Palo Alto Institute for Research and Education

Palo Alto, CA, United States

Palo Alto Institute for Research and Education

Palo Alto, CA, United States
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Corniola R.,Stanford University | Zou Y.,Stanford University | Leu D.,Palo Alto Institute for Research and Education | Leu D.,Geriatric Research | And 3 more authors.
PLoS ONE | Year: 2012

Radiation therapy of the CNS, even at low doses, can lead to deficits in neurocognitive functions. Reduction in hippocampal neurogenesis is usually, but not always, associated with cognitive deficits resulting from radiation therapy. Generation of reactive oxygen species is considered the main cause of radiation-induced tissue injuries, and elevated levels of oxidative stress persist long after the initial cranial irradiation. Consequently, mutant mice with reduced levels of the mitochondrial antioxidant enzyme, Mn superoxide dismutase (MnSOD or Sod2), are expected to be more sensitive to radiation-induced changes in hippocampal neurogenesis and the related functions. In this study, we showed that MnSOD deficiency led to reduced generation of immature neurons in Sod2-/+ mice even though progenitor cell proliferation was not affected. Compared to irradiated Sod2+/+ mice, which showed cognitive defects and reduced differentiation of newborn cells towards the neuronal lineage, irradiated Sod2-/+ mice showed normal hippocampal-dependent cognitive functions and normal differentiation pattern for newborn neurons and astroglia. However, we also observed a disproportional decrease in newborn neurons in irradiated Sod2-/+ following behavioral studies, suggesting that MnSOD deficiency may render newborn neurons more sensitive to stress from behavioral trainings following cranial irradiation. A positive correlation between normal cognitive functions and normal dendritic spine densities in dentate granule cells was observed. The data suggest that maintenance of synaptic connections, via maintenance of dendritic spines, may be important for normal cognitive functions following cranial irradiation.


Issa M.E.,Dalhousie University | Muruganandan S.,Dalhousie University | Ernst M.C.,Dalhousie University | Parlee S.D.,Dalhousie University | And 5 more authors.
American Journal of Physiology - Cell Physiology | Year: 2012

The chemokine-like receptor-1 (CMKLR1) is a G protein-coupled receptor that is activated by chemerin, a secreted plasma leukocyte attractant and adipokine. Previous studies identified that CMKLR1 is expressed in skeletal muscle in a stage-specific fashion during embryogenesis and in adult mice; however, its function in skeletal muscle remains unclear. Based on the established function of CMKLR1 in cell migration and differentiation, we investigated the hypothesis that CMKLR1 regulates the differentiation of myoblasts into myotubes. In C2C12 mouse myoblasts, CMKLR1 expression increased threefold with differentiation into multinucleated myotubes. Decreasing CMKLR1 expression by adenoviral-delivered small-hairpin RNA (shRNA) impaired the differentiation of C2C12 myoblasts into mature myotubes and reduced the mRNA expression of myogenic regulatory factors myogenin and MyoD while increasing Myf5 and Mrf4. At embryonic day 12.5 (E12.5), CMKLR1 knockout (CMKLR1-/-) mice appeared developmentally delayed and displayed significantly lower wet weights and a considerably diminished myotomal component of somites as revealed by immunolocalization of myosin heavy chain protein compared with wild-type (CMKLR1+/+) mouse embryos. These changes were associated with increased Myf5 and decreased MyoD protein expression in the somites of E12.5 CMKLR1-/- mouse embryos. Adult male CMKLR1-/- mice had significantly reduced bone-free lean mass and weighed less than the CMKLR1+/+ mice. We conclude that CMKLR1 is essential for myogenic differentiation of C2C12 cells in vitro, and the CMKLR1 null mice have a subtle skeletal muscle deficit beginning from embryonic life that persists during postnatal life. Copyright © 2012 the American Physiological Society.


Oderup C.,Stanford University | Oderup C.,Palo Alto Institute for Research and Education | LaJevic M.,Stanford University | LaJevic M.,Palo Alto Institute for Research and Education | And 3 more authors.
Journal of Immunology | Year: 2013

Ag-presenting dendritic cells (DCs) interpret environmental signals to orchestrate local and systemic immune responses. They govern the balance between tolerance and inflammation at epithelial surfaces, where the immune system must provide robust pathogen responses while maintaining tolerance to commensal flora and food Ags. The Wnt family of secreted proteins, which control epithelial and hematopoietic development and homeostasis, is emerging as an important regulator of inflammation. In this study, we show that canonical and noncanonical Wnts directly stimulate murine DC production of anti-inflammatory cytokines. Wnt3A triggers canonical β-catenin signaling and preferentially induces DC TGF-β and VEGF production, whereas Wnt5A induces IL-10 through alternative pathways. The Wnts also alter DC responses to microbe- or pathogen-associated molecular patterns, inhibiting proinflammatory cytokine induction in response to TLR ligands and promoting DC generation of Foxp3 + regulatory T cells. Moreover, although both Wnts suppress proinflammatory responses to bacterial endotoxin and to TLR1/2, TLR7, and TLR9 ligands, Wnt5A, but not Wnt3A, inhibits IL-6 production in response to the viral mimic, polyinosinic:polycytidylic acid. Thus, Wnt family members directly and differentially regulate DC functions, an ability that may contribute to the balance between tolerance and inflammation at epithelial sites of exposure to microbes and environmental Ags.


Li L.,CAS Shenzhen Institutes of Advanced Technology | Huang C.,CAS Shenzhen Institutes of Advanced Technology | Zhang X.,CAS Shenzhen Institutes of Advanced Technology | Wang J.,Chifeng University | And 7 more authors.
American Journal of Reproductive Immunology | Year: 2014

Problem: Chemerin is a novel chemo-attractant and adipokine involved in leukocyte recruitment, inflammation, adipogenesis, lipid/carbohydrate metabolism, and reproduction. Based on the bioinformatic search for putative small peptides in the conserved region of pre-pro-chemerin, an evolutionary conserved region flanked by potential convertase cleavage sites was identified and we named it as C-20. The binding capacity of C-20 to chemerin receptors and its potential bioactivities were investigated in this study. Method of study: Radioligand binding assay, receptor internalization assay, and early response gene C-FOS simulation, cAMP assay were carried out in chemokine-like receptor 1 (CMKLR1)/HEK293 transfectants and G protein-coupled receptor 1 (GPR1)/HEK293 transfectants. In vitro transwell chemotaxis assay in CMKLR1/L1.2 transfectants, primary Leydig cell culture, and antral follicle culture was explored to investigate the bioactivity of C-20. Results: C-20 bound to chemerin receptors CMKLR1 and GPR1 with high affinity triggered CMKLR1 internalization and stimulated subsequent signal C-FOS expression and cAMP production. C-20, such as chemerin, showed CMKLR1-dependent chemotactic property. Furthermore, in primary Leydig cells and antral follicles, C-20 showed similar but less potent suppressive effect on human chorionic gonadotropin-stimulated testosterone production and progesterone production, compared with chemerin. Conclusion: The novel chemerin-derived C-20 peptide binds to chemerin receptors CMKLR1 and GPR1 and showed similar but less potent bioactivity in chemotaxis and the suppression of gonadal steroidogenesis, suggesting that after optimization, C-20 is possible to be a useful experimental tool for the understanding of the biological functions of chemerin/CMKLR1 and chemerin/GPR1 signaling. © 2013 John Wiley & Sons A/S.


Li L.,CAS Shenzhen Institutes of Advanced Technology | Ma P.,CAS Shenzhen Institutes of Advanced Technology | Huang C.,CAS Shenzhen Institutes of Advanced Technology | Liu Y.,CAS Shenzhen Institutes of Advanced Technology | And 7 more authors.
Journal of Endocrinology | Year: 2014

The novel adipokine chemerin plays a role in the regulation of lipid and carbohydrate metabolism, and recent reports of elevated chemerin levels in polycystic ovarian syndrome and preeclampsia have pointed to an emerging role of chemerin in reproduction. We hypothesised that chemerin, like other adipokines, may function to regulate male gonadal steroidogenesis. In this study, we show that chemerin and its three receptors chemokine-like receptor 1 (CMKLR1), G-protein-coupled receptor 1 (GPR1) and chemokine (C-C motif) receptor-like 2 were expressed in male reproductive tracts, liver and white adipose tissue. CMKLR1 and GPR1 proteins were localised specifically in the Leydig cells of human and rat testes by immunohistochemistry. The expression of chemerin and its receptors in rat testes was developmentally regulated and highly expressed in Leydig cells. In vitro treatment with chemerin suppressed the human chorionic gonadotropin (hCG)- induced testosterone production from primary Leydig cells, which was accompanied by the inhibition of 3b-hydroxysteroid dehydrogenase gene and protein expression. The hCGactivated p44/42 MAPK (Erk1/2) pathway in Leydig cells was also inhibited by chemerin cotreatment. Together, these data suggest that chemerin is a novel regulator of male gonadal steroidogenesis. © 2014 Society for Endocrinology.


PubMed | Palo Alto Institute for Research and Education and Palo Alto University
Type: Journal Article | Journal: PloS one | Year: 2014

Despite circumstantial evidence postulating a protective role for NK cells in many fibrotic conditions, their contribution to the development of pulmonary fibrosis has yet to be tested. Lung-migrating NK cells are thought to attenuate the development of bleomycin induced pulmonary fibrosis (BIPF) by providing anti-fibrotic mediators and cytokines, such as IFN-. If true, we reasoned that depletion of NK cells during experimentally-induced fibrotic disease would lead to exacerbated fibrosis. To test this, we treated mice with NK cell-depleting antisera (anti-asialo GM1) and evaluated lung inflammation and fibrosis in the BIPF model. While NK cell infiltration into the airways was maximal at day 10 after bleomycin injection, NK cells represented a minor portion (1-3%) of the total leukocytes in BAL fluid. Anti-asialo GM1 significantly abrogated NK cell numbers over the course of the disease. Depletion of NK cells with anti-asialo GM1 before and throughout the BIPF model, or during just the fibrotic phase did not alter fibrosis development or affect the levels of any of the pro-inflammatory/pro-fibrotic cytokines measured (IL-1, IL-17, IFN-, TGF- and TNF-). In addition, adoptively transferred NK cells, which were detectable systemically and in the airways throughout BIPF, failed to impact lung fibrosis. These findings indicate that NK cells likely do not play an essential protective role in controlling pulmonary fibrosis development.


Hadeiba H.,Stanford University | Hadeiba H.,Palo Alto Institute for Research and Education | Butcher E.C.,Stanford University | Butcher E.C.,Palo Alto Institute for Research and Education | Butcher E.C.,The Center for Molecular Biology and Medicine
European Journal of Immunology | Year: 2013

Central tolerance is critical in establishing a peripheral T-cell repertoire purged of functional autoreactive T cells. One of the major requirements for effective central tolerance is the presentation of self and other innocuous antigens (Ags), including food, gut flora, or airway allergens, to developing T cells in the thymus. This seemingly challenging task can be mediated in some cases by ectopic expression of tissue-specific Ags by thymic epithelial cells or by entry of systemic blood-borne Ags into the thymus. More recently, thymic homing peripheral dendritic cells (DCs) have been proposed as cellular transporters of peripheral tissue-specific Ags or foreign innocuous Ags. The aim of this viewpoint is to discuss the three principal thymic DC populations and their trafficking properties in the context of central tolerance. We will first discuss the importance of peripheral DC trafficking to the thymus and then compare and contrast the three DC subsets. We will describe how they were characterized, describe their trafficking to and their microenvironmental positioning in the thymus, and discuss the functional consequence of thymic trafficking and localization on thymic selection events. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Banas M.,Jagiellonian University | Zabieglo K.,Jagiellonian University | Kasetty G.,Lund University | Kapinska-Mrowiecka M.,Zeromski Hospital | And 8 more authors.
PLoS ONE | Year: 2013

Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share similar tertiary structure with antibacterial cathelicidins. Recombinant chemerin has antimicrobial activity. Here we show that endogenous chemerin is abundant in human epidermis, and that inhibition of bacteria growth by exudates from organ cultures of primary human skin keratinocytes is largely chemerin-dependent. Using a panel of overlapping chemerin-derived synthetic peptides, we demonstrate that the antibacterial activity of chemerin is primarily mediated by Val66-Pro85, which causes direct bacterial lysis. Therefore, chemerin is an antimicrobial agent in human skin. © 2013 Banas et al.


Monnier J.,Stanford University | Monnier J.,Palo Alto Institute for Research and Education | Zabel B.A.,Palo Alto Institute for Research and Education
PLoS ONE | Year: 2014

Despite circumstantial evidence postulating a protective role for NK cells in many fibrotic conditions, their contribution to the development of pulmonary fibrosis has yet to be tested. Lung-migrating NK cells are thought to attenuate the development of bleomycin induced pulmonary fibrosis (BIPF) by providing anti-fibrotic mediators and cytokines, such as IFN-γ. If true, we reasoned that depletion of NK cells during experimentally-induced fibrotic disease would lead to exacerbated fibrosis. To test this, we treated mice with NK cell-depleting antisera (anti-asialo GM1) and evaluated lung inflammation and fibrosis in the BIPF model. While NK cell infiltration into the airways was maximal at day 10 after bleomycin injection, NK cells represented a minor portion (1-3%) of the total leukocytes in BAL fluid. Anti-asialo GM1 significantly abrogated NK cell numbers over the course of the disease. Depletion of NK cells with anti-asialo GM1 before and throughout the BIPF model, or during just the fibrotic phase did not alter fibrosis development or affect the levels of any of the pro-inflammatory/pro-fibrotic cytokines measured (IL-1β, IL-17, IFN-γ, TGF-β and TNF-α). In addition, adoptively transferred NK cells, which were detectable systemically and in the airways throughout BIPF, failed to impact lung fibrosis. These findings indicate that NK cells likely do not play an essential protective role in controlling pulmonary fibrosis development. © 2014 Monnier and zabel.


Deal E.M.,Stanford University | Lahl K.,Stanford University | Narvaez C.F.,Stanford University | Narvaez C.F.,South Colombian University | And 6 more authors.
Journal of Clinical Investigation | Year: 2013

B cell-dependent immunity to rotavirus, an important intestinal pathogen, plays a significant role in viral clearance and protects against reinfection. Human in vitro and murine in vivo models of rotavirus infection were used to delineate the role of primary plasmacytoid DCs (pDCs) in initiating B cell responses. Human pDCs were necessary and sufficient for B cell activation induced by rotavirus. Type I IFN recognition by B cells was essential for rotavirus-mediated B cell activation in vitro and murine pDCs and IFN-α/β-mediated B cell activation after in vivo intestinal rotavirus infection. Furthermore, rotavirus-specific serum and mucosal antibody responses were defective in mice lacking functional pDCs at the time of infection. These data demonstrate that optimal B cell activation and virus-specific antibody secretion following mucosal infection were a direct result of pDC-derived type I IFN. Importantly, viral shedding significantly increased in pDC-deficient mice, suggesting that pDC-dependent antibody production influences viral clearance. Thus, mucosal pDCs critically influence the course of rotavirus infection through rotavirus recognition and subsequent IFN production and display powerful adjuvant properties to initiate and enhance humoral immunity. Copyright © 2013, American Society for Clinical Investigation.

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