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PubMed1988

How the study of the biological activities of antiandrogens can be oriented towards the clinic.

Antiandrogens can be used in various androgen-dependent diseases. Depending upon the therapeutic indication, they can be administered systemically or topically. Systemic treatment with an antiandrogen will inhibit androgen action not only in the desired target site but also in all other target tissues; thus, it will block the androgen-dependent feedback regulating the secretion (hypothalamo-pituitary-testis axis) or the action (protein factors) of androgens. In contrast, topical treatment (acting through cutaneous receptors or local metabolism) should not produce systemic side effects especially in man. Pharmacological assays which can select antiandrogens irrespective of the mechanism measure changes in the final androgenic response, but they consume a great deal of time and test compound and bear little relation to therapeutic activity. Therefore, the biological strategy that we report here and which, at Roussel-Uclaf, has led to the selection of a systemic and a topical antiandrogen (RU 23908 and RU 38882) has consisted in successively performing: (1) in vitro assays which measure an effect at a specific level in the mechanism of antiandrogen action, e.g. interaction with the androgen receptor. Assessing interactions with other classes of steroid hormone receptor can be used to predict possible hormonal side-effects, (2) in vitro determinations of agonist or antagonist activity, e.g. in pituitary cells (LH response to LHRH) or mammary tumor cells (induction of androgen-dependent proteins), (3) in vivo antiandrogen assays after a single treatment (induction of mouse kidney proteins, rat prostatic binding protein) or after repeated treatment (inhibition of the growth of rat accessory glands or of hamster sebaceous glands), to determine the active dose of the compound and possibly the absence of systemic effects by the topical route, (4) assays in animal models designed to mimic a therapeutic context e.g. for prostate cancer: inhibition of the "flare-up" effect of LHRH-A or of the trophic effect of perfused adrenal androgens on rat prostate, antitumoral activity in experimental cancer models. For hyperseborrhoea and acne: histological and stereological analysis of rat skin biopsies to measure the volume density of the smooth endoplasmic reticulum vesicles of the differentiating cells of the sebaceous gland.

Androgen Antagonists↗

PubMed1992

Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-alpha. Characterization of mammary gland and skin proliferations.

Eight lines of transgenic mice expressing a mouse mammary tumor virus (MMTV) human transforming growth factor-alpha (TGF alpha) fusion gene were established. Three lines with distinctive phenotypes are presented. All have proliferative changes of the mammary gland. One line has sebaceous gland hyperplasia of the skin. Five histologic patterns of mammary gland hyperplasia based on two of these lines were identified: cystic hyperplasia, solid hyperplasia, dysplasia, adenoma, and adenocarcinoma. Human TGF alpha mRNA and protein were produced in all patterns but appeared reduced in solid hyperplasia, dysplasia, and adenocarcinoma. TGF alpha immunoreactivity in the mammary tissue, cystic fluid, and serum did not show significant differences; hyperplasia developed in 65% of multiparous mice and 45% of virgin mice by 12 months of age. Adenocarcinoma developed in 40% of multiparous mice and 30% of virgin mice by 16 months of age. These transgenic lines may provide useful models of mammary and sebaceous gland hyperplasia analogous to human disease.

Animals↗

PubMed1988

Effect of isotretinoin on serum levels of precursor and peripherally derived androgens in patients with acne.

Sebaceous glands are stimulated by androgens and can convert them to more active forms. Isotretinoin, however, has a profound inhibitory effect on sebaceous gland size and function. This study evaluated the effect of isotretinoin on serum levels of precursor and tissue-derived androgens. Twenty-four subjects (15 men and nine women) were treated for 20 weeks with 1 mg/kg/d of isotretinoin. Serum samples were obtained at baseline, 8, 16, and 24 weeks, and assayed for precursor androgens--total testosterone (TT), free testosterone (free T), dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S); and tissue androgens--dihydrotestosterone (DHT), and its metabolite, 3 alpha-androstanediol glucuronide (3 alpha-diol G). Isotretinoin had no meaningful effects on precursor androgens, except for producing an elevation of free T in women. In contrast, isotretinoin produced depressions in the serum levels of DHT and 3 alpha-diol G in women and in 3 alpha-diol G in men. These decreases are believed to be the result, rather than the cause, of a reduction in the size of the sebaceous glands: The magnitude of the observed decreases may represent the amount of tissue-derived androgens that sebaceous glands normally contribute to the circulating pool.

Acne Vulgaris↗

PubMed1988

Acute radiation injury of ocular adnexa.

Eyelids and lacrimal glands of monkeys examined histologically 24 and 48 hours after receiving 2.5 to 20.0 Gy (250 to 2000 rad) of cobalt 60 radiation contained acute inflammation. Cells of meibomian glands, other sebaceous glands, sweat glands, and goblet cells displayed no significant alterations. Acinar cells of major and accessory lacrimal glands and, to a lesser degree, lacrimal duct epithelium showed degeneration and necrosis that were increased in extent in proportion to the radiation dose. Reduced numbers of serous acini and decreased size of remaining acini indicate that atrophy of lacrimal glands can be recognized within two days after irradiation. The morphologic diagnosis for irradiated lacrimal glands was acute, necrotizing dacryoadenitis.

Acute Disease↗

PubMed2002

Immunohistochemical localization of acyl-CoA hydrolase/thioesterase multigene family members to rat epithelia.

Acyl-CoA hydrolases cleave acyl-CoA thioesters to free fatty acids and coenzyme A. The potency of these enzymes may serve to modulate cellular levels of acyl-CoAs to affect various cellular functions, including lipid metabolism. In this study, we investigated the tissue distribution of this multigene family of enzymes, focusing on cytosolic (CTE-I) and mitochondrial acyl-CoA thioesterases (MTE-I) in adult rats, using an anti-CTE-I antibody which recognizes both the isoforms. Western blotting detected them mainly in organs closely related to fatty acid oxidation, of which kidney contained the highest levels of both enzymes. Immunohistochemistry localized the enzymes primarily in the proximal tubules, where a large energy demand is expected and fatty acids represent a major fuel, correlating well with the intrarenal distribution of peroxisomal beta-oxidation. In situ hybridization suggested colocalization of CTE-I and MTE-I in the kidney. The immunoreactivity was also found in various epithelial tissues in the body, including Harderian gland and sebaceous gland. These results demonstrated the distribution of CTE-I and MTE-I in a wide variety of rat tissues, primarily characterized by an epithelial localization, being consistent with their involvement in fatty acid metabolism.

Adipose Tissue, Brown↗

PubMed1995

Immunohistochemical studies on postmortem lividity.

An immunohistochemical investigation of postmortem lividity was performed to illuminate localization of hemoglobin (Hb) and the mechanism of fixed lividity. The fixed lividity was defined as an unfading phenomenon by thumb finger pressure. Skin specimens were taken from 68 autopsy cases 7.5-336 h (2 weeks) postmortem. Localization of Hb of the specimens was examined by a labeled streptabidin biotin (LSAB) method using polyclonal (rabbit antihuman hemoglobin antibody) and monoclonal (mouse anti-human hemoglobin monoclonal antibody) antibodies. Positive staining for Hb was observed in various sites of the skin, i.e. in only intravascular erythrocytes, in vascular walls and perivascular tissue including sweat glands and sebaceous glands, in the dermal connective tissue, and in almost all of skin tissue except the horny layer. The diffusion of Hb into skin tissue was observed in 20 of 41 displaceable lividity cases (49%) and 11 of 27 fixed lividity cases (41%). Compared to displaceable lividity, superficial plexi in fixed lividity were filled with erythrocytes, which were markedly immunodetected. These findings support the hypothesis that the fixation of lividity is not due to diffusion of Hb into skin tissue but hemoconcentration in blood vessels.

Hemoglobins↗

PubMed1985

Spatial patterns produced by a reaction-diffusion system in primary hair follicles.

This paper is the third in a series examining the role of a reaction-diffusion (RD) system as the principal mechanism providing spatial information for cell differentiation during hair follicle initiation and development and hair fibre formation. A theoretical mechanism is described by which the RD system supplies positional information during hair follicle development. Solutions of the RD system within the primordial follicle are described as well as the sequence of spatial patterns provides the follicle/epidermis boundary conditions required to account for the density and grouping of follicles during initiation. At the same time the spatial patterns are also shown to be capable of providing the positional information which determines various geometrical aspects of follicle development; in particular the development of follicles at an angle to the skin surface and the initiation and location of sweat glands and sebaceous glands on the follicle.

Animals↗

PubMed1996

Localization of monocyte chemotactic and activating factor (MCAF/MCP-1) in psoriasis.

The monocyte chemotactic protein-1 (MCAF) also termed MCP-1, a strong chemotactic factor towards monocytes, is produced by several cell types present in the skin. The in situ presence of MCAF/MCP-1 protein in the skin has, however, not yet been established. Using immunohistochemical techniques we have investigated the distribution of MCAF in skin from patients with different types of psoriasis and normal healthy volunteers. We report the novel finding that psoriasis has strong positive immunostaining for MCAF located to all the layers of the epidermis, except the stratum granulosum, in pustular, guttate and chronic plaque psoriasis. In the dermis, infiltrating cells in the perivascular aggregates and the blood vessels stained positive for MCAF. No significant differences were observed between the different subtypes of psoriasis except that strongly positive infiltrating cells were observed in the epidermal pustules in pustular psoriasis. In normals positive staining was observed in all the layers of the epidermis and in a few perivascular cells and blood vessels in the dermis. Where present in normal and diseased skin, eccrine ducts of sweat glands and sebaceous glands stained positive for MCAF. Arrector pili muscles were in all cases negative. These findings are consistent with a role for MCAF in attracting inflammatory cells, including monocytes, into the skin in psoriasis.

Chemokine CCL2↗

PubMed2003

Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages.

Tissue kallikreins are a group of serine proteases that are found in many organs and biologic fluids. Tissue kallikrein genes (KLKs) are found on chromosome 19q13.3-4 as a gene cluster encoding 15 different serine proteases. In skin, two tissue kallikrein proteins, hK5 and hK7, are expressed in the stratum corneum and are known to be involved in desquamation of corneocytes. The possible involvement of other kallikrein proteins has not been clarified, however, nor has the significance of each member in the serine protease activity of skin been delineated. In the study described here, we examined expression and localization of KLK mRNA in normal human skin by means of RT-PCR and in situ hybridization. Quantitative RT-PCR analysis showed abundant expression of KLK1 and KLK11 mRNA, moderate expression of KLK4, KLK5, KLK6, KLK7, and KLK13 mRNA, and low expression of KLK8 mRNA in normal human skin. For KLK4, KLK8, and KLK13 mRNA, splice variants were identified to be their major mRNA species. Two variants for KLK13 mRNA were novel. The amount of the serine protease inhibitor Kazal-type 5 (SPINK5) mRNA was comparable to KLK1 and KLK11 mRNA. In situ hybridization revealed intense expression of all KLK mRNA studied except KLK12 mRNA in the stratum granulosum of normal epidermis, where SPINK5 mRNA coexisted. Excluding KLK13 mRNA, they are also expressed in hair sheath, eccrine sweat glands, and sebaceous glands. Coexpression of various KLK and SPINK5 mRNA suggests that their proteins are the candidates to balance and maintain serine protease activities in both the skin and appendages.

Alternative Splicing↗

PubMed1998

A large number of tandem repeats in the polymorphic epithelial mucin gene is associated with severe acne.

Polymorphic epithelial mucin (PEM) or MUC1 is a glycoprotein secreted from various epithelial gland tissues. In skin, PEM is detected in sweat glands and sebaceous glands by the DF3 monoclonal antibody. The gene of PEM includes an allele exhibiting length polymorphism due to a variable number of tandem repeats (VNTR); this is expressed co-dominantly, which may influence the microenvironment of the skin. The allelic size variation of the PEM gene was investigated in Japanese acne patients, atopic dermatitis patients, and healthy controls. The frequency of longer length alleles was significantly higher in severe acne patients.

Acne Vulgaris↗

PubMed1995

Immunohistochemical evidence for differential distribution of 5 alpha-reductase isoenzymes in human skin.

Antibodies raised against fragments of synthetic peptides of human 5 alpha-reductase isoenzymes 1 (h5 alpha r1) and 2 (h5 alpha r2) were applied to paraffin sections of human skin (scalp, eyelid, lip, breast, scrotum). Immunoreactive sites were differentially distributed, in that h5 alpha r1 immunoreactivity was present in the nuclei of cells in the stratum germinativum (basal and lower portion of the spinous layer) of the epidermis, subepithelial fibroblasts, adipocytes, smooth muscle cells of the scrotal tunica dartos, basal cells of sebaceous glands, excretory duct cells of sweat glands, cells of the dermal papilla and fibrous and outer epithelial sheath of hair roots, as well as endothelial cells of small vessels and Schwann cells of cutaneous myelinated nerves. In contrast, immunoreactivity for h5 alpha r2 was found in the cytoplasm of the cells of the spinous layer (and far less intensely in the basal layer) of the epidermis, subepidermal fibrocytes, and especially in subcutaneous adipocytes. Immunoreactivity was strongest in the non-keratinized portion of the inner epithelial sheath and the cuticle of hair follicles, whereas other portions of the hair root were negative. Sweat glands were stained, whereas sebaceous glands showed only weak diffuse immunoreactivity. In mucocutaneous zones, salivary glands and conjunctival epithelium showed immunoreactive cells. Vascular endothelium displayed immunoreactivity only in the genital region. We present experimental evidence for a differential distribution of 5 alpha-reductase isoenzymes in human skin. This might reflect a diversity in the response of different areas of the skin to androgenic challenge.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2004

Localization of tumour necrosis factor-alpha converting enzyme in normal human skin.

The tumour necrosis factor (TNF)-alpha converting enzyme (TACE) is a metalloproteinase-disintegrin that releases soluble TNF-alpha from cells by cleaving within the extracellular domain of membrane-bound pro-TNF-alpha. TACE knockout mice display a range of epithelial abnormalities. However, the localization of TACE in normal human skin is unclear. In this study, we examined the expression of TACE in normal skin by immunohistochemical analysis. The expression of TACE was seen throughout all layers of the epidermis, the hair follicles, eccrine ducts and glands, and sebaceous glands. There was also staining of blood vessels in the dermis. In particular, TACE was localized predominantly in mast cells, suggesting that these cells are an important source of TNF-alpha.

ADAM Proteins↗

PubMed2004

Immunohistochemical study of serotonin in lesions of psoriasis.

OBJECTIVE: To study the role of serotonin in the pathogenesis of psoriasis. METHODS: Immunohistochemical techniques were used to study the expression of serotonin in the lesions of patients with psoriasis. RESULTS: Expression of serotonin was significantly stronger in the prickle cells, sweat gland cells, sebaceous gland cells, and hair roots of the lesions in the progressive stage of psoriasis than in the static stage. There was no difference in serotonin expression between the vulgaris type and the pustular type. No expression of serotonin occurred in the specimens of normal skin. CONCLUSION: Serotonin probably plays an important role in the pathogenesis and activity of psoriasis.

Adolescent↗

PubMed2004

Immunohistochemical study of serotonin in lesions of chronic eczema.

BACKGROUND: Inflammatory mediators participate in the pathogenesis and pathophysiology of skin disease (e.g. eczema). Although some investigators have suggested that serotonin may participate in the eczematous process, there has been little substantial evidence. Our objective was to study further the participation of serotonin in the pathogenesis of chronic eczema. METHODS: Immunohistochemical techniques were used to study the expression of serotonin in the lesions of patients with chronic eczema. RESULTS: There was a significantly stronger expression of serotonin in the prickle cells, sweat gland cells, sebaceous gland cells, and hair roots of the lesions in patients with chronic eczema. There was no positive expression of serotonin in normal skin. CONCLUSIONS: Serotonin is probably important in the pathogenesis of chronic eczema. We demonstrated alterations in the expression of serotonin in chronic eczema lesions, which may in turn provide new insight into the pathogenesis of chronic eczema. Serotonin, along with cytokines, T lymphocytes, B lymphocytes, and macrophages, participates in the immune response and influences the inflammatory process by means of keratinocytes.

Adolescent↗

PubMed1983

Ocular, naso-maxillary, and neural anomalies in raccoons, Procyon lotor (L.).

Congenital ocular and related anomalies were studied in two unrelated young raccoons. One animal was anophthalmic and had severe anomalies of the central nervous system, consisting of meningoencephalocele, pachygyria, hydranencephaly, cerebellar cavitation, syringomyelia, and other defects. A second animal was microphthalmic with congenital defects of the nose, maxilla and teeth. Ocular lesions were severe and included chorioretinal coloboma, retinal folds, disorganized neuroectodermal cell layers, spherophakia, cataract and other defects. The nose had unilateral abnormal epithelium, hair follicles, sweat glands and sebaceous glands, and a lack of parietal cartilage on the affected side.

Abnormalities, Multiple↗

PubMed2006

Pseudomamma on the foot: an unusual presentation of supernumerary breast tissue.

A 22-year-old woman sought medical care for a lesion in the plantar region of her left foot, a well-formed nipple surrounded by areola and hair. Microscopic examination of the dermis showed hair follicles, eccrine glands, and sebaceous glands. Fat tissue was noted at the base of the lesion. Clinical and histopathologic findings were consistent with the diagnosis of supernumerary breast tissue, also known as pseudomamma. To our knowledge, this is the first report of supernumerary breast tissue on the foot.

Adult↗

PubMed1990

Immunohistochemical study of a monoclonal antibody 115D8 against human milk-fat globule membrane (MAM-6) in some histological types of breast cancer.

An antigen, MAM-6, in human milk-fat globule membranes, was detected with a monoclonal antibody 115D8, in paraffin-embedded sections of 148 cases including human breast cancers and other breast diseases with immunoperoxidase technique. There were some differences on the staining portion in the cells among the different types of breast cancers, although we could not find any differences in intensity of reaction with 115D8 among the different histochemical types of breast cancers. MAM-6 was mainly localized in the apical portion of the cells or the cytoplasms of the papillo-tubular carcinoma. The antigen was chiefly localized in the margin of the cells or cytoplasms of the solid- tubular carcinoma and scirrhous carcinoma. Normal mammary glands, sweat glands and sebaceous glands were reacted with 115D8 but epidermis, esophagus, stomach, small intestines, large intestines, pancreas, liver, lung, kidney, urinary bladder, thyroid, adrenal glands, heart, striated and smooth muscles, spleen, lymphnodes and brain were not reacted with 115D8 in this study. Although the antibody was not sufficient for differential diagnosis among the types of breast cancer, it may be useful to detect the breast cancer.

Antibodies, Monoclonal↗

PubMed1990

[Evaluation criteria for chemotherapeutics for malignant skin carcinomas].

Malignant skin carcinomas occur in a large variety of forms, among them malignant melanoma with a poor prognosis, such as squamous cell carcinoma, basal cell carcinoma, appendix tumors of skin (e.g., sweat gland carcinoma, sebaceous gland carcinoma), metastatic carcinomas of skin, intraepidermal carcinomas (e.g., Bowen's disease, Paget's disease) and mesenchymal carcinomas including mycosis fungoides (cutaneous T cell lymphoma). Furthermore, not only do they present with varied clinical symptoms, some forming tumors or erythemas, some being infiltrative in nature and some being flat in shape, but the clinical symptoms also vary with time during treatment. All these conditions conspire to make the evaluation of chemotherapeutics complicated and difficult. In the field of dermatology topical drugs provide a no less powerful weapon than drugs for systemic administration with which to combat skin carcinomas and are simple and easy to administer. In consideration of those clinical and therapeutic aspects of malignant skin carcinomas new evaluation criteria for chemotherapeutics for topical and systemic administration have been established by adding three-way measurement to the conventional methods of one- and two-way measurement for measurable lesions along with the evaluation of the response of clinical symptoms to chemotherapeutics in unmeasurable carcinomas. The new version of criteria is based in its general framework on the Japan Society for Cancer Therapy's Evaluation Criteria for Chemotherapeutics for Solid Carcinomas by Koyama and Saito and the new version has been approved at the 26th general meeting of the Japan Society for Cancer Therapy (1988, Niigata).

Administration, Cutaneous↗