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1.
J Invest Dermatol ; 140(10): 2032-2040.e1, 2020 10.
Article in English | MEDLINE | ID: mdl-32119868

ABSTRACT

Hyperpigmentary conditions can arise when melanogenesis in the epidermis is misregulated. Understanding the pathways underlying melanogenesis is essential for the development of effective treatments. Here, we report that a group of metabolites called polyamines are important in the control of melanogenesis in human skin. Polyamines are cationic molecules present in all cells and are essential for cellular function. We report that polyamine regulator ODC1 is upregulated in melanocytes from melasma lesional skin. We report that the polyamine putrescine can promote pigmentation in human skin explants and primary normal human epidermal melanocytes through induction of tyrosinase which is rate-limiting for the synthesis of melanin. Putrescine supplementation on normal human epidermal melanocytes results in the activation of polyamine catabolism, which results in increased intracellular H2O2. Polyamine catabolism is also increased in human skin explants that have been treated with putrescine. We further report that inhibition of polyamine catabolism prevents putrescine-induced promotion of tyrosinase levels and pigmentation in normal human epidermal melanocytes, showing that polyamine catabolism is responsible for the putrescine induction of melanogenesis. Our data showing that putrescine promotes pigmentation has important consequences for hyperpigmented and hypopigmented conditions. Further understanding of how polyamines control epidermal pigmentation could open the door for the development of new therapeutics.


Subject(s)
Epidermis/drug effects , Melanins/biosynthesis , Putrescine/pharmacology , Biogenic Polyamines/metabolism , Cells, Cultured , Dicarboxylic Acid Transporters/physiology , Epidermis/metabolism , Humans , Melanocytes/drug effects , Melanocytes/metabolism , Middle Aged , Mitochondrial Membrane Transport Proteins/physiology , Putrescine/analogs & derivatives , Skin Pigmentation/drug effects
2.
Methods Mol Biol ; 2109: 55-65, 2020.
Article in English | MEDLINE | ID: mdl-31161578

ABSTRACT

The study of skin pigmentation requires determining the rate of melanin production in melanocytes and quantifying the rate of melanosome transfer to keratinocytes. Here, we describe a method to quantify melanosome transfer using immunofluorescence microscopy coupled with automated image analysis of in vitro human melanocytes and keratinocytes in co-culture. In this method, the number of melanin capped keratinocyte nuclei is quantified.


Subject(s)
Keratinocytes/cytology , Melanocytes/cytology , Melanosomes/transplantation , Cells, Cultured , Coculture Techniques , Humans , Keratinocytes/metabolism , Melanins/metabolism , Melanocytes/metabolism , Melanosomes/metabolism , Microscopy, Fluorescence , Radiographic Image Interpretation, Computer-Assisted
3.
Virology ; 482: 72-8, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25827531

ABSTRACT

Heterosexual HIV-1 transmission has been identified as a genetic bottleneck and a single transmitted/founder (T/F) variant with reduced sensitivity to type I interferon initiates productive infection in most cases. We hypothesized that particularly active accessory protein(s) may confer T/F viruses with a selective advantage in establishing HIV infection. Thus, we tested vpu, vif and nef alleles from six T/F and six chronic (CC) viruses in assays for 9 immune evasion activities involving the counteraction of interferon-stimulated genes and modulation of ligands known to activate innate immune cells. All functions were highly conserved with no significant differences between T/F and CC viruses, suggesting that these accessory protein functions are important throughout the course of infection.


Subject(s)
HIV Infections/immunology , HIV-1/immunology , HIV-1/physiology , Human Immunodeficiency Virus Proteins/metabolism , Immune Evasion , Viral Regulatory and Accessory Proteins/metabolism , nef Gene Products, Human Immunodeficiency Virus/metabolism , vif Gene Products, Human Immunodeficiency Virus/metabolism , Cell Line , Female , HIV Infections/virology , HIV-1/isolation & purification , Humans , Male , Virus Replication
4.
Elife ; 42015 Mar 18.
Article in English | MEDLINE | ID: mdl-25783751

ABSTRACT

Dengue virus (DENV) is the most significant human arboviral pathogen and causes ∼400 million infections in humans each year. In previous work, we observed that mast cells (MC) mediate vascular leakage during DENV infection in mice and that levels of MC activation are correlated with disease severity in human DENV patients (St John et al., 2013b). A major risk factor for developing severe dengue is secondary infection with a heterologous serotype. The dominant theory explaining increased severity during secondary DENV infection is that cross-reactive but non-neutralizing antibodies promote uptake of virus and allow enhanced replication. Here, we define another mechanism, dependent on FcγR-mediated enhanced degranulation responses by MCs. Antibody-dependent mast cell activation constitutes a novel mechanism to explain enhanced vascular leakage during secondary DENV infection.


Subject(s)
Capillary Permeability/immunology , Cell Degranulation/immunology , Dengue Virus/immunology , Dengue/immunology , Mast Cells/immunology , Receptors, IgG/immunology , Animals , Antibody Specificity/immunology , Cell Line , Cell Line, Tumor , Cells, Cultured , Dengue/virology , Dengue Virus/physiology , Host-Pathogen Interactions/immunology , Humans , Immunization, Passive/methods , Immunoglobulin G/immunology , Mast Cells/physiology , Mast Cells/virology , Mice, Inbred C57BL , Mice, Knockout , Receptors, IgG/genetics , Receptors, IgG/metabolism
5.
J Virol ; 87(21): 11648-58, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23966397

ABSTRACT

A characteristic clinical feature of dengue virus infection is thrombocytopenia, though its underlying mechanism is not definitively determined. By adoptive transfer of human CD34(+) fetal liver cells into immunodeficient mice, we have constructed humanized mice with significant levels of human platelets, monocytes/macrophages, and hepatocytes. Infection of these mice with both lab-adapted and clinical strains of dengue virus induces characteristic human hematological changes, including transient leukopenia and thrombocytopenia. We show that the specific depletion of human platelets is not mediated by antibodies in the periphery or reduced production of human thrombopoietin in the liver but reduction of human megakaryocytes and megakaryocyte progenitors in the bone marrow of the infected mice. These findings identify inhibition of platelet production in the bone marrow as a key mechanism underlying dengue-induced thrombocytopenia and suggest the utility of the improved humanized mouse model in studying dengue virus infection and pathogenesis in a human cell context.


Subject(s)
Bone Marrow/pathology , Bone Marrow/virology , Dengue Virus/pathogenicity , Dengue/complications , Megakaryocytes/physiology , Megakaryocytes/virology , Thrombocytopenia/etiology , Animals , Humans , Mice , Mice, SCID
6.
Expert Rev Clin Immunol ; 8(1): 73-80, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22149342

ABSTRACT

The immune system has evolved to mount immune responses against foreign pathogens and to remain silent against self-antigens. A balance between immunity and tolerance is required as any disturbance may result in chronic inflammation or autoimmunity. Dendritic cells (DCs) actively participate in maintaining this balance. Under steady-state conditions, DCs remain in an immature state and do not mount an immune response against circulating self-antigens in the periphery, which maintains a state of tolerance. By contrast, foreign antigens result in DC maturation and DC-induced T-cell activation. Inappropriate maturation of DCs due to infections or tissue injury may cause alterations in the balance between the tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases. This article provides an overview of the effects of advancing age on DC functions and their implications in autoimmunity.


Subject(s)
Aging/immunology , Autoimmune Diseases/immunology , Autoimmunity , Dendritic Cells/immunology , Aging/pathology , Autoantigens/immunology , Autoimmune Diseases/pathology , Dendritic Cells/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
7.
Med Gas Res ; 1(1): 13, 2011 Jun 27.
Article in English | MEDLINE | ID: mdl-22146102

ABSTRACT

Medical gases are pharmaceutical molecules which offer solutions to a wide array of medical needs. This can range from use in burn and stroke victims to hypoxia therapy in children. More specifically however, gases such as oxygen, helium, xenon, and hydrogen have recently come under increased exploration for their potential theraputic use with various brain disease states including hypoxia-ischemia, cerebral hemorrhages, and traumatic brain injuries. As a result, this article will review the various advances in medical gas research and discuss the potential therapeutic applications and mechanisms with regards to the field of neurobiology.

8.
Age (Dordr) ; 33(3): 363-76, 2011 Sep.
Article in English | MEDLINE | ID: mdl-20953722

ABSTRACT

Increased susceptibility to infections, particularly respiratory viral infections, is a hallmark of advancing age. The underlying mechanisms are not well understood, and there is a scarcity of information regarding the contribution of the innate immune system, which is the first line of defense against infections. In the present study, we have investigated the effect of advancing age on plasmacytoid dendritic cell (PDC) function because they are critical in generating a robust antiviral response via the secretion of interferons (IFN). Our results indicate that PDCs from the aged are impaired in their capacity to secrete IFN-I in response to influenza virus and CPG stimulation. Additionally, we observed a severe reduction in the production of IFN-III, which plays an important role in defense against viral infections at respiratory mucosal surfaces. This reduction in IFN-I and IFN-III were a result of age-associated impaired phosphorylation of transcription factor, IRF-7. Furthermore, aged PDCs were observed to be impaired in their capacity to induce perforin and granzyme in CD8 T cells. Comparison of the antigen-presenting capacity of aged PDC with young PDC revealed that PDCs from aged subjects display reduced capacity to induce proliferation and IFN-gamma secretion in CD4 and CD8 T cells as compared with PDCs from young subjects. In summary, our study demonstrates that advancing age has a profound effect on PDC function at multiple levels and may therefore, be responsible for the increased susceptibility to infections in the elderly.


Subject(s)
Aging/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Immunity, Cellular/immunology , Immunity, Innate/immunology , Adult , Aged , Aged, 80 and over , Cell Proliferation , Female , Humans , Male , Young Adult
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