cells with BRAFV600E: New Insights in the Host Tissue Adaptation and Homeostasis of Tumor Microenvironment

    PubMed Central

    Duquette, Mark; Sadow, Peter M.; Lawler, Jack; Nucera, Carmelo

    2013-01-01

    Background and Rationale: Anaplastic thyroid cancer (ATC) is characterized by pleomorphic cells, has a poor prognosis, is highly devastating disease, and is not curable. No reliable biomarkers of metastatic potential, helpful for early diagnosis of ATC and therapeutic response have been found yet. Thrombospondin-1 (TSP-1) plays a fundamental role in cancer progression by regulating cell stromal cross-talk in the tumor microenvironment. Goals: Our goal was to understand whether TSP-1 could affect protein levels of its integrin receptors (e.g., ITGα3, α6, and β1) and cell morphology in BRAFV600E-ATC cells in vitro and in vivo. Experimental Design: Anaplastic thyroid cancer-derived cell cultures and western blotting were used to assess integrin protein expression upon TSP-1 silencing. Immunohistochemistry was performed on orthotopic primary human ATC and metastatic ATC in lung tissue to compare TSP-1 and integrin protein expression levels. Results: TSP-1 knock-down down-regulates ITGα3, α6, and β1 in BRAFV600E-human ATC cells. BRAFV600E-ATC cells with TSP-1 knock-down were rounded compared to control cells, which displayed a spread morphology. TSP-1 knock-down also reduced TSP-1, ITGα3, α6, and β1 protein expression levels in vivo in the ATC microenvironment, which is enriched in stromal and inflammatory cells. Conclusion: TSP-1 silencing causes changes in ITG levels and ATC cell morphology. The assessment of TSP-1 and ITG levels might contribute to earlier metastatic potential of BRAFV600E-positive aggressive thyroid cancers, and allow improved patient selection for clinical trials. PMID:24348463

  12. Gravity and positional homeostasis of the cell

    NASA Astrophysics Data System (ADS)

    Nace, George W.

    Normally bilateralization takes place in the presence of the Earth's gravity which produces torque, shear, tension and compression acting upon the naked aggregates of cytoplasm in the zygote which is only stabilized by a weak cytoskeleton. In an initial examination of the effects of these quantities on development, an expression is derived to describe the tendency of torque to rotate the egg and reorganize its constituents. This expression yields the net torque resulting from buoyancy and gravity acting upon a dumbbell shaped cell with heavy and light masses at either end and ``floating'' in a medium. Using crude values for the variables, torques of 2.5 × 10-13 to 8.5 × 10-1 dyne-cm are found to act upon cells ranging from 6.4 μm to 31 mm (chicken egg). By way of comparison six microtubules can exert a torque of 5 × 10-9 dyne-cm. (1) Gravity imparts torque to cells; (2) torque is reduced to zero as gravity approaches zero; and (3) torque is sensitive to cell size and particulate distribution. Cells must expend energy to maintain positional homeostasis against gravity. Although not previously recognized, Skylab 3 results support this hypothesis: tissue cultures used 58% more glucose on Earth than in space. The implications for developmental biology, physiology, genetics, and evolution are considered. At the cellular and tissue level the concept of ``gravity receptors'' may be unnecessary.

  13. Gravity and positional homeostasis of the cell

    NASA Technical Reports Server (NTRS)

    Nace, G. W.

    1983-01-01

    The effect of gravity upon cytoplasmic aggregates of the size present in eggs and upon cells is investigated. An expression is developed to describe the tendency of torque to rotate the egg and reorganize its constituents. This expression provides the net torque resulting from buoyancy and gravity acting upon a dumbbell-shaped cell, with heavy and light masses at either end and floating in a medium. Torques of approximately 2.5 x 10 to the -13th to 0.85 dyne-cm are found to act upon cells ranging from 6.4 microns to 31 mm (chicken egg). It is noted that cells must expend energy to maintain positional homeostasis against gravity, as demonstrated by results from Skylab 3, where tissue cultures used 58 percent more glucose on earth than in space. The implications for developmental biology, physiology, genetics, and evolution are discussed. It is argued that at the cellular and tissue levels the concept of gravity receptors may be unnecessary.

  14. Intestinal stem cells in the adult Drosophila midgut

    SciTech Connect

    Jiang, Huaqi; Edgar, Bruce A.

    2011-11-15

    Drosophila has long been an excellent model organism for studying stem cell biology. Notably, studies of Drosophila's germline stem cells have been instrumental in developing the stem cell niche concept. The recent discovery of somatic stem cells in adult Drosophila, particularly the intestinal stem cells (ISCs) of the midgut, has established Drosophila as an exciting model to study stem cell-mediated adult tissue homeostasis and regeneration. Here, we review the major signaling pathways that regulate the self-renewal, proliferation and differentiation of Drosophila ISCs, discussing how this regulation maintains midgut homeostasis and mediates regeneration of the intestinal epithelium after injury. -- Highlights: Black-Right-Pointing-Pointer The homeostasis and regeneration of adult fly midguts are mediated by ISCs. Black-Right-Pointing-Pointer Damaged enterocytes induce the proliferation of intestinal stem cells (ISC). Black-Right-Pointing-Pointer EGFR and Jak/Stat signalings mediate compensatory ISC proliferation. Black-Right-Pointing-Pointer Notch signaling regulates ISC self-renewal and differentiation.

  15. Muse Cells: Nontumorigenic Pluripotent Stem Cells Present in Adult Tissues—A Paradigm Shift in Tissue Regeneration and Evolution

    PubMed Central

    2016-01-01

    Muse cells are a novel population of nontumorigenic pluripotent stem cells, highly resistant to cellular stress. These cells are present in every connective tissue and intrinsically express pluripotent stem markers such as Nanog, Oct3/4, Sox2, and TRA1-60. Muse cells are able to differentiate into cells from all three embryonic germ layers both spontaneously and under media-specific induction. Unlike ESCs and iPSCs, Muse cells exhibit low telomerase activity and asymmetric division and do not undergo tumorigenesis or teratoma formation when transplanted into a host organism. Muse cells have a high capacity for homing into damaged tissue and spontaneous differentiation into cells of compatible tissue, leading to tissue repair and functional restoration. The ability of Muse cells to restore tissue function may demonstrate the role of Muse cells in a highly conserved cellular mechanism related to cell survival and regeneration, in response to cellular stress and acute injury. From an evolutionary standpoint, genes pertaining to the regenerative capacity of an organism have been lost in higher mammals from more primitive species. Therefore, Muse cells may offer insight into the molecular and evolutionary bases of autonomous tissue regeneration and elucidate the molecular and cellular mechanisms that prevent mammals from regenerating limbs and organs, as planarians, newts, zebrafish, and salamanders do. PMID:28070194

  16. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

    PubMed Central

    North, Trista E.; Goessling, Wolfram; Walkley, Carl R.; Lengerke, Claudia; Kopani, Kamden R.; Lord, Allegra M.; Weber, Gerhard J.; Bowman, Teresa V.; Jang, Il-Ho; Grosser, Tilo; FitzGerald, Garret A.; Daley, George Q.; Orkin, Stuart H.; Zon, Leonard I.

    2009-01-01

    Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs1,2. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes. PMID:17581586

  17. TISSUE-Tregs

    PubMed Central

    Panduro, Marisella; Benoist, Christophe; Mathis, Diane

    2016-01-01

    The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3+CD4+ regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations—those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work—as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular. PMID:27168246

  18. In Vitro Adult Astrocytes Are Derived from Mature Cells and Reproduce In Vivo Redox Profile.

    PubMed

    Souza, Débora Guerini; Bellaver, Bruna; Terra, Silvia Resende; Guma, Fatima Costa Rodrigues; Souza, Diogo Onofre; Quincozes-Santos, André

    2017-04-04

    Astrocytes are versatile cells involved in synaptic information processing, energy metabolism, redox homeostasis, inflammatory response and structural support of the brain. Recently, we established a routine protocol of cultured astrocytes derived from adult and aged Wistar rats, which present several different responses compared to newborn astrocytes, commonly used to characterize the role of the astrocytes in the central nervous system. Previous studies hypothesized that astrocyte cultures prepared from adult animals derive from immature precursors present in the adult tissue throughout life. Since our group has already demonstrated that the glial functionality of adult astrocytes differs from newborn cultures, the aim of this study was to confirm that our in vitro astrocytes were derived from mature cells. Therefore, we evaluated cytoskeleton proteins, such as glial fibrillary acidic protein and vimentin, as well as Sox10, an essential marker of immature glial cells, in ex vivo tissue and in in vitro astrocytes from the same animals (1, 90 and 180 days old). In addition, we examined the mitochondrial functionality and the cellular redox homeostasis. Our results suggest that adult and aged astrocytes are derived from mature cells and that changes in mitochondrial parameters in ex vivo tissue were reproduced in in vitro astrocytes. This article is protected by copyright. All rights reserved.

  19. Adipocytes as regulators of energy balance and glucose homeostasis

    PubMed Central

    Rosen, Evan D.; Spiegelman, Bruce M.

    2011-01-01

    Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions. PMID:17167472

  20. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism

    PubMed Central

    Park, Hyeong-Kyu; Ahima, Rexford S.

    2014-01-01

    Leptin is secreted by adipose tissue and regulates energy homeostasis, neuroendocrine function, metabolism, immune function and other systems through its effects on the central nervous system and peripheral tissues. Leptin administration has been shown to restore metabolic and neuroendocrine abnormalities in individuals with leptin-deficient states, including hypothalamic amenorrhea and lipoatrophy. In contrast, obese individuals are resistant to leptin. Recombinant leptin is beneficial in patients with congenital leptin deficiency or generalized lipodystrophy. However, further research on molecular mediators of leptin resistance is needed for the development of targeted leptin sensitizing therapies for obesity and related metabolic diseases. PMID:25199978

  1. A lysosome-centered view of nutrient homeostasis.

    PubMed

    Mony, Vinod K; Benjamin, Shawna; O'Rourke, Eyleen J

    2016-01-01

    Lysosomes are highly acidic cellular organelles traditionally viewed as sacs of enzymes involved in digesting extracellular or intracellular macromolecules for the regeneration of basic building blocks, cellular housekeeping, or pathogen degradation. Bound by a single lipid bilayer, lysosomes receive their substrates by fusing with endosomes or autophagosomes, or through specialized translocation mechanisms such as chaperone-mediated autophagy or microautophagy. Lysosomes degrade their substrates using up to 60 different soluble hydrolases and release their products either to the cytosol through poorly defined exporting and efflux mechanisms or to the extracellular space by fusing with the plasma membrane. However, it is becoming evident that the role of the lysosome in nutrient homeostasis goes beyond the disposal of waste or the recycling of building blocks. The lysosome is emerging as a signaling hub that can integrate and relay external and internal nutritional information to promote cellular and organismal homeostasis, as well as a major contributor to the processing of energy-dense molecules like glycogen and triglycerides. Here we describe the current knowledge of the nutrient signaling pathways governing lysosomal function, the role of the lysosome in nutrient mobilization, and how lysosomes signal other organelles, distant tissues, and even themselves to ensure energy homeostasis in spite of fluctuations in energy intake. At the same time, we highlight the value of genomics approaches to the past and future discoveries of how the lysosome simultaneously executes and controls cellular homeostasis.

  2. Differential effects of glucocorticoids on energy homeostasis in Syrian hamsters.

    PubMed

    Solomon, Matia B; Sakai, Randall R; Woods, Stephen C; Foster, Michelle T

    2011-08-01

    Syrian hamsters, like many humans, increase food intake and body adiposity in response to stress. We hypothesized that glucocorticoids (cortisol and corticosterone) mediate these stress-induced effects on energy homeostasis. Because Syrian hamsters are dual secretors of cortisol and corticosterone, differential effects of each glucocorticoid on energy homeostasis were investigated. First, adrenal intact hamsters were injected with varying physiological concentrations of cortisol, corticosterone, or vehicle to emulate our previously published defeat regimens (i.e., 1 injection/day for 5 days). Neither food intake nor body weight was altered following glucocorticoid injections. Therefore, we investigated the effect of sustained glucocorticoid exposure on energy homeostasis. This was accomplished by implanting hamsters with supraphysiological steady-state pellets of cortisol, corticosterone, or cholesterol as a control. Cortisol, but not corticosterone, significantly decreased food intake, body mass, and lean and fat tissue compared with controls. Despite decreases in body mass and adiposity, cortisol significantly increased circulating free fatty acids, triglyceride, cholesterol, and hepatic triglyceride concentrations. Although corticosterone did not induce alterations in any of the aforementioned metabolic end points, Syrian hamsters were responsive to the effects of corticosterone since glucocorticoids both induced thymic involution and decreased adrenal mass. These findings indicate that cortisol is the more potent glucocorticoid in energy homeostasis in Syrian hamsters. However, the data suggest that cortisol alone does not mediate stress-induced increases in food intake or body mass in this species.

  3. Collecting and Storing Tissue, Blood, and Bone Marrow Samples From Patients With Rhabdomyosarcoma or Other Soft Tissue Sarcoma

    ClinicalTrials.gov

    2016-09-23

    Adult Rhabdomyosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Chordoma; Desmoid Tumor; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Previously Untreated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  4. Zinc homeostasis and neurodegenerative disorders

    PubMed Central

    Szewczyk, Bernadeta

    2013-01-01

    Zinc is an essential trace element, whose importance to the function of the central nervous system (CNS) is increasingly being appreciated. Alterations in zinc dyshomeostasis has been suggested as a key factor in the development of several neuropsychiatric disorders. In the CNS, zinc occurs in two forms: the first being tightly bound to proteins and, secondly, the free, cytoplasmic, or extracellular form found in presynaptic vesicles. Under normal conditions, zinc released from the synaptic vesicles modulates both ionotropic and metabotropic post-synaptic receptors. While under clinical conditions such as traumatic brain injury, stroke or epilepsy, the excess influx of zinc into neurons has been found to result in neurotoxicity and damage to postsynaptic neurons. On the other hand, a growing body of evidence suggests that a deficiency, rather than an excess, of zinc leads to an increased risk for the development of neurological disorders. Indeed, zinc deficiency has been shown to affect neurogenesis and increase neuronal apoptosis, which can lead to learning and memory deficits. Altered zinc homeostasis is also suggested as a risk factor for depression, Alzheimer's disease (AD), aging, and other neurodegenerative disorders. Under normal CNS physiology, homeostatic controls are put in place to avoid the accumulation of excess zinc or its deficiency. This cellular zinc homeostasis results from the actions of a coordinated regulation effected by different proteins involved in the uptake, excretion and intracellular storage/trafficking of zinc. These proteins include membranous transporters (ZnT and Zip) and metallothioneins (MT) which control intracellular zinc levels. Interestingly, alterations in ZnT and MT have been recently reported in both aging and AD. This paper provides an overview of both clinical and experimental evidence that implicates a dysfunction in zinc homeostasis in the pathophysiology of depression, AD, and aging. PMID:23882214

  5. Effects of Neural Stem Cell and Olfactory Ensheathing Cell Co-transplants on Tissue Remodelling After Transient Focal Cerebral Ischemia in the Adult Rat.

    PubMed

    Augestad, Ingrid Lovise; Nyman, Axel Karl Gottfrid; Costa, Alex Ignatius; Barnett, Susan Carol; Sandvig, Axel; Håberg, Asta Kristine; Sandvig, Ioanna

    2017-01-24

    Effective transplant-mediated repair of ischemic brain lesions entails extensive tissue remodeling, especially in the ischemic core. Neural stem cells (NSCs) are promising reparative candidates for stroke induced lesions, however, their survival and integration with the host-tissue post-transplantation is poor. In this study, we address this challenge by testing whether co-grafting of NSCs with olfactory ensheathing cells (OECs), a special type of glia with proven neuroprotective, immunomodulatory, and angiogenic effects, can promote graft survival and host tissue remodelling. Transient focal cerebral ischemia was induced in adult rats by a 60-min middle cerebral artery occlusion (MCAo) followed by reperfusion. Ischemic lesions were verified by neurological testing and magnetic resonance imaging. Transplantation into the globus pallidus of NSCs alone or in combination with OECs was performed at two weeks post-MCAo, followed by histological analyses at three weeks post-transplantation. We found evidence of extensive vascular remodelling in the ischemic core as well as evidence of NSC motility away from the graft and into the infarct border in severely lesioned animals co-grafted with OECs. These findings support a possible role of OECs as part of an in situ tissue engineering paradigm for transplant mediated repair of ischemic brain lesions.

  6. Potential of Newborn and Adult Stem Cells for the Production of Vascular Constructs Using the Living Tissue Sheet Approach

    PubMed Central

    Bourget, Jean-Michel; Gauvin, Robert; Duchesneau, David; Remy, Murielle; Auger, François A.; Germain, Lucie

    2015-01-01

    Bypass surgeries using native vessels rely on the availability of autologous veins and arteries. An alternative to those vessels could be tissue-engineered vascular constructs made by self-organized tissue sheets. This paper intends to evaluate the potential use of mesenchymal stem cells (MSCs) isolated from two different sources: (1) bone marrow-derived MSCs and (2) umbilical cord blood-derived MSCs. When cultured in vitro, a proportion of those cells differentiated into smooth muscle cell- (SMC-) like cells and expressed contraction associated proteins. Moreover, these cells assembled into manipulable tissue sheets when cultured in presence of ascorbic acid. Tubular vessels were then produced by rolling those tissue sheets on a mandrel. The architecture, contractility, and mechanical resistance of reconstructed vessels were compared with tissue-engineered media and adventitia produced from SMCs and dermal fibroblasts, respectively. Histology revealed a collagenous extracellular matrix and the contractile responses measured for these vessels were stronger than dermal fibroblasts derived constructs although weaker than SMCs-derived constructs. The burst pressure of bone marrow-derived vessels was higher than SMCs-derived ones. These results reinforce the versatility of the self-organization approach since they demonstrate that it is possible to recapitulate a contractile media layer from MSCs without the need of exogenous scaffolding material. PMID:26504783

  7. Determination of malachite green residues in the eggs, fry, and adult muscle-tissue of rainbow-trout (Oncorhynchus-mykiss)

    USGS Publications Warehouse

    Allen, John L.; Gofus, J.E.; Meinertz, Jeffery R.

    1994-01-01

    Malachite green, an effective antifungal therapeutant used in fish culture, is a known teratogen. We developed a method to simultaneously detect both the chromatic and leuco forms of malachite green residues in the eggs, fry, and adult muscle tissue of rainbow trout (oncorhynchus mykiss). Homogenates of these tissues were fortified with [c-14] malachite green chloride and extracted with 1% (v/v) acetic acid in acetonitrile or in methanol. The extracts were partitioned with chloroform, dried, redissolved in mobile phase, and analyzed by liquid chromatography (lc) with postcolumn oxidation of leuco malachite green to the chromatic form. Lc fractions were collected every 30 s for quantitation by scintillation counting. Recoveries of total [c-14] malachite green chloride residue were 85 and 98% in eggs fortified with labeled malachite green at concentrations of 0.5 And 1.00 Mug/g, respectively; 68% in fry similarly fortified at a concentration of 0.65 Mug/g; and 66% in muscle homogenate similarly fortified at a level of 1.00 Mug/g. The method was tested under operational conditions by exposing adult rainbow trout to 1.00 Mg/l [c-14] malachite green chloride bath for 1 h. Muscle samples analyzed by sample oxidation and scintillation counting contained 1.3 And 0.5 Mug/g total malachite green chloride residues immediately after exposure and after a 5-day withdrawal period, respectively.

  8. Mast cells and histamine are triggering the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation

    PubMed Central

    Nizamutdinova, Irina Tsoy; Dusio, Giuseppina F.; Gasheva, Olga Yu.; Skoog, Hunter; Tobin, Richard; Peddaboina, Chander; Meininger, Cynthia J.; Zawieja, David C.; Newell-Rogers, M. Karen; Gashev, Anatoliy A.

    2016-01-01

    This study aimed to establish mechanistic links between the aging-associated changes in the functional status of mast cells and the altered responses of mesenteric tissue and mesenteric lymphatic vessels (MLVs) to acute inflammation. We used an in vivo model of acute peritoneal inflammation induced by lipopolysaccharide treatment of adult (9-month) and aged (24-month) F-344 rats. We analyzed contractility of isolated MLVs, mast cell activation, activation of nuclear factor-κB (NF-κB) without and with stabilization of mast cells by cromolyn or blockade of all types of histamine receptors and production of 27 major pro-inflammatory cytokines in adult and aged perilymphatic mesenteric tissues and blood. We found that the reactivity of aged contracting lymphatic vessels to LPS-induced acute inflammation was abolished and that activated mast cells trigger NF-κB signaling in the mesentery through release of histamine. The aging-associated basal activation of mesenteric mast cells limits acute inflammatory NF-κB activation in aged mesentery. We conclude that proper functioning of the mast cell/histamine/NF-κB axis is necessary for reactions of the lymphatic vessels to acute inflammatory stimuli as well as for interaction and trafficking of immune cells near and within the collecting lymphatics. PMID:27875806

  9. Klf15 orchestrates circadian nitrogen homeostasis

    PubMed Central

    Jeyaraj, Darwin; Scheer, Frank A.J.L.; Ripperger, Jürgen A.; Haldar, Saptarsi M.; Lu, Yuan; Prosdocimo, Domenick A.; Eapen, Sam J.; Eapen, Betty L.; Cui, Yingjie; Mahabeleshwar, Ganapathi H.; Lee, Hyoung-gon; Smith, Mark A.; Casadesus, Gemma; Mintz, Eric M.; Sun, Haipeng; Wang, Yibin; Ramsey, Kathryn M.; Bass, Joseph; Shea, Steven A.; Albrecht, Urs; Jain, Mukesh K.

    2012-01-01

    SUMMARY Diurnal variation in nitrogen homeostasis is observed across phylogeny. But whether these are endogenous rhythms, and if so, molecular mechanisms that link nitrogen homeostasis to the circadian clock remain unknown. Here, we provide evidence that a clock-dependent peripheral oscillator, Krüppel-like factor15 transcriptionally coordinates rhythmic expression of multiple enzymes involved in mammalian nitrogen homeostasis. In particular, Krüppel-like factor15-deficient mice exhibit no discernable amino acid rhythm, and the rhythmicity of ammonia to urea detoxification is impaired. Of the external cues, feeding plays a dominant role in modulating Krüppel-like factor15 rhythm and nitrogen homeostasis. Further, when all behavioral, environmental and dietary cues were controlled in humans, nitrogen homeostasis still expressed endogenous circadian rhythmicity. Thus, in mammals, nitrogen homeostasis exhibits circadian rhythmicity, and is orchestrated by Krüppel-like factor15. PMID:22405069

  10. Use of Anthropometry for the Prediction of Regional Body Tissue Distribution in Adults: Benefits and Limitations in Clinical Practice

    PubMed Central

    Scafoglieri, Aldo; Clarys, Jan Pieter; Cattrysse, Erik; Bautmans, Ivan

    2014-01-01

    Regional body composition changes with aging. Some of the changes in composition are considered major risk factors for developing obesity related chronic diseases which in turn may lead to increased mortality in adults. The role of anthropometry is well recognized in the screening, diagnosis and follow-up of adults for risk classification, regardless of age. Regional body composition is influenced by a number of intrinsic and extrinsic factors. Therapeutic measures recommended to lower cardiovascular disease risk include lifestyle changes. The aim of this review is to systematically summarize studies that assessed the relationships between anthropometry and regional body composition. The potential benefits and limitations of anthropometry for use in clinical practice are presented and suggestions for future research given. PMID:25489489

  11. De novo lipogenesis in metabolic homeostasis: More friend than foe?

    PubMed Central

    Solinas, Giovanni; Borén, Jan; Dulloo, Abdul G.

    2015-01-01

    Background An acute surplus of carbohydrates, and other substrates, can be converted and safely stored as lipids in adipocytes via de novo lipogenesis (DNL). However, in obesity, a condition characterized by chronic positive energy balance, DNL in non-adipose tissues may lead to ectopic lipid accumulation leading to lipotoxicity and metabolic stress. Indeed, DNL is dynamically recruited in liver during the development of fatty liver disease, where DNL is an important source of lipids. Nonetheless, a number of evidences indicates that DNL is an inefficient road for calorie to lipid conversion and that DNL may play an important role in sustaining metabolic homeostasis. Scope of review In this manuscript, we discuss the role of DNL as source of lipids during obesity, the energetic efficiency of this pathway in converting extra calories to lipids, and the function of DNL as a pathway supporting metabolic homeostasis. Major conclusion We conclude that inhibition of DNL in obese subjects, unless coupled with a correction of the chronic positive energy balance, may further promote lipotoxicity and metabolic stress. On the contrary, strategies aimed at specifically activating DNL in adipose tissue could support metabolic homeostasis in obese subjects by a number of mechanisms, which are discussed in this manuscript. PMID:25973385

  12. Homeostasis of IL-15 dependent lymphocyte subsets in the liver

    PubMed Central

    Cepero-Donates, Yuneivy; Rakotoarivelo, Volatiana; Mayhue, Marian; Ma, Averil; Chen, Yi-Guang; Ramanathan, Sheela

    2017-01-01

    IL-15 is a member of the gamma chain family of cytokines (γc – CD132). The IL-15 receptor (IL-15R) complex consists of 3 subunits: the ligand-binding IL-15Rα chain (CD215), the β chain (CD122; also used by IL-2), and the common γ chain. The biological activities of IL-15 are mostly mediated by the IL-15:IL-15Rα complex, produced by the same cell and ‘trans-presented’ to responder cells expressing the IL-15Rβγc. The peculiar and almost unique requirement for IL-15 to be trans-presented by IL-15Rα suggests that the biological effects of IL-15 signaling are tightly regulated even at the level of availability of IL-15. Tissue-specific deletion of IL-15Rα has shown macrophage-and dendritic cell-derived IL-15Rα mediate the homeostasis of different CD8+ T cell subsets. Here we show that hepatocyte and macrophage- specific expression of IL-15Rα is required to maintain the homeostasis of NK and NKT cells in the liver. Thus, homeostasis of IL-15-dependent lymphocyte subsets is also regulated by trans-presentation of IL-15 by non-hematopoietic cells in the tissue environment. PMID:26778709

  13. Phospholipid homeostasis and lipotoxic cardiomyopathy: a matter of balance.

    PubMed

    Lim, Hui-Ying; Bodmer, Rolf

    2011-01-01

    Obesity has reached pandemic proportions globally and is often associated with lipotoxic heart diseases. In the obese state, caloric surplus is accommodated in the adipocytes as triglycerides. As the storage capacity of adipocytes is exceeded or malfunctioning, lipids begin to infiltrate and accumulate in non-adipose tissues, including the myocardium of the heart, leading to organ dysfunction. While the disruption of caloric homeostasis has been widely viewed as a principal mechanism in contributing to peripheral tissue steatosis and lipotoxicity, our recent studies in Drosophila have led to the novel finding that deregulation of phospholipid homeostasis may also significantly contribute to the pathogenesis of lipotoxic cardiomyopathy. Fly mutants that bear perturbations in phosphatidylethanolamine (PE) biosynthesis, such as the easily-shocked (eas) mutants defective in ethanolamine kinase, incurred aberrant activation of the sterol regulatory element binding protein (SREBP) pathway, thereby causing chronic lipogenesis and cardiac steatosis that culminates in the development of lipotoxic cardiomyopathy. Here, we describe the potential relationship between SREBP and other eas-associated phenotypes, such as neuronal excitability defects. We will further discuss the additional implications presented by our work toward the effects of altered lipid metabolism on cellular growth and/or proliferation in response to defective phospholipid homeostasis.

  14. CNS Metastases from Bone and Soft Tissue Sarcomas in Children, Adolescents, and Young Adults: Are They Really So Rare?

    PubMed Central

    Duczkowska, Agnieszka; Duczkowski, Marek; Bragoszewska, Hanna; Romaniuk-Doroszewska, Anna; Iwanowska, Beata; Szkudlinska-Pawlak, Sylwia; Madzik, Jaroslaw; Bilska, Katarzyna; Raciborska, Anna

    2017-01-01

    Purpose. To check whether primary involvement of brain/spinal cord by bone/soft tissue sarcomas' metastases in children is as rare as described and to present various morphological forms of bone/soft tissue sarcomas' CNS metastases. Methods. Patients with first diagnosis in 1999–2014 treated at single center were included with whole course of disease evaluation. Brain/spinal canal magnetic resonance imaging (MRI)/computed tomography were performed in cases suspicious for CNS metastases. Extension from skull/vertebral column metastases was excluded. Results. 550 patients were included. MRI revealed CNS metastases in 19 patients (incidence 3.45%), 14 boys, aged 5–22 years. There were 12/250 osteosarcoma cases, 2/200 Ewing's sarcoma, 1/50 chondrosarcoma, 3/49 rhabdomyosarcoma (RMS), and 1/1 malignant mesenchymoma. There were 10 single metastases and 7 cases of multiple ones; in 2 RMS cases only leptomeningeal spread in brain and spinal cord was found. Calcified metastases were found in 3 patients and hemorrhagic in 4. In one RMS patient there were numerous solid, cystic, hemorrhagic lesions and leptomeningeal spread. Conclusions. CNS metastases are rare and late in children with bone/soft tissue sarcomas, although in our material more frequent (3.45%) than in other reports (0.7%). Hematogenous spread to brain and hemorrhagic and calcified lesions dominated in osteosarcoma. Ewing sarcoma tended to metastasize to skull bones. Soft tissue sarcomas presented various morphological forms. PMID:28243595

  15. Tissue Mercury Concentrations and Survival of Tree Swallow Embryos, Nestlings and Young Adult Females on a Contaminated Site.

    PubMed

    Taylor, Capwell E; Cristol, Daniel A

    2015-10-01

    Tree swallows nesting on mercury-contaminated sites along the South River in Virginia, USA were monitored for reproductive success. The bodies of nestlings found deceased in their nest boxes were collected, along with blood and feather samples from the adult parents and surviving siblings. We also measured hatching and fledging success of the clutches and the annual recapture rate of adults. We found that the body feathers of deceased nestlings contained significantly higher concentrations of mercury (12.89 ± 8.42 μg/g, n = 15) than those of nestlings that survived to fledge (7.41 ± 4.79 μg/g, n = 15). However, mothers of more successful clutches (>75 % hatching) did not differ in mercury concentrations from females with less successful clutches (<50 % hatching). Additionally, adult females breeding for the first time that returned to breed the following year did not differ in blood mercury from females of the same age that bred once but never returned. Our results suggest that mercury had its greatest effect on these songbirds during the nestling stage, whereas for embryos or first-time breeding females, other factors likely played larger roles in mortality.

  16. Comparison of specific absorption rate induced in brain tissues of a child and an adult using mobile phone

    NASA Astrophysics Data System (ADS)

    Lu, Mai; Ueno, Shoogo

    2012-04-01

    The steady increase of mobile phone usage, especially mobile phones by children, has led to a rising concern about the possible adverse health effects of radio frequency electromagnetic field exposure. The objective of this work is to study whether there is a larger radio frequency energy absorption in the brain of a child compared to that of an adult. For this reason, three high-resolution models, two child head models (6 - and 11-year old) and one adult head model (34-year old) have been used in the study. A finite-difference time-domain method was employed to calculate the specific absorption rate (SAR) in the models from exposure to a generic handset at 1750 MHz. The results show that the SAR distributions in the human brain are age-dependent, and there is a deeper penetration of the absorbed SAR in the child's brain. The induced SAR can be significantly higher in subregions of the child's brain. In all of the examined cases, the SAR values in the brains of a child and an adult are well below the IEEE safety standard.

  17. Biomaterials-Based Strategies for Salivary Gland Tissue Regeneration

    PubMed Central

    Ozdemir, Tugba; Fowler, Eric W.; Hao, Ying; Ravikrishan, Anitha; Harrington, Daniel A.; Witt, Robert L.; Farach-Carson, Mary C; Pradhan-Bhatt, Swati; Jia, Xinqiao

    2016-01-01

    The salivary gland is a complex, secretory tissue that produces saliva and maintains oral homeostasis. Radiation induced salivary gland atrophy, manifested as “dry mouth” or xerostomia, poses a significant clinical challenge. Tissue engineering recently has emerged as an alternative, long-term treatment strategy for xerostomia. In this review, we summarize recent efforts towards the development of functional and implantable salivary glands utilizing designed polymeric substrates or synthetic matrices/scaffolds. Although the in vitro engineering of a complex implantable salivary gland is technically challenging, opportunities exist for multidisciplinary teams to harvest the regenerative potential of stem/progenitor cells found in the adult glands and combine them with biomimetic and cell-instructive materials to assemble implantable tissue modules. PMID:26878077

  18. Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.

    PubMed

    Uzhachenko, Roman; Boyd, Kelli; Olivares-Villagomez, Danyvid; Zhu, Yueming; Goodwin, J Shawn; Rana, Tanu; Shanker, Anil; Tan, Winston J T; Bondar, Tanya; Medzhitov, Ruslan; Ivanova, Alla V

    2017-03-26

    Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.

  19. In vivo stage- and tissue-specific DNA-protein interactions at the D. melanogaster alcohol dehydrogenase distal promoter and adult enhancer.

    PubMed Central

    Jackson, J R; Benyajati, C

    1992-01-01

    We performed a high resolution analysis of the chromatin structure within the regions required for distal transcription of the Drosophila melanogaster alcohol dehydrogenase gene (Adh). Using dimethyl sulfate, DNase I, and micrococcal nuclease as structural probes, and comparing chromatin structure in tissues isolated from several developmental stages, we have identified several sites of stage- and tissue-specific DNA-protein interactions that correlate with distal transcription initiation. Most were within previously identified cis-acting elements and/or in vitro protein binding sites of the adult enhancer (AAE) and distal promoter, including the TATA box. We also detected a novel stage-specific DNA-protein interaction at the Adf-2a binding site where a non-histone protein was bound to the DNA on the surface of a positioned nucleosome previously identified between the distal promoter and adult enhancer. In addition to footprints, we have also revealed stage- and tissue-specific DNA helix deformations between many of the non-histone protein binding sites. These helix distortions suggest there are interactions among the adjacently bound proteins that result in bending or kinking of the intervening DNA. The distal promoter and AAE have an accessible chromatin conformation in fat body prior to the third larval instar and many of the regulatory proteins that bind in these regions are also available before distal transcription begins. Nevertheless, the timing of DNA-protein interactions in the distal promoter and AAE suggest these proteins do not bind individually or assemble progressively as they and their binding sites become available. Instead, there appears to be a coordinated assembly of a large cooperative complex of proteins interacting with the distal promoter, the positioned nucleosome, the enhancer of the distal promoter (the AAE), and each other. Images PMID:1437559

  20. Point-of-care musculoskeletal ultrasound is critical for the diagnosis of hemarthroses, inflammation and soft tissue abnormalities in adult patients with painful haemophilic arthropathy.

    PubMed

    Kidder, W; Nguyen, S; Larios, J; Bergstrom, J; Ceponis, A; von Drygalski, A

    2015-07-01

    We previously demonstrated in adult patients with haemophilia (PWH) that hemarthrosis is present in only ~1/3rd of acutely painful joints by using point-of-care-musculoskeletal ultrasound (MSKUS). Therefore, other unrecognized tissue abnormalities must contribute to pain. Using high resolution MSKUS, employing grey scale and power Doppler, we sought to retrospectively (i) investigate soft tissue abnormalities in painful haemophilic joints and (ii) to determine to what extent MSKUS findings, functional or radiographic joint scores correlate with biomarkers of inflammation in PWH. Findings were correlated with Hemophilia Joint Health Scores (HJHS), Pettersson scores, high sensitivity C-reactive protein and von Willebrand factor activity and antigen levels. A total of 65 MSKUS examinations for acute and chronic joint pains were performed for 34 adult haemophilia patients, mostly for chronic joint pains (72.3%). The most prominent findings (66.5%) pertained to inflammatory soft tissue changes including synovitis, tendinitis, enthesitis, bursitis and fat pad inflammation. Effusions were present in 55.5% and 46.8% of MSKUS performed for acute and chronic pain, respectively. Of those, 90.0% were bloody during acute and 47.6% during persistent pains. While inflammatory biomarkers correlated well with overall HJHS and total Pettersson scores (P < 0.05), they did not differ between those patients with synovitis and those without. MSKUS is emerging as an important modality to diagnose treatable musculoskeletal abnormalities contributing to pain in haemophilic arthropathy, and therefore seems critical for a personalized approach to haemophilia care. The role of biomarkers in this setting remains less clear and requires further investigation.

  1. Carbon Ion Radiation Therapy Improves the Prognosis of Unresectable Adult Bone and Soft-Tissue Sarcoma of the Head and Neck

    SciTech Connect

    Jingu, Keiichi; Tsujii, Hirohiko; Mizoe, Jun-Etsu; Hasegawa, Azusa; Bessho, Hiroki; Takagi, Ryo; Morikawa, Takamichi; Tonogi, Morio; Tsuji, Hiroshi; Kamada, Tadashi; Yamada, Shogo

    2012-04-01

    Purpose: To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) with 70.4 GyE for unresectable bone and soft-tissue sarcoma of the adult head and neck. Methods and Materials: Twenty-seven patients (mean age, 46.2 years) were enrolled in this prospective study on C-ion RT with 70.4 GyE/16 fractions (fr) between April 2001 and February 2008. The primary end points were acute and late reactions of normal tissues, local control rate, and overall survival rate. The secondary end point was efficacy of the treatment in comparison to historical results with 57.6 or 64.0 GyE/16 fr. Results: The 3-year local control rate and overall survival rate for all patients were 91.8% (95% confidence interval [CI] = 81.0-100%) and 74.1% (95% CI = 57.5-90.6%), respectively. Acute reaction of Grade 3 or more was observed in only 1 patient. With regard to late reactions, visual loss was observed in 1 patient and a Grade 3 reaction of the maxillary bone was observed in 4 patients. A comparison with historical results revealed that the local control rate with 70.4 GyE was significantly higher than that with 57.6 or 64.0 GyE (3-year, 91.8% vs. 23.6%, p < 0.0001). Furthermore, the overall survival with 70.4 GyE tended to be higher than that with 57.6 or 64.0 GyE (3-year, 74.1% vs. 42.9%, p = 0.09). Conclusion: C-ion RT with 70.4 GyE/16 fr for bone and soft-tissue sarcoma of the adult head and neck appears to be effective with acceptable toxicities in comparison to conventional RT and C-ion RT with lower doses.

  2. Lactate rescues neuronal sodium homeostasis during impaired energy metabolism

    PubMed Central

    Karus, Claudia; Ziemens, Daniel; Rose, Christine R

    2015-01-01

    Recently, we established that recurrent activity evokes network sodium oscillations in neurons and astrocytes in hippocampal tissue slices. Interestingly, metabolic integrity of astrocytes was essential for the neurons' capacity to maintain low sodium and to recover from sodium loads, indicating an intimate metabolic coupling between the 2 cell types. Here, we studied if lactate can support neuronal sodium homeostasis during impaired energy metabolism by analyzing whether glucose removal, pharmacological inhibition of glycolysis and/or addition of lactate affect cellular sodium regulation. Furthermore, we studied the effect of lactate on sodium regulation during recurrent network activity and upon inhibition of the glial Krebs cycle by sodium-fluoroacetate. Our results indicate that lactate is preferentially used by neurons. They demonstrate that lactate supports neuronal sodium homeostasis and rescues the effects of glial poisoning by sodium-fluoroacetate. Altogether, they are in line with the proposed transfer of lactate from astrocytes to neurons, the so-called astrocyte-neuron-lactate shuttle. PMID:26039160

  3. Glucosensing and glucose homeostasis: from fish to mammals.

    PubMed

    Polakof, Sergio; Mommsen, Thomas P; Soengas, José L

    2011-12-01

    This review is focused on two topics related to glucose in vertebrates. In a first section devoted to glucose homeostasis we describe how glucose levels fluctuate and are regulated in different classes of vertebrates. The detection of these fluctuations is essential for homeostasis and for other physiological processes such as regulation of food intake. The capacity of that detection is known as glucosensing, and the different mechanisms through which it occurs are known as glucosensors. Different glucosensor mechanisms have been demonstrated in different tissues and organs of rodents and humans whereas the information obtained for other vertebrates is scarce. In the second section of the review we describe the present knowledge regarding glucosensor mechanisms in different groups of vertebrates, with special emphasis in fish.

  4. Vitamin A homeostasis endangered by environmental pollutants

    SciTech Connect

    Zile, M.H. )

    1992-11-01

    Normal vitamin A function depends on adequate stores of the vitamin, a finely regulated supply of the vitamin to target tissues, and an ability of cells to generate functionally active forms of the vitamin. Both endogenous and exogenous factors can adversely affect vitamin A homeostasis. Polyhalogenated aromatic hydrocarbons are ubiquitous environmental pollutants and cause severe disturbances in vitamin A metabolism, manifested by an accelerated metabolism and breakdown of vitamin A and its metabolites and a depletion of vitamin A from the body; this sequence of events accounts for the vitamin A deficiency-like symptoms associated with PHAH intoxication. The mechanism(s) responsible for these events most likely includes altered activities of enzymes that are either directly or indirectly involved in critical vitamin A metabolic pathways. Human populations that continue to be exposed to environmental pollutants, may accumulate critical levels of polyhalogenated aromatic hydrocarbons and will be at risk for inadequate vitamin A function as well as for other health impairments that have been difficult to link to any specific causes. Therefore, it is important to seriously evaluate the similarities in physiological disturbances across species that have become apparent in studies with wildlife inhabiting polluted environments similar to ours; the relevance to human health is evident.197 references.

  5. Targeting adipose tissue via systemic gene therapy.

    PubMed

    O'Neill, S M; Hinkle, C; Chen, S-J; Sandhu, A; Hovhannisyan, R; Stephan, S; Lagor, W R; Ahima, R S; Johnston, J C; Reilly, M P

    2014-07-01

    Adipose tissue has a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing cytomegalovirus promoter-regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver-specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8 and administered intravenously to 9- to 10-week-old ob/ob mice. Phenotypic changes were measured over an 8-week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.

  6. Expressed sequence tag analysis of adult human optic nerve for NEIBank: Identification of cell type and tissue markers

    PubMed Central

    Bernstein, Steven L; Guo, Yan; Peterson, Katherine; Wistow, Graeme

    2009-01-01

    Background The optic nerve is a pure white matter central nervous system (CNS) tract with an isolated blood supply, and is widely used in physiological studies of white matter response to various insults. We examined the gene expression profile of human optic nerve (ON) and, through the NEIBANK online resource, to provide a resource of sequenced verified cDNA clones. An un-normalized cDNA library was constructed from pooled human ON tissues and was used in expressed sequence tag (EST) analysis. Location of an abundant oligodendrocyte marker was examined by immunofluorescence. Quantitative real time polymerase chain reaction (qRT-PCR) and Western analysis were used to compare levels of expression for key calcium channel protein genes and protein product in primate and rodent ON. Results Our analyses revealed a profile similar in many respects to other white matter related tissues, but significantly different from previously available ON cDNA libraries. The previous libraries were found to include specific markers for other eye tissues, suggesting contamination. Immune/inflammatory markers were abundant in the new ON library. The oligodendrocyte marker QKI was abundant at the EST level. Immunofluorescence revealed that this protein is a useful oligodendrocyte cell-type marker in rodent and primate ONs. L-type calcium channel EST abundance was found to be particularly low. A qRT-PCR-based comparative mammalian species analysis reveals that L-type calcium channel expression levels are significantly lower in primate than in rodent ON, which may help account for the class-specific difference in responsiveness to calcium channel blocking agents. Several known eye disease genes are abundantly expressed in ON. Many genes associated with normal axonal function, mRNAs associated with axonal transport, inflammation and neuroprotection are observed. Conclusion We conclude that the new cDNA library is a faithful representation of human ON and EST data provide an initial overview

  7. Coplanar Polychlorinated Biphenyls Impair Glucose Homeostasis in Lean C57BL/6 Mice and Mitigate Beneficial Effects of Weight Loss on Glucose Homeostasis in Obese Mice

    PubMed Central

    Baker, Nicki A.; Karounos, Michael; English, Victoria; Fang, Jun; Wei, Yinan; Stromberg, Arnold; Sunkara, Manjula; Morris, Andrew J.; Swanson, Hollie I.

    2012-01-01

    Background: Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote proinflammatory gene expression in adipocytes. PCBs are highly lipophilic and accumulate in adipose tissue, a site of insulin resistance in persons with type 2 diabetes. Objectives: We investigated the in vitro and in vivo effects of coplanar PCBs on adipose expression of tumor necrosis factor α (TNF-α) and on glucose and insulin homeostasis in lean and obese mice. Methods: We quantified glucose and insulin tolerance, as well as TNF-α levels, in liver, muscle, and adipose tissue of male C57BL/6 mice administered vehicle, PCB-77, or PCB-126 and fed a low fat (LF) diet. Another group of mice administered vehicle or PCB-77 were fed a high fat (HF) diet for 12 weeks; the diet was then switched from HF to LF for 4 weeks to induce weight loss. We quantified glucose and insulin tolerance and adipose TNF-α expression in these mice. In addition, we used in vitro and in vivo studies to quantify aryl hydrocarbon receptor (AhR)-dependent effects of PCB-77 on parameters of glucose homeostasis. Results: Treatment with coplanar PCBs resulted in sustained impairment of glucose and insulin tolerance in mice fed the LF diet. In PCB-77–treated mice, TNF-α expression was increased in adipose tissue but not in liver or muscle. PCB-77 levels were strikingly higher in adipose tissue than in liver or serum. Antagonism of AhR abolished both in vitro and in vivo effects of PCB-77. In obese mice, PCB-77 had no effect on glucose homeostasis, but glucose homeostasis was impaired after weight loss. Conclusions: Coplanar PCBs impaired glucose homeostasis in lean mice and in obese mice following weight loss. Adipose-specific elevations in TNF-α expression by PCBs may contribute to impaired glucose homeostasis. PMID:23099484

  8. Adult Stem Cells and Diseases of Aging

    PubMed Central

    Boyette, Lisa B.; Tuan, Rocky S.

    2014-01-01

    Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other causes contribute to tissue degeneration with age. Both progeria, an extreme example of early-onset aging, and heritable longevity have provided avenues to study regulation of the aging program and its impact on adult stem cell compartments. In this review, we discuss recent findings concerning the effects of aging on stem cells, contributions of stem cells to age-related pathologies, examples of signaling pathways at work in these processes, and lessons about cellular aging gleaned from the development and refinement of cellular reprogramming technologies. We highlight emerging therapeutic approaches to manipulation of key signaling pathways corrupting or exhausting adult stem cells, as well as other approaches targeted at maintaining robust stem cell pools to extend not only lifespan but healthspan. PMID:24757526

  9. The effect of tannic acid on the bone tissue of adult male Wistar rats exposed to cadmium and lead.

    PubMed

    Tomaszewska, Ewa; Dobrowolski, Piotr; Winiarska-Mieczan, Anna; Kwiecień, Małgorzata; Tomczyk, Agnieszka; Muszyński, Siemowit

    2017-03-02

    Toxic elements such as cadmium (Cd) and lead (Pb) accumulate to the largest extent in bones. Rats at the age of 12 weeks were used to check whether tannic acid (TA) at the concentration of 0.5%, 1.0%, 1.5%. 2.0% or 2.5% would have a protective effect on the structure and properties of bones in the case of exposure to Cd and Pb (diet: 7mg Cd/kg and 50mg Pb/kg) for 12 weeks. The effects of administration of TA in Cd- and Pb-poisoned rats on bone mechanical and geometric properties, trabecular histomorphometry as well as the morphology of articular and growth cartilages were determined. All the rats co-exposured to Cd and Pb had enhanced heavy metals concentration in blood plasma and bone and reduced bone Ca content irrespective of the tannic acid administration. Heave metals given to adult rats did not influence the morphology and geometry of the femur, but reduced the mechanical endurance and histomorphometric parameters of trabecular bone irrespective of the treatment. A diet rich in TA improved articular cartilage and growth plate constituents in heavy metal-poisoned rats, as indicated by the measurement of the thickness of particular zones. It seems that a use of alimentary TA supplementation in adult rats can counteract, in a dose-dependent manner, only some of the destructive changes evoked by Cd and Pb excess.

  10. Two distinct roles of the yorkie/yap gene during homeostasis in the planarian Dugesia japonica

    PubMed Central

    Hwang, Byulnim; An, Yang; Agata, Kiyokazu; Umesono, Yoshihiko

    2015-01-01

    Adult planarians possess somatic pluripotent stem cells called neoblasts that give rise to all missing cell types during regeneration and homeostasis. Recent studies revealed that the Yorkie (Yki)/Yes-associated protein (YAP) transcriptional coactivator family plays an important role in the regulation of tissue growth during development and regeneration, and therefore we investigated the role of a planarian yki-related gene (termed Djyki) during regeneration and homeostasis of the freshwater planarian Dugesia japonica. We found that knockdown of the function of Djyki by RNA interference (RNAi) downregulated neoblast proliferation and caused regeneration defects after amputation. In addition, Djyki RNAi caused edema during homeostasis. These seemingly distinct defects induced by Djyki RNAi were rescued by simultaneous RNAi of a planarian mats-related gene (termed Djmats), suggesting an important role of Djmats in the negative regulation of Djyki, in accordance with the conservation of the functional relationship of these two genes during the course of evolution. Interestingly, Djyki RNAi did not prevent normal protonephridial structure, suggesting that Djyki RNAi induced the edema phenotype without affecting the excretory system. Further analyses revealed that increased expression of the D. japonica gene DjaquaporinA (DjaqpA), which belongs to a large gene family that encodes a water channel protein for the regulation of transcellular water flow, promoted the induction of edema, but not defects in neoblast dynamics, in Djyki(RNAi) animals. Thus, we conclude that Djyki plays two distinct roles in the regulation of active proliferation of stem cells and in osmotic water transport across the body surface in D. japonica. PMID:25708270

  11. WNT Signaling in Bone Development and Homeostasis

    PubMed Central

    Zhong, Zhendong; Ethen, Nicole J.; Williams, Bart O.

    2014-01-01

    The balance between bone formation and bone resorption controls postnatal bone homeostasis. Research over the last decade has provided a vast amount of evidence that WNT signaling plays a pivotal role in regulating this balance. Therefore, understanding how the WNT signaling pathway regulates skeletal development and homeostasis is of great value for human skeletal health and disease. PMID:25270716

  12. Developmental changes in Ca2+ homeostasis and contractility in gallbladder smooth muscle.

    PubMed

    Camello-Almaraz, Cristina; Macias, Beatriz; Gomez-Pinilla, Pedro J; Alcon, Soledad; Martin-Cano, Francisco E; Baba, Akemishi; Matsuda, Toshio; Camello, Pedro J; Pozo, María J

    2009-04-01

    Relatively little is known about the contribution of Ca(2+)-dependent and -independent mechanisms in the contractility of neonatal gastrointestinal smooth muscle. We therefore studied Ca(2+) homeostasis and Ca(2+) sensitization mechanisms in 10-day-old and adult guinea pig gallbladder smooth muscle to elucidate developmental changes in these processes. Gallbladder contractility was evaluated by isometrical tension recordings from strips, intracellular Ca(2+) concentration was estimated by epifluorescence microscopy of fura-2-loaded isolated cells, and protein expression and phosphorylation were assessed by Western blot analysis. The neonatal gallbladder contracted significantly less to CCK than adult tissue, but this correlated with an increased Ca(2+) mobilization, suggesting immaturity of Ca(2+) sensitization mechanisms. The enhanced Ca(2+) release in the newborn gallbladder was the result of the increase in the size of the releasable Ca(2+) pool. Moreover, in neonatal smooth muscle cells, neither the plasma membrane Ca(2+) pump nor the Na(+)/Ca(2+) exchanger collaborate in the extrusion of Ca(2+). In contrast, in these cells, there is an increase in phospholamban phosphorylation, which could drive to an overactivity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase pump. The reduced Ca(2+) sensitivity in neonatal tissues was demonstrated by the lack of effect to Y-27362, an inhibitor of Rho kinase (ROCK), and GF-109203X, an inhibitor of PKC, on agonist-induced contraction. In addition, the neonatal gallbladder showed lower levels of RhoA, ROCK, PKC, and two effectors [C-kinase-dependent inhibitor of 17 kDa (CPI-17) and myosin phosphatase targetting 1 (MYPT1)] as well as an absence of CPI-17 and MYPT1 phosphorylation in response to agonists. In conclusion, our results indicate that the main mechanisms involved in smooth muscle contractility are under developmental regulation.

  13. Age, Plasticity, and Homeostasis In Childhood Brain Disorders

    PubMed Central

    Dennis, Maureen; Spiegler, Brenda J.; Juranek, Jenifer J.; Bigler, Erin D.; Snead, O. Carter; Fletcher, Jack M.

    2013-01-01

    It has been widely accepted that the younger the age and/or immaturity of the organism, the greater the brain plasticity, the young age plasticity privilege. This paper examines the relation of a young age to plasticity, reviewing human pediatric brain disorders, as well as selected animal models, human developmental and adult brain disorder studies. As well, we review developmental and childhood acquired disorders that involve a failure of regulatory homeostasis. Our core arguments are: Plasticity is neutral with respect to outcome. Although the effects of plasticity are often beneficial, the outcome of plasticity may be adaptive or maladaptive.The young age plasticity privilege has been overstated.Plastic change operates in concert with homeostatic mechanisms regulating change at every point in the lifespan.The same mechanisms that propel developmental change expose the immature brain to adverse events, making it more difficult for the immature than for the mature brain to sustain equilibrium between plasticity and homeostasis.Poor outcome in many neurodevelopmental disorders and childhood acquired brain insults is related to disequilibrium between plasticity and homeostasis. PMID:24096190

  14. Ageing and apoE change DHA homeostasis: relevance to age-related cognitive decline.

    PubMed

    Hennebelle, Marie; Plourde, Mélanie; Chouinard-Watkins, Raphaël; Castellano, Christian-Alexandre; Barberger-Gateau, Pascale; Cunnane, Stephen C

    2014-02-01

    Epidemiological studies fairly convincingly suggest that higher intakes of fatty fish and n-3 fatty acids are associated with reduced risk of Alzheimer's disease (AD). DHA in plasma is normally positively associated with DHA intake. However, despite being associated with lower fish and DHA intake, unexpectedly, plasma (or brain) DHA is frequently not lower in AD. This review will highlight some metabolic and physiological factors such as ageing and apoE polymorphism that influence DHA homeostasis. Compared with young adults, blood DHA is often slightly but significantly higher in older adults without any age-related cognitive decline. Higher plasma DHA in older adults could be a sign that their fish or DHA intake is higher. However, our supplementation and carbon-13 tracer studies also show that DHA metabolism, e.g. transit through the plasma, apparent retroconversion and β-oxidation, is altered in healthy older compared with healthy young adults. ApoE4 increases the risk of AD, possibly in part because it too changes DHA homeostasis. Therefore, independent of differences in fish intake, changing DHA homeostasis may tend to obscure the relationship between DHA intake and plasma DHA which, in turn, may contribute to making older adults more susceptible to cognitive decline despite older adults having similar or sometimes higher plasma DHA than in younger adults. In conclusion, recent development of new tools such as isotopically labelled DHA to study DHA metabolism in human subjects highlights some promising avenues to evaluate how and why DHA metabolism changes during ageing and AD.

  15. Differences in compact bone tissue microscopic structure between adult humans (Homo sapiens) and Assam macaques (Macaca assamensis).

    PubMed

    Nganvongpanit, Korakot; Phatsara, Manussabhorn; Settakorn, Jongkolnee; Mahakkanukrauh, Pasuk

    2015-09-01

    This study investigated the osteon structure of adult humans and Assam macaques, which served as a nonhuman primate model, to find an adequate key for species identification. Samples of compact bone from humans (n=5) and Assam macaques (n=5) - including humerus (n=20), radius (n=20), ulna (n=20), femur (n=20), tibia (n=20) and fibula (n=20) - were processed using conventional histological techniques. 100 secondary osteons from each sample were evaluated under light microscopy. Parameter measurements included: diameter, perimeter and area of Haversian canal and osteon; distance between centers of Haversian canals; and ratio between diameter of Haversian canal and osteon. Four parameters, including diameters and areas of Haversian canal and osteon, demonstrated significantly higher (P<0.05) values in humans than in Assam macaques. Therefore, compact bone microstructure could thus be used as a potential tool to differentiate human and nonhuman primates.

  16. Long-term physical exercise induces changes in sirtuin 1 pathway and oxidative parameters in adult rat tissues.

    PubMed

    Bayod, S; Del Valle, J; Lalanza, J F; Sanchez-Roige, S; de Luxán-Delgado, B; Coto-Montes, A; Canudas, A M; Camins, A; Escorihuela, R M; Pallàs, M

    2012-12-01

    The protein deacetylase, sirtuin 1, is suggested as a master regulator of exercise-induced beneficial effects. Sirtuin 1 modulates mitochondrial biogenesis, primarily via its ability to deacetylate and activate proliferator-activated receptor-γ coactivator-1α (PGC-1α), interacting with AMPK kinase. Redox cell status can also influence this regulatory axis and together they form an important convergence point in hormesis during the aging process. Here, we tested whether treadmill training (36weeks), as a paradigm of long-term moderate exercise, modifies the AMPK-sirtuin 1-PGC-1α axis and redox balance in rat gastrocnemius muscle, liver and heart. Physical activity induced increases in sirtuin 1 protein levels in all the aged rat tissues studied, as well as total PGC-1α levels. However, no changes in AMPK activation or significant differences in mitochondrial biogenesis (by measuring electron transport chain protein content) were found after exercise training. Parallel to these changes, we observed an improvement of oxidative stress defenses, mainly in muscle, with modification of the antioxidant enzyme machinery resulting in a reduction in lipid peroxidation and protein carbonylation. Thus, we demonstrate that moderate long-term exercise promotes tissue adaptations, increasing muscle, liver and heart sirtuin 1 protein content and activity and increasing PGC-1α protein expression. However, AMPK activation or mitochondrial biogenesis is not modified, but it cannot be discarded that its participation in the adaptive mechanism which prevents the development of the deleterious effects of age.

  17. The E3 ligase axotrophin/MARCH-7: protein expression profiling of human tissues reveals links to adult stem cells.

    PubMed

    Szigyarto, Cristina A; Sibbons, Paul; Williams, Gill; Uhlen, Mathias; Metcalfe, Su M

    2010-04-01

    Axotrophin/MARCH-7 was first identified in mouse embryonic stem cells as a neural stem cell gene. Using the axotrophin/MARCH-7 null mouse, we discovered profound effects on T lymphocyte responses, including 8-fold hyperproliferation and 5-fold excess release of the stem cell cytokine leukemia inhibitory factor (LIF). Our further discovery that axotrophin/MARCH-7 is required for targeted degradation of the LIF receptor subunit gp190 implies a direct role in the regulation of LIF signaling. Bioinformatics studies revealed a highly conserved RING-CH domain in common with the MARCH family of E3-ubiquitin ligases, and accordingly, axotrophin was renamed "MARCH-7." To probe protein expression of human axotrophin/MARCH-7, we prepared antibodies against different domains of the protein. Each antibody bound its specific target epitope with high affinity, and immunohistochemistry cross-validated target specificity. Forty-eight human tissue types were screened. Epithelial cells stained strongly, with trophoblasts having the greatest staining. In certain tissues, specific cell types were selectively positive, including neurons and neuronal progenitor cells in the hippocampus and cerebellum, endothelial sinusoids of the spleen, megakaryocytes in the bone marrow, crypt stem cells of the small intestine, and alveolar macrophages in the lung. Approximately 20% of central nervous system neuropils were positive. Notably, axotrophin/MARCH-7 has an expression profile that is distinct from that of other MARCH family members. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

  18. Ecdysone Receptor-based Singular Gene Switches for Regulated Transgene Expression in Cells and Adult Rodent Tissues

    PubMed Central

    Lee, Seoghyun; Sohn, Kyung-Cheol; Choi, Dae-Kyoung; Won, Minho; Park, Kyeong Ah; Ju, Sung-Kyu; Kang, Kidong; Bae, Young-Ki; Hur, Gang Min; Ro, Hyunju

    2016-01-01

    Controlled gene expression is an indispensable technique in biomedical research. Here, we report a convenient, straightforward, and reliable way to induce expression of a gene of interest with negligible background expression compared to the most widely used tetracycline (Tet)-regulated system. Exploiting a Drosophila ecdysone receptor (EcR)-based gene regulatory system, we generated nonviral and adenoviral singular vectors designated as pEUI(+) and pENTR-EUI, respectively, which contain all the required elements to guarantee regulated transgene expression (GAL4-miniVP16-EcR, termed GvEcR hereafter, and 10 tandem repeats of an upstream activation sequence promoter followed by a multiple cloning site). Through the transient and stable transfection of mammalian cell lines with reporter genes, we validated that tebufenozide, an ecdysone agonist, reversibly induced gene expression, in a dose- and time-dependent manner, with negligible background expression. In addition, we created an adenovirus derived from the pENTR-EUI vector that readily infected not only cultured cells but also rodent tissues and was sensitive to tebufenozide treatment for regulated transgene expression. These results suggest that EcR-based singular gene regulatory switches would be convenient tools for the induction of gene expression in cells and tissues in a tightly controlled fashion. PMID:27673563

  19. The amount of periosteal apposition required to maintain bone strength during aging depends on adult bone morphology and tissue-modulus degradation rate.

    PubMed

    Jepsen, Karl J; Andarawis-Puri, Nelly

    2012-09-01

    Although the continued periosteal apposition that accompanies age-related bone loss is a biomechanically critical target for prophylactic treatment of bone fragility, the magnitude of periosteal expansion required to maintain strength during aging has not been established. A new model for predicting periosteal apposition rate for men and women was developed to better understand the complex, nonlinear interactions that exist among bone morphology, tissue-modulus, and aging. Periosteal apposition rate varied up to eightfold across bone sizes, and this depended on the relationship between cortical area and total area, which varies with external size and among anatomical sites. Increasing tissue-modulus degradation rate from 0% to -4%/decade resulted in 65% to 145% increases in periosteal apposition rate beyond that expected for bone loss alone. Periosteal apposition rate had to increase as much as 350% over time to maintain stiffness for slender diaphyses, whereas robust bones required less than a 32% increase over time. Small changes in the amount of bone accrued during growth (ie, adult cortical area) affected periosteal apposition rate of slender bones to a much greater extent compared to robust bones. This outcome suggested that impaired bone growth places a heavy burden on the biological activity required to maintain stiffness with aging. Finally, sex-specific differences in periosteal apposition were attributable in part to differences in bone size between the two populations. The results indicated that a substantial proportion of the variation in periosteal expansion required to maintain bone strength during aging can be attributed to the natural variation in adult bone width. Efforts to identify factors contributing to variation in periosteal expansion will benefit from developing a better understanding of how to adjust clinical data to differentiate the biological responses attributable to size-effects from other genetic and environmental factors.

  20. Enhanced propagation of adult human renal epithelial progenitor cells to improve cell sourcing for tissue-engineered therapeutic devices for renal diseases.

    PubMed

    Westover, Angela J; Buffington, Deborah A; Humes, H D

    2012-08-01

    Renal cell therapy employing cells derived from adult renal epithelial cell (REC) progenitors promises to reduce the morbidity of patients with renal insufficiency due to acute renal failure and end stage renal disease. To this end, tissue engineered devices addressing the neglected biologic component of renal replacement therapy are being developed. Because human donor tissue is limited, novel enhanced progenitor cell propagation (EP) techniques have been developed and applied to adult human kidney transplant discards from six donors. Changes include more efficient digestion and the amplification of progenitors prior to terminal epithelial differentiation promoted by contact inhibition and the addition of retinoic acid. Differentiated morphology in EP populations was demonstrated by the ability to form polarized epithelium with tight junctions, apical central cilia and expression of brush border membrane enzymes. Evaluation of lipopolysaccharide stimulated interleukin-8 secretion and γ-glutamyl transpeptisade activity in EP derived cells was used to confirm therapeutic equivalence to REC obtained using published techniques, which have previously shown efficacy in large animal models and clinical trials. Yield exceeded 10(16) cells/gram cortex from the only kidney obtained due to an anatomical defect, while the average yield from diseased kidneys ranged from 1.1 × 10(9) to 8.8 × 10(11) cells/gram cortex, representing an increase of more than 10 doublings over standard methods. Application of the EP protocol to REC expansion has solved the problem of cell sourcing as the limiting factor to the manufacture of cell based therapies targeting renal diseases and may provide a method for autologous device fabrication from core kidney biopsies.

  1. Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern.

    PubMed

    Haller, Florian; Knopf, Jasmin; Ackermann, Anne; Bieg, Matthias; Kleinheinz, Kortine; Schlesner, Matthias; Moskalev, Evgeny A; Will, Rainer; Satir, Ali Abdel; Abdelmagid, Ibtihalat E; Giedl, Johannes; Carbon, Roman; Rompel, Oliver; Hartmann, Arndt; Wiemann, Stefan; Metzler, Markus; Agaimy, Abbas

    2016-04-01

    Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA-NTRK1 gene fusion in an index case of paediatric haemangiopericytoma-like sarcoma by combined whole-genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma-like, but with clear-cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick-walled dysplastic-like vessels with segmental or diffuse nodular myxohyaline myo-intimal proliferations of smooth muscle actin-positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion-positive neoplasms, recognition of this rare but likely under-reported sarcoma variant is strongly encouraged.

  2. The Drosophila melanogaster importin alpha3 locus encodes an essential gene required for the development of both larval and adult tissues.

    PubMed Central

    Mason, D Adam; Máthé, Endre; Fleming, Robert J; Goldfarb, David S

    2003-01-01

    The nuclear transport of classical nuclear localization signal (cNLS)-containing proteins is mediated by the cNLS receptor importin alpha. The conventional importin alpha gene family in metazoan animals is composed of three clades that are conserved between flies and mammals and are referred to here as alpha1, alpha2, and alpha3. In contrast, plants and fungi contain only alpha1 genes. In this study we report that Drosophila importin alpha3 is required for the development of both larval and adult tissues. Importin alpha3 mutant flies die around the transition from first to second instar larvae, and homozygous importin alpha3 mutant eyes are defective. The transition to second instar larvae was rescued with importin alpha1, alpha2, or alpha3 transgenes, indicating that Importin alpha3 is normally required at this stage for an activity shared by all three importin alpha's. In contrast, an alpha3-specific biochemical activity(s) of Importin alpha3 is probably required for development to adults and photoreceptor cell development, since only an importin alpha3 transgene rescued these processes. These results are consistent with the view that the importin alpha's have both overlapping and distinct functions and that their role in animal development involves the spatial and temporal control of their expression. PMID:14704178

  3. Sustained Sleep Fragmentation Induces Sleep Homeostasis in Mice

    PubMed Central

    Baud, Maxime O.; Magistretti, Pierre J.; Petit, Jean-Marie

    2015-01-01

    Study Objectives: Sleep fragmentation (SF) is an integral feature of sleep apnea and other prevalent sleep disorders. Although the effect of repetitive arousals on cognitive performance is well documented, the effects of long-term SF on electroencephalography (EEG) and molecular markers of sleep homeostasis remain poorly investigated. To address this question, we developed a mouse model of chronic SF and characterized its effect on EEG spectral frequencies and the expression of genes previously linked to sleep homeostasis including clock genes, heat shock proteins, and plasticity-related genes. Design: N/A. Setting: Animal sleep research laboratory. Participants : Sixty-six C57BL6/J adult mice. Interventions: Instrumental sleep disruption at a rate of 60/h during 14 days Measurements and Results: Locomotor activity and EEG were recorded during 14 days of SF followed by recovery for 2 days. Despite a dramatic number of arousals and decreased sleep bout duration, SF minimally reduced total quantity of sleep and did not significantly alter its circadian distribution. Spectral analysis during SF revealed a homeostatic drive for slow wave activity (SWA; 1–4 Hz) and other frequencies as well (4–40 Hz). Recordings during recovery revealed slow wave sleep consolidation and a transient rebound in SWA, and paradoxical sleep duration. The expression of selected genes was not induced following chronic SF. Conclusions: Chronic sleep fragmentation (SF) increased sleep pressure confirming that altered quality with preserved quantity triggers core sleep homeostasis mechanisms. However, it did not induce the expression of genes induced by sleep loss, suggesting that these molecular pathways are not sustainably activated in chronic diseases involving SF. Citation: Baud MO, Magistretti PJ, Petit JM. Sustained sleep fragmentation induces sleep homeostasis in mice. SLEEP 2015;38(4):567–579. PMID:25325477

  4. The E2F2 Transcription Factor Sustains Hepatic Glycerophospholipid Homeostasis in Mice

    PubMed Central

    Maldonado, Eduardo N.; Delgado, Igotz; Furland, Natalia E.; Buqué, Xabier; Iglesias, Ainhoa; Aveldaño, Marta I.; Zubiaga, Ana; Fresnedo, Olatz; Ochoa, Begoña

    2014-01-01

    Increasing evidence links metabolic signals to cell proliferation, but the molecular wiring that connects the two core machineries remains largely unknown. E2Fs are master regulators of cellular proliferation. We have recently shown that E2F2 activity facilitates the completion of liver regeneration after partial hepatectomy (PH) by regulating the expression of genes required for S-phase entry. Our study also revealed that E2F2 determines the duration of hepatectomy-induced hepatic steatosis. A transcriptomic analysis of normal adult liver identified “lipid metabolism regulation” as a major E2F2 functional target, suggesting that E2F2 has a role in lipid homeostasis. Here we use wild-type (E2F2+/+) and E2F2 deficient (E2F2−/−) mice to investigate the in vivo role of E2F2 in the composition of liver lipids and fatty acids in two metabolically different contexts: quiescence and 48-h post-PH, when cellular proliferation and anabolic demands are maximal. We show that liver regeneration is accompanied by large triglyceride and protein increases without changes in total phospholipids both in E2F2+/+ and E2F2−/− mice. Remarkably, we found that the phenotype of quiescent liver tissue from E2F2−/− mice resembles the phenotype of proliferating E2F2+/+ liver tissue, characterized by a decreased phosphatidylcholine to phosphatidylethanolamine ratio and a reprogramming of genes involved in generation of choline and ethanolamine derivatives. The diversity of fatty acids in total lipid, triglycerides and phospholipids was essentially preserved on E2F2 loss both in proliferating and non-proliferating liver tissue, although notable exceptions in inflammation-related fatty acids of defined phospholipid classes were detected. Overall, our results indicate that E2F2 activity sustains the hepatic homeostasis of major membrane glycerolipid components while it is dispensable for storage glycerolipid balance. PMID:25396754

  5. Ion homeostasis in a salt-secreting halophytic grass

    PubMed Central

    Sanadhya, Payal; Agarwal, Parinita; Agarwal, Pradeep K.

    2015-01-01

    Salinity adversely affects plant growth and development, and disturbs intracellular ion homeostasis, resulting in cellular toxicity. Plants that tolerate salinity, halophytes, do so by manifesting numerous physiological and biochemical processes in coordination to alleviate cellular ionic imbalance. The present study was undertaken to analyse the salt tolerance mechanism in Aeluropus lagopoides (L.) trin. Ex Thw. (Poaceae) at both physiological and molecular levels. Plants secreted salt from glands, which eventually produced pristine salt crystals on leaves and leaf sheaths. The rate of salt secretion increased with increasing salt concentration in the growth medium. Osmotic adjustment was mainly achieved by inorganic osmolytes (Na+) and at 100 mM NaCl no change was observed in organic osmolytes in comparison to control plants. At 300 mM NaCl and with 150 mM NaCl + 150 mM KCl, the concentration of proline, soluble sugars and amino acids was significantly increased. Transcript profiling of transporter genes revealed differential spatial and temporal expressions in both shoot and root tissues in a manner synchronized towards maintaining ion homeostasis. In shoots, AlHKT2;1 transcript up-regulation was observed at 12 and 24 h in all the treatments, whereas in roots, maximum induction was observed at 48 h with K+ starvation. The HAK transcript was relatively abundant in shoot tissue with all the treatments. The plasma membrane Na+/H+ antiporter, SOS1, and tonoplast Na+/H+ antiporter, NHX1, were found to be significantly up-regulated in shoot tissue. Our data demonstrate that AlHKT2;1, HAK, SOS1, NHX1 and V-ATPase genes play a pivotal role in regulating the ion homeostasis in A. lagopoides. PMID:25990364

  6. The promise of perfect adult tissue repair and regeneration in mammals: Learning from regenerative amphibians and fish.

    PubMed

    Godwin, James

    2014-09-01

    Regenerative medicine promises to greatly impact on human health by improving repair outcomes in a range of tissues and injury contexts. Successful therapies will rely on identifying both intrinsic and extrinsic biological circuits that control wound healing, proliferation, cell survival, and developmental cell fate. Animals such as the zebrafish and the salamander display powerful examples of near-perfect regeneration and scar-free healing in a range of injury contexts not attained in mammals. By studying regeneration in a range of highly regenerative species that maintain regenerative potential throughout life, many instructive and permissive factors have been identified that could assist in the development of regenerative therapies. This review highlights some of the recent observations in immune regulation, epigenetic regulation, stem cell mobilization, and regenerative signatures that have improved our understanding of the regenerative process. Potential opportunities in harnessing this knowledge for future translation into the clinic are discussed.

  7. Circadian clocks in fuel harvesting and energy homeostasis.

    PubMed

    Ramsey, K M; Bass, J

    2011-01-01

    Circadian systems have evolved in plants, eubacteria, neurospora, and the metazoa as a mechanism to optimize energy acquisition and storage in synchrony with the rotation of the Earth on its axis. In plants, circadian clocks drive the expression of genes involved in oxygenic photosynthesis during the light and nitrogen fixation during the dark, repeating this cycle each day. In mammals, the core clock in the suprachiasmatic nucleus (SCN) functions to entrain extra-SCN and peripheral clocks to the light cycle, including regions central to energy homeostasis and sleep, as well as peripheral tissues involved in glucose and lipid metabolism. Tissue-specific gene targeting has shown a primary role of clock genes in endocrine pancreas insulin secretion, indicating that local clocks play a cell-autonomous role in organismal homeostasis. A present focus is to dissect the consequences of clock disruption on modulation of nuclear hormone receptor signaling and on posttranscriptional regulation of intermediary metabolism. Experimental genetic studies have pointed toward extensive interplay between circadian and metabolic systems and offer a means to dissect the impact of local tissue molecular clocks on fuel utilization across the sleep-wake cycle.

  8. A physiologist's view of homeostasis

    PubMed Central

    Cliff, William; Michael, Joel; McFarland, Jenny; Wenderoth, Mary Pat; Wright, Ann

    2015-01-01

    Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the “milieu interieur,” but his discussion was rather abstract. Walter Cannon introduced the term “homeostasis” and expanded Bernard's notion of “constancy” of the internal environment in an explicit and concrete way. In the 1960s, homeostatic regulatory mechanisms in physiology began to be described as discrete processes following the application of engineering control system analysis to physiological systems. Unfortunately, many undergraduate texts continue to highlight abstract aspects of the concept rather than emphasizing a general model that can be specifically and comprehensively applied to all homeostatic mechanisms. As a result, students and instructors alike often fail to develop a clear, concise model with which to think about such systems. In this article, we present a standard model for homeostatic mechanisms to be used at the undergraduate level. We discuss common sources of confusion (“sticky points”) that arise from inconsistencies in vocabulary and illustrations found in popular undergraduate texts. Finally, we propose a simplified model and vocabulary set for helping undergraduate students build effective mental models of homeostatic regulation in physiological systems. PMID:26628646

  9. Neutrophil Functions in Periodontal Homeostasis.

    PubMed

    Cortés-Vieyra, Ricarda; Rosales, Carlos; Uribe-Querol, Eileen

    2016-01-01

    Oral tissues are constantly exposed to damage from the mechanical effort of eating and to microorganisms, mostly bacteria. In healthy gingiva tissue remodeling and a balance between bacteria and innate immune cells are maintained. However, excess of bacteria biofilm (plaque) creates an inflammation state that recruits more immune cells, mainly neutrophils to the gingiva. Neutrophils create a barrier for bacteria to reach inside tissues. When neutrophils are insufficient, bacteria thrive causing more inflammation that has been associated with systemic effects on other conditions such as atherosclerosis, diabetes, and cancer. But paradoxically when neutrophils persist, they can also promote a chronic inflammatory state that leads to periodontitis, a condition that leads to damage of the bone-supporting tissues. In periodontitis, bone loss is a serious complication. How a neutrophil balance is needed for maintaining healthy oral tissues is the focus of this review. We present recent evidence on how alterations in neutrophil number and function can lead to inflammatory bone loss, and how some oral bacteria signal neutrophils to block their antimicrobial functions and promote an inflammatory state. Also, based on this new information, novel therapeutic approaches are discussed.

  10. Neutrophil Functions in Periodontal Homeostasis

    PubMed Central

    Cortés-Vieyra, Ricarda; Rosales, Carlos

    2016-01-01

    Oral tissues are constantly exposed to damage from the mechanical effort of eating and to microorganisms, mostly bacteria. In healthy gingiva tissue remodeling and a balance between bacteria and innate immune cells are maintained. However, excess of bacteria biofilm (plaque) creates an inflammation state that recruits more immune cells, mainly neutrophils to the gingiva. Neutrophils create a barrier for bacteria to reach inside tissues. When neutrophils are insufficient, bacteria thrive causing more inflammation that has been associated with systemic effects on other conditions such as atherosclerosis, diabetes, and cancer. But paradoxically when neutrophils persist, they can also promote a chronic inflammatory state that leads to periodontitis, a condition that leads to damage of the bone-supporting tissues. In periodontitis, bone loss is a serious complication. How a neutrophil balance is needed for maintaining healthy oral tissues is the focus of this review. We present recent evidence on how alterations in neutrophil number and function can lead to inflammatory bone loss, and how some oral bacteria signal neutrophils to block their antimicrobial functions and promote an inflammatory state. Also, based on this new information, novel therapeutic approaches are discussed. PMID:27019855

  11. Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma

    ClinicalTrials.gov

    2014-09-08

    Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Synovial Sarcoma; Childhood Alveolar Soft-part Sarcoma; Childhood Angiosarcoma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Neurofibrosarcoma; Childhood Synovial Sarcoma; Dermatofibrosarcoma Protuberans; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  12. Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight.

    PubMed

    Sisley, Stephanie R; Arble, Deanna M; Chambers, Adam P; Gutierrez-Aguilar, Ruth; He, Yanlin; Xu, Yong; Gardner, David; Moore, David D; Seeley, Randy J; Sandoval, Darleen A

    2016-09-01

    Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis. Indeed, we found that small doses of active vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3) (calcitriol), into the third ventricle of the brain improved glucose tolerance and markedly increased hepatic insulin sensitivity, an effect that is dependent upon VDR within the paraventricular nucleus of the hypothalamus. In addition, chronic central administration of 1,25D3 dramatically decreased body weight by lowering food intake in obese rodents. Our data indicate that 1,25D3-mediated changes in food intake occur through action within the arcuate nucleus. We found that VDR colocalized with and activated key appetite-regulating neurons in the arcuate, namely proopiomelanocortin neurons. Together, these findings define a novel pathway for vitamin D regulation of metabolism with unique and divergent roles for central nervous system VDR signaling. Specifically, our data suggest that vitamin D regulates glucose homeostasis via the paraventricular nuclei and energy homeostasis via the arcuate nuclei.

  13. Role of Galectin-3 in Obesity and Impaired Glucose Homeostasis

    PubMed Central

    Menini, Stefano; Iacobini, Carla; Blasetti Fantauzzi, Claudia; Pesce, Carlo M.; Pugliese, Giuseppe

    2016-01-01

    Galectin-3 is an important modulator of several biological functions. It has been implicated in numerous disease conditions, particularly in the long-term complications of diabetes because of its ability to bind the advanced glycation/lipoxidation end products that accumulate in target organs and exert their toxic effects by triggering proinflammatory and prooxidant pathways. Recent evidence suggests that galectin-3 may also participate in the development of obesity and type 2 diabetes. It has been shown that galectin-3 levels are higher in obese and diabetic individuals and parallel deterioration of glucose homeostasis. Two studies in galectin-3 knockout mice fed a high-fat diet (HFD) have shown increased adiposity and adipose tissue and systemic inflammation associated with altered glucose homeostasis, suggesting that galectin-3 negatively modulates the responsiveness of innate and adaptive immunity to overnutrition. However, these studies have also shown that impaired glucose homeostasis occurs in galectin-3 knockout animals independently of obesity. Moreover, another study reported decreased weight and fat mass in HFD-fed galectin-3 knockout mice. In vitro, galectin-3 was found to stimulate differentiation of preadipocytes into mature adipocytes. Altogether, these data indicate that galectin-3 deserves further attention in order to clarify its role as a potential player and therapeutic target in obesity and type 2 diabetes. PMID:26770660

  14. The Yin and Yang of chromatin dynamics in adult stem cell fate selection

    PubMed Central

    Adam, Rene C.; Fuchs, Elaine

    2015-01-01

    Adult organisms rely on tissue stem cells for maintenance and repair. During homeostasis, the concerted action of local niche signals and epigenetic regulators establish stable gene expression patterns to ensure that stem cells are not lost over time. However, stem cells also provide host tissues with a remarkable plasticity to respond to perturbations. How adult stem cells choose and acquire new fates is unknown, but the genome-wide mapping of epigenetic landscapes suggests a critical role for chromatin remodeling in these processes. Here, we explore the emerging role of chromatin modifiers and pioneer transcription factors in adult stem cell fate decisions and plasticity, which ensure that selective lineage choices are only made when environmentally cued. PMID:26689127

  15. Apoptosis, Necrosis, and Necroptosis in the Gut and Intestinal Homeostasis

    PubMed Central

    Negroni, Anna; Cucchiara, Salvatore; Stronati, Laura

    2015-01-01

    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. PMID:26483605

  16. Apoptosis, Necrosis, and Necroptosis in the Gut and Intestinal Homeostasis.

    PubMed

    Negroni, Anna; Cucchiara, Salvatore; Stronati, Laura

    2015-01-01

    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.

  17. Pancreas-Specific Deletion of Prox1 Affects Development and Disrupts Homeostasis of the Exocrine Pancreas

    PubMed Central

    WESTMORELAND, JOBY J.; KILIC, GAMZE; SARTAIN, CAROLINE; SIRMA, SEMA; BLAIN, JENNIFER; REHG, JEROLD; HARVEY, NATASHA; SOSA–PINEDA, BEATRIZ

    2012-01-01

    BACKGROUND & AIMS The exocrine portion of the pancreas functions in digestion and preserves pancreatic homeostasis. Learning how this tissue forms during embryogenesis could improve our understanding of human pancreatic diseases. Expression of the homeo-box gene Prox1 in the exocrine pancreas changes throughout development in mice. We investigated the role of Prox1 in development of the exocrine pancreas in mice. METHODS Mice with pancreas-specific deletion of Prox1 (Prox1ΔPanc) were generated and their pancreatic tissues were analyzed using immunohistochemistry, transmission electron microscopy, histologic techniques, quantitative real-time polymerase chain reaction, immunoblotting, and morphometric analysis. RESULTS Loss of Prox1 from the pancreas led to multiple exocrine alterations, most notably premature acinar cell differentiation, increased ductal cell proliferation, altered duct morphogenesis, and imbalanced expression of claudin proteins. Prox1ΔPanc mice also had some minor alterations in islet cells, but beta-cell development was not affected. The exocrine congenital defects of Prox1ΔPanc pancreata appeared to initiate a gradual process of deterioration that resulted in extensive loss of acinar cells, lipomatosis, and damage to ductal tissue in adult mice. CONCLUSIONS Pancreas-specific deletion of Prox1 causes premature differentiation of acinar cells and poor elongation of epithelial branches; these defects indicate that Prox1 controls the expansion of tip progenitors in the early developing pancreas. During later stages of embryogenesis, Prox1 appears to regulate duct cell proliferation and morphogenesis. These findings identify Prox1 as an important regulator of pancreatic exocrine development. PMID:22178591

  18. Planarian immobilization, partial irradiation, and tissue transplantation.

    PubMed

    Guedelhoefer, Otto C; Sánchez Alvarado, Alejandro

    2012-08-06

    culture of large animals, immobilization, preparation for partial irradiation, tissue transplantation, and the optimization of animal recovery. Furthermore, the work described here demonstrates the first application of the partial irradiation method for use with the most widely studied planarian, Schmidtea mediterranea. Additionally, efficient tissue grafting in planaria opens the door for the functional testing of subpopulations of naïve or treated stem cells in repopulation assays, which has long been the gold-standard method of assaying adult stem cell potential in mammals. Broad adoption of these techniques will no doubt lead to a better understanding of the cellular behaviors of adult stem cells during tissue homeostasis and regeneration.

  19. Planarian Immobilization, Partial Irradiation, and Tissue Transplantation

    PubMed Central

    Guedelhoefer IV, Otto C.; Sánchez Alvarado, Alejandro

    2012-01-01

    cover the culture of large animals, immobilization, preparation for partial irradiation, tissue transplantation, and the optimization of animal recovery. Furthermore, the work described here demonstrates the first application of the partial irradiation method for use with the most widely studied planarian, Schmidtea mediterranea. Additionally, efficient tissue grafting in planaria opens the door for the functional testing of subpopulations of naïve or treated stem cells in repopulation assays, which has long been the gold-standard method of assaying adult stem cell potential in mammals8. Broad adoption of these techniques will no doubt lead to a better understanding of the cellular behaviors of adult stem cells during tissue homeostasis and regeneration. PMID:23007410

  20. Comparison of human adult stem cells from adipose tissue and bone marrow in the treatment of experimental autoimmune encephalomyelitis

    PubMed Central

    2014-01-01

    Introduction While administration of ex vivo culture-expanded stem cells has been used to study immunosuppressive mechanisms in multiple models of autoimmune diseases, less is known about the uncultured, nonexpanded stromal vascular fraction (SVF)-based therapy. The SVF is composed of a heterogeneous population of cells and has been used clinically to treat acute and chronic diseases, alleviating symptoms in a range of tissues and organs. Methods In this study, the ability of human SVF cells was compared with culture-expanded adipose stem cells (ASCs) and bone-derived marrow stromal cells (BMSCs) as a treatment of myelin oligodendrocyte glycoprotein (35–55)-induced experimental autoimmune encephalitis in C57Bl/6J mice, a well-studied multiple sclerosis model (MS). A total of 1 × 106 BMSCs, ASCs, or SVF cells were administered intraperitoneally concomitantly with the induction of disease. Mice were monitored daily for clinical signs of disease by three independent, blinded investigators and rated on a scale of 0 to 5. Spinal cords were obtained after euthanasia at day 30 and processed for histological staining using luxol fast blue, toluidine blue, and hematoxylin and eosin to measure myelin and infiltrating immune cells. Blood was collected from mice at day 30 and analyzed by enzyme-linked immunosorbent assay to measure serum levels of inflammatory cytokines. Results The data indicate that intraperitoneal administration of all cell types significantly ameliorates the severity of disease. Furthermore, the data also demonstrate, for the first time, that the SVF was as effective as the more commonly cultured BMSCs and ASCs in an MS model. All cell therapies also demonstrated a similar reduction in tissue damage, inflammatory infiltrates, and sera levels of IFNγ and IL-12. While IFNγ levels were reduced to comparable levels between treatment groups, levels of IL-12 were significantly lower in SVF-treated than BMSC-treated or ASC-treated mice. Conclusions Based

  1. Calcium homeostasis in diabetes mellitus.

    PubMed

    Heath, H; Lambert, P W; Service, F J; Arnaud, S B

    1979-09-01

    Experimentally diabetic rats have low serum 1,25-dihydroxyvitamin D, intestinal malabsorption of calcium, secondary hyperparathyroidism, and bone loss. To examine the hypothesis that abnormalities similar to those in the diabetic rat might explain human diabetic osteopenia, we studied calcium metabolism in 40 healthy control and 82 diabetic patients aged 18--75 yr [47 untreated: fasting plasma glucose (mean +/- SE), 267 +/- 8 mg/dl; 19 treated but hyperglycemic: glucose 305 +/- 24 mg/dl; 16 treated and in better control: glucose, 146 +/- 8 mg/dl]. Serum total calcium, ionic calcium, immunoreactive parathyroid hormone (Arnaud method, GP-1M and CH-12M antisera), 25-hydroxyvitamin D (Haddad method), and 1,25-dihydroxyvitamin D (Lambert method) concentrations were normal in all 3 groups of diabetics and were not significantly different from values in the control group. We determined absorption of calcium from the intestine by a double isotope method (100 mg Ca carrier; normal range, 40--80%) in 11 control and 13 untreated, uncontrolled diabetics (mean plasma glucose, 285 +/- 17 mg/dl). Absorption of calcium in controls was 60 +/- 3% and in diabetics was 56 +/- 3% (not significantly different). We have found no derangement of calcium metabolism in adults with insulin-requiring juvenile- and adult-onset diabetes regardless of treatment status. The experimental diabetic rat model does not appear to be useful for determining the pathogenesis of adult human diabetic osteopenia.

  2. Targeted mutation of NOV/CCN3 in mice disrupts joint homeostasis and causes osteoarthritis-like disease

    PubMed Central

    Roddy, K.A.; Boulter, C.A.

    2015-01-01

    Summary Objective The matricellular protein NOV/CCN3, is implicated in osteoarthritis (OA) and targeted mutation of NOV in mice (Novdel3) leads to joint abnormalities. This investigation tested whether NOV is required for joint homeostasis and if its disruption causes joint degeneration. Method NOV expression in the adult mouse joint was characterized by immunohistochemistry. A detailed comparison of the joints of Novdel3−/− and Novdel3+/+ (wild-type) males and females at 2, 6 and 12 months of age was determined by X-ray, histology and immunohistochemistry. Results NOV protein was found in specific cells in articular cartilage, meniscus, synovium and ligament attachment sites in adult knees. Novdel3−/− males exhibited severe OA-like pathology at 12 months (OARSI score 5.0 ± 0.5, P < 0.001), affecting all tissues of the joint: erosion of the articular cartilage, meniscal enlargement, osteophytic outgrowths, ligament degeneration and expansion of fibrocartilage. Subchondral sclerosis and changes in extracellular matrix composition consistent with OA, were also seen. The density of articular cartilage cells in Novdel3+/+ knee joints is maintained at a constant level from 2 to 12 months of age whereas this is not the case in Novdel3−/− mice. Compared with age and sex-matched Novdel3+/+ mice, a significant increase in articular cartilage density was seen in Novdel3−/− males at 2 months, whereas a significant decrease was seen at 6 and 12 months in both Novdel3−/− males and females. Conclusion NOV is required for the maintenance of articular cartilage and for joint homeostasis, with disruption of NOV in ageing Novdel3−/− male mice causing OA-like disease. PMID:25541297

  3. Impact of low dose prenatal ethanol exposure on glucose homeostasis in Sprague-Dawley rats aged up to eight months.

    PubMed

    Probyn, Megan E; Parsonson, Kylie R; Gårdebjer, Emelie M; Ward, Leigh C; Wlodek, Mary E; Anderson, Stephen T; Moritz, Karen M

    2013-01-01

    Excessive exposure to alcohol prenatally has a myriad of detrimental effects on the health and well-being of the offspring. It is unknown whether chronic low-moderate exposure of alcohol prenatally has similar and lasting effects on the adult offspring's health. Using our recently developed Sprague-Dawley rat model of 6% chronic prenatal ethanol exposure, this study aimed to determine if this modest level of exposure adversely affects glucose homeostasis in male and female offspring aged up to eight months. Plasma glucose concentrations were measured in late fetal and postnatal life. The pancreas of 30 day old offspring was analysed for β-cell mass. Glucose handling and insulin action was measured at four months using an intraperitoneal glucose tolerance test and insulin challenge, respectively. Body composition and metabolic gene expression were measured at eight months. Despite normoglycaemia in ethanol consuming dams, ethanol-exposed fetuses were hypoglycaemic at embryonic day 20. Ethanol-exposed offspring were normoglycaemic and normoinsulinaemic under basal fasting conditions and had normal pancreatic β-cell mass at postnatal day 30. However, during a glucose tolerance test, male ethanol-exposed offspring were hyperinsulinaemic with increased first phase insulin secretion. Female ethanol-exposed offspring displayed enhanced glucose clearance during an insulin challenge. Body composition and hepatic, muscle and adipose tissue metabolic gene expression levels at eight months were not altered by prenatal ethanol exposure. Low-moderate chronic prenatal ethanol exposure has subtle, sex specific effects on glucose homeostasis in the young adult rat. As aging is associated with glucose dysregulation, further studies will clarify the long lasting effects of prenatal ethanol exposure.

  4. The Effects of Partial Mechanical Loading and Ibandronate on Skeletal Tissues in the Adult Rat Hindquarter Suspension Model for Microgravity

    NASA Technical Reports Server (NTRS)

    Schultheis, Lester W.

    1999-01-01

    We report initial data from a suspended rat model that quantitatively relates chronic partial weightbearing to bone loss. Chronic partial weightbearing is our simulation of the effect of limited artificial gravity aboard spacecraft or reduced planetary gravity. Preliminary analysis of bone by PQCT, histomorphometry, mechanical testing and biochemistry suggest that chronic exposure to half of Earth gravity is insufficient to prevent severe bone loss. The effect of episodic full weightbearing activity (Earth Gravity) on rats otherwise at 50% weightbearing was also explored. This has similarity to treatment by an Earth G-rated centrifuge on a spacecraft that normally maintained artificial gravity at half of Earth G. Our preliminary evidence, using the above techniques to analyze bone, indicate that 2 hours daily of full weightbearing was insufficient to prevent the bone loss observed in 50% weightbearing animals. The effectiveness of partial weightbearing and episodic full weightbearing as potential countermeasures to bone loss in spaceflight was compared with treatment by ibandronate. Ibandronate, a long-acting potent bisphosphonate proved more effective in preventing bone loss and associated functionality based upon structure than our first efforts at mechanical countermeasures. The effectiveness of ibandronate was notable by each of the testing methods we used to study bone from gross structure and strength to tissue and biochemistry. These results appear to be independent of generalized systemic stress imposed by the suspension paradigm. Preliminary evidence does not suggest that blood levels of vitamin D were affected by our countermeasures. Despite the modest theraputic benefit of mechanical countermeasures of partial weightbearing and episodic full weightbearing, we know that some appropriate mechanical signal maintains bone mass in Earth gravity. Moreover, the only mechanism that correctly assigns bone mass and strength to oppose regionally specific force

  5. Seasonal variation in plasma catecholamines and adipose tissue lipolysis in adult female green sea turtles (Chelonia mydas).

    PubMed

    Hamann, Mark; Limpus, Colin J; Whittier, Joan M

    2003-02-15

    We investigated three aspects of potential interrenal regulation of reproduction in female green sea turtles, Chelonia mydas. First, seasonal trends in plasma catecholamines were examined from female C. mydas at different stages of their reproductive cycles. Second, variation in catecholamine levels during a nesting season were analysed in relation to restraint time, and ecological variables such as nesting habitat, body size, and reproductive investment. Third, catecholamine and corticosterone (CORT) induced lipolysis was investigated with adipose tissue collected from gravid green turtles, using in vitro incubations. Plasma epinephrine (EPI) was lowest in non-vitellogenic (1.55 +/- 0.26 ng/ml) and post-breeding (1.57 +/- 0.22 ng/ml) females, and highest in courting females (2.87 +/- 0.28). Concentrations of norepinephrine (NE) and EPI were relatively constant throughout a nesting season, and not significantly related to restraint time, reproductive investment or nesting habitat. In vitro concentrations of CORT (>3 ng/ml) and NE (2 ng/ml) induced significant release of glycerol after 6h of incubation. Epinephrine tended to induce an antilipolytic affect at low concentrations (0.25 ng/ml) and a net lipolytic response at higher concentrations (>1 ng/ml). Our data suggest that EPI may play a role in regulating body condition during vitellogenesis, and maintaining energy stores during prolonged aphagia during courtship and nesting in female green sea turtles. Furthermore, we provide preliminary evidence that suggests that catecholamine production may be either down regulated or de-sensitised in gravid female C. mydas.

  6. Does microbiota composition affect thyroid homeostasis?

    PubMed

    Virili, Camilla; Centanni, Marco

    2015-08-01

    The intestinal microbiota is essential for the host to ensure digestive and immunologic homeostasis. When microbiota homeostasis is impaired and dysbiosis occurs, the malfunction of epithelial barrier leads to intestinal and systemic disorders, chiefly immunologic and metabolic. The role of the intestinal tract is crucial in the metabolism of nutrients, drugs, and hormones, including exogenous and endogenous iodothyronines as well as micronutrients involved in thyroid homeostasis. However, the link between thyroid homeostasis and microbiota composition is not yet completely ascertained. A pathogenetic link with dysbiosis has been described in different autoimmune disorders but not yet fully elucidated in autoimmune thyroid disease which represents the most frequent of them. Anyway, it has been suggested that intestinal dysbiosis may trigger autoimmune thyroiditis. Furthermore, hypo- and hyper-thyroidism, often of autoimmune origin, were respectively associated to small intestinal bacterial overgrowth and to changes in microbiota composition. Whether some steps of this thyroid network may be affected by intestinal microbiota composition is briefly discussed below.

  7. Air pollution particles and iron homeostasis

    EPA Science Inventory

    Background: The mechanism underlying biological effects of particles deposited in the lung has not been defined. Major Conclusions: A disruption in iron homeostasis follows exposure of cells to all particulate matter including air pollution particles. Following endocytosis, fun...

  8. ADAR1 is essential for intestinal homeostasis and stem cell maintenance

    PubMed Central

    Qiu, W; Wang, X; Buchanan, M; He, K; Sharma, R; Zhang, L; Wang, Q; Yu, J

    2013-01-01

    Adenosine deaminase acting on RNA 1 (ADAR1) is a double-stranded RNA-editing enzyme that converts adenosine (A) to inosine (I), and essential for normal development. In this study, we reported an essential role of ADAR1 in the survival and maintenance of intestinal stem cells and intestinal homoeostasis by suppressing endoplasmic reticulum (ER) stress and interferon (IFN) signaling. ADAR1 was highly expressed in the Lgr5+ cells, and its deletion in adult mice led to a rapid apoptosis and loss of these actively cycling stem cells in the small intestine and colon. ADAR1 deletion resulted in a drastic expansion of progenitors and Paneth cells but a reduction of three other major epithelial lineages. Moreover, loss of ADAR1 induced ER stress and activation of IFN signaling, and altered expression in WNT targets, followed by intestinal inflammation. An ER stress inhibitor partially suppressed crypt apoptosis. Finally, data from cultured intestinal crypts demonstrated that loss of ADAR1 in the epithelial cells is the primary cause of these effects. These results support an essential role of ADAR1 and RNA editing in tissue homeostasis and stem cells. PMID:23598411

  9. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy.

    PubMed

    Pessina, Patrizia; Kharraz, Yacine; Jardí, Mercè; Fukada, So-ichiro; Serrano, Antonio L; Perdiguero, Eusebio; Muñoz-Cánoves, Pura

    2015-06-09

    Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.

  10. Multilayer structure formation via homophily and homeostasis

    NASA Astrophysics Data System (ADS)

    Makarov, Vladimir V.; Koronovskii, Alexey A.; Maksimenko, Vladimir A.; Khramova, Marina V.; Hramov, Alexander E.; Pavlov, Alexey N.; Moskalenko, Olga I.; Buldú, Javier M.; Boccaletti, Stefano

    2016-03-01

    The competition of homophily and homeostasis mechanisms taking place in the multilayer network where several layers of connection topologies are simultaneously present as well as the interaction between layers is considered. We have shown that the competition of homophily and homeostasis leads in such networks to the formation of synchronous patterns within the different layers of the network, which may be both the distinct and identical.

  11. CARNITINE HOMEOSTASIS, MITOCHONDRIAL FUNCTION, AND CARDIOVASCULAR DISEASE

    PubMed Central

    Sharma, Shruti; Black, Stephen M.

    2009-01-01

    Carnitines are involved in mitochondrial transport of fatty acids and are of critical importance for maintaining normal mitochondrial function. This review summarizes recent experimental and clinical studies showing that mitochondrial dysfunction secondary to a disruption of carnitine homeostasis may play a role in decreased NO signaling and the development of endothelial dysfunction. Future challenges include development of agents that can positively modulate L-carnitine homeostasis which may have high therapeutic potential. PMID:20648231

  12. AZD0530 in Treating Patients With Recurrent Locally Advanced or Metastatic Soft Tissue Sarcoma

    ClinicalTrials.gov

    2015-07-02

    Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Rhabdomyosarcoma; Dermatofibrosarcoma Protuberans; Endometrial Stromal Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Uterine Carcinosarcoma; Uterine Leiomyosarcoma

  13. Epoxyeicosatrienoic acids and glucose homeostasis in mice and men.

    PubMed

    Luther, James M; Brown, Nancy J

    2016-09-01

    Epoxyeicosatrienoic acids (EETs) are formed from arachidonic acid by the action of P450 epoxygenases (CYP2C and CYP2J). Effects of EETs are limited by hydrolysis by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. Studies in rodent models provide compelling evidence that epoxyeicosatrienoic acids exert favorable effects on glucose homeostasis, either by enhancing pancreatic islet cell function or by increasing insulin sensitivity in peripheral tissues. Specifically, the tissue expression of soluble epoxide hydrolase appears to be increased in rodent models of obesity and diabetes. Pharmacological inhibition of epoxide hydrolase or deletion of the gene encoding soluble epoxide hydrolase (Ephx2) preserves islet cells in rodent models of type 1 diabetes and enhances insulin sensitivity in models of type 2 diabetes, as does administration of epoxyeicosatrienoic acids or their stable analogues. In humans, circulating concentrations of epoxyeicosatrienoic acids correlate with insulin sensitivity, and a loss-of-function genetic polymorphism in EPHX2 is associated with insulin sensitivity.

  14. Nutritional status induces divergent variations of GLUT4 protein content, but not lipoprotein lipase activity, between adipose tissues and muscles in adult cattle.

    PubMed

    Bonnet, Muriel; Faulconnier, Yannick; Hocquette, Jean-François; Bocquier, François; Leroux, Christine; Martin, Patrice; Chilliard, Yves

    2004-10-01

    Metabolic adaptations to variations in food supply are incompletely understood in ruminant animal adipose tissue (AT) and muscle. To explore this, we studied lipid metabolism and glucose transport potential in one internal and one external AT, as well as in one oxidative and one glycolytic muscle from control, 7 d underfed and 21 d refed adult cows. Refeeding increased (+79 to +307 %) the activities of enzymes involved in de novo lipogenesis (fatty acid synthase, malic enzyme, glucose-6-phosphate dehydrogenase) in perirenal and subcutaneous AT; underfeeding did not modify these variables. Underfeeding decreased the activities of lipoprotein lipase (LPL) in perirenal AT (-70 %) and cardiac muscle (-67 %), but did not modify the activities in subcutaneous AT and longissimus thoracis. Refeeding increased LPL activities in all tissues (+40 to +553 %) to levels comparable with (cardiac muscle) or greater than (AT, longissimus thoracis) those observed in control cows. Such variations in perirenal and cardiac muscle LPL activities did not result from variations in LPL mRNA levels, but suggest a post-transcriptional regulation of LPL in these nutritional conditions. Underfeeding did not modify GLUT4 contents in perirenal AT and muscles, while refeeding increased it only in perirenal AT (+250 %). Our present results contrast with previous results in rats, where LPL is regulated in opposite directions in AT and muscles, and GLUT4 is generally increased by fasting and decreased by refeeding in skeletal muscles. The present results highlight the bovine specificity of the response, which probably arises in part from peculiarities of ruminant animals for nutrient digestion and absorption.

  15. Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity

    PubMed Central

    Prawitt, Janne; Abdelkarim, Mouaadh; Stroeve, Johanna H.M.; Popescu, Iuliana; Duez, Helene; Velagapudi, Vidya R.; Dumont, Julie; Bouchaert, Emmanuel; van Dijk, Theo H.; Lucas, Anthony; Dorchies, Emilie; Daoudi, Mehdi; Lestavel, Sophie; Gonzalez, Frank J.; Oresic, Matej; Cariou, Bertrand; Kuipers, Folkert; Caron, Sandrine; Staels, Bart

    2011-01-01

    OBJECTIVE Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed. RESEARCH DESIGN AND METHODS Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity. RESULTS FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism. CONCLUSIONS Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis. PMID:21593203

  16. Adipose-derived adult stem cells: available technologies for potential clinical regenerative applications in dentistry.

    PubMed

    Catalano, Enrico; Cochis, Andrea; Varoni, Elena; Rimondini, Lia; Carrassi, Antonio; Azzimonti, Barbara

    2013-01-01

    Tissue homeostasis depends closely on the activity and welfare of adult stem cells. These cells represent a promising tool for biomedical research since they can aid in treatment and promote the regeneration of damaged organs in many human disorders. Adult stem cells indefinitely preserve their ability to self-renew and differentiate into various phenotypes; this capacity could be promoted in vitro by particular culture conditions (differentiation media) or spontaneously induced in vivo by exploiting the biochemical and mechanical properties of the tissue in which the stem cells are implanted. Among the different sources of adult stem cells, adipose tissue is an attractive possibility thanks to its ready availability and the standard extraction techniques at our disposal today. This review discusses the isolation, characterization, and differentiation of human adipose-derived adult stem cells, as well as regeneration strategies, therapeutic uses, and adverse effects of their delivery. In particular, since oral disorders (e.g., trauma, erosion, and chronic periodontitis) often cause the loss of dental tissue along with functional, phonetic, and aesthetic impairment, this review focuses on the application of human adipose-derived adult stem cells, alone or in combination with biomaterials, in treating oral diseases.

  17. Iron homeostasis and eye disease

    PubMed Central

    Loh, Allison; Hadziahmetovic, Majda; Dunaief, Joshua L.

    2009-01-01

    Summary Iron is necessary for life, but excess iron can be toxic to tissues. Iron is thought to damage tissues primarily by generating oxygen free radicals through the Fenton reaction. We present an overview of the evidence supporting iron's potential contribution to a broad range of eye disease using an anatomical approach. Firstly, iron can be visualized in the cornea as iron lines in the normal aging cornea as well as in diseases like keratoconus and pterygium. In the lens, we present the evidence for the role of oxidative damage in cataractogenesis. Also, we review the evidence that iron may play a role in the pathogenesis of the retinal disease age-related macular degeneration. Although currently there is no direct link between excess iron and development of optic neuropathies, ferrous iron's ability to form highly reactive oxygen species may play a role in optic nerve pathology. Lastly, we discuss recent advances in prevention and therapeutics for eye disease with antioxidants and iron chelators,. PMID:19059309

  18. The zinc homeostasis network of land plants.

    PubMed

    Sinclair, Scott Aleksander; Krämer, Ute

    2012-09-01

    The use of the essential element zinc (Zn) in the biochemistry of land plants is widespread, and thus comparable to that in other eukaryotes. Plants have evolved the ability to adjust to vast fluctuations in external Zn supply, and they can store considerable amounts of Zn inside cell vacuoles. Moreover, among plants there is overwhelming, but yet little explored, natural genetic diversity that phenotypically affects Zn homeostasis. This results in the ability of specific races or species to thrive in different soils ranging from extremely Zn-deficient to highly Zn-polluted. Zn homeostasis is maintained by a tightly regulated network of low-molecular-weight ligands, membrane transport and Zn-binding proteins, as well as regulators. Here we review Zn homeostasis of land plants largely based on the model plant Arabidopsis thaliana, for which our molecular understanding is most developed at present. There is some evidence for substantial conservation of Zn homeostasis networks among land pants, and this review can serve as a reference for future comparisons. Major progress has recently been made in our understanding of the regulation of transcriptional Zn deficiency responses and the role of the low-molecular-weight chelator nicotianamine in plant Zn homeostasis. Moreover, we have begun to understand how iron (Fe) and Zn homeostasis interact as a consequence of the chemical similarity between their divalent cations and the lack of specificity of the major root iron uptake transporter IRT1. The molecular analysis of Zn-hyperaccumulating plants reveals how metal homeostasis networks can be effectively modified. These insights are important for sustainable bio-fortification approaches. This article is part of a Special Issue entitled: Cell Biology of Metals.

  19. Molecular characterization, tissue distribution, and mRNA expression profiles of two Kiss genes in the adult male and female chub mackerel (Scomber japonicus) during different gonadal stages.

    PubMed

    Selvaraj, Sethu; Kitano, Hajime; Fujinaga, Yoichiro; Ohga, Hirofumi; Yoneda, Michio; Yamaguchi, Akihiko; Shimizu, Akio; Matsuyama, Michiya

    2010-10-01

    Kisspeptins, encoded by the Kiss1 gene, have emerged as key modulators of reproduction in mammals. In contrast to the placental mammals, some teleosts express two Kiss genes, Kiss1 and Kiss2. In the present study, full-length cDNAs of Kiss1 and Kiss2 in the chub mackerel were cloned and sequenced. Chub mackerel Kiss1 and Kiss2 cDNAs encode 105 and 123 amino acids, respectively. A comparison of the deduced amino acid sequences of chub mackerel Kiss1 and Kiss2 with those of other vertebrate species showed a high degree of conservation only in the kisspeptin-10 region (Kp-10). The Kp-10 of chub mackerel Kiss1 (YNFNSFGLRY) and Kiss2 (FNFNPFGLRF) showed variations at three amino acids. Tissue distribution analysis using quantitative real-time PCR (qRT-PCR) revealed that the Kiss1 and Kiss2 transcripts were expressed in different tissues of adult chub mackerel. In addition, their levels in the adipose tissue exhibited sexually dimorphic expression. Further, to have a basic understanding on the involvement of Kiss1 and Kiss2 in the seasonal gonadal development, their relative mRNA expression profiles in the brain, pituitary, and gonads at different gonadal stages were analyzed using qRT-PCR. Kiss1 and Kiss2 levels in the brain showed a differential expression profile between male and female fish. In males, Kiss1 and Kiss2 levels gradually decreased from the immature stage to spermiation and reached a minimal level during the post-spawning period. In contrast, Kiss1 levels in the brain of females did not vary significantly among the different gonadal stages. However, Kiss2 levels fluctuated as that of males, gradually declining from the immature stage to the post-spawning period. The pituitary Kiss1 levels did not show significant fluctuations. However, Kiss1 levels in the gonads were highly elevated during spermiation and late vitellogenesis compared to the immature and post-spawning period. These results suggest the possible involvement of two Kiss genes in the brain and

  20. DNA-methylation dependent regulation of embryo-specific 5S ribosomal DNA cluster transcription in adult tissues of sea urchin Paracentrotus lividus.

    PubMed

    Bellavia, Daniele; Dimarco, Eufrosina; Naselli, Flores; Caradonna, Fabio

    2013-10-01

    We have previously reported a molecular and cytogenetic characterization of three different 5S rDNA clusters in the sea urchin Paracentrotus lividus and recently, demonstrated the presence of high heterogeneity in functional 5S rRNA. In this paper, we show some important distinctive data on 5S rRNA transcription for this organism. Using single strand conformation polymorphism (SSCP) analysis, we demonstrate the existence of two classes of 5S rRNA, one which is embryo-specific and encoded by the smallest (700 bp) cluster and the other which is expressed at every stage and encoded by longer clusters (900 and 950 bp). We also demonstrate that the embryo-specific class of 5S rRNA is expressed in oocytes and embryonic stages and is silenced in adult tissue and that this phenomenon appears to be due exclusively to DNA methylation, as indicated by sensitivity to 5-azacytidine, unlike Xenopus where this mechanism is necessary but not sufficient to maintain the silenced status.

  1. The gene encoding the VP16-accessory protein HCF (HCFC1) resides in human Xq28 and is highly expressed in fetal tissues and the adult kidney

    SciTech Connect

    Wilson, A.C.; Herr, W.; Parrish, J.E.; Massa, H.F.

    1995-01-20

    After herpes simplex virus (HSV) infection, the viral regulatory protein VP16 activates transcription of the HSV immediate-early promoters by directing complex formation with two cellular proteins, the POU-homeodomain transcription factor Oct-1 and the host cell factor HCF. The function of HCF in uninfected cells is unknown. Here we show by fluorescence in situ hybridization and somatic cell hybrid analysis that the gene encoding human HCF, HCFC1, maps to the q28 region of the X chromosome. Yeast artificial chromosome and cosmid mapping localizes the HCFC1 gene within 100 kb distal of the renal vasopressin type-2 receptor (V2R) gene and adjacent to the renin-binding protein gene (RENBP). The HCFC1 gene is apparently unique. HCF transcripts and protein are most abundant in fetal and placental tissues and cell lines, suggesting a role in cell proliferation. In adults, HCF protein is abundant in the kidney, but not in the brain, a site of latent HSV infection and where HCF levels may influence progression of HSV infection. 42 refs., 3 figs.

  2. Roles of innervation in developing and regenerating orofacial tissues.

    PubMed

    Pagella, Pierfrancesco; Jiménez-Rojo, Lucia; Mitsiadis, Thimios A

    2014-06-01

    The head is innervated by 12 cranial nerves (I-XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.

  3. miRNA Control of Tissue Repair and Regeneration

    PubMed Central

    Sen, Chandan K.; Ghatak, Subhadip

    2016-01-01

    Tissue repair and regeneration rely on the function of miRNA, molecular silencers that enact post-transcriptional gene silencing of coding genes. Disruption of miRNA homeostasis is developmentally lethal, indicating that fetal tissue development is tightly controlled by miRNAs. Multiple critical facets of adult tissue repair are subject to control by miRNAs, as well. Sources of cell pool for tissue repair and regeneration are diverse and provided by processes including cellular dedifferentiation, transdifferentiation, and reprogramming. Each of these processes is regulated by miRNAs. Furthermore, induced pluripotency may be achieved by miRNA-based strategies independent of transcription factor manipulation. The observation that miRNA does not integrate into the genome makes miRNA-based therapeutic strategies translationally valuable. Tools to manipulate cellular and tissue miRNA levels include mimics and inhibitors that may be specifically targeted to cells of interest at the injury site. Here, we discuss the extraordinary importance of miRNAs in tissue repair and regeneration based on emergent reports and rapid advances in miRNA-based therapeutics. PMID:26056933

  4. Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology.

    PubMed

    Guzel, Elif; Arlier, Sefa; Guzeloglu-Kayisli, Ozlem; Tabak, Mehmet Selcuk; Ekiz, Tugba; Semerci, Nihan; Larsen, Kellie; Schatz, Frederick; Lockwood, Charles Joseph; Kayisli, Umit Ali

    2017-04-08

    The endoplasmic reticulum (ER), comprises 60% of the total cell membrane and interacts directly or indirectly with several cell organelles i.e., Golgi bodies, mitochondria and proteasomes. The ER is usually associated with large numbers of attached ribosomes. During evolution, ER developed as the specific cellular site of synthesis, folding, modification and trafficking of secretory and cell-surface proteins. The ER is also the major intracellular calcium storage compartment that maintains cellular calcium homeostasis. During the production of functionally effective proteins, several ER-specific molecular steps sense quantity and quality of synthesized proteins as well as proper folding into their native structures. During this process, excess accumulation of unfolded/misfolded proteins in the ER lumen results in ER stress, the homeostatic coping mechanism that activates an ER-specific adaptation program, (the unfolded protein response; UPR) to increase ER-associated degradation of structurally and/or functionally defective proteins, thus sustaining ER homeostasis. Impaired ER homeostasis results in aberrant cellular responses, contributing to the pathogenesis of various diseases. Both female and male reproductive tissues undergo highly dynamic cellular, molecular and genetic changes such as oogenesis and spermatogenesis starting in prenatal life, mainly controlled by sex-steroids but also cytokines and growth factors throughout reproductive life. These reproductive changes require ER to provide extensive protein synthesis, folding, maturation and then their trafficking to appropriate cellular location as well as destroying unfolded/misfolded proteins via activating ER-associated degradation mediated proteasomes. Many studies have now shown roles for ER stress/UPR signaling cascades in the endometrial menstrual cycle, ovarian folliculogenesis and oocyte maturation, spermatogenesis, fertilization, pre-implantation embryo development and pregnancy and parturition

  5. Activation of Wnt Signaling by Chemically Induced Dimerization of LRP5 Disrupts Cellular Homeostasis

    PubMed Central

    Pond, Adam C.; Seethammagari, Mamatha; Chiou, Shin-Heng; Cho, Kyucheol; Carstens, Julienne L.; Decker, William K.; McCrea, Pierre D.; Ittmann, Michael M.; Rosen, Jeffrey M.; Spencer, David M.

    2012-01-01

    Wnt signaling is crucial for a variety of biological processes, including body axis formation, planar polarity, stem cell maintenance and cellular differentiation. Therefore, targeted manipulation of Wnt signaling in vivo would be extremely useful. By applying chemical inducer of dimerization (CID) technology, we were able to modify the Wnt co-receptor, low-density lipoprotein (LDL)-receptor-related protein 5 (LRP5), to generate the synthetic ligand inducible Wnt switch, iLRP5. We show that iLRP5 oligomerization results in its localization to disheveled-containing punctate structures and sequestration of scaffold protein Axin, leading to robust β-catenin-mediated signaling. Moreover, we identify a novel LRP5 cytoplasmic domain critical for its intracellular localization and casein kinase 1-dependent β-catenin signaling. Finally, by utilizing iLRP5 as a Wnt signaling switch, we generated the Ubiquitous Activator of β-catenin (Ubi-Cat) transgenic mouse line. The Ubi-Cat line allows for nearly ubiquitous expression of iLRP5 under control of the H-2Kb promoter. Activation of iLRP5 in isolated prostate basal epithelial stem cells resulted in expansion of p63+ cells and development of hyperplasia in reconstituted murine prostate grafts. Independently, iLRP5 induction in adult prostate stroma enhanced prostate tissue regeneration. Moreover, induction of iLRP5 in male Ubi-Cat mice resulted in prostate tumor progression over several months from prostate hyperplasia to adenocarcinoma. We also investigated iLRP5 activation in Ubi-Cat-derived mammary cells, observing that prolonged activation results in mammary tumor formation. Thus, in two distinct experimental mouse models, activation of iLRP5 results in disruption of tissue homeostasis, demonstrating the utility of iLRP5 as a novel research tool for determining the outcome of Wnt activation in a precise spatially and temporally determined fashion. PMID:22303459

  6. Gut microbiota and oxalate homeostasis

    PubMed Central

    2017-01-01

    This perspective focuses on how the gut microbiota can impact urinary oxalate excretion in the context of hyperoxaluria, a major risk factor in kidney stone disease. In the genetic disease of Primary Hyperoxaluria Type 1 (PH1), an increased endogenous production of oxalate, due to a deficiency of the liver enzyme alanine-glyoxylate aminotransferase (AGT), results in hyperoxaluria and oxalate kidney stones. The constant elevation in urinary oxalate in PH1 patients ultimately leads to tissue deposition of oxalate, renal failure and death and the only known cure for PH1 is a liver or liver-kidney transplant. The potential impact of a probiotic/therapeutic approach may be clinically significant in PH1 and could also extend to a much larger population of idiopathic oxalate stone formers who comprise ~12% of Americans, individuals with enteric hyperoxaluria, and an emerging population of hyperoxaluric patients who have undergone bariatric surgery and develop kidney stone disease as a consequence. PMID:28217701

  7. Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling.

    PubMed

    Muguruma, Yukari; Hozumi, Katsuto; Warita, Hiroyuki; Yahata, Takashi; Uno, Tomoko; Ito, Mamoru; Ando, Kiyoshi

    2016-10-13

    Adult bone mass is maintained through a balance of the activities of osteoblasts and osteoclasts. Although Notch signaling has been shown to maintain bone homeostasis by controlling the commitment, differentiation, and function of cells in both the osteoblast and osteoclast lineages, the precise mechanisms by which Notch performs such diverse and complex roles in bone physiology remain unclear. By using a transgenic approach that modified the expression of delta-like 1 (DLL1) or Jagged1 (JAG1) in an osteoblast-specific manner, we investigated the ligand-specific effects of Notch signaling in bone homeostasis. This study demonstrated for the first time that the proper regulation of DLL1 expression, but not JAG1 expression, in osteoblasts is essential for the maintenance of bone remodeling. DLL1-induced Notch signaling was responsible for the expansion of the bone-forming cell pool by promoting the proliferation of committed but immature osteoblasts. However, DLL1-Notch signaling inhibited further differentiation of the expanded osteoblasts to become fully matured functional osteoblasts, thereby substantially decreasing bone formation. Osteoblast-specific expression of DLL1 did not alter the intrinsic differentiation ability of cells of the osteoclast lineage. However, maturational arrest of osteoblasts caused by the DLL1 transgene impaired the maturation and function of osteoclasts due to a failed osteoblast-osteoclast coupling, resulting in severe suppression of bone metabolic turnover. Taken together, DLL1-mediated Notch signaling is critical for proper bone remodeling as it regulates the differentiation and function of both osteoblasts and osteoclasts. Our study elucidates the importance of ligand-specific activation of Notch signaling in the maintenance of bone homeostasis. This article is protected by copyright. All rights reserved.

  8. Dopaminergic drugs in type 2 diabetes and glucose homeostasis.

    PubMed

    Lopez Vicchi, Felicitas; Luque, Guillermina Maria; Brie, Belen; Nogueira, Juan Patricio; Garcia Tornadu, Isabel; Becu-Villalobos, Damasia

    2016-07-01

    The importance of dopamine in central nervous system function is well known, but its effects on glucose homeostasis and pancreatic β cell function are beginning to be unraveled. Mutant mice lacking dopamine type 2 receptors (D2R) are glucose intolerant and have abnormal insulin secretion. In humans, administration of neuroleptic drugs, which block dopamine receptors, may cause hyperinsulinemia, increased weight gain and glucose intolerance. Conversely, treatment with the dopamine precursor l-DOPA in patients with Parkinson's disease reduces insulin secretion upon oral glucose tolerance test, and bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients as well as in non diabetic obese animals and humans. The actions of dopamine on glucose homeostasis and food intake impact both the autonomic nervous system and the endocrine system. Different central actions of the dopamine system may mediate its metabolic effects such as: (i) regulation of hypothalamic noradrenaline output, (ii) participation in appetite control, and (iii) maintenance of the biological clock in the suprachiasmatic nucleus. On the other hand, dopamine inhibits prolactin, which has metabolic functions; and, at the pancreatic beta cell dopamine D2 receptors inhibit insulin secretion. We review the evidence obtained in animal models and clinical studies that posited dopamine receptors as key elements in glucose homeostasis and ultimately led to the FDA approval of bromocriptine in adults with type 2 diabetes to improve glycemic control. Furthermore, we discuss the metabolic consequences of treatment with neuroleptics which target the D2R, that should be monitored in psychiatric patients to prevent the development in diabetes, weight gain, and hypertriglyceridemia.

  9. Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring.

    PubMed

    Ramírez-López, María Teresa; Arco, Raquel; Decara, Juan; Vázquez, Mariam; Noemí Blanco, Rosario; Alén, Francisco; Suárez, Juan; Gómez de Heras, Raquel; Rodríguez de Fonseca, Fernando

    2016-01-01

    Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS). In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a) the adult expression of endocannabinoid-related behaviors, b) the metabolic profile of adult offspring and c) the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a) sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b) features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c) tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed.

  10. Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring

    PubMed Central

    Ramírez-López, María Teresa; Arco, Raquel; Decara, Juan; Vázquez, Mariam; Noemí Blanco, Rosario; Alén, Francisco; Suárez, Juan; Gómez de Heras, Raquel

    2016-01-01

    Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS). In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a) the adult expression of endocannabinoid-related behaviors, b) the metabolic profile of adult offspring and c) the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a) sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b) features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c) tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed. PMID:27806128

  11. Nuclear hormone receptor functions in keratinocyte and melanocyte homeostasis, epidermal carcinogenesis and melanomagenesis

    PubMed Central

    Hyter, Stephen; Indra, Arup K

    2013-01-01

    Skin homeostasis is maintained, in part, through regulation of gene expression orchestrated by type II nuclear hormone receptors in a cell and context specific manner. This group of transcriptional regulators is implicated in various cellular processes including epidermal proliferation, differentiation, permeability barrier formation, follicular cycling and inflammatory responses. Endogenous ligands for the receptors regulate actions during skin development and maintenance of tissue homeostasis. Type II nuclear receptor signaling is also important for cellular crosstalk between multiple cell types in the skin. Overall, these nuclear receptors are critical players in keratinocyte and melanocyte biology and present targets for cutaneous disease management. PMID:23395795

  12. Iron homeostasis: new tales from the crypt.

    PubMed

    Roy, C N; Enns, C A

    2000-12-15

    The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)-transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

  13. Chronic social stress leads to altered sleep homeostasis in mice.

    PubMed

    Olini, Nadja; Rothfuchs, Iru; Azzinnari, Damiano; Pryce, Christopher R; Kurth, Salome; Huber, Reto

    2017-03-15

    Disturbed sleep and altered sleep homeostasis are core features of many psychiatric disorders such as depression. Chronic uncontrollable stress is considered an important factor in the development of depression, but little is known on how chronic stress affects sleep regulation and sleep homeostasis. We therefore examined the effects of chronic social stress (CSS) on sleep regulation in mice. Adult male C57BL/6 mice were implanted for electrocortical recordings (ECoG) and underwent either a 10-day CSS protocol or control handling (CON). Subsequently, ECoG was assessed across a 24-h post-stress baseline, followed by a 4-h sleep deprivation, and then a 20-h recovery period. After sleep deprivation, CSS mice showed a blunted increase in sleep pressure compared to CON mice, as measured using slow wave activity (SWA, electroencephalographic power between 1 - 4Hz) during non-rapid eye movement (NREM) sleep. Vigilance states did not differ between CSS and CON mice during post-stress baseline, sleep deprivation or recovery, with the exception of CSS mice exhibiting increased REM sleep during recovery sleep. Behavior during sleep deprivation was not affected by CSS. Our data provide evidence that CSS alters the homeostatic regulation of sleep SWA in mice. In contrast to acute social stress, which results in a faster SWA build-up, CSS decelerates the homeostatic build up. These findings are discussed in relation to the causal contribution of stress-induced sleep disturbance to depression.

  14. Hepatocytes: critical for glucose homeostasis.

    PubMed

    Klover, Peter J; Mooney, Robert A

    2004-05-01

    Maintaining blood glucose levels within a narrow range is a critical physiological function requiring multiple metabolic pathways and involving several cell types, including a prominent role for hepatocytes. Under hormonal control, hepatocytes can respond to either feeding or fasting conditions by storing or producing glucose as necessary. In the fasting state, the effects of glucagon avoid hypoglycemia by stimulating glucogenesis and glycogenolysis and initiating hepatic glucose release. Postprandially, insulin prevents hyperglycemia, in part, by suppressing hepatic gluconeogenesis and glycogenolysis and facilitating hepatic glycogen synthesis. Both transcriptional regulation of rate limiting enzymes and modulation of enzyme activity through phosphorylation and allosteric regulation are involved. Type 2 diabetes mellitus is the most common serious metabolic condition in the world, and results from a subnormal response of tissues to insulin (insulin resistance) and a failure of the insulin-secreting beta cells to compensate. In type 2 diabetes, glucose is overproduced by the hepatocyte and is ineffectively metabolized by other organs. Impairments in the insulin signal transduction pathway appear to be critical lesions contributing to insulin resistance and type 2 diabetes.

  15. [Lymphatic system and water homeostasis].

    PubMed

    Borodin, Iu I; Golubeva, I A; Mashak, A N

    2005-01-01

    Using the methods of light and electron microscopy as well as histochemistry, the complex study of structural-cellular state of the wall of small intestine and its grouped lymphoid nodules, mesenterial and iliac lymph nodes and thymus was performed in rats subjected to the changes of a type of drinking water. Tap, distilled and radon waters were used. The organism was found to respond to the changes in the type of drinking water by both non-specific (increase in sectional area of lymphatic vessels and the number of eosinophilic granulocytes in the wall of small intestine, in lymphoid nodule number containing germinal centers in lymph nodes, in proportion of thymus connective tissue component, increased lymphocyte dehydrogenase activity) and specific reactions, which were characteristic only to a given type of water. The latter, for example, included the activation of the function of protein synthesis in endothelial cells of lymphatic capillaries of the small intestine and increased numbers of plasma cells and dividing cells in lymphoid organs in rats consuming distilled water; increased proportion of blood capillaries in the wall of the small intestine, accompanied by the ultrastructural signs of reduction of plastic processes in them in animals drinking radon water. The response of the wall of the small intestine and lymphoid organs of an animal to the effect of drinking waters, different in their mineral content and radon concentrations, was subjected to general biological regularities and took place in two phases of an adaptation process, functional stress and resistivity.

  16. Taurine supplementation modulates glucose homeostasis and islet function.

    PubMed

    Carneiro, Everardo M; Latorraca, Marcia Q; Araujo, Eliana; Beltrá, Marta; Oliveras, Maria J; Navarro, Mónica; Berná, Genoveva; Bedoya, Francisco J; Velloso, Licio A; Soria, Bernat; Martín, Franz

    2009-07-01

    Taurine is a conditionally essential amino acid for human that is involved in the control of glucose homeostasis; however, the mechanisms by which the amino acid affects blood glucose levels are unknown. Using an animal model, we have studied these mechanisms. Mice were supplemented with taurine for 30 d. Blood glucose homeostasis was assessed by intraperitoneal glucose tolerance tests (IPGTT). Islet cell function was determined by insulin secretion, cytosolic Ca2+ measurements and glucose metabolism from isolated islets. Islet cell gene expression and translocation was examined via immunohistochemistry and quantitative real-time polymerase chain reaction. Insulin signaling was studied by Western blot. Islets from taurine-supplemented mice had: (i) significantly higher insulin content, (ii) increased insulin secretion at stimulatory glucose concentrations, (iii) significantly displaced the dose-response curve for glucose-induced insulin release to the left, (iv) increased glucose metabolism at 5.6 and 11.1-mmol/L concentrations; (v) slowed cytosolic Ca2+ concentration ([Ca2+]i) oscillations in response to stimulatory glucose concentrations; (vi) increased insulin, sulfonylurea receptor-1, glucokinase, Glut-2, proconvertase and pancreas duodenum homeobox-1 (PDX-1) gene expression and (vii) increased PDX-1 expression in the nucleus. Moreover, taurine supplementation significantly increased both basal and insulin stimulated tyrosine phosphorylation of the insulin receptor in skeletal muscle and liver tissues. Finally, taurine supplemented mice showed an improved IPGTT. These results indicate that taurine controls glucose homeostasis by regulating the expression of genes required for glucose-stimulated insulin secretion. In addition, taurine enhances peripheral insulin sensitivity.

  17. Relatively high rates of G:C → A:T transitions at CpG sites were observed in certain epithelial tissues including pancreas and submaxillary gland of adult big blue® mice.

    PubMed

    Prtenjaca, Anita; Tarnowski, Heather E; Marr, Alison M; Heney, Melanie A; Creamer, Laura; Sathiamoorthy, Sarmitha; Hill, Kathleen A

    2014-01-01

    With few exceptions, spontaneous mutation frequency and pattern are similar across tissue types and relatively constant in young to middle adulthood in wild type mice. Underrepresented in surveys of spontaneous mutations across murine tissues is the diversity of epithelial tissues. For the first time, spontaneous mutations were detected in pancreas and submaxillary gland and compared with kidney, lung, and male germ cells from five adult male Big Blue® mice. Mutation load was assessed quantitatively through measurement of mutant and mutation frequency and qualitatively through identification of mutations and characterization of recurrent mutations, multiple mutations, mutation pattern, and mutation spectrum. A total of 9.6 million plaque forming units were screened, 226 mutants were collected, and 196 independent mutations were identified. Four novel mutations were discovered. Spontaneous mutation frequency was low in pancreas and high in the submaxillary gland. The submaxillary gland had multiple recurrent mutations in each of the mice and one mutant had two independent mutations. Mutation patterns for epithelial tissues differed from that observed in male germ cells with a striking bias for G:C to A:T transitions at CpG sites. A comprehensive review of lacI spontaneous mutation patterns in young adult mice and rats identified additional examples of this mutational bias. An overarching observation about spontaneous mutation frequency in adult tissues of the mouse remains one of stability. A repeated observation in certain epithelial tissues is a higher rate of G:C to A:T transitions at CpG sites and the underlying mechanisms for this bias are not known.

  18. Effect of alpha lipoic acid co-administration on structural and immunohistochemical changes in subcutaneous tissue of anterior abdominal wall of adult male albino rat in response to polypropylene mesh implantation.

    PubMed

    Mazroa, Shireen A; Asker, Samar A; Asker, Waleed; Abd Ellatif, Mohamed

    2015-06-01

    Polypropylene mesh is commonly used in the treatment of abdominal hernia. Different approaches were addressed to improve their tissue integration and consequently reduce long-term complications. This study aimed to investigate the effect of alpha-lipoic acid (ALA) co-administration on structural and immunohistochemical (IHC) changes in the subcutaneous tissues of the anterior abdominal wall of the adult rat in response to polypropylene mesh implantation. Forty adult male albino rats were divided into: group I (control), group II (receiving ALA), group III (polypropylene mesh implantation) and group IV (mesh implantation + ALA co-administration). After 4 weeks, subcutaneous tissue samples were prepared for light microscopy and IHC study of CD34 as a marker for angiogenesis. In groups I and II rats, positive CD34 expression was demonstrated by IHC reaction, localized to endothelial cells lining small blood vessels. Group III showed an excess inflammatory reaction, deposition of both regular and irregularly arranged collagen fibres around mesh pores and few elastic fibres. CD34-positive was detected not only in cells lining small blood vessels but also in other cells scattered in the connective tissue indicating angiogenesis. In group IV, ALA co-administration resulted in less inflammatory reaction, regular collagen deposition, enhanced elastic fibres synthesis and a significant increase in CD34-positive cells and small blood vessels reflecting improved angiogenesis. ALA co-administration with polypropylene mesh implantation controlled the inflammatory reaction, helped regular collagen deposition, enhanced elastic fibres synthesis and improved angiogenesis in the subcutaneous tissue of anterior abdominal wall of adult albino rats, suggesting a possible role of ALA in optimizing mesh integration in subcutaneous tissue.

  19. Effect of alpha lipoic acid co-administration on structural and immunohistochemical changes in subcutaneous tissue of anterior abdominal wall of adult male albino rat in response to polypropylene mesh implantation

    PubMed Central

    Mazroa, Shireen A; Asker, Samar A; Asker, Waleed; Abd Ellatif, Mohamed

    2015-01-01

    Polypropylene mesh is commonly used in the treatment of abdominal hernia. Different approaches were addressed to improve their tissue integration and consequently reduce long-term complications. This study aimed to investigate the effect of alpha-lipoic acid (ALA) co-administration on structural and immunohistochemical (IHC) changes in the subcutaneous tissues of the anterior abdominal wall of the adult rat in response to polypropylene mesh implantation. Forty adult male albino rats were divided into: group I (control), group II (receiving ALA), group III (polypropylene mesh implantation) and group IV (mesh implantation + ALA co-administration). After 4 weeks, subcutaneous tissue samples were prepared for light microscopy and IHC study of CD34 as a marker for angiogenesis. In groups I and II rats, positive CD34 expression was demonstrated by IHC reaction, localized to endothelial cells lining small blood vessels. Group III showed an excess inflammatory reaction, deposition of both regular and irregularly arranged collagen fibres around mesh pores and few elastic fibres. CD34-positive was detected not only in cells lining small blood vessels but also in other cells scattered in the connective tissue indicating angiogenesis. In group IV, ALA co-administration resulted in less inflammatory reaction, regular collagen deposition, enhanced elastic fibres synthesis and a significant increase in CD34-positive cells and small blood vessels reflecting improved angiogenesis. ALA co-administration with polypropylene mesh implantation controlled the inflammatory reaction, helped regular collagen deposition, enhanced elastic fibres synthesis and improved angiogenesis in the subcutaneous tissue of anterior abdominal wall of adult albino rats, suggesting a possible role of ALA in optimizing mesh integration in subcutaneous tissue. PMID:25891652

  20. Adherence to consensus-based diagnosis and treatment guidelines in adult soft-tissue sarcoma patients: a French prospective population-based study†

    PubMed Central

    Mathoulin-Pélissier, S.; Chevreau, C.; Bellera, C.; Bauvin, E.; Savès, M.; Grosclaude, P.; Albert, S.; Goddard, J.; Le Guellec, S.; Delannes, M.; Bui, B. N.; Mendiboure, J.; Stoeckle, E.; Coindre, J. M.; Kantor, G.; Kind, M.; Cowppli-Bony, A.; Hoppe, S.; Italiano, A.

    2014-01-01

    Background Soft-tissue sarcomas (STSs) are rare tumors with varied histological presentations. Management and treatment are thus complex, but crucial for patient outcomes. We assess adherence to adult STS management guidelines across two French regions (10% of the French population). We also report standardized incidence. Patients and methods STS patients diagnosed from 1 November 2006 to 31 December 2007 were identified from pathology reports, medical hospital records, and cancer registries. Guideline adherence was assessed by 23 criteria (validated by Delphi consensus method), and age and sex-standardized incidence rates estimated. Associations between patient, treatment, and institutional factors and adherence with three major composite criteria relating to diagnostic imaging and biopsy as well as multidisciplinary team (MDT) case-review are reported. Results Two hundred and seventy-four patients were included (57.7% male, mean age 60.8 years). Practices were relatively compliant overall, with over 70% adherence for 10 criteria. Three criteria with perfect Delphi consensus had low adherence: receiving histological diagnosis before surgery, adequacy of histological diagnosis (adherence around 50% for both), and MDT discussion before surgery (adherence <30%). Treatment outside of specialized centers was associated with lower adherence for all three composite criteria, and specific tumor sites and/or features were associated with lower adherence for diagnostic imaging, methods, and MDT meetings. STS standardized incidence rates were 4.09 (European population) and 3.33 (World) /100 000 inhabitants. Conclusions Initial STS diagnosis and treatment across all stages (imaging, biopsy, and MDT meetings) need improving, particularly outside specialized centers. Educational interventions to increase surgeon's sarcoma awareness and knowledge and to raise patients' awareness of the importance of seeking expert care are necessary. PMID:24285018

  1. Fibroblast growth factor receptors in in vitro and in vivo chondrogenesis: relating tissue engineering using adult mesenchymal stem cells to embryonic development.

    PubMed

    Hellingman, Catharine A; Koevoet, Wendy; Kops, Nicole; Farrell, Eric; Jahr, Holger; Liu, Wei; Baatenburg de Jong, Robert J; Frenz, Dorothy A; van Osch, Gerjo J V M

    2010-02-01

    Adult mesenchymal stem cells (MSCs) are considered promising candidate cells for therapeutic cartilage and bone regeneration. Because tissue regeneration and embryonic development may involve similar pathways, understanding common pathways may lead to advances in regenerative medicine. In embryonic limb development, fibroblast growth factor receptors (FGFRs) play a role in chondrogenic differentiation. The aim of this study was to investigate and compare FGFR expression in in vivo embryonic limb development and in vitro chondrogenesis of MSCs. Our study showed that in in vitro chondrogenesis of MSCs three sequential stages can be found, as in embryonic limb development. A mesenchymal condensation (indicated by N-cadherin) is followed by chondrogenic differentiation (indicated by collagen II), and hypertrophy (indicated by collagen X). FGFR1-3 are expressed in a stage-dependent pattern during in vitro differentiation and in vivo embryonic limb development. In both models FGFR2 is clearly expressed by cells in the condensation phase. No FGFR expression was observed in differentiating and mature hyaline chondrocytes, whereas hypertrophic chondrocytes stained strongly for all FGFRs. To evaluate whether stage-specific modulation of chondrogenic differentiation in MSCs is possible with different subtypes of FGF, FGF2 and FGF9 were added to the chondrogenic medium during different stages in the culture process (early or late). FGF2 and FGF9 differentially affected the amount of cartilage formed by MSCs depending on the stage in which they were added. These results will help us understand the role of FGF signaling in chondrogenesis and find new tools to monitor and control chondrogenic differentiation.

  2. Asthma as a disruption in iron homeostasis | Science ...

    EPA Pesticide Factsheets

    Over several decades, asthma has evolved from being recognized as a single disease to include a diverse group of phenotypes with dissimilar natural histories, pathophysiologies, responses to treatment, and distinctive molecular pathways. With the application of Occam’s razor to asthma, it is proposed that there is one cause underlying the numerous phenotypes of this disease and that the responsible molecular pathway is a deficiency of iron in the lung tissues. This deficiency can be either absolute (e.g. asthma in the neonate and during both pregnancy and menstruation) or functional (e.g. asthma associated with infections, smoking, and obesity). Comparable associations between asthma co-morbidity (e.g. eczema, urticaria, restless leg syndrome, and pulmonary hypertension) with iron deficiency support such a shared mechanistic pathway. Therapies directed at asthma demonstrate a capacity to impact iron homeostasis, further strengthening the relationship. Finally, pathophysiologic events producing asthma, including inflammation, increases in Th2 cells, and muscle contraction, can correlate with iron availability. Recognition of a potential association between asthma and an absolute and/or functional iron deficiency suggests specific therapeutic interventions including inhaled iron. Asthma is a public health issue that has environmental triggers. Iron homeostasis is an essential mechanism whereby the body manages the impact of environmental agents on overall

  3. Splicing regulator SLU7 is essential for maintaining liver homeostasis

    PubMed Central

    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

    2014-01-01

    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. PMID:24865429

  4. Physiology and role of irisin in glucose homeostasis.

    PubMed

    Perakakis, Nikolaos; Triantafyllou, Georgios A; Fernández-Real, José Manuel; Huh, Joo Young; Park, Kyung Hee; Seufert, Jochen; Mantzoros, Christos S

    2017-02-17

    Irisin is a myokine that leads to increased energy expenditure by stimulating the 'browning' of white adipose tissue. In the first description of this hormone, increased levels of circulating irisin, which is cleaved from its precursor fibronectin type III domain-containing protein 5, were associated with improved glucose homeostasis by reducing insulin resistance. Consequently, several studies attempted to characterize the role of irisin in glucose regulation, but contradictory results have been reported, and even the existence of this hormone has been questioned. In this Review, we present the current knowledge on the physiology of irisin and its role in glucose homeostasis. We describe the mechanisms involved in the synthesis, secretion, circulation and regulation of irisin, and the controversies regarding the measurement of irisin. We also discuss the direct effects of irisin on glucose regulatory mechanisms in different organs, the indirect effects and interactions with other hormones, and the important open questions with regard to irisin in those organs. Finally, we present the results from animal interventional studies and from human clinical studies investigating the association of irisin with obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome.

  5. Evolving roles of circadian rhythms in liver homeostasis and pathology.

    PubMed

    Zhou, Dexi; Wang, Yaqin; Chen, Lu; Jia, Leijuan; Yuan, Jie; Sun, Mei; Zhang, Wen; Wang, Peipei; Zuo, Jian; Xu, Zhenyu; Luan, Jiajie

    2016-02-23

    Circadian clock in mammals is determined by a core oscillator in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronized peripheral clocks in other tissues. The coherent timing systems could sustain robust output of circadian rhythms in response to the entrainment controlled environmentally. Disparate approaches have discovered that clock genes and clock-controlled genes (CCGs) exist in nearly all mammalian cell types and are essential for establishing the mechanisms and complexity of internal time-keeping systems. Accumulating evidence demonstrates that the control of homeostasis and pathology in the liver involves intricate loops of transcriptional and post-translational regulation of clock genes expression. This review will focus on the recent advances with great importance concerning clock rhythms linking liver homeostasis and diseases. We particularly highlight what is currently known of the evolving insights into the mechanisms underlying circadian clock . Eventually , findings during recent years in the field might prompt new circadian-related chronotherapeutic strategies for the diagnosis and treatment of liver diseases by coupling these processes.

  6. Bone Marrow Stem Cell Contribution to Pulmonary Homeostasis and Disease

    PubMed Central

    McDonald, Lindsay T; LaRue, Amanda C

    2015-01-01

    The understanding of bone marrow stem cell plasticity and contribution of bone marrow stem cells to pathophysiology is evolving with the advent of innovative technologies. Recent data has led to new mechanistic insights in the field of mesenchymal stem cell (MSC) research, and an increased appreciation for the plasticity of the hematopoietic stem cell (HSC). In this review, we discuss current research examining the origin of pulmonary cell types from endogenous lung stem and progenitor cells as well as bone marrow-derived stem cells (MSCs and HSCs) and their contributions to lung homeostasis and pathology. We specifically highlight recent findings from our laboratory that demonstrate an HSC origin for pulmonary fibroblasts based on transplantation of a clonal population of cells derived from a single HSC. These findings demonstrate the importance of developing an understanding of the sources of effector cells in disease state. Finally, a perspective is given on the potential clinical implications of these studies and others addressing stem cell contributions to lung tissue homeostasis and pathology. PMID:26798846

  7. Systemic Control of Bone Homeostasis by FGF23 Signaling

    PubMed Central

    Clinkenbeard, Erica L.; White, Kenneth E.

    2016-01-01

    The regulation of phosphate metabolism as an influence on bone homeostasis is profound. Recent advances in understanding the systemic control of Fibroblast growth factor-23 (FGF23) has uncovered novel effectors of endocrine feedback loops for calcium, phosphate, and vitamin D balance that interact with ‘traditional’ feedback loops for mineral metabolism. Not only are these findings re-shaping research studying phosphate handling and skeletal interactions, they have provided new therapeutic interventions. Emerging data support that the control of FGF23 production in bone and its circulating concentrations is a multi-layered process, with some influences affecting FGF23 transcription and some post-translational modification of the secreted, bioactive protein. Additionally, the actions of FGF23 on its target tissues via its co-receptor αKlotho, are subject to regulatory events just coming to light. The recent findings of systemic influences on circulating FGF23 and the downstream manifestations on bone homeostasis will be reviewed herein. PMID:27134818

  8. Combinatory effects of siRNA‐induced myostatin inhibition and exercise on skeletal muscle homeostasis and body composition

    PubMed Central

    Mosler, Stephanie; Relizani, Karima; Mouisel, Etienne; Amthor, Helge; Diel, Patrick

    2014-01-01

    Abstract Inhibition of myostatin (Mstn) stimulates skeletal muscle growth, reduces body fat, and induces a number of metabolic changes. However, it remains unexplored how exercise training modulates the response to Mstn inhibition. The aim of this study was to investigate how siRNA‐mediated Mstn inhibition alone but also in combination with physical activity affects body composition and skeletal muscle homeostasis. Adult mice were treated with Mstn‐targeting siRNA and subjected to a treadmill‐based exercise protocol for 4 weeks. Effects on skeletal muscle and fat tissue, expression of genes, and serum concentration of proteins involved in myostatin signaling, skeletal muscle homeostasis, and lipid metabolism were investigated and compared with Mstn−/− mice. The combination of siRNA‐mediated Mstn knockdown and exercise induced skeletal muscle hypertrophy, which was associated with an upregulation of markers for satellite cell activity. SiRNA‐mediated Mstn knockdown decreased visceral fat and modulated lipid metabolism similar to effects observed in Mstn−/− mice. Myostatin did not regulate its own expression via an autoregulatory loop, however, Mstn knockdown resulted in a decrease in the serum concentrations of myostatin propeptide, leptin, and follistatin. The ratio of these three parameters was distinct between Mstn knockdown, exercise, and their combination. Taken together, siRNA‐mediated Mstn knockdown in combination with exercise stimulated skeletal muscle hypertrophy. Each intervention or their combination induced a specific set of adaptive responses in the skeletal muscle and fat metabolism which could be identified by marker proteins in serum. PMID:24760516

  9. Iron homeostasis in the Rhodobacter genus

    PubMed Central

    Zappa, Sébastien; Bauer, Carl E.

    2013-01-01

    Metals are utilized for a variety of critical cellular functions and are essential for survival. However cells are faced with the conundrum of needing metals coupled with e fact that some metals, iron in particular are toxic if present in excess. Maintaining metal homeostasis is therefore of critical importance to cells. In this review we have systematically analyzed sequenced genomes of three members of the Rhodobacter genus, R. capsulatus SB1003, R. sphaeroides 2.4.1 and R. ferroxidans SW2 to determine how these species undertake iron homeostasis. We focused our analysis on elemental ferrous and ferric iron uptake genes as well as genes involved in the utilization of iron from heme. We also discuss how Rhodobacter species manage iron toxicity through export and sequestration of iron. Finally we discuss the various putative strategies set up by these Rhodobacter species to regulate iron homeostasis and the potential novel means of regulation. Overall, this genomic analysis highlights surprisingly diverse features involved in iron homeostasis in the Rhodobacter genus. PMID:24382933

  10. Circadian dysregulation disrupts bile acid homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile acids are potentially toxic compounds and their levels of hepatic production, uptake, and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. Both restricted feedi...

  11. Protein Homeostasis at the Plasma Membrane

    PubMed Central

    2014-01-01

    The plasma membrane (PM) and endocytic protein quality control (QC) in conjunction with the endosomal sorting machinery either repairs or targets conformationally damaged membrane proteins for lysosomal/vacuolar degradation. Here, we provide an overview of emerging aspects of the underlying mechanisms of PM QC that fulfill a critical role in preserving cellular protein homeostasis in health and diseases. PMID:24985330

  12. A different TIPE of immune homeostasis.

    PubMed

    Freundt, Eric C; Bidere, Nicolas; Lenardo, Michael J

    2008-05-02

    Proteins with death effector domains (DED) are key signal transducers involved in cell death and inflammation. In this issue of Cell, Sun et al. (2008) describe TIPE2, a DED protein that negatively regulates both T cell receptor and Toll-like receptor signaling. These findings reveal a new element critical to the maintenance of homeostasis in both the adaptive and innate immune systems.

  13. Stem cells as vehicles for youthful regeneration of aged tissues.

    PubMed

    Rando, Thomas A; Wyss-Coray, Tony

    2014-06-01

    Stem cells hold great promise for regenerative therapies for a wide spectrum of diseases and disorders of aging by virtue of their ability to regenerate tissues and contribute to their homeostasis. Aging is associated with a marked decline in these functionalities of adult stem cells. As such, regeneration of aged tissues is both less efficient and less effective than that of young tissues. Recent studies have revealed the remarkably dynamic responses of stem cells to systemic signals, including the ability of "youthful" factors in the blood of young animals to enhance the functionality of aged stem cells. Thus, there is much hope that even aged stem cells retain a remarkable regenerative potential if provided with the correct cues and environment to engage in tissue repair. The overall focus of the presentations of this session is to address the determinants of changes in stem cell functionality with age, the key characteristics of stem cells in aged tissues, the extent to which those characteristics are capable of being rejuvenated and by what signals, and the potential for stem cell therapeutics for chronic diseases and acute injuries in aged individuals.

  14. Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis.

    PubMed

    Shin, Jaehoon; Berg, Daniel A; Zhu, Yunhua; Shin, Joseph Y; Song, Juan; Bonaguidi, Michael A; Enikolopov, Grigori; Nauen, David W; Christian, Kimberly M; Ming, Guo-li; Song, Hongjun

    2015-09-03

    Somatic stem cells contribute to tissue ontogenesis, homeostasis, and regeneration through sequential processes. Systematic molecular analysis of stem cell behavior is challenging because classic approaches cannot resolve cellular heterogeneity or capture developmental dynamics. Here we provide a comprehensive resource of single-cell transcriptomes of adult hippocampal quiescent neural stem cells (qNSCs) and their immediate progeny. We further developed Waterfall, a bioinformatic pipeline, to statistically quantify singe-cell gene expression along a de novo reconstructed continuous developmental trajectory. Our study reveals molecular signatures of adult qNSCs, characterized by active niche signaling integration and low protein translation capacity. Our analyses further delineate molecular cascades underlying qNSC activation and neurogenesis initiation, exemplified by decreased extrinsic signaling capacity, primed translational machinery, and regulatory switches in transcription factors, metabolism, and energy sources. Our study reveals the molecular continuum underlying adult neurogenesis and illustrates how Waterfall can be used for single-cell omics analyses of various continuous biological processes.

  15. microRNAs in Cartilage Development, Homeostasis, and Disease

    PubMed Central

    Mirzamohammadi, Fatemeh; Papaioannou, Garyfallia

    2014-01-01

    microRNAs (miRNAs) regulate gene expression mainly at the posttranscriptional level. Many different miRNAs are expressed in chondrocytes, and each individual miRNA can regulate hundreds of target genes, creating a complex gene regulatory network. Experimental evidence suggests that miRNAs play significant roles in various aspects of cartilage development, homeostasis, and pathology. The possibility that miRNAs can be novel therapeutic targets for cartilage diseases led to vigorous investigations to understand the role of individual miRNAs in skeletal tissues. Here, we summarize our current understanding of miRNAs in chondrocytes and cartilage. In the first part, we discuss roles of miRNAs in growth plate development and chondrocyte differentiation. In the second part, we put a particular focus on articular cartilage and discuss the significance of variety of findings in the context of osteoarthritis, the most common degenerative joint disease. PMID:25091054

  16. Regulation of immune cell homeostasis and function by coronin 1.

    PubMed

    Jayachandran, Rajesh; Pieters, Jean

    2015-10-01

    Coronin 1 is the most recent candidate in the list of genes causing severe combined immunodeficiency (SCID) in humans. A distinctive feature of the SCID induced by coronin 1 deficiency is selective naïve T cell lymphopenia in the presence of a normal thymus as well as normal B cell and natural killer cell numbers (T(-)B(+)NK(+)). Coronin 1 is a member of the evolutionarily conserved coronin protein family, members of which are widely expressed across the eukaryotic kingdom. Mammals express seven coronin molecules, numbered from coronin 1 to 7. The different coronin proteins have a distinct but overlapping tissue expression and have been reported to be involved in a wide array of cellular functions including calcium homeostasis, cytoskeletal dynamics, immune and inflammatory responses, neuromuscular transmission as well as cognition and behavior. In this minireview, we describe the role of coronin 1 in the maintenance of immune cell diversity and function.

  17. Partial Redundancy and Morphological Homeostasis: Reliable Development through Overlapping Mechanisms.

    PubMed

    Brodsky, Micah

    2016-01-01

    How might organisms grow into their desired physical forms in spite of environmental and genetic variation? How do they maintain this form in spite of physical insults? This article presents a case study in simulated morphogenesis, using a physics-based model for embryonic epithelial tissue. The challenges of the underlying physics force the introduction of closed-loop controllers for both spatial patterning and geometric structure. Reliable development is achieved not through elaborate control procedures or exact solutions, but through crude layering of independent, overlapping mechanisms. As a consequence, development and regeneration together become one process, morphological homeostasis, which, owing to its internal feedbacks and partially redundant architecture, is remarkably robust to both knockout damage and environmental variation. The incomplete nature of such redundancy furnishes an evolutionary rationale for its preservation, in spite of individual knockout experiments that may suggest it has little purpose.

  18. Thyroid hormone signaling in energy homeostasis and energy metabolism.

    PubMed

    McAninch, Elizabeth A; Bianco, Antonio C

    2014-04-01

    The thyroid hormone (TH) plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. TH signaling modulates energy expenditure through both central and peripheral pathways. At the cellular level, the TH exerts its effects after concerted mechanisms facilitate binding to the TH receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma TH at the appropriate level to preserve energy homeostasis. At the tissue level, TH actions on metabolism are controlled by transmembrane transporters, deiodinases, and TH receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and, thus, understanding the contribution of the TH to cellular and organism metabolism is increasingly relevant.

  19. Thyroid hormone signaling in energy homeostasis and energy metabolism

    PubMed Central

    McAninch, Elizabeth A.; Bianco, Antonio C.

    2014-01-01

    The thyroid hormone plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. Thyroid hormone signaling modulates energy expenditure through both central and peripheral pathways. At the cellular level, the thyroid hormone exerts its effects after concerted mechanisms facilitate binding to the thyroid hormone receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma thyroid hormone at the appropriate level to preserve energy homeostasis. At the tissue level, thyroid hormone actions on metabolism are controlled by transmembrane transporters, deiodinases, and thyroid hormone receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and thus understanding the contribution of the thyroid hormone to cellular and organism metabolism is increasingly relevant. PMID:24697152

  20. The importance of the renin-angiotensin system in normal cardiovascular homeostasis

    NASA Technical Reports Server (NTRS)

    Haber, E.

    1975-01-01

    Studies were carried out on adult mongrel dogs (20 to 30 kilograms) to investigate the importance of the renin-angiotensin system. Results indicate that the renin-angiotensin system plays a major role in the maintenance of circulatory homeostasis when extracellular fluid volume is depleted. It was also found that angiotensin II concentration, in addition to renal perfusion pressure, is a factor in the regulation of renin release.

  1. Relevance of the plasma membrane calcium-ATPase in the homeostasis of calcium in the fetal liver

    PubMed Central

    Delgado-Coello, Blanca; Mas-Oliva, Jaime

    2014-01-01

    During the early stages of development, the embryo depends on the placenta as provider of oxygen and calcium, among other essential compounds. Although fetal liver accomplishes a well-known haematopoietic function, its contribution to calcium homeostasis upon development is poorly understood. The homeostasis of cell calcium contributes to diverse signaling pathways across developmental stages of most tissues and the calcium-ATPase located at the plasma membrane (PMCA) helps pumping excess calcium into the extracellular space. To date, the understanding of the equilibrium shift between PMCA isoforms during liver development is still missing. This review focuses on the chara