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  • human  (28)
  • ACTIVATION  (14)
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  • 1
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; Germany ; human ; INHIBITION ; KINASE ; PATHWAYS ; VOLUME ; DEATH ; PROTEIN ; cell line ; DIFFERENTIATION ; ACCUMULATION ; RELEASE ; DNA ; REDUCTION ; INDUCTION ; SKIN ; FLOW ; protein kinase ; PROTEIN-KINASE ; treatment ; culture ; CELL-DEATH ; fragmentation ; DAMAGE ; CYTOCHROME-C ; lipids ; sebaceous gland ; SEBACEOUS GLANDS ; ARACHIDONIC-ACID ; OIL ; TERMINAL DIFFERENTIATION ; RETINOIC ACID ; retinoids ; 13-CIS-RETINOIC ACID ; BCL- 2 ; EPIDERMAL- KERATINOCYTES ; TRANS-RETINOIC ACID
    Abstract: Increased cell volume, accumulation of lipid droplets in the cytoplasm, and nuclear degeneration are phenomena indicating terminal differentiation of human sebocytes followed by holocrine secretion and cell death. The molecular pathways of natural and induced sebocyte elimination are still unknown, however. In this study, SZ95 sebocytes were found to exhibit DNA fragmentation after a 6 h culture followed by increased lactate dehydrogenase release after 24 h, indicating cell damage. With the help of morphologic studies and using Oil Red detection of cellular lipids, cell enlargement, accumulation of lipid droplets in the cytoplasm, and nuclear fragmentation could be observed under treatment with arachidonic acid. Staurosporine, a potent inhibitor of phospholipid Ca2+ - dependent protein kinase, increased externalized phosphatidylserine levels on SZ95 sebocytes, detected by annexin V/propidium iodide flow cytometry, as early as after 1 h, whereas dose-dependent reduction of bcl-2 mRNA and protein expression, enhanced DNA fragmentation, and increased caspase 3 levels, detected by caspase 3 inhibitor/propidium iodide flow cytometry, were found after 6 h of treatment. SZ95 sebocyte death was detected as early as after 6 h of SZ95 sebocyte treatment with high staurosporine concentrations (10(-6) -10(- 5) M). 5alpha-Dihydrotestosterone (10(-8) -10(-5) M) did not affect externalized phosphatidylserine levels and DNA fragmentation in SZ95 sebocytes but slightly decreased lactate dehydrogenase cell release. Neither acitretin nor 13-cis retinoic acid (10(-8) -10(-5) M) affected externalized phosphatidylserine levels, DNA fragmentation, and lactate dehydrogenase cell release, despite the increased caspase 3 levels under treatment with 13-cis retinoic acid. The combined staurosporine and 13-cis retinoic acid treatment enhanced DNA fragmentation in SZ95 sebocytes to the same magnitude as in cells only treated with staurosporine. In conclusion, SZ95 sebocytes in vitro undergo apoptosis, which can be enhanced by the terminal differentiation inductor arachidonic acid or by staurosporine and leads to cell death. 5alpha- Dihydrotestosterone inhibits SZ95 sebocyte death without involving apoptotic pathways, and retinoids did not affect the programmed death of human sebocytes. The latter result fits well with the currently reported inability of normal skin cells to undergo apoptosis after treatment with retinoids, in contrast to their malignant counterparts
    Type of Publication: Journal article published
    PubMed ID: 12542519
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  • 2
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; CELL ; CELL-PROLIFERATION ; Germany ; human ; GENERATION ; SYSTEM ; DISTINCT ; PROTEIN ; PROTEINS ; cell line ; LINES ; ACTIVATION ; RESPONSES ; REDUCTION ; KERATINOCYTES ; SKIN ; CELL-LINES ; ISOFORM ; SUBUNIT ; Western-blot ; MEMBRANE ; CELL-LINE ; LINE ; CYTOCHROME-C ; EPITHELIAL-CELLS ; PROTEIN LEVELS ; western blot ; HaCaT ; MUCOSA ; HOST-DEFENSE ; DEFENSE ; human skin and oral epithelial cells,oxidoreductase,p67phox,spin trapping,superoxide radical ; NAD(P)H OXIDASE ; OXYGEN RADICALS ; P47(PHOX) ; SUPEROXIDE-PRODUCTION
    Abstract: In non-phagocytic cells, superoxide has been implicated in physiological and pathological cellular functions in the skin and mucosa, such as, host defense, mitogenic responses, and malignant conversion. Here, we identify a constitutively expressed heme-flavoprotein NADPH oxidase (Nox) system as a source of superoxide in human skin (HaCaT) and gingival mucosal (GM16) keratinocyte cell lines. Western blot analysis showed that both cell lines expressed the phagocyte oxidase (phox) cytosolic proteins Rac1, p40phox, and p67phox. With respect to the catalytic flavoheme protein subunit, HaCaT membranes, which expressed p22phox, showed an absorbance peak at 558 nm indicative of a b-type cytochrome. At mRNA levels, both GM16 and HaCaT cells expressed gp91phox homologs Nox1, Nox2, and Nox4, however, HaCaT cells expressed very low levels of Nox1 mRNA. At protein levels, Nox1 was readily detected in HaCaT but was nearly undetectable in GM16 cells. Consistently, Nox activity of HaCaT membranes was demonstrated by electron paramagnetic resonance spin-trapping and cytochrome c reduction, and the activity was sensitive to the flavoprotein inhibitor diphenylene iodonium. V-max values were 20-fold lower than those reported for phagocytic oxidase. In conclusion, keratinocytes expressed a Nox distinct from the phox isoform of phagocytes providing molecular evidence for a source of superoxide that may regulate cell proliferation and host defense in skin and oral mucosa
    Type of Publication: Journal article published
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  • 3
    Keywords: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; PATHWAY ; GENE ; GENE-EXPRESSION ; GENES ; DIFFERENTIATION ; TUMORS ; COMPLEX ; COMPLEXES ; INDUCTION ; CONTRAST ; SKIN ; LOCALIZATION ; BENIGN ; keratin ; skin tumors ; epidermis ; FOLLICLE ; HAIR-FOLLICLES ; HUMAN TYPE-I ; MATRIX ; BETA-CATENIN EXPRESSION ; CORTEX ; HAIR FOLLICLE ; hair follicles,human,transcription factors,tumors ; HOXC13 ; INVOLUCRIN
    Abstract: Human hair follicles exhibit a complex pattern of sequential hair keratin expression in the hair matrix, cuticle, and cortex. In pilomatricomas, that is, benign skin tumors thought to arise from germinative matrix cells of the hair follicle and retaining morphological signs of cortical differentiation, this differential hair keratin pattern has been shown to be faithfully preserved in the lower and upper transitional cell compartments of the tumors. Here we show that also the co-expression of hair keratin hHa5 with its regulatory nuclear homeoprotein HOXC13 in matrix cells of the hair follicle is maintained in lower transitional cells of pilomatricomas. In contrast, the nuclear co-expression of LEF1 and beta-catenin, which in the hair follicle has been postulated to initiate cortex cell differentiation through the induction of hair keratin hHa1 expression (Merill et al, Genes Dev 15:1688-1705, 2001), is not preserved in upper transitional cells of pilomatricomas. Although these cells correctly express hHa1, they are completely devoid of LEF1 and nuclear LEF1/beta-catenin co-expression is shifted to a subpopulation of hair keratin-free basaloid cells of the tumors. These data imply that unlike the normal hair follicle, cortical differentiation in pilomatricomas is not under the control of the canonical Wnt signaling pathway
    Type of Publication: Journal article published
    PubMed ID: 15140206
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  • 4
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; Germany ; THERAPY ; VITRO ; DISEASE ; DISEASES ; MICE ; ACTIVATION ; MECHANISM ; REDUCTION ; ANTIGEN ; DENDRITIC CELLS ; SKIN ; T cell activation ; T cells ; T-CELLS ; treatment ; MIGRATION ; RECRUITMENT ; ANTIGEN-PRESENTING CELLS ; C3H/HEJ MICE ; FOLLICLE ; SUBSET ; RE ; HAIR FOLLICLE ; LYMPHOID ORGANS ; REGULATORY T-CELLS ; DELAYED-TYPE HYPERSENSITIVITY ; RECOVERY ; HAIR LOSS ; lymph node ; LYMPH-NODE ; RELEVANCE ; AA ; autoimmune disease ; PROGRESS ; ACID DIBUTYLESTER SADBE ; ACTIVATED T-CELLS ; ATOPIC-DERMATITIS ; SKIN-ASSOCIATED CHEMOKINE
    Abstract: Long-lasting allergen treatment is the most efficient therapy in alopecia areata (AA). The underlying mechanism is unknown. We here asked whether treatment with a contact sensitizer influences leukocyte migration such that dendritic cell (DC) migration or the recruitment of activated T-cells towards the skin become hampered. Allergen treatment of AA mice was not accompanied by a decrease in skin- infiltrating leukocytes or draining lymph node cells (LNC). However, the distribution of leukocyte subsets was changed with a dominance of monocytes in the skin and a reduced percentage of DCs in draining nodes. Chemokine and chemokine receptor expression in skin and draining nodes was strikingly increased and LNC from untreated and allergen-treated AA mice showed high migratory activity in vitro and readily homed in draining nodes and skin after intravenous injection. However, FITC labelling of the skin and subcutaneous transfer of dye-labelled DC revealed that allergen treatment created a chemokine milieu severely hampering DC migration from the skin towards the draining node. An allergic eczema. Induced reduction in DC migration and antigen transfer could well contribute to insufficient T-cell activation and the recovery of hair follicle in AA and possibly be of relevance for other skin- related autoimmune diseases
    Type of Publication: Journal article published
    PubMed ID: 16675965
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; IN-VITRO ; proliferation ; CELL ; Germany ; INHIBITION ; VITRO ; SYSTEM ; DEATH ; PROTEIN ; PROTEINS ; DRUG ; DIFFERENTIATION ; EPITHELIA ; ACTIVATION ; MARKER ; CONTRAST ; SKIN ; treatment ; ALPHA ; culture ; MATURATION ; CELL-DEATH ; ADHESION ; CELL-ADHESION ; RECEPTORS ; PROGRAMMED CELL-DEATH ; BARRIER FUNCTION ; TERMINAL DIFFERENTIATION ; AUTOIMMUNITY ; FUNCTIONAL-CHARACTERIZATION ; cell adhesion ; DRUGS ; ORGANOTYPIC COCULTURE ; cholinergic ; DARIERS-DISEASE ; KERATINOCYTE ADHESION ; NICOTINIC ACETYLCHOLINE-RECEPTOR ; PEMPHIGUS-VULGARIS
    Abstract: The aim of this study was to analyze the influence of cholinergic and anticholinergic drugs on epidermal physiology using organotypic cocultures (OTCs). Blocking of all acetylcholine receptors (AChRs) by combined treatment with mecamylamine and atropine or treatment with strychnine (blocking alpha 9nAChR) for 7-14 days resulted in a complete inhibition of epidermal differentiation and proliferation. Blockage of nicotinic (n) AChR with mecamylamine led to a less pronounced delay in epidermal differentiation and proliferation than blockage of muscarinic ( m) AChR with atropine, evidenced by reduced epithelial thickness and expression of terminal differentiation markers like cytokeratin 2e or filaggrin. In OTCs treated with atropine, mecamylamine, or strychnine, we could demonstrate intracellular lipid accumulation in the lower epidermal layers, indicating a severely disturbed epidermal barrier. In addition, we observed prominent acantholysis in the basal and lower suprabasal layers in mecamylamine-, atropine-, and strychnine-treated cultures, accompanied by a decreased expression of cell adhesion proteins. This globally reduced cell adhesion led to cell death via intrinsic activation of apoptosis. In contrast, stimulation of nAChR and mAChR with cholinergic drugs resulted in a significantly thickened epithelium, accompanied by an improved epithelial maturation. In summary, we show that epidermal AChR are crucially involved in the regulation of epidermal homeostasis
    Type of Publication: Journal article published
    PubMed ID: 16810300
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  • 6
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; CLINICAL-TRIAL ; COMBINATION ; evaluation ; Germany ; human ; IN-VIVO ; MODEL ; THERAPY ; NEW-YORK ; EFFICIENCY ; TRANSDUCTION ; primary ; prognosis ; DOMAIN ; culture ; GLYCOPROTEIN ; virus ; TRIAL ; TRIALS ; VECTORS ; VECTOR ; MEMBRANE ; CLINICAL-TRIALS ; chemotherapy ; EFFICIENT ; MELANOMA ; MALIGNANT-MELANOMA ; malignant melanoma ; CUTANEOUS MELANOMA ; ADENOVIRUS ; DACARBAZINE ; DOMAINS ; THERAPIES ; MELANOMA-CELLS ; VIROTHERAPY ; USA ; EFFICIENT TRANSDUCTION ; SHORT-TERM ; xenograft ; clinical trial ; ONCOLYTIC ADENOVIRUSES ; B ADENOVIRUSES ; CELLULAR RECEPTOR ; FUSOGENIC MEMBRANE-GLYCOPROTEINS ; REPLICATING ADENOVIRUS ; SUICIDE GENE-THERAPY ; ADENOVIRUS VECTORS ; IMMUNE-MEDIATED CONTROL ; oncolytic adenovirus
    Abstract: Advanced melanoma is associated with poor prognosis warranting the development of new therapeutics, such as oncolytic adenoviruses for immunovirotherapy. Since this approach critically depends on efficient transduction of targeted tumor cells, we screened a panel of 22 different adenovirus types for their internalization efficiency in melanoma cells. We demonstrated that the virions of Ad35, Ad38, and Ad3 have significantly higher internalization efficiency in melanoma cells than Ad5, so far the only adenovirus type used in clinical trials for melanoma. Therefore, we developed a conditionally replication-competent Ad5-based vector with the Ad35 fiber shaft and knob domains (Ad5/35) and compared its therapeutic efficacy with the homologous vector carrying the native Ad5 fiber. To further enhance virotherapy, we combined the oncolytic adenovirus vectors with intratumoral expression of measles virus fusogenic membrane glycoproteins H and F (MV-H/F) and dacarbazine chemotherapy. In a human melanoma xenograft model, established from a short-term culture of primary melanoma cells, we demonstrated that the Ad5/35-based therapy had a significantly greater anti-neoplastic effect than the homologous Ad5-based therapy. Furthermore, the combination of virotherapy, intratumoral expression of MV-H/F, and chemotherapy was clearly superior to single- or double-agent therapy. In conclusion, Ad35-based vectors are promising for the treatment of melanoma
    Type of Publication: Journal article published
    PubMed ID: 17960177
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  • 7
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; CELL ; Germany ; human ; MODEL ; GENE ; GENES ; transcription ; LIGAND ; SKIN ; BIOLOGY ; fibroblasts ; TARGET ; IN-SITU ; MONOCLONAL-ANTIBODIES ; EPITHELIAL-CELLS ; INDIVIDUALS ; TARGETS ; RECEPTORS ; DISSECTION ; SERUM ; mRNA ; hair ; USA ; THYROTROPIN RECEPTOR ; HPA axis ; CONNECTIVE-TISSUE ; CORTICOTROPIN-RELEASING HORMONE ; FUNCTIONAL-ROLE ; PIGMENTARY UNIT ; SMOOTH MUSCLE ACTIN ; TSH RECEPTOR
    Abstract: Pituitary thyroid-stimulating hormone (TSH) regulates thyroid hormone synthesis via receptors (TSH-R) expressed on thyroid epithelial cells. As the hair follicle (HF) is uniquely hormone-sensitive and, hypothyroidism with its associated, increased TSH serum levels clinically can lead to hair loss, we asked whether human HFs are a direct target for TSH. Here, we report that normal human scalp skin and microdissected human HFs express TSH-R mRNA. TSH-R- like immunoreactivity is limited to the mesenchymal skin compartments in situ. TSH may alter HF mesenchymal functions, as it upregulates alpha-smooth muscle actin expression in HF fibroblasts. TSH-R stimulation by its natural ligand in organ culture changes the expression of several genes of human scalp HFs (for example keratin K5), upregulates the transcription of classical TSH target genes and enhances cAMP production. Although the functional role of TSH in human HF biology awaits further dissection, these findings document that intracutaneous TSH-Rs are fully functional in situ and that HFs of female individuals are direct targets for nonclassical, extrathyroidal TSH bioregulation. This suggests that organ-cultured scalp HFs provide an instructive and physiologically relevant human model for exploring nonclassical functions of TSH, in and beyond the skin
    Type of Publication: Journal article published
    PubMed ID: 19052559
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  • 8
    Keywords: CELLS ; tumor ; CELL ; human ; COMMON ; DISEASE ; SITES ; PROTEINS ; SAMPLE ; SAMPLES ; TUMORS ; TIME ; PATIENT ; DNA ; SKIN ; papillomavirus ; antibody ; IN-SITU ; LESIONS ; COPY NUMBER ; human papillomavirus ; GENOTYPES ; HPV ; REPLICATION ; glutathione-S-transferase ; PSORIASIS ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; hair ; GENOTYPE ; NONMELANOMA SKIN-CANCER ; USA ; PLUCKED EYEBROW HAIRS ; CLINICAL-ASPECTS ; HAIRS ; HUMAN-PAPILLOMAVIRUS-DNA
    Abstract: Epidermodysplasia verruciformis (EV) is a rare disease, characterized by cutaneous warts and associated with a strong predisposition to beta-genus human papillomavirus (HPV). Earlier studies reported high copy numbers of HPV-DNA in nearly all skin tumors from EV patients, but neither HPV replication status in non-lesional skin nor anti-HPV seroreactivity in these patients have been reported yet. We therefore performed a comprehensive viral load analysis for the more common beta-HPV types on skin samples and plucked eyebrow hairs from four EV patients treated at our dermatology department. The results clearly demonstrate that they carry a multiplicity (up to eighteen types) of beta-HPV genotypes in both skin sites. Worthy of note, a high intrapatient concordance for specific types between hair bulbs and skin biopsies was observed and the same beta-PV profile was maintained over time. Viral load analysis revealed a load range between less than one HPV-DNA copy per 100 cells to more than 400 HPV-DNA copies per cell in both eyebrow hairs and skin proliferative lesions. Evaluation of seroreactivity to beta-HPV types in the four EV patients revealed that antibodies against the 16 beta-HPV were significantly more prevalent and showed higher titers than in the controls
    Type of Publication: Journal article published
    PubMed ID: 18923444
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  • 9
    Keywords: CELLS ; ACTIVATION ; KERATINOCYTES ; SKIN ; CYCLE ; MIGRATION ; E6 ; E-cadherin ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; LIFE ; DNA LOADS
    Abstract: Human papillomaviruses (HPVs), which are contained in the alpha, beta, gamma, mu, and nu genera, differ in their oncogenic potential and their tropism for cutaneous or mucosal epidermis. Langerhans cells (LC), the only epidermal professional antigen-presenting cells, are readily detected in normal mucosal and cutaneous epithelium. The aim of this study is to determine whether LC loss, which has been reported for HPV16, occurs in other HPV genera and establish its significance in viral pathology. We found that, as for HPV16, LCs were reduced in lesions infected with high-risk mucosal (alpha 7 and alpha 9 species) and low-risk cutaneous (gamma and mu) types. Lesions infected with alpha 10 low-risk genital types had reduced LC but contained epidermal LC patches, coincident with dermis-localized regulatory T cells (T-regs). In contrast to other genera, LCs were common in the epidermis, and T-regs occupied the dermis of the potentially high-risk cutaneous beta-HPV type infected lesions. Therefore, LC loss in the infected lesions occurred irrespective of tropism or oncogenic potential of the HPV type. LC depletion in the HPV-infected epidermis may create an environment that is permissive for viral persistence and in HPV lesions in which LCs are found, the presence of typically immunosuppressive T-regs may compensate for their continued presence
    Type of Publication: Journal article published
    PubMed ID: 19759549
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  • 10
    Keywords: CELLS ; EXPRESSION ; Germany ; human ; CLONING ; GENE ; GENES ; HYBRIDIZATION ; DIFFERENTIATION ; DOMAIN ; IN-SITU ; PATTERNS ; gene expression ; cytoskeleton ; intermediate filaments ; keratin ; LAYER ; CELLS FLUGELZELLEN ; CUTICLE CELLS ; CYTOKERATINS ; GENE DOMAIN ; human hair follicle ; HUXLEY ; MAMMALIAN-TISSUES
    Abstract: In this study we report on the cloning of two novel human type II keratin cDNAs, K6irs3 and K6irs4, which were specifically expressed in the inner root sheath of the hair follicle. Together with the genes of two previously described type II inner root sheath keratins, K6irs1 and K6irs2, the K6irs3 and K6irs4 genes were subclustered in the type II keratin/hair keratin gene domain on chromosome 12q13. Evolutionary tree analysis using all known type II epithelial and hair keratins revealed that the K6irs1-4 formed a branch separate from the other epithelial and hair keratins. RNA in situ hybridization and indirect immunofluorescence studies of human hair follicles, which also included the K6irs2 keratin, demonstrated that both K6irs2 and K6irs3 were specifically expressed in the inner root sheath cuticle, but showed a different onset of expression in this compartment. Whereas the K6irs3 expression began in the lowermost bulb region, that of K6irs2 was delayed up to the height of the apex of the dermal papilla. In contrast, the K6irs4 keratin was specifically expressed in the Huxley layer. Moreover, K6irs4 was ideally suited to further investigate the occurrence of Flugelzellen, i.e., Huxley cells, characterized by horizontal cell extensions that pass through the Henle layer, abut upon the companion layer, and form desmosomal connections with the surrounding cells. Previously, we detected Flugelzellen only in the region along the differentiated Henle layer. Using the Huxley-cell-specific K6irs4 antiserum, we now demonstrate this cell type to be clearly apposed to the entire Henle layer. We provide evidence that Flugelzellen penetrate the Henle layer actively and may play a role in conferring plasticity and resilience to the otherwise rigid upper Henle layer
    Type of Publication: Journal article published
    PubMed ID: 12648212
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