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Biomedical subjects

G Mahrle

Publications and source records attributed to G Mahrle.

At least 37 records · Page 2Linked to original sources
PubMed1994

Anthralin: how does it act and are there more favourable derivatives?

Anthralin is still the most effective and safest therapeutic agent for treatment of psoriasis. Our data may assist toward an understanding of its mode of action and introduce new derivatives, more antiproliferative and less toxic than anthralin in vitro. Anthralin exerts a direct effect on keratinocytes and leukocytes. In time-lapse studies it significantly prolonged the prophase of mitotic keratinocytes in subtoxic doses and suppressed the expression of keratin 6 mRNA in the immediately suprabasal layer of psoriatic epidermis in vivo. Anthralin inhibits the transformation of lymphocytes and the release of reactive oxygen species from activated leukocytes, in vitro. We provide evidence that these effects of anthralin are mediated by protein kinase C. Twelve new hydrophilic derivatives of anthralin, including a 1,8-dimethoxy compound, as well as C-2 and C-10 substituted anthrones were tested on human keratinocytes. The antiproliferative effect of those derivatives bearing lacton rings at a C-10, consisting of 4, 5, or 6 C atoms, exceeded that of anthralin and were equally or less cytotoxic than the parent drug. These compounds had no pro-drug character in vitro, since they did not metabolize via anthralin, as shown by HPLC. These data indicate that there may be anthralin derivatives with more favourable properties for topical therapy than anthralin itself.

Anthralin↗
PubMed1993

Immunohistochemical and immunoelectron microscopic demonstration of chromogranin A in formalin-fixed tissue of Merkel cell carcinoma.

BACKGROUND: Chromogranin A (CGA) is the major protein of neurosecretory granules (NSG) of cells of the diffuse neuroendocrine system, and the amount of CGA corresponds to the number of NSGs. OBJECTIVE: Because formalin fixation may destroy NSGs, a study was performed to examine the presence of CGA in Merkel cell carcinoma (MCC) to determine whether CGA depends on the presence of intact NSGs. METHODS: Formalin-fixed, paraffin-embedded tissue of 15 MCCs was investigated by immunohistochemistry and immunoelectron microscopy for the presence of CGA and NSGs. RESULTS: CGA was demonstrated in 12 of 15 MCCs by immunochemistry and in 6 of 10 MCCs by immunoelectron microscopy although intact NSGs could not be discerned in all cases. CONCLUSION: CGA remains demonstrable even when no morphologically intact NSGs are present, which suggests that CGA is not exclusively responsible for the electron density of NSGs.

Adult↗
PubMed1993

Keratin pattern of acanthosis nigricans in syndromelike association with polythelia, polycystic kidneys, and syndactyly.

BACKGROUND: Acanthosis nigricans (AN) comprises a broad spectrum of etiologic subtypes. The underlying pathomechanisms have not yet been completely clarified. We present a patient affected with a syndromelike AN subtype including disturbed epidermopoiesis as evidenced by immunohistologic findings and in situ hybridization. OBSERVATIONS: A 54-year-old white man contracted AN during childhood. There were connate malformations consisting of webbed toes II/III on the right side and a supernumerary left mammilla. As an adult he developed psoriasis vulgaris, obesity, and latent diabetes mellitus, polycystic kidney and liver disease. With regard to keratin 6 mRNA, and the protein expression of keratin 6/16, KI-67, and proliferating cell nuclear antigen, the AN lesion showed moderate hyperproliferation. A much higher degree of hyperproliferation was evident in psoriatic areas of the patient's skin. In contrast to psoriatic tissue, basal keratinocytes of the AN showed an unusually high expression of keratin 18 and 19 protein. CONCLUSIONS: The observation thus deals with a unique, syndromelike constellation of AN characterized by a particular epidermal pattern of moderate hyperproliferation. A further dysregulation of protein expression in the epidermis is indicated by the demonstration of the rare keratins 18 and 19 in basal keratinocytes of the AN lesion.

Abnormalities, Multiple↗
PubMed1993

[Therapeutic problem. Angiolymphoid hyperplasia with eosinophilia].

A 35-year-old female patient suffered from angiolymphoid hyperplasia with eosinophilia for 9 years, with multiple, exophytic tumours on her left pinna and the surrounding skin. Systemic treatment with gamma interferon and glucocorticoids, intralesional injections of glucocorticoids and argon laser therapy had no effect. After the tumours had been pared away by electrocautery the patient was free of symptoms for 1 year and then developed a small local recurrence. Recurrences are common in angiolymphoid hyperplasia with eosinophilia. Malignant transformation has not been observed. We therefore regard non-radical surgery as the therapy of choice.

Aged↗
PubMed1992

The antipsoriatic drug, anthralin, inhibits protein kinase C--implications for its mechanism of action.

In psoriatic patients, anthralin is known to attenuate lesional inflammation, but often generates perilesional dermatitis. This phenomenon is well reflected by the contrasting action of anthralin on human leukocytes. The release of reactive oxygen species (ROS) is inhibited by anthralin in phorbol ester-activated leukocytes, whereas anthralin directly induces this cellular response in unstimulated cells. In order to elaborate further the underlying mechanisms, we compared the kinetics of anthralin and different well-characterized stimuli, including the phorbol ester, phorbol-12-myristate-13-acetate, in this test system. Compared with standard stimuli, anthralin only marginally induced the release of ROS from human leukocytes and displayed different kinetics. Protein kinase C (PKC), the major cellular phorbol ester receptor, is considered to be involved in the regulation of this cellular response. Furthermore, its involvement in the pathophysiology of psoriasis has been suggested. Therefore, we also investigated the effects of anthralin on purified PKC. Anthralin was found to inhibit the enzyme activity in a dose-dependent manner but not to display any stimulatory effects. The present results provide first evidence that the therapeutic activity of anthralin, at least in part, might be mediated by inhibition of PKC.

Animals↗
PubMed1992

Epidermal Merkel cells in psoriatic lesions: immunohistochemical investigations on neuroendocrine antigen expression.

Biopsy specimens from lesional psoriatic skin and from normal controls were investigated by immunohistochemistry for the presence of epidermal Merkel cells (MC). MC were defined as epidermal cells expressing simple-type keratins, i.e. nos. 8, 18, and 19. A significant number of MC could be found at the bottom of the rete ridges of psoriatic lesions (about 19.6 MC per square mm skin surface area) and of normal skin (about 14.0 MC per square mm surface area). In contrast to normal skin, MC of psoriatic lesions were positive for synaptophysin (21.7% of simple-type keratin positive epidermal cells, i.e. MC), pancreatic polypeptide (14.8%), somatostatin (7.0%), and chromogranin A (less than 3%). The immunostaining was rather faint though significantly different from normal skin. The findings suggest that in psoriasis, epidermal MC show variations of the expression of neuropeptides compared to normal skin. Since some of the neuropeptides are thought to be involved in hyperproliferation and/or skin immunology, our findings might suggest a functional activity of epidermal MC in psoriatic lesions different from normal controls.

Antibodies, Monoclonal↗
PubMed1992

Changes of epidermal cell morphology and keratin expression induced by inhibitors of protein kinase C.

Several lines of evidence show protein kinase C as being involved in various regulatory processes in keratinocyte biology, e.g. proliferation and differentiation. In the present study, we investigated the effects of three different inhibitors of protein kinase C, staurosporine, CP 46'665-1, and tiflucarbine, on cell morphology and keratin expression in a non-tumorigenic human keratinocyte cell line (HaCaT cells). Staurosporine, being the most potent inhibitor of protein kinase C activity in vitro, and CP 46'665-1 induced morphological transformation to a fibroblast-like cell shape. In contrast, no changes in cell morphology were observed after exposure to tiflucarbine. The investigation of keratin expression in HaCaT cells grown in the presence of the different compounds revealed the following changes: After 72 h of cultivation, keratins 8 and 18 were still expressed in treated cells, whereas expression of keratin 13 was decreased as compared to control cells. Immunoblotting to detect vimentin demonstrated its absence in treated and control cells. Since tiflucarbine is known as a dual protein kinase C/calmodulin inhibitor whereas staurosporine and CP 46'665-1 do not antagonize calmodulin function, it might be possible that not only protein kinase C but also calmodulin is involved in the process leading to the morphological changes.

Alkaloids↗
PubMed1992

Anti-proliferative effects of protein kinase C inhibitors in human keratinocytes.

Various lines of evidence indicate that protein kinase C, a key enzyme in transmembraneous signal transduction, is involved in the regulation of keratinocyte proliferation. In the present study we have investigated the effects of various structurally unrelated protein kinase C inhibitors on the proliferation of HaCa T cells, a non-tumorigenic human keratinocyte cell line. All protein kinase C inhibitors dose-dependently inhibited cell proliferation as assessed by the incorporation of radioactively labelled thymidine and amino acids as well as the increase in total protein content in keratinocytes. The potencies of the drugs to inhibit cell proliferation were strongly correlated to their inhibitory potency on purified protein kinase C, displaying a correlation coefficient of 0.97. Methotrexate, an anti-proliferative drug, was found not to inhibit protein kinase C. Therefore, our data provide evidence that protein kinase C is crucially involved in the regulation of keratinocyte proliferation but is not the only target of anti-proliferative drug action.

Cell Division↗
PubMed1992

Anthralin is a potent inhibitor of pityrosporum orbiculare/ovale in vitro.

Two strains of Pityrosporum orbiculare/ovale were grown in a liquid medium and exposed to different concentrations of the imidazoles ketoconazole and clotrimazole as well as anthralin, liquor carbonis detergens and salicylic acid. With regard to growth inhibition of yeast cells, the efficacies of anthralin and the imidazoles were similar, a half-maximal inhibition being achieved with an anthralin concentration of 7 mg/l. Liquor carbonis detergens and salicylic acid also inhibited growth of Pityrosporum orbiculare/ovale, but only at much higher concentrations. The response to salicylic acid was mainly due to its acid pH.

Anthralin↗
PubMed1992

[Chronic lichenoid keratosis].

We report on a 41-year-old woman with keratosis lichenoides chronica, a disorder first described by Kaposi in 1886 as "lichen moniliformis", who later also developed chronic lymphatic leukaemia. Since Kaposi's original report, 38 additional cases have been reported. Occurrence of keratosis lichenoides chronica associated with malignant disorders has not previously been described.

Adult↗
PubMed1991

Structure-function relationship of new anthralin derivatives assayed for growth inhibition and cytotoxicity in human keratinocyte cultures.

HaCaT keratinocyte cultures were exposed to twelve hydrophilic anthralin derivatives 1 to 12 with substituents at C-1 and C-8 of the anthrone skeleton, of one H at C-10 and of both H's at C-10 by lacton rings. After 3 microM treatment growth was determined by cellular protein content, 3H-thymidine- and 14C-amino-acid-uptake and cytotoxicity by the release of cytoplasmic LDH into the culture medium. In comparison to acetone control (100%) anthralin suppressed mean protein content, as well as DNA- and protein-synthesis to 33, 28, and 21%, respectively, and the drug revealed an enzyme release of 660%. In relation to the parent drug we found similar cell growth inhibitory effects of compounds 4, 6, 8, 9, 10, and 12. Deriv. 4, 8, and 10 were, however, to some extent less cytotoxic than anthralin, whereas deriv. 6, 9, and 12 were in the same range. An extreme suppression of growth parameters which differed from the anthralin effect by a factor 0.5-0.8 was caused by deriv. 11, showing the same cytotoxicity. Deriv. 1, 2, 3, 5, and 7 did not demonstrate any cytotoxicity. Concerning growth parameters, deriv. 2 induced a slight stimulation, deriv. 3 and 7 were completely ineffective, deriv. 1 and 5 induced slightly to moderately inhibited proliferation but both being much less effective than anthralin. These data indicate that the "minimum structure" concept by Krebs and Schaltegger--claiming 1-hydroxy-9-anthrone as a precondition for clinical antipsoriatic potency--is not valid at least in cell-biological tests and point toward possible usefulness of some experimental model compounds as alternative antipsoriatics.

Anthralin↗
PubMed1991

Effects of tiflucarbine as a dual protein kinase C/calmodulin antagonist on proliferation of human keratinocytes and release of reactive oxygen species from human leukocytes.

Various studies have suggested that calmodulin (CaM) is involved in the pathophysiology of psoriasis. Protein kinase C (PKC) is also accepted as playing a regulatory role in cell proliferation as well as in inflammatory processes. Therefore, we investigated the effects of the known CaM antagonist tiflucarbine (BAY/TVX P 4495) on two cellular systems related to the major clinical symptoms of psoriasis: proliferation of cultured human keratinocytes (HaCa T cell line) and release of reactive oxygen species (ROS) from human polymorphonuclear leukocytes (PMNL). Tiflucarbine inhibited both cellular responses in a dose dependent manner. Furthermore, tiflucarbine directly affected PKC, and may thus be considered to be a dual PKC/CaM antagonist with putative antipsoriatic activity. The effects of tiflucarbine on the different parameters were compared with those of the structurally unrelated dual PKC/CaM inhibitor W-7 and those of the potent PKC inhibitor staurosporine. The potencies of all three compounds were found to be in the same range as their PKC-inhibiting potency. Our data indicate that PKC, rather than CaM, may play a regulatory role in the release of ROS as well as in keratinocyte proliferation. Therefore, inhibition of PKC in general might have a therapeutic benefit in psoriasis.

Alkaloids↗
PubMed1991

Repeated treatment with dithranol induces a tolerance reaction in keratinocytes in vitro.

The hyperproliferative human keratinocyte line (HaCaT) was tested for dithranol tolerance (tachyphylaxis) at the cellular level. At day 4 after seeding, keratinocytes were treated with 0.3 or 1.0 microM dithranol. Data were compared with those from experiments including additional pretreatments with 0.3 microM at day 3, or at days 1 and 3. Protein content, DNA synthesis and protein synthesis (incorporation of 3H-thymidine and 14C-amino acids per protein) were determined at 24, 48 and 72 h after the last drug exposure. Protein content of attached cells decreased in relation to dose and frequency of treatments. Inhibition of DNA and protein synthesis (38.2% and 32.3%, respectively) also occurred 24 h after a single treatment with 0.3 microM dithranol, but was only 18.4% and 9.1% after pretreatment twice with 0.3 microM dithranol. This tolerance reaction in vitro, after repeated dithranol exposure of human keratinocytes, may be explained by a selective loss of drug-sensitive cells.

Anthralin↗
PubMed1991

Palmoplantar keratoderma with tonotubular keratin.

A 61-year-old man with palmoplantar keratoderma with an unusual tonotubular keratin is reported. The histologic findings, genetic transmission, and clinical course were similar to epidermolytic palmoplantar keratoderma (Voerner type), but keratinocytes ultrastructurally displayed a tonotubular cytoskeleton, which has not been previously described, instead of a tonofilamentous one. Electrophoretically, we found no difference in the keratin pattern of normal plantar skin, skin in palmoplantar keratoderma of Voerner, and that of our patient's skin. Therefore the tubular keratin most likely formed as a result of a posttranslational change of keratin polymerization.

Humans↗
PubMed1991

Antiproliferative potential of zidovudine in human keratinocyte cultures.

Because the beneficial effects of zidovudine in human immunodeficiency virus infection-associated psoriasis have recently been observed, this study focused on the drug's action on the rapidly proliferating human HaCaT keratinocyte line as an in vitro model for epidermal hyperproliferation. Cultures in log growth phase were exposed to zidovudine for 2 days. Zidovudine slowed proliferation in a dose-dependent fashion as evidenced by 50% inhibition concentrations of 33 mumol/L (cell number), 30 mumol/L (protein content), 0.9 mumol/L (protein synthesis), and 0.7 mumol/L (DNA synthesis). Significant (p less than 0.01) reduction of cell viability to 94.6% and 87.2%, as well as morphologic manifestations of cytotoxicity, were first evident after 2 days' exposure to maximal drug concentrations of 10 and 100 mumol/L, respectively. Control viability, assayed by trypan blue exclusion, was 98.0%. Direct cytotoxic plasma membrane injury could be ruled out by the absence of any increase in cytoplasmic lactate dehydrogenase release into supernatants at least during the 1 day of maximal dosage exposure. The drug-induced inhibition of proliferation was reversible within 7 days after a 2-day exposure to 100 mumol/L zidovudine. Two days of treatment with a 10 mumol/L dose did not alter the pattern and synthesis of keratins in vitro. Thus the known antipsoriatic efficacy of zidovudine might be explained, at least partly, by the drug's cytostatic potency.

Amino Acids↗