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1.
Exp Dermatol ; 28(9): 1051-1057, 2019 09.
Article in English | MEDLINE | ID: mdl-31338881

ABSTRACT

Differentiation and proliferation of keratinocyte are controlled by various signalling pathways. The epidermal growth factor receptor (EGFR) is known to be an important regulator of multiple epidermal functions. Inhibition of EGFR signalling disturbs keratinocyte proliferation, differentiation and migration. Previous studies have revealed that one of the EGFR downstream signalling molecules, phospholipase Cγ1 (PLCγ1), regulates differentiation, proliferation and migration of keratinocytes in in vitro cell culture system. However, the role of PLCγ1 in the regulation of keratinocyte functions in animal epidermis remains unexplored. In this study, we generated keratinocyte-specific PLCγ1 knockout (KO) mice (PLCγ1 cKO mice). Contrary to our expectations, loss of PLCγ1 did not affect differentiation, proliferation and migration of interfollicular keratinocytes. We further examined the role of PLCγ1 in irritant contact dermatitis (ICD), in which epidermal cells play a pivotal role. Upon irritant stimulation, PLCγ1 cKO mice showed exaggerated ICD responses. Further study revealed that epidermal loss of PLCγ1 induced sebaceous gland hyperplasia, indicating that PLCγ1 regulates homeostasis of one of the epidermal appendages. Taken together, our results indicate that, although PLCγ1 is dispensable in interfollicular keratinocyte for normal differentiation, proliferation and migration, it is required for normal ICD responses. Our results also indicate that PLCγ1 regulates homeostasis of sebaceous glands.


Subject(s)
Dermatitis, Irritant/enzymology , Keratinocytes/enzymology , Phospholipase C gamma/physiology , Sebaceous Glands/enzymology , Animals , Cell Differentiation , Cell Movement , Cell Proliferation , Croton Oil/toxicity , Dermatitis, Irritant/etiology , Epidermis/drug effects , Epidermis/enzymology , Epidermis/pathology , Homeostasis , Hyperplasia , Irritants , Keratinocytes/drug effects , Mice , Mice, Knockout , Mice, Transgenic , Phospholipase C gamma/deficiency , Phospholipase C gamma/genetics , Sebaceous Glands/drug effects , Sebaceous Glands/pathology
2.
Clin Pharmacol Drug Dev ; 8(3): 270-280, 2019 04.
Article in English | MEDLINE | ID: mdl-30650256

ABSTRACT

Stearoyl-coenzyme A desaturase 1 (SCD-1) in sebaceous glands is a key enzyme in the synthesis of monounsaturated fatty acids essential for acne development. GSK1940029 gel, a novel SCD-1 inhibitor, is being developed as a potential treatment for acne. To assess the irritation potential, pharmacokinetics (PK), and safety of topical GSK1940029 to the skin of healthy adults, two interdependent studies were conducted in parallel. Study 1 (n = 54) investigated the irritation potential of GSK1940029 (0.3% and 1%, occluded application) to allow for its application to larger surface areas in study 2 (n = 39), which investigated the safety, tolerability, and PK of GSK1940029 after single and repeat doses as occluded and nonoccluded applications. GSK1940029 was not a primary or cumulative irritant after 2 and 21 days of dosing in study 1. In study 2, single and repeat applications of GSK1940029 (0.1% to 1%) doses were well tolerated with little or no influence on AUC and Cmax under occluded or unoccluded conditions. Systemic exposure increased proportionally with surface area and was higher in occluded conditions. Design of these interdependent studies allowed for the assessment of the irritation potential for topical GSK1940029 in parallel with the investigation of PK and safety profiles.


Subject(s)
Acne Vulgaris/drug therapy , Enzyme Inhibitors , Sebaceous Glands/enzymology , Stearoyl-CoA Desaturase/antagonists & inhibitors , Triazoles , Administration, Cutaneous , Adolescent , Adult , Aged , Dermatitis, Irritant/etiology , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/blood , Female , Gels , Healthy Volunteers , Humans , Male , Middle Aged , Sebaceous Glands/drug effects , Single-Blind Method , Skin Irritancy Tests , Therapeutic Occlusion , Triazoles/administration & dosage , Triazoles/adverse effects , Triazoles/blood , Young Adult
3.
Toxicol Sci ; 160(2): 230-243, 2017 Dec 01.
Article in English | MEDLINE | ID: mdl-28973660

ABSTRACT

We have previously shown that cytochrome P450 1A1 (CYP1A1) was highly induced for a long period of time in a patient who had been poisoned by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound known to activate the aryl hydrocarbon receptor (AhR). During that period of time, no sebaceous glands could be observed in the skin of this patient. In this study, starting from observations in the patient exposed to TCDD, we analyzed the seboatrophy induced by dioxins in mice. We observed a very different pattern of AhR and CYP1A1 immunostaining in skin biopsies of the patient. When applying TCDD and beta-naphthoflavone, another AhR agonist, on the ears of C57BL/6J mice, we reproduced (1) an atrophy of sebaceous glands, (2) a strong induction of CYP1A1 within the glands, and (3) a dramatic repression of the genes encoding the sebogenic enzymes AWAT1, ELOVL3, and SCD1. These effects were reversible. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) expressing progenitor cells, found in the vicinity of sebaceous glands, were shown to be the initial skin cellular targets of AhR agonists. These cells retained the DNA label BrdU and colocalized with the CYP1A1 protein for at least 30 days. A downregulation of LRIG1 by siRNA in cultured sebocytes significantly decreased the CYP1A1 response to TCDD, indicating that LRIG1 contributes to a higher susceptibility of AhR agonists. In conclusion, these observations provide for the first time a strong experimental support to the concept that dioxin-induced skin pathology may be driven by a molecular switch in progenitor cells involved in the physiological turnover of sebaceous glands.


Subject(s)
Environmental Pollutants/toxicity , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Polychlorinated Dibenzodioxins/toxicity , Sebaceous Glands/drug effects , Stem Cells/drug effects , Animals , Atrophy , Basic Helix-Loop-Helix Transcription Factors/agonists , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation/drug effects , Cells, Cultured , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A1/metabolism , Gene Expression Regulation , Humans , Male , Mice, Inbred C57BL , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Sebaceous Glands/enzymology , Sebaceous Glands/pathology , Signal Transduction/drug effects , Stem Cells/enzymology , Stem Cells/pathology , Time Factors
4.
Histopathology ; 71(6): 985-988, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28677299

ABSTRACT

AIMS: Terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase expressed in immature, normal and neoplastic, lymphoid or haematopoietic cells and in neuroendocrine carcinomas, such as Merkel cell carcinoma and small-cell carcinoma. It has not yet been described in cells of epithelial origin. After observing TdT immunoreactivity in normal sebaceous glands, we analysed its spectrum of expression in cases of sebaceous cell hyperplasia (SGH) and sebaceous cell neoplasm. METHODS AND RESULTS: Twelve cases of SGH and three cases of other benign lesions, namely sebaceoma, sebaceous adenoma, and sebaceous naevus, along with four archived cases of sebaceous cell carcinoma (SC) were collected and stained with TdT antibody. In addition, tissue microarrays were constructed from 11 cases of basal cell carcinoma (BCC) and 10 cases of squamous cell carcinoma (SCC), which had nine evaluable cases each, and, after carcinoma type confirmation with immunostaining for epithelial membrane antigen, TdT immunohistochemistry was performed. All cases of SGH and sebaceous cell neoplasm were positive for TdT. The staining intensity was variable, being often weak to moderate in a significant proportion of cells, apart from one case of SC and the case of sebaceous naevus, which were only focally positive. No BCCs and only one SCC showed immunoreactivity. CONCLUSIONS: TdT protein can be found in cells of epithelial origin and specifically sebaceous cells, both benign and malignant. It can be hypothesized that this expression is due to sebaceous cell differentiation as a prelude to apoptosis and holocrine secretion. Additional studies are needed to further elucidate its biological role.


Subject(s)
Adenoma/enzymology , Carcinoma, Basal Cell/enzymology , Carcinoma, Squamous Cell/enzymology , DNA Nucleotidylexotransferase/metabolism , Sebaceous Gland Neoplasms/enzymology , Sebaceous Glands/enzymology , Adenoma/pathology , Carcinoma, Basal Cell/pathology , Carcinoma, Squamous Cell/pathology , Epithelial Cells/enzymology , Epithelial Cells/pathology , Humans , Hyperplasia/enzymology , Hyperplasia/pathology , Immunohistochemistry , Mucin-1 , Sebaceous Gland Neoplasms/pathology , Sebaceous Glands/pathology , Skin Neoplasms/enzymology , Skin Neoplasms/pathology
5.
J Pathol ; 239(3): 374-83, 2016 07.
Article in English | MEDLINE | ID: mdl-27126290

ABSTRACT

The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Subject(s)
Alkaline Ceramidase/metabolism , Alopecia/enzymology , Ceramides/metabolism , Energy Metabolism , Homeostasis , Alkaline Ceramidase/genetics , Alopecia/physiopathology , Animals , Cell Differentiation , Epidermis/abnormalities , Epidermis/enzymology , Female , Hair Follicle/abnormalities , Hair Follicle/enzymology , Humans , Keratinocytes/enzymology , Keratinocytes/physiology , Male , Mice , Mice, Inbred C57BL , Pituitary Gland/abnormalities , Pituitary Gland/enzymology , Sebaceous Glands/abnormalities , Sebaceous Glands/enzymology , Skin/enzymology , Skin Abnormalities , Sphingolipids/metabolism
6.
Nat Chem Biol ; 12(4): 218-25, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26829472

ABSTRACT

A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.


Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Drug Discovery/methods , Lung Neoplasms/enzymology , Oxamic Acid/analogs & derivatives , Stearoyl-CoA Desaturase/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Benzothiazoles/pharmacokinetics , Benzothiazoles/therapeutic use , Benzothiazoles/toxicity , Cell Line, Tumor , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 4 , Female , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, SCID , Molecular Structure , Molecular Targeted Therapy , Oxamic Acid/pharmacokinetics , Oxamic Acid/pharmacology , Oxamic Acid/therapeutic use , Oxamic Acid/toxicity , Protein Binding , Sebaceous Glands/drug effects , Sebaceous Glands/enzymology , Sebaceous Glands/pathology , Xenograft Model Antitumor Assays
7.
Am J Dermatopathol ; 38(8): 580-5, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26381116

ABSTRACT

Malic enzymes (MEs) are involved in fatty acid biosynthesis and lipid accumulation, and their expression in sebocytes and sebaceous lesions has not been investigated. The aims of this study were to examine ME1 and ME2 expression in normal skin and sebaceous lesions. A total of 68 cases including 5 specimens of normal skin, 12 facial lesions showing sebaceous hyperplasia, 18 sebaceous adenomas, 10 sebaceomas, 13 steatocystomas, and 10 sebaceous carcinomas were examined for the expression of ME1 and ME2. All benign and malignant sebaceous lesions showed ME1 in clear cells and ME2 in nonclear cells, respectively. ME1/ME2 phenotype is seen in basal sebocytes, basal keratinocytes, sweat glands, and outer root sheath cells and hence not specific. This study demonstrates that ME1/ME2 expression phenotype may have a potential to be a valuable marker for sebaceous differentiation. It is necessary to perform large-scale studies including skin tumors with a clear cell morphology that may mimic sebaceous differentiation.


Subject(s)
Adenoma/enzymology , Biomarkers, Tumor/analysis , Carcinoma/enzymology , Malate Dehydrogenase/analysis , Sebaceous Gland Neoplasms/enzymology , Sebaceous Glands/enzymology , Adenoma/pathology , Adult , Aged , Aged, 80 and over , Biopsy , Carcinoma/pathology , Case-Control Studies , Cell Differentiation , Female , Humans , Hyperplasia , Immunohistochemistry , Male , Middle Aged , Phenotype , Sebaceous Gland Neoplasms/pathology , Sebaceous Glands/pathology , Young Adult
8.
Curr Mol Pharmacol ; 9(4): 311-319, 2016.
Article in English | MEDLINE | ID: mdl-26159490

ABSTRACT

The androgen receptor plays a pivotal role in the sebaceous glands. Its primary function is to stimulate cell proliferation and differentiation in the sebaceous and its associate with acne. Previous studies have demonstrated expression of AR and steroidogenic enzymes in normal sebaceous glands and in all sebaceous disorders present evidence that androgen receptor may be a sensitive marker of sebaceous differentiation. It has been previously suggested that AR and steroidogenic enzymes immunohistochemistry may be useful particularly in identifying poorly sebaceous carcinoma. This review will provide an overview of the AR functions in the sebaceous glands and discussion of the therapeutic targets in acne and carcinoma.


Subject(s)
Androgens/metabolism , Molecular Targeted Therapy , Sebaceous Glands/metabolism , Sebaceous Glands/pathology , Acne Vulgaris/pathology , Acne Vulgaris/therapy , Androgens/blood , Humans , Sebaceous Glands/enzymology , Signal Transduction
9.
FEBS Lett ; 589(12): 1376-82, 2015 May 22.
Article in English | MEDLINE | ID: mdl-25889637

ABSTRACT

The roles of the epidermal growth factor receptor (EGFR) in sebaceous glands remain poorly explored. We show that human sebocytes express EGFR and lower levels of ERBB2 and ERBB3, all receptors being downregulated after the induction of lipid synthesis. Nile red staining showed that siRNA-mediated downregulation of EGFR or ERBB3 increases lipid accumulation, whereas ERBB2 downregulation has no effect. Spectrometry confirmed induction of triglycerides after EGFR or ERBB3 downregulation and revealed induction of cholesteryl esters after downregulation of EGFR, ERBB2 or ERBB3. Thus, EGFR/ERBB receptors differentially modulate sebaceous lipogenesis, a key feature of sebaceous gland physiology and of several skin diseases.


Subject(s)
ErbB Receptors/metabolism , Gene Expression Regulation, Enzymologic , Lipogenesis , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/metabolism , Sebaceous Glands/metabolism , Biomarkers/metabolism , Cell Line , Cholesterol Esters/metabolism , Down-Regulation , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Fatty Acids, Nonesterified/metabolism , Humans , Ligands , Linoleic Acid/metabolism , RNA Interference , RNA, Small Interfering , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/genetics , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/genetics , Sebaceous Glands/enzymology , Triglycerides/metabolism , Up-Regulation
10.
J Endocrinol ; 222(3): 301-12, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24938708

ABSTRACT

Androgens are well known to influence sebum synthesis and secretion. Various factors related to androgen biosynthesis are expressed in human sebaceous glands. In this study, immunohistochemical analysis of human skin specimens from 43 subjects indicated that various androgen-producing and -metabolizing enzymes were functionally localized to sebocytes accumulating lipid droplets and that the exclusive expression of 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2 (HSD17B2)) in sebaceous glands was negatively correlated with that of peroxisome proliferator-activated receptor gamma (PPARγ (PPARG)), which also significantly changed in an age-dependent manner. We also demonstrated that the changes of 17ß-HSD2 expression in human immortalized sebocytes (SZ95) influenced the expressions of sebogenesis-related factors. In addition, the overexpression of 17ß-HSD2 in SZ95 significantly increased the androstenedione production and markedly decreased the amounts of testosterone and dihydrotestosterone when DHEA was added externally. On the other hand, the phosphorylation of mammalian target of rapamycin, which is well known to induce sebum secretion and the onset and/or aggravation of acne, was increased by the addition of testosterone in the presence of IGF1 in hamster sebocytes. These results all indicated that local androgen biosynthesis and metabolism in human sebaceous glands could play a pivotal role in sebum synthesis and secretion.


Subject(s)
Androgens/biosynthesis , Estradiol Dehydrogenases/genetics , Estradiol Dehydrogenases/metabolism , Sebaceous Glands/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Androstenedione/biosynthesis , Animals , Cell Line , Child , Cricetinae , Dihydrotestosterone/metabolism , Female , Gene Expression , Humans , Immunohistochemistry , Lipid Metabolism , Male , Middle Aged , PPAR gamma/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sebaceous Glands/cytology , Sebaceous Glands/enzymology , Sebum/metabolism , Skin/cytology , Skin/metabolism , TOR Serine-Threonine Kinases/metabolism , Testosterone/biosynthesis , Transfection , Young Adult
11.
Arch Pharm (Weinheim) ; 347(5): 320-6, 2014 May.
Article in English | MEDLINE | ID: mdl-24497156

ABSTRACT

Flank organs are an androgen-dependent pilosebaceous complex present in male and female hamsters. These organs have been used for the evaluation of antiandrogenic drugs, which could be used for the treatment of androgen-dependent afflictions. This study demonstrated the role of four different steroidal carbamates 7-10 in the expression of mRNAs coding for different enzymes involved in the lipid metabolism in flank organs. To determine the biological effects of compounds 7-10 on the expression of mRNA coding for lipid enzymes, steroids 7-10, testosterone (T), progesterone (P), and/or 7-10 were applied on the flank organs. Later, the mRNA expression for the enzymes was determined by polymerase chain reaction. The binding of 8 and 9 to the progesterone receptor (PR) as well as their effects on the activity of 5α-reductase were also evaluated. Treatments with T, P, and 7-10 increased the mRNA expression for glycerol 3-phosphate acyl transferase (GPAT), ß-hydroxy-ß-methylglutaryl-CoA synthase (HMG-CoA-S), ß-hydroxy-ß-methylglutaryl-CoA reductase (HMG-CoA-R), phosphatidylinositol synthase (PI-S), and squalene-synthase (SQ-S). However, the combined treatments with P + 7-10 decreased the expression of GPAT, HMG-CoA-S, and HMG-CoA-R. Expression of mRNA for all enzymes was variable under treatment with T + 7-10. Data showed that these carbamates did not bind to the PR, but inhibited the activity of 5α-reductase. Carbamates 7-10 changed the mRNA expression model induced by T and P in flank organs.


Subject(s)
Carbamates/pharmacology , RNA, Messenger/genetics , Sebaceous Glands/drug effects , Sebaceous Glands/enzymology , Steroids/pharmacology , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism , Animals , Binding, Competitive , CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase/genetics , Carbamates/chemistry , Cricetinae , Farnesyl-Diphosphate Farnesyltransferase/genetics , Female , Glycerol-3-Phosphate O-Acyltransferase/genetics , Humans , Hydroxymethylglutaryl CoA Reductases/genetics , Male , Mesocricetus , Molecular Structure , Ovariectomy , Prostate/drug effects , Prostate/enzymology , RNA, Messenger/metabolism , Rabbits , Receptors, Progesterone/metabolism , Skin/drug effects , Skin/enzymology , Steroids/chemistry
12.
J Histochem Cytochem ; 62(1): 50-9, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24004857

ABSTRACT

Studies of human genetic disorders and mouse models reveal the important roles of matriptase in hair growth. Here, we investigate matriptase expression and zymogen activation in hair follicles. We show: 1) layer-dependent distribution patterns, with much higher matriptase expression in cells of the outer root sheath and matrix cells of the hair bulb than in cells of the inner root sheath; 2) cycle-dependent expression patterns, with matriptase expressed in the anagen and catagen phases of the hair lifecycle, but not in the telogen phase; 3) reduced expression of the matriptase inhibitor, HAI-1, in the catagen phase, suggesting increased proteolytic activity in this phase; and 4) definitive matriptase zymogen activation patterns, with the highest matriptase activation observed in matrix cells and outer root sheath cells in the isthmus/bulge region. In sebaceous glands, matriptase is highly expressed in basal and ductal cells, with much lower expression in the differentiated, lipid-filled cells of the interior. We also show that matriptase potently activates hepatocyte growth factor (HGF) in vitro, and that the HGF receptor, c-Met, is co-expressed in those cells that express activated matriptase. Our observations suggest that the matriptase-HGF-c-MET pathway has the potential to be engaged, primarily in proliferative cells rather than terminally differentiated epithelial cells of the human pilosebaceous unit.


Subject(s)
Enzyme Precursors/metabolism , Gene Expression Regulation, Enzymologic , Sebaceous Glands/enzymology , Serine Endopeptidases/metabolism , Animals , Cell Differentiation , Cell Line , Cell Proliferation , Enzyme Activation , Hair Follicle/cytology , Hair Follicle/enzymology , Hair Follicle/growth & development , Humans , Keratinocytes/cytology , Keratinocytes/metabolism , Proteinase Inhibitory Proteins, Secretory/metabolism , Proto-Oncogene Proteins c-met/metabolism , Sebaceous Glands/cytology , Sebaceous Glands/metabolism , Signal Transduction
14.
Arch Dermatol Res ; 305(5): 379-87, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23377137

ABSTRACT

Caspase-14 is a seemingly non-apoptotic caspase involved in keratinocyte differentiation and cornification of the skin. Keratin-19 is an epithelial marker and a potential marker of epidermal stem cells that is expressed during human fetal skin development. We examined the immunohistochemical expression of caspase-14 in relation to CK-19 in the human fetal skin during development and perinatally, to assess their role in human skin maturation. Skin samples were received at autopsy. In the fetal epidermis, caspase-14 was predominantly expressed in the more differentiated layers, gradually disappearing from the basal layer toward term. By contrast, keratin-19 expression gradually decreased with epidermal maturation through gestation (rho = -0.949; p = 0.0001) and was a marker of the germinative layers. Keratin-19 was preserved in scarce basal cell nests at term and postnatally. Caspase-14 and keratin-19 were inversely expressed in the differentiating epidermal layers through gestation (p < 0.0001). Concerning the appendages, in hair follicles and sebaceous glands, caspase-14 located preferentially in the more differentiated layers of the inner root sheath, whereas keratin-19 was expressed in the outer sheath. Eccrine sweat glands showed a variable pattern of caspase-14 and keratin-19 expression. In conclusion, caspase-14 emerged as a marker of human skin differentiation during development, while keratin-19 marked the germinative epithelial layers in the fetal epidermis and appendages and possibly the nests of epidermal stem cells.


Subject(s)
Caspases/analysis , Epidermis/chemistry , Epithelial Cells/chemistry , Hair Follicle/chemistry , Keratin-19/analysis , Sebaceous Glands/chemistry , Sweat Glands/chemistry , Autopsy , Biomarkers/analysis , Cell Differentiation , Epidermis/embryology , Epidermis/enzymology , Epithelial Cells/enzymology , Gestational Age , Hair Follicle/embryology , Hair Follicle/enzymology , Humans , Immunohistochemistry , Infant, Newborn , Retrospective Studies , Sebaceous Glands/embryology , Sebaceous Glands/enzymology , Sweat Glands/embryology , Sweat Glands/enzymology
15.
J Biol Chem ; 286(29): 25922-34, 2011 Jul 22.
Article in English | MEDLINE | ID: mdl-21628453

ABSTRACT

2-Hydroxylated fatty acid (HFA)-containing sphingolipids are abundant in mammalian skin and are believed to play a role in the formation of the epidermal barrier. Fatty acid 2-hydroxylase (FA2H), required for the synthesis of 2-hydroxylated sphingolipids in various organs, is highly expressed in skin, and previous in vitro studies demonstrated its role in the synthesis of HFA sphingolipids in human keratinocytes. Unexpectedly, however, mice deficient in FA2H did not show significant changes in their epidermal HFA sphingolipids. Expression of FA2H in murine skin was restricted to the sebaceous glands, where it was required for synthesis of 2-hydroxylated glucosylceramide and a fraction of type II wax diesters. Absence of FA2H resulted in hyperproliferation of sebocytes and enlarged sebaceous glands during hair follicle morphogenesis and anagen (active growth phase) in adult mice. This was accompanied by a significant up-regulation of the epidermal growth factor receptor ligand epigen in sebocytes. Loss of FA2H significantly altered the composition and physicochemical properties of sebum, which often blocked the hair canal, apparently causing a delay in the hair fiber exit. Furthermore, mice lacking FA2H displayed a cycling alopecia with hair loss in telogen. These results underline the importance of the sebaceous glands and suggest a role of specific sebaceous gland or sebum lipids, synthesized by FA2H, in the hair follicle homeostasis.


Subject(s)
Amidohydrolases/genetics , Amidohydrolases/metabolism , Gene Expression Regulation, Developmental , Hair/growth & development , Sebaceous Glands/metabolism , Sebum/metabolism , Alopecia/metabolism , Alopecia/pathology , Amidohydrolases/deficiency , Animals , Cell Proliferation , Epidermis/anatomy & histology , Epidermis/metabolism , Hair/enzymology , Male , Mice , Organ Size , Organ Specificity , Sebaceous Glands/anatomy & histology , Sebaceous Glands/cytology , Sebaceous Glands/enzymology , Sebum/enzymology , Sphingolipids/chemistry , Sphingolipids/metabolism , Transition Temperature
16.
Br J Dermatol ; 165(2): 269-76, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21457203

ABSTRACT

BACKGROUND: Treatment of SZ95 sebocytes with the essential fatty acid linoleic acid (LA) and the polyunsaturated fatty acid arachidonic acid (AA) leads to sebaceous lipogenesis. Animal data indicate that stearoyl-coenzyme A desaturase (SCD), a key enzyme in fatty acid biosynthesis, is involved in sebaceous lipogenesis and proinflammatory signalling in the sebaceous gland. On the other hand, fatty acid delta-6 desaturase-2 (FADS2) catalyses the conversion of LA to AA. OBJECTIVES: To identify the effects of LA and AA on the expression of SCD and FADS2 and to detect its biological relevance. METHODS: SZ95 sebocytes were treated with LA (10(-5) and 10(-4) mol L(-1) ), AA (10(-6) and 10(-5) mol L(-1) ) and the combination of LA (10(-4) mol L(-1) ) and testosterone (2 × 10(-8) mol L(-1) ), with or without addition of the SCD inhibitor FPCA (10(-8) and 10(-6) mol L(-1) ). Cytotoxicity was determined by the lactate dehydrogenase assay. SCD and FACS2 mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction and protein expression by Western blot analysis. SZ95 sebocyte lipid content and cell number were measured by the Nile red and the fluorescein diacetate microassays, respectively. Determination of interleukin (IL)-6 and IL-8 release was evaluated by enzyme-linked immunosorbent assay. RESULTS: LA treatment induced an increase of SCD and FADS2 at mRNA and protein levels in SZ95 sebocytes after 1·5 h. Treatment with AA led to an increase of SCD but to a decrease of FADS2 mRNA levels. LA/testosterone cotreatment stimulated lipogenesis in SZ95 sebocytes. A distinct proinflammatory pattern was registered: whereas LA strongly upregulated IL-6 secretion only, AA induced a mild level of IL-6 and IL-8 release from SZ95 sebocytes. Treatment with the SCD inhibitor FPCA reduced the LA/testosterone-upregulated SCD and FADS2 mRNA levels and resulted in an anti-inflammatory effect, but did not affect sebaceous lipogenesis. CONCLUSIONS: LA-induced sebaceous lipogenesis is likely to be an SCD-independent effect. Regulation of SCD and FADS2 expression by LA and AA leads to enhancement of proinflammatory activity but does not affect lipogenesis in human sebocytes.


Subject(s)
Acyl Coenzyme A/metabolism , Arachidonic Acid/pharmacology , Linoleic Acid/pharmacology , Linoleoyl-CoA Desaturase/metabolism , Sebaceous Glands/enzymology , Acyl Coenzyme A/antagonists & inhibitors , Acyl Coenzyme A/drug effects , Androgens/pharmacology , Cells, Cultured , Enzyme Inhibitors/pharmacology , Humans , Interleukin-6/metabolism , Interleukin-8/metabolism , Linoleoyl-CoA Desaturase/drug effects , Lipid Metabolism/drug effects , Lipogenesis/physiology , RNA, Messenger/metabolism , Sebaceous Glands/cytology , Testosterone/pharmacology
17.
Morfologiia ; 137(2): 66-70, 2010.
Article in Russian | MEDLINE | ID: mdl-20572399

ABSTRACT

This work presents the results of the semi-quantitative evaluation of histochemical phosphatase activity in the sebaceous glands of the Kopetdag pine vole (Microtus socialis paradoxus Ognev et Heptner, 1928). The studies included the conversion of standard histochemical designations of enzymatic activity into digital analogues, allowing to evaluate the level of enzymatic activity and sexual dimorphism. In male voles, the index of the acid phosphatase enzymatic activity was 16% higher in summer than in winter. This index in female voles was less in winter than in summer by 28%. The index of the alkaline phosphatase enzymatic activity in male voles in summer higher than in winter by 4%. Female voles had the same seasonal differences. Male voles had higher July adenosine triphosphatase activity indexes in comparison with December indexes, but in females this situation was the opposite--summer values of activity were 16% less than winter values. Sexual dimorphism of acid phosphatase activity was greater in summer than in winter. Index of sexual dimorphism of alkaline phosphatase activity was twice less in summer than in winter, but their actual values were small. Maximum sexual dimorphism was observed in adenosine triphosphatase activity of during summer period, and it was greatly reduced in winter (from 27.0 to 4.0%).


Subject(s)
Arvicolinae/metabolism , Sebaceous Glands/enzymology , Acid Phosphatase/metabolism , Adenosine Triphosphatases/metabolism , Alkaline Phosphatase/metabolism , Animals , Female , Male , Seasons , Sex Characteristics
18.
J Dermatol ; 37(2): 156-62, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20175850

ABSTRACT

Acne is a very widespread cosmesis problem. Isotretinoin, a synthetic oral retinoid is used to treat acne, which is androgen dependent. Numerous side-effects occur from this treatment. 5-alpha-Reductase plays a critical role in normal and pathological androgen-dependent processes. We have taken the approach to develop a selective, effective, topically-applied 5-alpha-reductase inhibitor to modify unwanted or pathological processes in the pilosebaceous unit such as acne. Toward this goal, we have previously developed a selective liposome hair follicle targeting system. We demonstrate in this report that the 5-alpha-reductase inhibitor N,N-diethyl-4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide (4-MA) incorporated into liposomes induces apoptosis and inhibits growth of the dihydrotestosterone (DHT)-dependent hamster flank organ sebaceous gland. We have compared topical application of liposome 4-MA and solvent-formulated 4-MA and observed selective efficacy of topical application of liposome 4-MA by the reduction of size and induction of apoptosis only in the treated hamster flank organ. Apoptosis induced by liposome 4-MA in the treated flank organ sebaceous gland cells was observed both by assays for DNA fragments (transferase deoxytidyl uridine end labeling) and by observation of condensed and fragmented nuclei. When 4-MA was topically applied formulated in ethanol and glycerol without liposomes, the selective efficacy was lost. Liposome 4-MA did not significantly affect prostate weight, testosterone/DHT ratios or bodyweight gain compared to controls indicating safety as well as efficacy of topical application of liposome 4-MA for pathological processes such as acne.


Subject(s)
Acne Vulgaris/drug therapy , Apoptosis , Azasteroids/therapeutic use , Cholestenone 5 alpha-Reductase/antagonists & inhibitors , Dihydrotestosterone/analogs & derivatives , Sebaceous Glands/drug effects , Acne Vulgaris/enzymology , Administration, Topical , Animals , Azasteroids/administration & dosage , Cricetinae , Dihydrotestosterone/administration & dosage , Dihydrotestosterone/therapeutic use , Liposomes , Male , Prostate/drug effects , Sebaceous Glands/enzymology
19.
J Cutan Pathol ; 37(4): 446-51, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19638170

ABSTRACT

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR), also known as P504S, is a protein that plays an important role in mitochondrial and peroxisomal beta-oxidation of branched-chain fatty acid and bile acid intermediates. AMACR has been established as a valuable diagnostic marker for prostate cancer and has recently been shown to be useful in the diagnosis of colorectal carcinoma. Despite the importance of lipid metabolism in sebum production by sebaceous glands of the skin, there are no studies evaluating the expression of AMACR in sebaceous neoplasms. METHODS: Five samples of normal sebaceous glands as well as five cases each of sebaceous hyperplasia (SH), sebaceous adenoma (SA), basal cell carcinoma (BCC) with sebaceous differentiation and extraocular sebaceous carcinoma (SC) were evaluated for immunohistochemical (IHC) expression of AMACR. Each case was reviewed by a single dermatopathologist and graded using a semi-objective grading schema. RESULTS: Normal sebaceous glands showed strong (4+) expression of AMACR. Among sebaceous neoplasms, SH showed the highest expression (4+), SA and BCC with sebaceous differentiation showed varied expression (2+ and 1+, respectively), and extraocular SC showed no expression of AMACR. CONCLUSIONS: The expression of AMACR is increased in benign sebaceous glands and SH; with decreasing AMACR expression in tumors with less sebaceous differentiation (i.e. SA and SC). These findings provide insight into the potential pathogenesis of sebaceous neoplasms while assisting in the microscopic distinction of SA from SC.


Subject(s)
Adenoma/enzymology , Carcinoma/enzymology , Racemases and Epimerases/metabolism , Sebaceous Gland Neoplasms/enzymology , Sebaceous Glands/enzymology , Adenoma/pathology , Carcinoma/pathology , Humans , Hyperplasia/enzymology , Hyperplasia/pathology , Immunohistochemistry , Patient Selection , Sebaceous Gland Neoplasms/pathology , Sebaceous Glands/pathology
20.
Am J Dermatopathol ; 31(5): 427-31, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19542914

ABSTRACT

Recently, the antioxidant repair enzymes methionine-S-sulfoxide reductase A (MSRA) and methionine-R-sulfoxide reductase B (MSRB) were described in human epidermal keratinocytes and melanocytes. Methionine sulfoxide reductases (MSRs) are thought to protect against reactive oxygen species-induced oxidative damage in many organs, including the most environmentally exposed organ, human skin. We sought to examine the expression and distribution of this enzyme family (MSRA, MSRB1, MSRB2, and MSRB3) within the various compartments of healthy and diseased human skin. Expression was assessed using polyclonal MSR antibodies and immunohistochemical staining of human skin biopsies from various anatomical sites. Remarkably, MSRA expression was not only found in the epidermis as previously described but also in hair follicles and eccrine glands and was most pronounced in sebaceous glands. Furthermore, MSRB2 expression was found in melanocytes while MSRB1 and MSRB3 were both expressed within vascular endothelial cells. In conclusion, MSR enzymes are differentially expressed in human skin. Thus, modulation of MSR repair antioxidants may have implications for cutaneous aging and carcinogenesis.


Subject(s)
Gene Expression , Oxidoreductases/biosynthesis , Skin/enzymology , Eccrine Glands/enzymology , Endothelium, Vascular/enzymology , Hair Follicle/enzymology , Humans , Immunohistochemistry , Keratinocytes/enzymology , Melanocytes/enzymology , Methionine Sulfoxide Reductases , Sebaceous Glands/enzymology , Skin/blood supply , Skin Diseases/enzymology
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