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[Modifying effects of beraprost sodium (TRK-100) on N-methyl-N-nitrosourea (MNU) carcinogenesis in F344 rats].

The potential tumor-promoting effects of beraprost sodium (TRK-100), stable analogue of prostacyclin (PGI2), were investigated in rats pretreated with N-methyl-N-nitrosourea (MNU) which is a potent initiator of tumor development in a variety of organ or tissues. Male F344 rats were initially given injections of MNU (20 mg/kg b.w. i.p.) twice a week for 3 weeks, and then administered drinking water containing 6, 2, 0.7 or 0.2 ppm of beraprost sodium for the next 29 weeks. For comparison, positive control groups received N-propyl-N-nitrosourea (PNU), which is a carcinogen in hematopoietic system and small intestine on F344 rat, at the dose of 200, 50 and 12.5 ppm in their drinking water. Appropriate non-treated controls were also included. Numerous tumors were observed in many organs including the hematopoietic system, digestive tract, nervous system, Zymbal's gland (auditory sebaceous glands) and peritoneal mesothelium. However, no tumor-enhancing effects of beraprost sodium were observed. In contrast, the groups treated with PNU demonstrated increased development of tumors in the tongue, forestomach, large intestine and Zymbal's gland. These results thus indicate that beraprost sodium is not capable of modulating the development of MNU-induced tumors.

Animals↗

Postauricular sebaceous carcinoma arising in association with nevus sebaceus.

BACKGROUND: Sebaceous carcinoma is an uncommon malignant neoplasm usually associated with the ocular adnexa. Despite the widespread anatomic distribution of sebaceous glands, extraocular sebaceous carcinoma occurs with far less frequency. METHODS: A 27-year-old man was examined with the presenting complaint of a slowly enlarging subcutaneous mass. It was associated with an overlying, irregular, verrucoid epidermal plaque. RESULTS: Histologic and electron microscopic examination of the mass revealed a malignant sebaceous neoplasm occurring in conjunction with an overlying nevus sebaceus. The dermal neoplasm contained numerous cytoplasmic and stromal hyaline globules. CONCLUSIONS: We report a case of extraocular sebaceous carcinoma arising in the postauricular region in association with a nevus sebaceus and exhibiting the unusual histologic feature of hyaline globules.

Adult↗

NAD(P)H nitroblue tetrazolium reductase levels in apparently normoxic tissues: a histochemical study correlating enzyme activity with binding of radiolabelled misonidazole.

Hack and Helmy's method for the histochemical identification of NAD(P)H nitroblue tetrazolium reductase activity was employed to pinpoint reductase activity in certain cells in the mouse. High activity was observed in the following: lower airway epithelium, liver (centrilobular zone), eyelid (meibomian and sebaceous glands), vulval gland and parotid gland (striated cells of intralobular ducts). All of these cells had previously been identified as sites of binding of the reactive metabolites formed from the enzymic reduction of misonidazole (MISO) (Cobb et al., 1989). It had previously been thought that MISO binding would only take place in significant amounts in hypoxic tissues (tumour and possibly liver) since in normoxic tissues oxygen should reverse the initial one electron enzymic reduction, thus preventing progressive reduction to reactive species. We suggest that the very high levels of reductase in the above listed, probably normoxic, tissues contribute significantly to the accumulation of bound reactive MISO metabolite(s).

Animals↗

Cyclic AMP-receptor protein activity in rat preputial cells.

Cells from the rat preputial gland--a type of sebaceous gland--exhibited specific responsiveness of cyclic 3',5'-adenosine monophosphate (AMP) dependent protein kinase to stimulation by agents that elevate intracellular cyclic AMP. Electron microscopy shows that the rat preputial gland resembles the human sebaceous gland, not only in terms of containing a sebocyte-like population of cells in an acinar arrangement at different maturational stages, but also in the morphology of its organelles such as abundant and sometimes atypical mitochondria, many perinuclear lysosomes with crystalline inclusions, lipid droplets of various sizes, and peroxisomes. Other cell types, among them duct and inflammatory cells, were evident in the tissue sections, but constituted a minor component. Responses to stimulation of the adenylate cyclase-protein kinase pathways were determined using preputial cells that had been both freshly dispersed and grown in monolayer culture. Stimulation with isoproterenol (IPR) or forskolin (FS) resulted in both cases in an increase of cyclic AMP binding of the regulatory (R) subunits of cyclic AMP-dependent protein kinase, as determined by photoaffinity labeling of R subunits with an azido analog of cyclic AMP ([32P]-8-azido cyclic AMP). Cells from the epidermis under comparable conditions responded to a lesser degree and with a different distribution of R subunit isoforms. There are, therefore, differences in receptor activity as well as in the transduction pathways between the two types of epithelial cell populations. These results indicate that the preputial gland contains precursor cells that differentiate in culture to retain specific molecular mechanisms of action mediated via cyclic AMP.

Animals↗

New aspects in acne inflammation.

There is ample clinical evidence suggesting that the nervous system such as emotional stress can influence the course of acne. We examined possible participation of cutaneous neurogenic factors including neuropeptides, neuropeptide-degrading enzymes and neurotrophic factors, in association with inflammation in the pathogenesis of acne. Immunohistochemical studies revealed that substance P (SP)-immunoreactive nerve fibers were in close apposition to the sebaceous glands, and that neutral endopeptidase (NEP) was expressed in the germinative cells of the sebaceous glands in the skin from acne patients. Nerve growth factor showed immunoreactivity only within the germinative cells. In addition, an increase in the number of mast cells and a strong expression of endothelial leukocyte adhesion molecule-1 on the postcapillary venules were observed in adjacent areas to the sebaceous glands. In vitro, the levels and the expression of stem cell factor by fibroblasts were upregulated by SP. When organ-cultured normal skin specimens were exposed to SP, we observed significant increases in the sizes of the sebaceous glands and in the number of sebum vacuoles in sebaceous cells. Furthermore, supplementation of SP to organ-cultured skin induced expression of NEP, and we demonstrated the subcellular localization of NEP in the endoplasmic reticulum and the Golgi apparatus within the sebaceous germinative cells using preembedding immunoelectron microscopy. These findings suggest that SP may stimulate lipogenesis of the sebaceous glands which may be followed by proliferation of Propionibacterium acnes, and may yield a potent influence on the sebaceous glands by provocation of inflammatory reactions via mast cells. Thus, cutaneous neurogenic factors should contribute to onset and/or exacerbation of acne inflammation.

Acne Vulgaris↗

Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne.

BACKGROUND: Hirsutism is the presence of excessive hair growth in women and is an important cosmetic condition often resulting in severe distress. Hirsutism is most often caused by increased production of male sex hormones also known as androgens. It is also affected by increased sensitivity to androgens in the hair follicles, and the secretory glands around the hair follicles, called sebaceous glands. Spironolactone is an antiandrogen and aldosterone antagonist used to treat hirsutism. Since 1978, many studies have been conducted to determine its effectiveness. OBJECTIVES: The objective of this review was to investigate the effectiveness of spironolactone and/or in combination with steroids (oral contraceptive pill included) in reducing excess hair growth and/or acne in women. SEARCH STRATEGY: All publications of randomised controlled trials of spironolactone versus placebo and/or in combination with steroids (oral contraceptive pill included) were identified. Search strategy was developed by the Menstrual Disorder Group. All accessable electronic databases were searched. In addition, all reference lists of relevant trials were searched and drug companies contacted for details of unpublished trials. SELECTION CRITERIA: All randomised controlled comparisons of spironolactone versus: placebo steroids (oral contraceptive pill included)) spironolactone of varying dosages or spironolactone and steroids versus steroids alone when used to reduce hair growth and acne in women. DATA COLLECTION AND ANALYSIS: Four trials were included in the review, seven trials were excluded. Two other trials are awaiting assessment. All included trials were small (no more than 31 participants) randomised and controlled. Only one trial studied acne as an outcome, the remaining three were concerned with hirsutism. One trial investigated spironolactone versus placebo; one trial was a dosage studies of spironolactone; one trial compared spironolactone with spironolactone in combination with dexamethasone; the remaining trial used topical spironolactone for the treatment of acne. Major outcome measures include the following: - subjective observations - Ferriman and Gallwey hair scores - hormonal and biochemical parameters - side effects - sebum production measurement MAIN RESULTS: All sample populations were small and confidence intervals were wide. There was no significant difference between treatments for any of the observed outcomes. REVIEWER'S CONCLUSIONS: The effectiveness of treatment for either acne vulgaris or hirsutism cannot be determined due to the small sample populations involved in the trials. Its value in clinical practice is difficult to assess from currently available research.

Acne Vulgaris↗

Simultaneous occurrence of idiopathic lipemic tears and massive seborrhea.

A 42-year-old man had idiopathic lipemic tears and massive seborrhea. Recent investigations have shown that cholesterol and other lipids occasionally found in tears are produced by meibomian rather than lacrimal glands. The finding in this patient of hypersecretion by both sebaceous glands and meibomian glands, a sebaceous gland variant, suggests that a common mechanism may regulate secretory control of both of these glands.

Adult↗

c-Myc and epidermal stem cell fate determination.

The epidermis is sustained by a multipotent stem cell population that gives rise to cells of different fates including those forming hair follicles, interfollicular epidermis and associated glands such as sebaceous glands. The most intriguing evidence comes from using a variety of mouse models with which studies have found the WNT pathway to be involved in regulating stem cell fate decisions. These mouse models have been used to analyze different members of the WNT pathway in the epidermis and altogether suggest that different levels of beta-catenin correlate with the adoption of different epidermal stem cell fates. Recent data specifically analyzing c-Myc, a downstream target of the WNT pathway, has found that c-Myc can divert epidermal stem cells to a sebaceous gland fate at the expense of hair follicles. Also, newly emerging data using gene expression profiling techniques have uncovered a more direct role of c-Myc in stem cell fate determination.

Animals↗

Hyperplasia and tumours in lung, breast and other tissues in mice carrying a RAR beta 4-like transgene.

Transgenic mice were generated which express a truncated nuclear retinoic acid receptor beta (RAR beta), closely resembling the natural isoform RAR beta 4, under the control of the MMTV promoter. The transgene was expressed in salivary gland, testis, lung and mammary tissue in two different lines. At approximately 11-14 months virtually all the transgenic mice showed hyperplasia of the lung alveolar epithelium with an excess of type II pneumocytes. Hyperplasia of the mammary alveoli and terminal ducts was also seen in some females. Salivary glands and some sebaceous glands were hyperplastic in most male transgenic mice, but only rarely in females or in non-transgenics. Primary benign and malignant tumours were more numerous in transgenic mice than in controls, with a total of 23 in 43 mice versus two in 33 non-transgenic animals. Treatment with dexamethasone to increase transgene expression resulted in exaggerated versions of the above phenotypes. Overexpression of RAR beta 4 therefore appears to predispose various tissues to hyperplasia and neoplasia, and this by contrast to the RAR beta 2 isoform, which has tumour suppressor activity. A survey of ratios of RAR beta 4:RAR beta 2 expression in human lung tumour cell lines showed an increase compared with normal lung tissue, suggesting that RAR beta 4 may play a similar role in human tumorigenesis.

Animals↗

Hair follicle response of the golden Syrian hamster flank organ to continuous testosterone stimulation using silastic capsules.

The hamster flank organ has served as a model to study androgen-dependent responses of the skin, but the quantitative response of hair follicles to androgenic stimulation has been neglected. We assayed the hair follicle response to testosterone (T) and compared it to the response of the sebaceous glands and of the dermal pigment in the Golden Syrian hamster flank organ. Because of biologic variation in male animals and uneven absorption of hormone from parenteral injections, we implanted silastic capsules 0.25, 0.5, 1, and 2 cm in length filled with crystalline T subcutaneously into female hamsters for 6 weeks. Hair follicle response to T was more sensitive than sebaceous gland or pigment. Diameters of hairs under the sebaceous gland increased significantly from control values of 27.7 +/- 1.0 micron to 38.0 +/- 1.6 micron at the lowest dose of T tested, the 0.25-cm capsule (p less than 0.001). There was an increase in the absolute number of hairs under the sebaceous gland as the flank organ enlarged, from 27.9 +/- 9.9 control to 55.3 +/- 5.8 with the 2-cm T capsule. There was no concomitant increase in hair density, 14.4 +/- 3.5 hairs/mm control vs 12.5 +/- 1.1 hairs/mm with the 2-cm capsule. Hair follicles lateral to the sebaceous gland did not show the same response to androgen stimulation. Sebaceous gland and pigmentation responded in a dose-dependent fashion, the maximum effect being achieved with a 1-cm T capsule. We conclude that T affects hair by specifically stimulating growth of individual hairs physically under the sebaceous gland. As the whole flank organ enlarges more hairs are recruited to become larger but no new follicles appear. These studies also confirm that there are different sensitivities to androgen within the various androgen-dependent components of the hamster flank organ, with increase in hair diameter being highly sensitive. This model should be useful for the specific and quantitative assessment of androgenic and antiandrogenic substances on hair growth and ultimately by useful for therapy of hirsutism.

Animals↗

[Therapeutic aspects of seborrhea oleosa and pityriasis simplex capillitii].

The treatment of seborrhoea oleosa capillitii should aim at inhibiting depletion of the sebaceous glands, lipid synthesis in the sebaceous gland and microbial lipolysis of the triglycerides in the scalp and hair lipids. The use of isopropyl alcohol as a vehicle in a hair tonic reduces sebum depletion. Coal tar and estrogens reduce the lipid synthesis in the sebaceous gland. The lipolysis can be inhibited by various surfactants, isopropyl alcohol, colloidal sulphur, selenium disulphide, Omadine MDS and benzoyl peroxide. In the treatment of pityriasis simplex capillitii (dandruff) one aims at achieving inhibition of mitosis in the epidermis and, if possible, an additional "keratolytic" effect. Inhibition of mitosis could be demonstrated for coal tar, corticosteroids, selenium disulphide, cadmium sulphide, Omadine MDS, Zn Omadine and ichthyol sodium. Colloidal sulphur, salicylic acid, Omadine MDS and various surfactants act "keratolytically".

Adrenal Cortex Hormones↗

Solitary tumors of meibomian gland origin and Torre's syndrome.

We examined ten patients with solitary sebaceous gland tumors of the eyelid for Torre's syndrome (sebaceous gland tumors and visceral malignancy). In all of the benign and hyperplastic sebaceous lesions, an associated visceral malignancy was noted (predominantly colonic). Only one patient with a sebaceous carcinoma had an associated visceral malignancy. Our data suggest that the presence of a solitary sebaceous gland lesion of the eyelid excluding sebaceous carcinoma is clinically significant and should warrant a thorough history and physical examination to exclude a visceral malignancy, primarily of the gastrointestinal tract. The solitary sebaceous lesions excluding sebaceous carcinoma may represent part of the histologic spectrum associated with Torre's syndrome.

Adenocarcinoma↗

The human sebocyte culture model provides new insights into development and management of seborrhoea and acne.

Seborrhoea and acne are exclusively human diseases and sebaceous gland differentiation is species specific. Therefore, fundamental research on human sebaceous cell function and control requires human in vitro models. The human sebocyte culture model, introduced in 1989, has been used in several studies to elucidate sebaceous gland activity and its regulation at the cellular level. Cultured human sebocytes have been shown to preserve important sebocytic characteristics, although they undergo an incomplete terminal differentiation in vitro. In vitro synthesis of free fatty acids without bacterial involvement and marked interleukin 1 alpha expression at the mRNA and protein levels with no further induction by lipopolysaccharides lead to the assumption that human sebocytes may initiate acne lesions by an intrinsic mechanism. Androgens affected sebocyte activity in vitro in a manner dependent on the localization of the sebaceous glands. In vitro stimulation of sebocyte proliferation by androgens could be completely abolished by spironolactone. Cultured sebocytes strongly expressed type 1 5 alpha-reductase and metabolized testosterone to androstenedione, 5 alpha-androstanedione, 5 alpha-dihydrotestosterone, androsterone and 5 alpha-androstanediol, whereas the levels of 5 alpha-reductase activity were probably not feedback regulated. 4,7 beta-Dimethyl-4-aza-5 alpha-cholestan-3-one, a type 1 5 alpha-reductase inhibitor, induced an early, marked down-regulation of 5 alpha-reductase activity in human sebocytes in vitro, while hydrofinasteride, a type 2 inhibitor, required 10(3)-fold higher concentrations to induce similar effects. Stimulation of sebocyte proliferation by insulin, thyroid-stimulating hormone and hydrocortisone indicates that the hormonal control of the sebaceous gland could be a complex mechanism. Retinoids inhibited sebocyte proliferation in a dose-dependent manner and down-regulated lipid synthesis and sebocyte differentiation in vitro. Isotretinoin was the most potent compound. On the other hand, vitamin A was found essential for sebocyte activity and differentiation in vitro and could be partially substituted by synthetic retinoids. The inhibitory effect of isotretinoin on sebocyte proliferation was barely affected by the presence of vitamin A. The low persistent isotretinoin levels or, more likely, the considerably elevated tretinoin concentrations detected in human sebocytes after treatment with isotretinoin in vitro may be responsible for the inhibitory effect of this compound on sebocyte activity.

Acne Vulgaris↗

Activity of testosterone 5 alpha-reductase in various tissues of human skin.

In order to know the distribution of testosterone 5 alpha-reductase activity in human skin, we developed a micro-method, in which we used 20-50 micrograms of various tissues microdissected from freeze-dried sections. The characteristics of this enzyme in the sebaceous gland are briefly described, as follows: the identified 5 alpha-reduced metabolites are 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 beta, 17 beta-diol and 5 alpha-androstanedione; the optimal pH is about 7.5; and the apparent Km is approximately 2.4 x 10(-5) M. The measurement of 5 alpha-reductase activity of various components of the skin obtained from 7 men and 5 women revealed that the sweat gland (probably apocrine) in the axillary skin possessed the highest activity of 5 alpha-reductase: the value was nearly 400 pmoles/mg dry weight/hr in the standardized condition. The sebaceous gland also showed a high activity of 85-261 pmoles/mg/hr. The hair follicles exhibited a significantly lower activity than the sebaceous gland. The enzyme activity was negligible in the epidermis, while it was detected in the dermis though the values determined were variable probably because of contamination with other components such as sweat glands and hair follicles. Thus, the present study demonstrates that the 5 alpha-reductase activity is mainly located in the apocrine sweat gland and sebaceous gland. This suggests that 5 alpha-reduction of testosterone is an important step in mediating the action of androgens in these tissues.

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

13-cis-Retinoic acid in rosacea. Clinical and laboratory findings.

The paper presents clinical and laboratory data on 13-CIS-retinoic acid treatment in rosacea. Good-to-excellent results are reported for severe forms of rosacea. Side effects were tolerable and could easily be controlled. The role of sebaceous gland function was documented by both histological and skin sebum parameters. Diminution of sebaceous gland size and the decrease of skin sebum with alteration of single sebum fractions correspond with findings in acne. According to the findings the alteration of sebaceous gland function is one model of drug action in rosacea. Thus sebaceous gland dysfunction may play an important role in the pathogenesis of rosacea.

Adult↗

Adenocarcinoma of the lacrimal gland with sebaceous differentiation. A clinical study using light and electronmicroscopy.

A case of metastasizing adenocarcinoma of the lacrimal gland with sebaceous differentiation is described, which probably originated in a benign mixed tumour (BMT), with infiltration of the orbital muscles, the bony orbital wall, the neck lymph nodes, and the parotid gland. The patient was a 69-year-old male with a proptosis that had persisted for 31 years. An orbital exenteration was performed. Death occurred due to cerebral tumour infiltration. In view of the sebaceous pattern meibomian gland carcinoma has to be ruled out in the differential diagnosis.

Adenocarcinoma↗

Effect of the application of an anionic detergent combined with FABRY's tincture and its components on human skin resident flora. Part 2: Dermofug solution combined with either salicylic acid tincture or phenol acid tincture.

Using the forehead skin test, we investigated the combined application of 10 v/v% Dermofug solution and 3 w/v% salicylic acid tincture or 1 v/v% phenol acid tincture. The former combination showed better antibacterial efficacy against the coagulase-negative staphylococci and Propionibacterium spp. in the stratum corneum/acroinfundibulum as well as in the infrainfundibulum of the sebaceous glands. No antibacterial efficacy could be determined against Propionibacterium spp. in the infrainfundibulum of the sebaceous glands after the combined application of Dermofug solution and 1 v/v% phenol acid tincture. In contrast, the combined application of Dermofug solution and 3 w/v% salicylic acid tincture led to a long-term reduction of the cfu-counts of Propionibacterium spp. in the infrainfundibulum of the sebaceous glands. The following conclusions can be drawn from our study and applied to external therapy: a detergent like Dermofug should be used instead of an alcohol to enhance the penetration of a drug into the infrainfundibulum of the sebaceous glands, since the former can block the growth of Propionibacterium spp. in the infrainfundibulum. Secondly, it should be kept in mind that the addition of salicylic acid to a topical antibiotic ointment does not only enhance the penetration of the antibiotic into the infrainfundibulum of the sebacous glands, but that the antibacterial effect of the salicylic acid itself may be the reason for the better clinical antibacterial efficacy of such combinations.

Bacteria↗