Biomedical subjects
Publications and source records attributed to Mark Berneburg.
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Treatment of melasma involves the use of a range of topical depigmenting agents and physical therapies. Varying degrees of success have been achieved with these therapies. The Pigmentary Disorders Academy (PDA) undertook to evaluate the clinical efficacy of the different treatments of melasma in order to generate a consensus statement on its management. Clinical papers published during the past 20 years were identified through MEDLINE searches and methodology and outcome assessed according to guidelines adapted from the US Preventive Services Task Force (USPSTF). The consensus of the group was that first-line therapy for melasma should consist of effective topical therapies, mainly fixed triple combinations. Where patients have either sensitivity to the ingredients or a triple combination therapy is unavailable, other compounds with dual ingredients (hydroquinone plus glycolic acid) or single agents (4% hydroquinone, 0.1% retinoic acid, or 20% azelaic acid) may be considered as an alternative. In patients who failed to respond to therapy, options for second-line therapy include peels either alone or in combination with topical therapy. Some patients will require therapy to maintain remission status and a combination of topical therapies should be considered. Lasers should rarely be used in the treatment of melasma and, if applied, skin type should be taken into account.
The role of mitochondria in energy production and apoptosis is well known. The role of mitochondria and particularly the role of the mitochondria's own genome, mitochondrial (mt) DNA, in the process of ageing were postulated decades ago. However, this was discussed, debated and more or less disposed of. Recent data from elegant mouse models now confirm that mutations of mtDNA do indeed play a central and pivotal role in the ageing process. Newer reports also indicate a possible role of mtDNA mutations in the carcinogenesis of several organs. But is damaged mtDNA repaired, or is it simply degraded and discarded? This question appears to be answered now. According to recent data, mitochondria possess functional repair mechanisms such as base excision repair, double-strand break repair and mismatch repair, yet nucleotide excision repair has so far not been detected.
Mitochondria are responsible for the generation of energy in the form of adenosine triphosphate. These organelles contain their own genetic material, mitochondrial (mt) DNA. This mtDNA has been hypothesized to play a role in the processes of aging and carcinogenesis. Initial reports have shown that there is no repair of cyclobutylpyrimidine dimers (CPD). More recent reports indicate however, that the mitochondrion contains several defence mechanisms against endogenous or exogenous damaging agents such as ultraviolet radiation or oxidative damage. The role of these defence mechanisms in the removal of mitochondrial DNA damage and the link to aging and carcinogenesis-associated processes are discussed in this review.
Phototherapy with ultraviolet (UV) radiation of wavelengths between 280 and 320 nm (UVB) is a safe and effective treatment for a variety of diseases. In addition to standard broadband UVB (bUVB), narrowband phototherapy with fluorescent bulbs emitting near monochromatic UV around 311 nm (nUVB) has become an important treatment for diseases such as psoriasis, atopic dermatitis and vitiligo. In addition to these indications, the number of diseases for which nUVB phototherapy is reported to be effective is continuously growing. The differential effects of nUVB phototherapy in comparison to other UV wavelengths as well as established and new indications for this treatment modality are reviewed.
Mutations of mitochondrial (mt) DNA play a role in neurodegeneration, normal aging, premature aging of the skin (photoaging), and tumors. We and others could demonstrate that mtDNA mutations can be induced in skin cells in vitro and in normal human skin in vivo by repetitive, sublethal ultraviolet (UV)-A-irradiation. These mutations are mediated by singlet oxygen and persist in human skin as long-term biomarkers of UV exposure. Although mtDNA exclusively encodes for the respiratory chain, involvement of the energy metabolism in mtDNA mutagenesis and a protective role of the energy precursor creatine have thus far not been shown. We assessed the amount of a marker mutation of mtDNA, the so-called common deletion, by real-time PCR. Induction of the common deletion was paralleled by a measurable decrease of oxygen consumption, mitochondrial membrane potential, and ATP content, as well as an increase of matrix metalloproteinase-1. Mitochondrial mutagenesis as well as functional consequences could be normalized by increasing intracellular creatine levels. These data indicate that increase of the energy precursor creatine protects from functionally relevant, aging-associated mutations of mitochondrial DNA.
Phototherapy with ultraviolet (UV) irradiation of wavelengths between 280 and 320 nm (UV-B) is a safe and effective treatment for a variety of inflammatory skin diseases. In addition to standard broad band UVB, narrow band phototherapy with fluorescent bulbs emitting near monochromatic UV between 310-315 nm has become an important treatment for diseases such as psoriasis, atopic dermatitis or vitiligo. Other diseases respond favorably to narrow band UV-B phototherapy, the number of potential indications for such phototherapy is continuously growing. The differential effects of narrow band UV-B phototherapy in comparison to other UV phototherapies, as well as new and established indications for this treatment modality are reviewed.
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Phototherapy of skin diseases such as psoriasis is an effective and safe treatment modality. However, increasing the risk of skin cancer by phototherapy is a serious concern. An increased skin cancer risk occurs after prolonged photochemotherapy (PUVA). In contrast, the role of broadband UVB or narrowband UVB therapy in skin carcinogenesis of humans with psoriasis is less clear. Therefore, we investigated the incidence of skin tumours in a total of 195 psoriasis patients, receiving broadband (n=69) or narrowband (n=126) UVB from 1994 to 2000 with follow-up until 2003. Data were raised from the regional interdisciplinary cancer centre of the University of Tuebingen, Germany and compared with the tumour incidences given for the German population. In this study, with 80% statistical power to detect a 6-7-fold increase in skin cancer with broadband UVB and 83% power to detect a 5-6-fold increase with narrow band UVB at p=0.05, only one patient developed skin cancer - an in situ melanoma. The tumour occurred within the same year that phototherapy was initiated. Thus, the present study does not provide evidence for an increased skin cancer risk for patients treated with either broadband or narrowband UVB phototherapy
Mutations of mitochondrial (mt) DNA such as the 4977 base-pair large-scale deletion, also called common deletion, are increased in photoaged skin. Direct evidence for their induction by chronic exposure to ultraviolet (UV) radiation in vivo in human skin has remained elusive however. Furthermore, their fate after induction is unclear. Previously unirradiated skin of 52 normal human individuals was repetitively exposed to physiological doses of UVA light. Skin and blood specimens were investigated for the presence of mtDNA mutations employing semiquantitative nested PCR, as well as real-time PCR, after 2 weeks of UV exposure and the content of the common deletion was followed up for up to 16 mo after cessation of irradiation. As assessed by both methods, repetitive UV exposure led to an approximately 40% increase in the levels of the common deletion in normal human skin. The majority of deletions were detectable in the dermis also showing the biggest increase, whereas in the epidermis only residual levels and no increase were found. Nine individuals were examined up to 16 mo after cessation of UV exposure and some showed accumulation up to 32-fold. Thus, mtDNA mutations are induced in the human skin by repetitive UV exposure. In addition, these mutations seem to represent long-term in-vivo biomarkers for actinic damage in the human skin.
Mutations of mitochondrial DNA accumulate during normal aging and can be detected at elevated levels in skin prematurely aged by chronic exposure to ultraviolet (UV) light (photoaging). In normal human fibroblasts, we have previously demonstrated that mtDNA deletions are induced by repetitive exposure to sublethal doses of UVA radiation mediated through singlet oxygen. Betacarotene is a known quencher of ROS and singlet oxygen in particular, and it is widely applied in photoprotective compounds. Therefore we investigated whether in our in vitro system, betacarotene is capable of protecting from the induction of photoaging-associated mtDNA deletions. All-E (trans) betacarotene was tested at doses from 0.25 to 3.0 microM for uptake into cells as well as its protective capacity. Assessment of cellular uptake of all-E betacarotene measured by HPLC revealed a dose dependent increase of intracellular concentrations, as well as an increase in oxidative metabolites. UVA-exposure led to a decrease of all-E-betacarotene, its Z-isomers and oxidative metabolites. Assessment of mtDNA deletions by PCR revealed reduced levels of mtDNA mutagenesis in cells coincubated with betacarotene at concentrations of 0.5 microM and higher. Taken together, these results indicate that betacarotene (i) is taken up into the cell in a dose dependent manner, (ii) interacts with UVA radiation in the cell and (iii) shows protective properties from the induction of a photoaging-associated mtDNA mutation.
Induction of apoptosis of keratinocytes by ultraviolet (UV) radiation is a protective phenomenon relevant in limiting the survival of cells with irreparable DNA damage. Changes in UV-induced apoptosis may therefore have significant impact on photocarcinogenesis. We have found that the immunomodulatory cytokine IL-12 suppresses UV-mediated apoptosis of keratinocytes both in vitro and in vivo. IL-12 caused a remarkable reduction in UV-specific DNA lesions which was due to induction of DNA repair. In accordance with this, IL-12 induced the expression of particular components of the nucleotide-excision repair complex. Our results show that cytokines can protect cells from apoptosis induced by DNA-damaging UV radiation by inducing DNA repair, and that nucleotide-excision repair can be manipulated by cytokines.
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