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C C Zouboulis

Publications and source records attributed to C C Zouboulis.

At least 19 recordsLinked to original sources
PubMed2006

Effect of 5alpha-dihydrotestosterone and testosterone on apoptosis in human dermal papilla cells.

Pathogenetic mechanisms in androgenetic alopecia are not yet fully understood; however, it is commonly accepted that androgens like testosterone (T) and 5alpha-dihydrotestosterone (5alpha-DHT) inhibit hair follicle activity with early induction of the catagen. Thus, we investigated the influence of T and 5alpha-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. T and 5alpha-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10(-5) M was found. Interestingly, bcl-2 protein expression was decreased in T- and 5alpha-DHT-treated cells, leading to an increase in the bax/bcl-2 ratio. In addition, T and 5alpha-DHT induced proteolytic cleavage of caspase 8 and inhibited proliferation of DPC at 10(-5) M. High concentrations of T and 5alpha-DHT were needed to induce apoptotic effects in DPC. These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus. The present study provides an interesting new pathogenetic approach in androgenetic alopecia.

Apoptosis↗
PubMed2006

Expression of sex-determining genes in human sebaceous glands and their possible role in the pathogenesis of acne.

BACKGROUND: The human skin, especially the sebaceous gland, is a steroidogenic organ similar to the gonads and adrenal cortex, possessing all the enzymes required for steroid sex-hormone synthesis and metabolism. Factors regulating cutaneous steroidogenesis associated with disease status remain largely unknown. OBJECTIVE: We hypothesized that transcription factors involved in sex formation and regulation of steroidogenesis in the classical steroidogenic organs are also expressed in the sebaceous glands. Their possible role in the pathogenesis of acne were investigated. METHODS: We used reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization and Western blotting to analyse the expression of SF-1, WT-1, SRY, SOX-9 and DAX-1 mRNAs and their proteins in cultured human sebocytes and the facial skin of acne patients. RESULTS: The in situ hybridization study showed SOX-9 mRNA mainly localized in basal keratinocytes, the basal layer of the sebaceous glands and eccrine glands. Immortalized human sebaceous gland cells (SZ95) expressed mRNA for SOX-9, WT-1 and DAX-1 but not for SF-1 or SRY. The expression of DAX-1 protein was slightly inhibited by 10(-6) m oestradiol (E2) at 6 h but enhanced by 10(-6) m dihydrotestosterone (DHT) at 48 h. The facial expression of SOX-9 seemed to be higher in the acne-prone male patients, while DAX-1 was stronger in subjects without acne, although both were statistically insignificant. CONCLUSION: Our findings confirm the expression of some sex-determining genes in human sebaceous glands. Further studies on a larger patient population including the normal controls are needed to elucidate the functional significance of these transcription factors in the pathogenesis of acne.

Acne Vulgaris↗
PubMed2006

A review of the European Directive for prescribing systemic isotretinoin for acne vulgaris.

Since the introduction of generic oral isotretinoin there have been discussions around harmonizing the summary of product characteristics of each formulation. As a result of these discussions, a European Directive concerned with the prescribing of oral isotretinoin has been introduced and the FDA (Food and Drugs Administration) has recently implemented new regulations. The aims of this article are to summarize the history of the processes involved, outline the new recommendations and discuss the impact of these changes in clinical practice.

Acne Vulgaris↗
PubMed2005

[Cryosurgical treatment of actinic keratoses and evidence-based review].

BACKGROUND: Actinic keratoses are focal epithelial carcinomas in situ, which are considered precursors of squamous cell carcinoma and must therefore be treated. In the USA, cryosurgery is the most frequent surgical procedure for the treatment of actinic keratoses and considered the treatment of choice. METHODS: Our own results of cryosurgical treatment of actinic keratoses were evaluated. Original publications and reviews on the treatment of actinic keratoses with cryosurgery were retrieved from MEDLINE and classified according to their evidence level. RESULTS: Two months after the procedure, 97.0% of the lesions (n=99) were considered sufficiently treated. Local pain during and shortly after treatment (15%) and pigmentary changes (5%) were the most frequent side effects. Recurrences were detected in 2.1% of the lesions during the 1st year and in 11,5% after 3 years. In 2 further monotherapy studies recurrences occurred in 1,2-9% of the lesions after one year in 30% after 3 years. Literature data suggest that photodynamic therapy is equally or even more effective than cryosurgery after a 3-month follow-up. The cryosurgical results were strongly dependent on the attending physician. CONCLUSIONS: Cryosurgery is beneficial in the treatment of actinic keratoses. This method is equivalent to photodynamic therapy.

Aged↗
PubMed2005

What is the pathogenesis of acne?

For a long time, the mantra of acne pathogenesis debates has been that acne vulgaris lesions develop when (supposedly largely androgen-mediated) increased sebum production, ductal hypercornification, and propionibacteria come together with local inflammatory process in the unlucky affected individual. And yet, the exact sequence, precise interdependence, and choreography of pathogenic events in acne, especially the 'match that lights the fire' have remained surprisingly unclear, despite the venerable tradition of acne research over the past century. However, exciting recent progress in this--conceptually long somewhat stagnant, yet clinically, psychologically, and socioeconomically highly relevant--everyday battlefield of skin pathology encourages one to critically revisit conventional concepts of acne pathogenesis. Also, this provides a good opportunity for defining more sharply key open questions and intriguing acne characteristics whose underlying biological basis has far too long remained uninvestigated, and to emphasize promising new acne research avenues off-the-beaten-track--in the hope of promoting the corresponding development of innovative strategies for acne management.

Acne Vulgaris↗
PubMed2003

A novel tetracycline-controlled transactivator-transrepressor system enables external control of oncolytic adenovirus replication.

The use of restricted replication-competent adenoviruses (RRCAs) inducing tumor cell-specific lysis is a promising approach in cancer gene therapy. However, the use of RRCAs in humans carries considerable risk, since after injection into the patient, further regulation or inhibition of virus replication from the outside is impossible. Therefore, we have developed a novel system allowing external pharmacological control of RRCA replication. We show here that a tumor-selective E1B-deleted RRCA can be tightly regulated by use of doxycycline (dox)-controlled adenoviral E1A gene expression, which in turn determines vector replication. RRCA replication is switched on by addition and switched off by withdrawal of dox. The system results in efficient tumor cell killing after induction by dox, whereas cells are unaffected by the uninduced system. It was also employed for efficient external control of transgene expression from cotransfected replication-deficient adenovectors. Furthermore, the use of a liver cell-specific human alpha1-antitrypsin (hAAT)-promoter driving a tetracycline-controlled transcriptional silencer allowed specific protection of cells with hAAT-promoter activity in the absence of dox in vitro and in vivo, delineating a new principle of 'tissue protective' gene therapy. The concept of external control of RRCAs may help to improve the safety of cancer gene therapy.

Adenoviridae↗
PubMed2002

Epidermodysplasia verruciformis associated with neurofibromatosis type 1: coincidental association or model for understanding the underlying mechanism of the disease?

We describe a 25-year-old man with epidermodysplasia verruciformis (EV) associated with neurofibromatosis type 1 (NF1). The lesions, persisting for more than 15 years, consisted of widespread planar warts on the backs of the hands and wrists, and reddish-brown macules on the trunk, neck and face. During the last 5 years, our patient developed several epithelial tumours, namely solar keratoses, plaques of Bowen's disease and squamous cell carcinomas (SCCs). He also presented with NF1 lesions with neurofibromas, café-au-lait macules, axillary freckling and Lisch nodules. He had left tibial bowing. Polymerase chain reaction analysis of the skin lesions demonstrated the presence of human papillomavirus (HPV) 15 in a flat wart, HPV 20 in a plaque of Bowen's disease, and HPV 15 and HPV 20 in an SCC lesion. Both EV and NF1 show an inherited predisposition to malignancy but the molecular mechanism underlying tumour development is not fully understood. The appearance of both diseases in our patient may be a coincidental association but may also contribute to the identification of loci for susceptibility to NF1 and EV on chromosome 17.

Adult↗
PubMed2001

[Schonlein-Henoch purpura associated with hepatitis B in a patient with HIV infection].

HISTORY AND CLINICAL FINDINGS: A 23-year-old man with HIV-infection and recently diagnosed hepatitis B infection developed painful swelling and palpable purpura in the limbs. In addition, relapsing diarrhoea, arthralgia and pain at the level of the right kidney were noted. The liver, the palpable lymph nodes and the tonsils were enlarged. INVESTIGATIONS: The following laboratory parameters were abnormal: sedimentation rate 64/70 mmHg, CD4+ cells 462/ml, CD4/CD8 ratio 0.3, serum CRP 16 mg/l, antistreptolysin titre 542 kU/l, complement C3 < 0.1 g/l, GPT 37 U/l, albumin 49.5% and gamma-globulin 28.5%, in urine, leukocytes 25/microliter and protein 0.25 g/l. Hepatitis serology: anti-HBc, HBs-Ag and HBe-Ag positive, anti-HBs and anti-HBe negative, hepatitis A-Ab (IgG) positive, hepatitis A-Ab (IgM) negative, hepatitis C-Ab negative. Pharyngial swab: beta-haemolytic streptococci of group A. Stool examination: amoeba cysts, corona virus and fungi 10(4)-10(5)/ml (control specimen negative). Abdominal sonography showed minor hepatomegaly, splenomegaly and two 0.8 cm-large lymph nodes near the liver entrance. The histology of a skin lesion revealed a florid leukocytoclastic vasculitis at the upper and middle dermal vessels. The immunohistological examination detected IgA, IgM and C3 deposits. TREATMENT AND COURSE: The multiple bacterial infections had initially been considered as triggering the Schönlein-Henoch purpura. However despite successful treatment of these infections severe relapses of both the skin lesions and the systemic manifestations occurred. A drug reaction, autoimmune diseases and tumours were excluded. Only after treatment of hepatitis B infection with recombinant interferon alpha together with administration of zidovudine (treatment of choice at that time) the lesions quickly disappeared without further relapses. During the 5-year-follow-up, recurrent bacterial infections did not induce relapses of the disease, whereas the hepatitis B infection was seroconverted. CONCLUSION: It is likely that the hepatitis B may have been the trigger for the Schönlein-Hennoch-purpura.

Adult↗
PubMed2001

Comparative analysis of the association of HLA-B*51 suballeles with Behçet's disease in patients of German and Turkish origin.

The distribution of the different HLA-B*51 suballeles among patients with Behçet's disease (BD) of German (n=33) and Turkish (n=92) origin in comparison to their presence in the respective ethnically matched healthy control groups (German: n=325, Turkish: n=93) was studied. HLA-B*51x was significantly increased in both patient groups in comparison to the controls (Germans: 58% vs. 12%, OR 9.76, P<0.001; Turkish: 75% vs. 25%, OR 9.13, P<0.001). Molecular subtyping of B*51x revealed HLA-B*51011 and B*5108 as the predominant suballeles in both patient groups and controls although with a slightly increased frequency of HLA-B*5108 in the diseased individuals. HLA-B*5105 was the only further HLA-B*51x subtype detected in one Turkish patient heterozygous also for HLA-B*5101. HLA-B*5107 although present in a Turkish as well as German control was absent in the patient groups. There was also a tendency towards a higher degree of homozygosity for HLA-B*51x in both patient groups versus the matched controls (Germans: 10% in patients vs. 2,5% in controls; Turkish: 27% in patients vs. 13% in controls). Our study further supports previous hypothesis of an association of BD with B51 suballeles which share amino-acid residues at positions 63 and 67 as well as at positions 77-83 for specific peptide binding and natural killer (NK)-cell interactions. This applies to HLA-B*5101 and B*5108, but not to HLA-B*5107 different at position 67, which could be negatively associated with BD.

Alleles↗
PubMed2001

Exploration of retinoid activity and the role of inflammation in acne: issues affecting future directions for acne therapy.

The review summarizes new results concerned with several important issues in the treatment of patients with acne. The first section reviews studies which show that 13-cis retinoic acid, a molecule with strong biological activity but low binding affinity for retinoid receptors and cellular-binding proteins in sebocytes, undergoes rapid intracellular conversion to all-trans retinoic acid. This active metabolite exerts its actions on sebocyte gene expression by binding to the nuclear retinoic acid receptor rather than the retinoid X receptor. Importantly, 13-cis retinoic acid, unlike all-trans retinoic acid, does not induce cytochrome P450 1A1, an enzyme responsible for the metabolism of xenobiotics. Thus, administration of 13-cis retinoic acid permits high long-term intracellular accumulation of its active metabolite. The second section reviews studies which suggest that leukotriene B4 may play a key role in acne-related inflammation. Results from a preliminary clinical study indicate that therapy with a specific lipoxygenase inhibitor is clinically effective in the treatment of patients with inflammatory acne and that its clinical efficacy is correlated with the drug's ability to reduce total lipid levels, and especially pro-inflammatory lipids, in sebum. Interestingly, 13-cis retinoic acid has been shown to modulate the activities of LTB4 and inflammatory events in the development of acne. Therefore, future compounds targeting acne have to inhibit pro-inflammatory lipids in sebum, and thus down-regulate acne-related inflammatory signals and reduce the LTB4-induced migration of inflammatory cells.

Acne Vulgaris↗
PubMed2001

Chronological ageing and photoageing of the human sebaceous gland.

The human sebaceous gland undergoes both extrinsic and intrinsic ageing. The latter is associated with morphological changes and alteration in the sebaceous gland activity. The high androgen-dependent sebum secretion in neonates falls during childhood, starts to rise again during puberty and reaches its maximum in young adults. While the number of sebaceous glands remains the same during life, sebum levels tend to decrease after menopause in females, whereas no major changes appear until the eighth decade of life in men. Reduced androgen levels in aged individuals lead to a slow cellular turnover in the sebaceous glands resulting in hyperplasia of the facial sebaceous glands in advanced age. Ultraviolet radiation and immune suppression (cyclosporin A with corticosteroids) represent cofactors for the development of sebaceous gland hyperplasia. Current molecular findings indicate that overexpression of the ageing-associated gene Smad7 and parathormone-related protein correlate with sebaceous gland hyperplasia, whereas c-myc overexpression is associated with enhanced sebum production. On the other hand, down-regulation of the mismatch repair genes hMLH-1 and hMSH-2 may promote the development of sebaceous gland carcinoma. In addition to spontaneous single tumours, sebaceous gland carcinomas have been reported in immune-suppressed transplant recipients (azathiorpine, cisplatin, cyclosporin A) and in association with the Muir-Torre syndrome. Microsatellite instability with a loss of the mismatch repair gene hMSH-2 has been detected in immune suppressed patients and under photo-induced DNA damage. Topical and systemic oestrogens offer treatment options for skin xerosis in menopausal females. A combination of isotretinoin and interferon-alpha may prevent tumour development in patients with Muir-Torre syndrome.

Androgens↗
PubMed2001

Sebocytes are the key regulators of androgen homeostasis in human skin.

The mRNA expression patterns of the androgen receptor and the androgen metabolizing enzymes 3beta-hydroxysteroid dehydrogenase/Delta(5-4)-isomerase, 17beta-hydroxysteroid dehydrogenase, 5alpha-reductase, and 3alpha-hydroxysteroid dehydrogenase were investigated in three different cell populations originating from human skin, SZ95 sebocytes, HaCaT keratinocytes, and MeWo melanoma cells, by means of reverse transcription polymerase chain reaction. Restriction analysis of cDNA fragments was performed to identify isozymes of 3beta-hydroxysteroid dehydrogenase/Delta(5-4)-isomerase and 3alpha-hydroxysteroid dehydrogenase. In addition, 3H-dihydroepiandrosterone and 3H-testosterone were used as substrates to determine the metabolic activity of these enzymes in SZ95 sebocytes, primary sebocyte cultures, and HaCaT keratinocytes. Furthermore, the effects of the selective 5alpha-reductase type 1 and 2 inhibitors, 4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one and dihydrofinasteride, respectively, and of the 3beta-hydroxysteroid dehydrogenase/Delta(5-4)-isomerase inhibitor cyproterone acetate on androgen metabolism were investigated. Androgen receptor mRNA was detected in SZ95 sebocytes and HaCaT keratinocytes but not in MeWo melanoma cells, whereas 3beta-hydroxysteroid dehydrogenase/Delta(5-4)-isomerase isotype 1 mRNA and metabolic activity were only found in SZ95 sebocytes. The enzyme activity could be inhibited by cyproterone acetate. Type 2 17beta-hydroxysteroid dehydrogenase, type 1 5alpha-reductase, and 3alpha-hydroxysteroid dehydrogenase mRNA were expressed in all three cell populations tested, whereas type 3 17beta-hydroxysteroid dehydrogenase mRNA could only be detected in SZ95 sebocytes. The major metabolic steps of testosterone in SZ95 sebocytes, primary sebocyte cultures, and HaCaT keratinocytes were its conversion to androstenedione by 17beta-hydroxysteroid dehydrogenase and further to 5alpha-androstanedione by 5alpha-reductase. The type 1 5alpha-reductase selective inhibitor 4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one, but not the type 2 selective inhibitor dihydrofinasteride, inhibited 5alpha-reductase at low concentrations in SZ95 sebocytes and HaCaT keratinocytes. 5alpha-androstanedione was degraded to androsterone by 3alpha-hydroxysteroid dehydrogenase, which exhibited a stronger activity in HaCaT keratinocytes than in SZ95 sebocytes and in primary sebocyte cultures. Lower levels of 5alpha-dihydrotestosterone and 5alpha-androstanediol were also detected in all cells tested. Our investigations show that specific enzyme expression and activity in cultured sebocytes and keratinocytes seem to allocate different duties to these cells in vitro. Sebocytes are able to synthesize testosterone from adrenal precursors and to inactivate it in order to maintain androgen homeostasis, whereas keratinocytes are responsible for androgen degradation.

Androgens↗