Bodo Melnik - Academia.edu (original) (raw)
Papers by Bodo Melnik
Current Nutrition Reports, Feb 2, 2023
Purpose of Review This review evaluates cow milk's impact on breast carcinogenesis by linking rec... more Purpose of Review This review evaluates cow milk's impact on breast carcinogenesis by linking recent epidemiological evidence and new insights into the molecular signaling of milk and its constituents in breast cancer (BCa) pathogenesis. Recent Findings Recent prospective cohort studies support the association between cow's milk consumption and the risk of estrogen receptor-α-positive (ER +) BCa. Milk is a complex biological fluid that increases systemic insulin-like growth factor 1 (IGF-1), insulin and estrogen signaling, and interacting hormonal promoters of BCa. Further potential oncogenic components of commercial milk include exosomal microRNAs (miR-148a-3p, miR-21-5p), bovine meat and milk factors, aflatoxin M1, bisphenol A, pesticides, and micro-and nanoplastics. Individuals with BRCA1 loss-of-function mutations and FTO and IGF1 gain-of-function polymorphisms enhancing IGF-1/mTORC1 signaling may be at increased risk for milk-induced ER + BCa. Summary Recent prospective epidemiological and pathobiochemical studies identify commercial milk consumption as a critical risk factor of ER + BCa. Large meta-analyses gathering individuals of different ethnic origins with milk derived from dairy cows of varying genetic backgrounds and diverse feeding procedures as well as missing data on thermal processing of milk (pasteurization versus ultra-heat treatment) make multinational meta-analyses unsuitable for BCa risk estimations in susceptible populations. Future studies are required that consider all vulnerable periods of breast carcinogenesis to cow's milk exposure, beginning during the perinatal period and puberty, since these are the most critical periods of mammary gland morphogenesis. Notwithstanding the need for better studies including detailed information on milk processing and vulnerable periods of human breast carcinogenesis, the available evidence suggests that dietary guidelines on milk consumption may have to be reconsidered.
MMW - Fortschritte der Medizin, 2021
BACKGROUND Recent epidemiological studies associate the consumption of non-fermented cow's mi... more BACKGROUND Recent epidemiological studies associate the consumption of non-fermented cow's milk, but not fermented milk products, with an increased risk of diseases of civilization. OBJECTIVES Presentation of epidemiological and pathophysiological data on health risks associated with milk consumption. METHOD Selective PubMed surveys between 2005-2020 considering epidemiological studies which clearly differentiate between non-fermented versus fermented milk and its potential health risks. RESULTS Epidemiological studies confirm a correlation between milk consumption and birthweight, linear growth during puberty, acne vulgaris, type 2 diabetes mellitus, prostate cancer, breast cancer, hepatocellular carcinoma, non-Hodgkin lymphoma, Parkinson's disease and over-all mortality. In comparison to milk consumption, the intake of fermented milk/milk products exhibits neutral to beneficial health effects, which are explained by attenuated mTORC1 signaling due to bacterial fermentation of milk. CONCLUSIONS Long-term persistent consumption of non-fermented milk, but not fermented milk/milk products, might increase the risk of diseases of civilization. The avoidance of milk, especially pasteurized fresh milk, may enhance the prevention and reduce the recurrence of common Western diseases of civilization.
Journal of the European Academy of Dermatology and Venereology, 2021
BackgroundHidradenitis suppurativa (HS) is a chronic inflammatory disease affecting apocrine glan... more BackgroundHidradenitis suppurativa (HS) is a chronic inflammatory disease affecting apocrine gland‐bearing skin in the axilla, groin and under the breasts. Mutations of the gamma secretase gene complex, which is essential in the activation of Notch signalling pathways, were shown in some families with HS and in a few sporadic cases. Although an imbalance in Notch signalling is implicated in the pathogenesis, the exact mechanism of HS development is yet unknown.ObjectivesWe aim to investigate the genetic basis of HS by determining the presence of mutations of gamma secretase gene complex in a cohort of HS patients and by searching for a disease‐causing pathogenic variant in a multi‐generational HS family using parametric linkage analysis.MethodsThirty‐eight patients clinically diagnosed with HS were included in this study. All exons and exon–intron boundaries of the genes encoding gamma secretase complex consisting of six genes: APH1A, APH1B, PSENEN, NCSTN, PSEN1 and PSEN2 were seque...
Cancers, 2020
DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chr... more DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exoso...
Best practice & research. Clinical endocrinology & metabolism, 2017
Our perception of milk has changed from a "simple food" to a highly sophisticated mater... more Our perception of milk has changed from a "simple food" to a highly sophisticated maternal-neonatal nutrient and communication system orchestrating early programming of the infant. Milk miRNAs delivered by exosomes and milk fat globules derived from mammary gland epithelial cells play a key role in this process. Exosomes resist the harsh intestinal environment, are taken up by intestinal cells via endocytosis, and reach the systemic circulation of the milk recipient. The most abundant miRNA found in exosomes and milk fat globules of human and cow's milk, miRNA-148a, attenuates the expression of DNA methyltransferase 1, which is critically involved in epigenetic regulation. Another important miRNA of milk, miRNA-125b, targets p53, the guardian of the genome, and its diverse transcriptional network. The deficiency of exosomal miRNAs in infant formula and the persistent uptake of milk miRNAs after the nursing period via consumption of cow's milk are two epigenetic abe...
Journal of Translational Medicine, 2017
This review based on translational research predicts that the transcription factor p53 is the key... more This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin's sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.
Journal of Translational Medicine, 2015
Single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity-associated) gene... more Single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity-associated) gene are associated with enhanced FTO expression, increased body weight, obesity and type 2 diabetes mellitus (T2DM). The N 6-methyladenosine (m 6 A) demethylase FTO plays a pivotal regulatory role for postnatal growth and energy expenditure. The purpose of this review is to provide translational evidence that links milk signaling with FTO-activated transcription of the milk recipient. FTO-dependent demethylation of m 6 A regulates mRNA splicing required for adipogenesis, increases the stability of mRNAs, and affects microRNA (miRNA) expression and miRNA biosynthesis. FTO senses branched-chain amino acids (BCAAs) and activates the nutrient sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), which plays a key role in translation. Milk provides abundant BCAAs and glutamine, critical components increasing FTO expression. CpG hypomethylation in the first intron of FTO has recently been associated with T2DM. CpG methylation is generally associated with gene silencing. In contrast, CpG demethylation generally increases transcription. DNA de novo methylation of CpG sites is facilitated by DNA methyltransferases (DNMT) 3A and 3B, whereas DNA maintenance methylation is controlled by DNMT1. MiRNA-29s target all DNMTs and thus reduce DNA CpG methylation. Cow´s milk provides substantial amounts of exosomal miRNA-29s that reach the systemic circulation and target mRNAs of the milk recipient. Via DNMT suppression, milk exosomal miRNA-29s may reduce the magnitude of FTO methylation, thereby epigenetically increasing FTO expression in the milk consumer. High lactation performance with increased milk yield has recently been associated with excessive miRNA-29 expression of dairy cow mammary epithelial cells (DCMECs). Notably, the galactopoietic hormone prolactin upregulates the transcription factor STAT3, which induces miRNA-29 expression. In a retrovirus-like manner milk exosomes may transfer DCMECderived miRNA-29s and bovine FTO mRNA to the milk consumer amplifying FTO expression. There is compelling evidence that obesity, T2DM, prostate and breast cancer, and neurodegenerative diseases are all associated with increased FTO expression. Maximization of lactation performance by veterinary medicine with enhanced miRNA-29s and FTO expression associated with increased exosomal miRNA-29 and FTO mRNA transfer to the milk consumer may represent key epigenetic mechanisms promoting FTO/mTORC1-mediated diseases of civilization.
The Journal of allergy and clinical immunology, Sep 12, 2016
To the Editor: Kirchner et al recently implicated microRNAs of unprocessed cow’s milk in mediatin... more To the Editor: Kirchner et al recently implicated microRNAs of unprocessed cow’s milk in mediating the allergy-preventive effect of farm milk. On the basis of translational evidence, we predicted that the transmission of milk-derived immune-regulatory exosomal microRNAs including microRNA-148a, microRNA-155, microRNA-29b, and microRNA-21 prevent atopy by inducing FoxP31 regulatory T (Treg)-cell differentiation. Notably, farm milk intake is associated with higher FOXP3 demethylation and higher Treg-cell numbers. Stable expression of FoxP3 in Treg cells depends on DNA demethylation at the Treg-cell–specific demethylated region, a conserved CpG-rich region within the FOXP3 locus. DNA methylation is mediated by DNA methyltransferases (DNMTs). Both DNMT1 and DNMT3b are associated with the FOXP3 locus in CD41 cells. DNMT1 deficiency results in highly efficient FoxP3 induction following T-cell receptor stimulation. Importantly, DNMT1 is a direct target of microRNA-148a, which is abundant in bovine colostrum, mature cow’s milk, and human breast milk. MicroRNA-148a is highly expressed in bovine milk fat and milk fat globules of human breast milk. Boiling of cow’s milk results in substantial loss of microRNA148a-3p.Remarkably, nucleotide sequences ofmicroRNA-148a-3p of Homo sapiens and Bos taurus are identical. MicroRNA-148a directly downregulates the expression of DNMT1 and DNMT3b, whereas microRNA-21 indirectly inhibits DNMT1 expression by targeting RASGRP1. MicroRNA-29b, which dose-dependently
Der Hautarzt, 2000
Erysipelas carcinomatosum ist eine inflammatorische, einem Erysipel ähnlich sehende Hautveränderu... more Erysipelas carcinomatosum ist eine inflammatorische, einem Erysipel ähnlich sehende Hautveränderung, die bei einem lymphogen metastasierenden Karzinom auftritt.Es handelt sich meist um Adenokarzinome, insbesondere Mammakarzinome.Wir weisen darauf hin, dass in der Literatur in der jüngsten Zeit anstelle des Begriffs Erysipelas carcinomatosum des Öfteren der Terminus Lymphangiosis carcinomatosa verwendet wird.Wir berichten über einen 51-jährigen männlichen Patienten, der ein Erysipelas carcinomatosum auf der rechten Thoraxhälfte bei einem tubulären Adenokarzinom des Magens entwickelte.
Clinica Chimica Acta, 1982
Serum was incubated in vitro with and without inhibition of lecithin:cholesterol acyltransferase ... more Serum was incubated in vitro with and without inhibition of lecithin:cholesterol acyltransferase (LCAT, EC 2.3.1.43). High density lipoprotein2 (HDL2) and high density lipoprotein3 (HDL3) were separated by zonal ultracentrifugation and analysed for lipid and apoprotein contents. The incubation of fresh sera resulted in a time-dependent decrease in HDL3 and an increase in HDL2. At the end of 24 h incubation HDL3 disappeared completely and the HDL2 peak had reached its maximum. The newly formed HDL2 was relatively enriched in total protein (apoprotein A-I, C-apoproteins) and cholesteryl esters, and depleted in phosphatidylcholine. Its migration in polyacrylamide gel electrophoresis was identical with HDL2 contained in fresh serum or HDL2 isolated from serum by zonal ultracentrifugation. The generated HDL2 particles exhibited the same electron microscopical characteristics as reference HDL2 samples prior to incubation. Addition of Ellman's reagent to the incubation mixture or heat inactivation of the samples prior to incubation resulted in a complete inhibition of HDL3/HDL2 interconversion, whereas addition of 1 mol/l NaCl had no detectable influence. There was also a substantial increase in HDL2 when VLDL-deficient serum was incubated at 37 degrees C. Similarly, in fresh serum from a patient affected with familial lipoprotein lipase deficiency, HDL3 was completely converted to HDL2. Our experiments demonstrate that LCAT promotes HDL3/HDL2 interconversion in native serum irrespective of the presence or absence of triglyceride-rich lipoproteins and lipoprotein lipase.
Biomolecules, 2021
Multiple biologically active components of human milk support infant growth, health and developme... more Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing infant, the majority of recent studies report on the MEV subfraction of milk exosomes (MEX) and their miRNA cargo, which are in the focus of this review. MEX and the dominant miRNA-148a play a key role in intestinal maturation, barrier function and suppression of nuclear factor-κB (NF-κB) signaling and may thus be helpful for the prevention and treatment of necrotizing enterocolitis. MEX and their miRNAs reach the systemic circulation and may impact epigenetic programming of various organs including the liver, thymus, brain, pancreatic islets, beige, brown and white adipose tissue as well as bones. Translational evidence indicates that MEX and their miRNAs control the expression of glo...
Archives of Dermatological Research
The transcriptomic regulation induced by isotretinoin (13-cis retinoic acid) is still a matter of... more The transcriptomic regulation induced by isotretinoin (13-cis retinoic acid) is still a matter of debate as short-term exposures of immortalized sebocytes with isotretinoin produced conflicting results. Based on translational evidence, it has been hypothesized that oral isotretinoin treatment upregulates the expression of the transcription factor p53. Twenty-five patients suffering from acne vulgaris were treated with isotretinoin (0.6 mg/kg body weight) for 6 weeks. Biopsies from back skin were taken before and after isotretinoin treatment for the determination of p53 expression by immunohistochemical staining, quantification of p53 protein concentration by enzyme-linked immunosorbent assay and TP53 gene expression by quantitative reverse transcription real time PCR. Fifteen socio-demographically cross-matched healthy volunteers served as controls. Isotretinoin treatment significantly increased the nuclear expression of p53 in sebaceous glands of treated patients compared to pre-tr...
Braun-Falco’s Dermatologie, Venerologie und Allergologie, 2018
Plewig and Kligman´s Acne and Rosacea, 2019
Human skin provides a favorable habitat for the growth of bacteria, yeasts, and mites. These are ... more Human skin provides a favorable habitat for the growth of bacteria, yeasts, and mites. These are mostly commensals; they nourish themselves on and flourish in hair follicles, but curiously not within sweat glands and their acrosyringa, where the secretion of IgA into the acrosyringium and the constitutive expression of antimicrobial peptides like dermcidin may provide protective effect. A certain kind of mutualistic interaction between human Demodex mites and humans is likely based on the speculation that Demodex mites may play a scavenger role by removing excess sebum products and proteins or by feeding on the P. acnes that inhabit the same sebaceous follicles. Our skin may be likened to a botanical and zoological garden, supporting a diversity of species.
Plewig and Kligman´s Acne and Rosacea, 2019
Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise s... more Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise status
Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise s... more Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise status
Plewig and Kligman´s Acne and Rosacea, 2019
There is substantial evidence that hereditary factors play an important role in acne pathogenesis... more There is substantial evidence that hereditary factors play an important role in acne pathogenesis. They enhance the risk for disease or aggravate its course and outcome and modify the time of onset, persistence after puberty, response to treatment, tissue remodeling and healing, the extent of scaring, and the disposition for keloid. Acne genetics have been overestimated during the last decades because a single genetic polymorphism or a rare mutation cannot explain the high and fast raising prevalence rates in adolescents living in developed countries. The high acne prevalence in developed countries underlines the predominance of environmental factors including Western-style nutrition.
Current Nutrition Reports, Feb 2, 2023
Purpose of Review This review evaluates cow milk's impact on breast carcinogenesis by linking rec... more Purpose of Review This review evaluates cow milk's impact on breast carcinogenesis by linking recent epidemiological evidence and new insights into the molecular signaling of milk and its constituents in breast cancer (BCa) pathogenesis. Recent Findings Recent prospective cohort studies support the association between cow's milk consumption and the risk of estrogen receptor-α-positive (ER +) BCa. Milk is a complex biological fluid that increases systemic insulin-like growth factor 1 (IGF-1), insulin and estrogen signaling, and interacting hormonal promoters of BCa. Further potential oncogenic components of commercial milk include exosomal microRNAs (miR-148a-3p, miR-21-5p), bovine meat and milk factors, aflatoxin M1, bisphenol A, pesticides, and micro-and nanoplastics. Individuals with BRCA1 loss-of-function mutations and FTO and IGF1 gain-of-function polymorphisms enhancing IGF-1/mTORC1 signaling may be at increased risk for milk-induced ER + BCa. Summary Recent prospective epidemiological and pathobiochemical studies identify commercial milk consumption as a critical risk factor of ER + BCa. Large meta-analyses gathering individuals of different ethnic origins with milk derived from dairy cows of varying genetic backgrounds and diverse feeding procedures as well as missing data on thermal processing of milk (pasteurization versus ultra-heat treatment) make multinational meta-analyses unsuitable for BCa risk estimations in susceptible populations. Future studies are required that consider all vulnerable periods of breast carcinogenesis to cow's milk exposure, beginning during the perinatal period and puberty, since these are the most critical periods of mammary gland morphogenesis. Notwithstanding the need for better studies including detailed information on milk processing and vulnerable periods of human breast carcinogenesis, the available evidence suggests that dietary guidelines on milk consumption may have to be reconsidered.
MMW - Fortschritte der Medizin, 2021
BACKGROUND Recent epidemiological studies associate the consumption of non-fermented cow's mi... more BACKGROUND Recent epidemiological studies associate the consumption of non-fermented cow's milk, but not fermented milk products, with an increased risk of diseases of civilization. OBJECTIVES Presentation of epidemiological and pathophysiological data on health risks associated with milk consumption. METHOD Selective PubMed surveys between 2005-2020 considering epidemiological studies which clearly differentiate between non-fermented versus fermented milk and its potential health risks. RESULTS Epidemiological studies confirm a correlation between milk consumption and birthweight, linear growth during puberty, acne vulgaris, type 2 diabetes mellitus, prostate cancer, breast cancer, hepatocellular carcinoma, non-Hodgkin lymphoma, Parkinson's disease and over-all mortality. In comparison to milk consumption, the intake of fermented milk/milk products exhibits neutral to beneficial health effects, which are explained by attenuated mTORC1 signaling due to bacterial fermentation of milk. CONCLUSIONS Long-term persistent consumption of non-fermented milk, but not fermented milk/milk products, might increase the risk of diseases of civilization. The avoidance of milk, especially pasteurized fresh milk, may enhance the prevention and reduce the recurrence of common Western diseases of civilization.
Journal of the European Academy of Dermatology and Venereology, 2021
BackgroundHidradenitis suppurativa (HS) is a chronic inflammatory disease affecting apocrine glan... more BackgroundHidradenitis suppurativa (HS) is a chronic inflammatory disease affecting apocrine gland‐bearing skin in the axilla, groin and under the breasts. Mutations of the gamma secretase gene complex, which is essential in the activation of Notch signalling pathways, were shown in some families with HS and in a few sporadic cases. Although an imbalance in Notch signalling is implicated in the pathogenesis, the exact mechanism of HS development is yet unknown.ObjectivesWe aim to investigate the genetic basis of HS by determining the presence of mutations of gamma secretase gene complex in a cohort of HS patients and by searching for a disease‐causing pathogenic variant in a multi‐generational HS family using parametric linkage analysis.MethodsThirty‐eight patients clinically diagnosed with HS were included in this study. All exons and exon–intron boundaries of the genes encoding gamma secretase complex consisting of six genes: APH1A, APH1B, PSENEN, NCSTN, PSEN1 and PSEN2 were seque...
Cancers, 2020
DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chr... more DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exoso...
Best practice & research. Clinical endocrinology & metabolism, 2017
Our perception of milk has changed from a "simple food" to a highly sophisticated mater... more Our perception of milk has changed from a "simple food" to a highly sophisticated maternal-neonatal nutrient and communication system orchestrating early programming of the infant. Milk miRNAs delivered by exosomes and milk fat globules derived from mammary gland epithelial cells play a key role in this process. Exosomes resist the harsh intestinal environment, are taken up by intestinal cells via endocytosis, and reach the systemic circulation of the milk recipient. The most abundant miRNA found in exosomes and milk fat globules of human and cow's milk, miRNA-148a, attenuates the expression of DNA methyltransferase 1, which is critically involved in epigenetic regulation. Another important miRNA of milk, miRNA-125b, targets p53, the guardian of the genome, and its diverse transcriptional network. The deficiency of exosomal miRNAs in infant formula and the persistent uptake of milk miRNAs after the nursing period via consumption of cow's milk are two epigenetic abe...
Journal of Translational Medicine, 2017
This review based on translational research predicts that the transcription factor p53 is the key... more This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin's sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.
Journal of Translational Medicine, 2015
Single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity-associated) gene... more Single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity-associated) gene are associated with enhanced FTO expression, increased body weight, obesity and type 2 diabetes mellitus (T2DM). The N 6-methyladenosine (m 6 A) demethylase FTO plays a pivotal regulatory role for postnatal growth and energy expenditure. The purpose of this review is to provide translational evidence that links milk signaling with FTO-activated transcription of the milk recipient. FTO-dependent demethylation of m 6 A regulates mRNA splicing required for adipogenesis, increases the stability of mRNAs, and affects microRNA (miRNA) expression and miRNA biosynthesis. FTO senses branched-chain amino acids (BCAAs) and activates the nutrient sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), which plays a key role in translation. Milk provides abundant BCAAs and glutamine, critical components increasing FTO expression. CpG hypomethylation in the first intron of FTO has recently been associated with T2DM. CpG methylation is generally associated with gene silencing. In contrast, CpG demethylation generally increases transcription. DNA de novo methylation of CpG sites is facilitated by DNA methyltransferases (DNMT) 3A and 3B, whereas DNA maintenance methylation is controlled by DNMT1. MiRNA-29s target all DNMTs and thus reduce DNA CpG methylation. Cow´s milk provides substantial amounts of exosomal miRNA-29s that reach the systemic circulation and target mRNAs of the milk recipient. Via DNMT suppression, milk exosomal miRNA-29s may reduce the magnitude of FTO methylation, thereby epigenetically increasing FTO expression in the milk consumer. High lactation performance with increased milk yield has recently been associated with excessive miRNA-29 expression of dairy cow mammary epithelial cells (DCMECs). Notably, the galactopoietic hormone prolactin upregulates the transcription factor STAT3, which induces miRNA-29 expression. In a retrovirus-like manner milk exosomes may transfer DCMECderived miRNA-29s and bovine FTO mRNA to the milk consumer amplifying FTO expression. There is compelling evidence that obesity, T2DM, prostate and breast cancer, and neurodegenerative diseases are all associated with increased FTO expression. Maximization of lactation performance by veterinary medicine with enhanced miRNA-29s and FTO expression associated with increased exosomal miRNA-29 and FTO mRNA transfer to the milk consumer may represent key epigenetic mechanisms promoting FTO/mTORC1-mediated diseases of civilization.
The Journal of allergy and clinical immunology, Sep 12, 2016
To the Editor: Kirchner et al recently implicated microRNAs of unprocessed cow’s milk in mediatin... more To the Editor: Kirchner et al recently implicated microRNAs of unprocessed cow’s milk in mediating the allergy-preventive effect of farm milk. On the basis of translational evidence, we predicted that the transmission of milk-derived immune-regulatory exosomal microRNAs including microRNA-148a, microRNA-155, microRNA-29b, and microRNA-21 prevent atopy by inducing FoxP31 regulatory T (Treg)-cell differentiation. Notably, farm milk intake is associated with higher FOXP3 demethylation and higher Treg-cell numbers. Stable expression of FoxP3 in Treg cells depends on DNA demethylation at the Treg-cell–specific demethylated region, a conserved CpG-rich region within the FOXP3 locus. DNA methylation is mediated by DNA methyltransferases (DNMTs). Both DNMT1 and DNMT3b are associated with the FOXP3 locus in CD41 cells. DNMT1 deficiency results in highly efficient FoxP3 induction following T-cell receptor stimulation. Importantly, DNMT1 is a direct target of microRNA-148a, which is abundant in bovine colostrum, mature cow’s milk, and human breast milk. MicroRNA-148a is highly expressed in bovine milk fat and milk fat globules of human breast milk. Boiling of cow’s milk results in substantial loss of microRNA148a-3p.Remarkably, nucleotide sequences ofmicroRNA-148a-3p of Homo sapiens and Bos taurus are identical. MicroRNA-148a directly downregulates the expression of DNMT1 and DNMT3b, whereas microRNA-21 indirectly inhibits DNMT1 expression by targeting RASGRP1. MicroRNA-29b, which dose-dependently
Der Hautarzt, 2000
Erysipelas carcinomatosum ist eine inflammatorische, einem Erysipel ähnlich sehende Hautveränderu... more Erysipelas carcinomatosum ist eine inflammatorische, einem Erysipel ähnlich sehende Hautveränderung, die bei einem lymphogen metastasierenden Karzinom auftritt.Es handelt sich meist um Adenokarzinome, insbesondere Mammakarzinome.Wir weisen darauf hin, dass in der Literatur in der jüngsten Zeit anstelle des Begriffs Erysipelas carcinomatosum des Öfteren der Terminus Lymphangiosis carcinomatosa verwendet wird.Wir berichten über einen 51-jährigen männlichen Patienten, der ein Erysipelas carcinomatosum auf der rechten Thoraxhälfte bei einem tubulären Adenokarzinom des Magens entwickelte.
Clinica Chimica Acta, 1982
Serum was incubated in vitro with and without inhibition of lecithin:cholesterol acyltransferase ... more Serum was incubated in vitro with and without inhibition of lecithin:cholesterol acyltransferase (LCAT, EC 2.3.1.43). High density lipoprotein2 (HDL2) and high density lipoprotein3 (HDL3) were separated by zonal ultracentrifugation and analysed for lipid and apoprotein contents. The incubation of fresh sera resulted in a time-dependent decrease in HDL3 and an increase in HDL2. At the end of 24 h incubation HDL3 disappeared completely and the HDL2 peak had reached its maximum. The newly formed HDL2 was relatively enriched in total protein (apoprotein A-I, C-apoproteins) and cholesteryl esters, and depleted in phosphatidylcholine. Its migration in polyacrylamide gel electrophoresis was identical with HDL2 contained in fresh serum or HDL2 isolated from serum by zonal ultracentrifugation. The generated HDL2 particles exhibited the same electron microscopical characteristics as reference HDL2 samples prior to incubation. Addition of Ellman's reagent to the incubation mixture or heat inactivation of the samples prior to incubation resulted in a complete inhibition of HDL3/HDL2 interconversion, whereas addition of 1 mol/l NaCl had no detectable influence. There was also a substantial increase in HDL2 when VLDL-deficient serum was incubated at 37 degrees C. Similarly, in fresh serum from a patient affected with familial lipoprotein lipase deficiency, HDL3 was completely converted to HDL2. Our experiments demonstrate that LCAT promotes HDL3/HDL2 interconversion in native serum irrespective of the presence or absence of triglyceride-rich lipoproteins and lipoprotein lipase.
Biomolecules, 2021
Multiple biologically active components of human milk support infant growth, health and developme... more Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing infant, the majority of recent studies report on the MEV subfraction of milk exosomes (MEX) and their miRNA cargo, which are in the focus of this review. MEX and the dominant miRNA-148a play a key role in intestinal maturation, barrier function and suppression of nuclear factor-κB (NF-κB) signaling and may thus be helpful for the prevention and treatment of necrotizing enterocolitis. MEX and their miRNAs reach the systemic circulation and may impact epigenetic programming of various organs including the liver, thymus, brain, pancreatic islets, beige, brown and white adipose tissue as well as bones. Translational evidence indicates that MEX and their miRNAs control the expression of glo...
Archives of Dermatological Research
The transcriptomic regulation induced by isotretinoin (13-cis retinoic acid) is still a matter of... more The transcriptomic regulation induced by isotretinoin (13-cis retinoic acid) is still a matter of debate as short-term exposures of immortalized sebocytes with isotretinoin produced conflicting results. Based on translational evidence, it has been hypothesized that oral isotretinoin treatment upregulates the expression of the transcription factor p53. Twenty-five patients suffering from acne vulgaris were treated with isotretinoin (0.6 mg/kg body weight) for 6 weeks. Biopsies from back skin were taken before and after isotretinoin treatment for the determination of p53 expression by immunohistochemical staining, quantification of p53 protein concentration by enzyme-linked immunosorbent assay and TP53 gene expression by quantitative reverse transcription real time PCR. Fifteen socio-demographically cross-matched healthy volunteers served as controls. Isotretinoin treatment significantly increased the nuclear expression of p53 in sebaceous glands of treated patients compared to pre-tr...
Braun-Falco’s Dermatologie, Venerologie und Allergologie, 2018
Plewig and Kligman´s Acne and Rosacea, 2019
Human skin provides a favorable habitat for the growth of bacteria, yeasts, and mites. These are ... more Human skin provides a favorable habitat for the growth of bacteria, yeasts, and mites. These are mostly commensals; they nourish themselves on and flourish in hair follicles, but curiously not within sweat glands and their acrosyringa, where the secretion of IgA into the acrosyringium and the constitutive expression of antimicrobial peptides like dermcidin may provide protective effect. A certain kind of mutualistic interaction between human Demodex mites and humans is likely based on the speculation that Demodex mites may play a scavenger role by removing excess sebum products and proteins or by feeding on the P. acnes that inhabit the same sebaceous follicles. Our skin may be likened to a botanical and zoological garden, supporting a diversity of species.
Plewig and Kligman´s Acne and Rosacea, 2019
Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise s... more Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise status
Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise s... more Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise status
Plewig and Kligman´s Acne and Rosacea, 2019
There is substantial evidence that hereditary factors play an important role in acne pathogenesis... more There is substantial evidence that hereditary factors play an important role in acne pathogenesis. They enhance the risk for disease or aggravate its course and outcome and modify the time of onset, persistence after puberty, response to treatment, tissue remodeling and healing, the extent of scaring, and the disposition for keloid. Acne genetics have been overestimated during the last decades because a single genetic polymorphism or a rare mutation cannot explain the high and fast raising prevalence rates in adolescents living in developed countries. The high acne prevalence in developed countries underlines the predominance of environmental factors including Western-style nutrition.