Alexander Haslberger - Academia.edu (original) (raw)

Papers by Alexander Haslberger

Environmental Sciences Europe, 2020

Background The insertion of a transgene into a plant organism can, in addition to the intended ef... more Background The insertion of a transgene into a plant organism can, in addition to the intended effects, lead to unintended effects in the plants. To uncover such effects, we compared maize grains of two genetically modified varieties containing NK603 (AG8025RR2, AG9045RR2) to their non-transgenic counterparts (AG8025conv, AG9045conv) using high-throughput RNA sequencing. Moreover, in-depth analysis of these data was performed to reveal the biological meaning of detected differences. Results Uniquely mapped reads corresponded to 29,146 and 33,420 counts in the AG8025 and AG9045 varieties, respectively. An analysis using the R-Bioconductor package EdgeR revealed 3534 and 694 DEGs (significant differentially expressed genes) between the varieties AG8025RR2 and AG9045RR2, respectively, and their non-transgenic counterparts. Furthermore, a Deseq2 package revealed 2477 and 440 DEGs between AG8025RR2 and AG9045RR2, respectively, and their counterparts. We were able to confirm the RNA-seq r...

Experimental Gerontology, Jun 1, 2009

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

British Journal of Pharmacology, Aug 22, 2012

The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by... more The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-Lhomocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy.

Epigenomes, Jan 10, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Annals of Nutrition and Metabolism, 2010

genistein 200 mol/l: 2.1-fold; resveratrol 50 mol/l: 6.3fold) and ESR2 (2.6-and 3.6-fold, respect... more genistein 200 mol/l: 2.1-fold; resveratrol 50 mol/l: 6.3fold) and ESR2 (2.6-and 3.6-fold, respectively). Genistein and resveratrol treatment increased promoter methylation of ESR1 (genistein 200 mol/l: 2.9-fold; resveratrol 50 mol/l: 1.4-fold). For p16 INK4a , increased methylation was found after exposure to 10 mol/l resveratrol, but for p15 INK4b , decreased methylation was found. Both components showed growthinhibitory activities. For EGCG, growth inhibition at 100 mol/l and suppressed promoter methylation of tumor suppressor genes (p16 INK4a : 0.9-fold; p15 INK4b : 0.6-fold) was seen. Conclusions: Our results show that these food compounds regulate ESR and tumor suppressor gene expression by multiple mechanisms including epigenetic processes. An improved understanding of these epigenetic effects could therefore support specific dietary concepts of epigenetic cancer prevention and intervention.

Current Opinion in Clinical Nutrition and Metabolic Care, Jul 1, 2015

Nutrients or even diets affect the epigenome by lifelong remodeling. Nutritional imbalances are a... more Nutrients or even diets affect the epigenome by lifelong remodeling. Nutritional imbalances are associated with noncommunicable diseases. Thus, nutriepigenomics is a promising field in the treatment of complex human diseases. The epigenome is susceptible to changes and can be shaped by nutritional states, especially in prenatal period through transgenerational mechanisms and in early postnatal life when critical developmental processes are taking place. Although more stable, the epigenetic marks in adulthood are also dynamic and modifiable by environmental factors including diet. The present review is focused on the most recent knowledge of epigenetically active nutrients/diets including transgenerational inheritance and prenatal predispositions related to increased risk for cancer, metabolic syndrome, and neurodegenerative diseases.

Comparative Immunology Microbiology and Infectious Diseases, May 1, 2009

PCR detection of microbial pathogens in blood from patients is a promising issue for rapid diagno... more PCR detection of microbial pathogens in blood from patients is a promising issue for rapid diagnosis of sepsis and early targeted therapy. However, for PCR assays detecting all bacterial groups, broad range primers, in particular the 16S rDNA targeting primers have to be used. Upcoming false signals and reduced sensitivity are a common problem as a consequence of unspecific amplification reactions with the human DNA background. Here we show that, using total DNA extracts from blood, unspecific signals occurred in general 16S rDNA PCRs as a result of the amplification of human sequences. To address this problem, we developed a protocol by which the human background DNA is removed and bacterial DNA is enriched during sample preparation, a method we termed background-free enrichment method (BFEM). In general, we aimed to exclude false signals due to the human background DNA yielded from 16S rDNA PCR, Real-Time-PCR and IGS-PCR analyses. We applied the BFEM to the analysis of blood samples from 22 patients and obtained results similar to standard blood culture methods.

Beneficial Microbes, Mar 1, 2014

Metabolic syndrome is associated with alterations in the structure of the gut microbiota leading ... more Metabolic syndrome is associated with alterations in the structure of the gut microbiota leading to low-grade inflammatory responses. An increased penetration of the impaired gut membrane by bacterial components is believed to induce this inflammation, possibly involving epigenetic alteration of inflammatory molecules such as Toll-like receptors (TLRs). We evaluated changes of the gut microbiota and epigenetic DNA methylation of TLR2 and TLR4 in three groups of subjects: type 2 diabetics under glucagon-like peptide-1 agonist therapy, obese individuals without established insulin resistance, and a lean control group. Clostridium cluster IV, Clostridium cluster XIVa, lactic acid bacteria, Faecalibacterium prausnitzii and Bacteroidetes abundances were analysed by PCR and 454 high-throughput sequencing. The epigenetic methylation in the regulatory region of TLR4 and TLR2 was analysed using bisulfite conversion and pyrosequencing. We observed a significantly higher ratio of Firmicutes/ Bacteroidetes in type 2 diabetics compared to lean controls and obese. Major differences were shown in lactic acid bacteria, with the highest abundance in type 2 diabetics, followed by obese and lean participants. In comparison, F. prausnitzii was least abundant in type 2 diabetics, and most abundant in lean controls. Methylation analysis of four CpGs in the first exon of TLR4 showed significantly lower methylation in obese individuals, but no significant difference between type 2 diabetics and lean controls. Methylation of seven CpGs in the promoter region of TLR2 was significantly lower in type 2 diabetics compared to obese subjects and lean controls. The methylation levels of both TLRs were significantly correlated with body mass index. Our data suggest that changes in gut microbiota and thus cell wall components are involved in the epigenetic regulation of inflammatory reactions. An improved diet targeted to induce gut microbial balance and in the following even epigenetic changes of pro-inflammatory genes may be effective in the prevention of metabolic syndrome.

Functional Foods in Health and Disease, Mar 9, 2021

Introduction: Topical investigations have demonstrated that oxidative stress and inflammation pla... more Introduction: Topical investigations have demonstrated that oxidative stress and inflammation play key roles in biological aging and determine incidence and course of age-related diseases. Lifestyle and environmental factors hugely impact epigenetic regulation and DNA stability with telomere attrition and epigenetic instability providing a potential record of the cumulative burden of endogenous and exogenous oxidative noxae. Certain physiologically active plant components exhibit antioxidative activities affecting epigenetic regulation of inflammation response and DNA repair. Methods: Against this background, the present study investigated green tea polyphenol epigallocatechin gallate (EGCG) in the context of telomere regulation in Caco-2 colorectal adenocarcinoma cells vs. ES-1 primary skin fibroblasts. Cell lines were treated with 20 and 200 µM EGCG for 36, 72 and 144 hours, respectively. Telomerase

Lifestyle genomics, 2015

Background/Aims: Diabetes mellitus type 2 (DMT2) is accompanied by systemic low-grade inflammatio... more Background/Aims: Diabetes mellitus type 2 (DMT2) is accompanied by systemic low-grade inflammation with elevated levels of interleukin-6 (IL-6), which is encoded by a gene (IL-6) previously shown to be regulated by DNA methylation. We investigated seven CpG sites in IL-6 in individuals with DMT2, obese individuals and lean controls. Further, the DMT2 group received the glucagon-like peptide 1 agonist liraglutide. Methods: Blood samples were taken at the beginning of the study and after 4 months. The DNA methylation was assessed using pyrosequencing. Results: Methylation levels at the CpG sites-664,-628 and +13 at the first sampling time point (T1) and at-666 and-664 at the second sampling time point (T2) correlated negatively with initial body weight in the DMT2 group. We found positive correlations for the obese and the lean control group. In the obese group, CpG +27 methylation at T1 correlated with initial body weight (r = 0.685; p = 0.014). In the lean group, CpG-664 at T1 (r = 0.874; p = 0.005) and CpG-628 at T2 (r = 0.632; p = 0.050) correlated with initial body weight. Conclusion: These findings are an informative basis for further studies to elucidate epigenetic mechanisms underlying DMT2. Additionally, our results might provide starting points for the development of biomarkers for prevention and therapy strategies.

Medical Hypotheses, 2006

Interactions between adaptative and selective processes are illustrated in the model of recursive... more Interactions between adaptative and selective processes are illustrated in the model of recursive causality as defined in Rupert Riedl's systems theory of evolution. One of the main features of this theory also termed as theory of evolving complexity is the centrality of the notion of 'recursive' or 'feedback' causality-'the idea that every biological effect in living systems, in some way, feeds back to its own cause'. Our hypothesis is that ''recursive'' or ''feedback'' causality provides a model for explaining the consequences of interacting genetic and epigenetic mechanisms which are known to play a key role in development of cancer. Epigenetics includes any process that alters gene activity without changes of the DNA sequence. The most important epigenetic mechanisms are DNA-methylation and chromatin remodeling. Hypomethylation of so-called oncogenes and hypermethylation of tumor suppressor genes appear to be critical determinants of cancer. Folic acid, vitamin B12 and other nutrients influence the function of enzymes that participate in various methylation processes by affecting the supply of methyl groups into a variety of molecules which may be directly or indirectly associated with cancerogenesis. We present an example from our own studies by showing that vitamin D3 has the potential to de-methylate the osteocalcin-promoter in MG63 osteosarcoma cells. Consequently, a stimulation of osteocalcin synthesis can be observed. The above mentioned enzymes also play a role in development and differentiation of cells and organisms and thus illustrate the close association between evolutionary and developmental mechanisms. This enabled new ways to understand the interaction between the genome and environment and may improve biomedical concepts including environmental health aspects where epigenetic and genetic modifications are closely associated. Recent observations showed that methylated nucleotides in the gene promoter may serve as a target for solar UV-induced mutations of the p53 tumor suppressor gene. This illustrates the close interaction of genetic and epigenetic mechanisms in cancerogenesis resulting from changes in transcriptional regulation and its contribution to a phenotype at the micro-or macroevolutionary level. Abovementioned interactions of genetic and epigenetic mechanisms in oncogenesis defy explanation by plain linear causality, things like the continuing adaptability of complex systems. They can be explained by the concept of recursive causality and has introduced molecular biology into the realm of cognition science and systems theory: based

British Journal of Pharmacology, Dec 15, 2014

Many nutrients are known for a wide range of activities in prevention and alleviation of various ... more Many nutrients are known for a wide range of activities in prevention and alleviation of various diseases. Recently, their potential role in regulating human health through effects on epigenetics has become evident, although specific mechanisms are still unclear. Thus, nutriepigenetics/nutriepigenomics has emerged as a new and promising field in current epigenetics research in the past few years. In particular, polyphenols, as part of the central dynamic interaction between the genome and the environment with specificity at physiological concentrations, are well known to affect mechanisms underlying human health. This review summarizes the effects of dietary compounds on epigenetic mechanisms in the regulation of gene expression including expression of enzymes and other molecules responsible for drug absorption, distribution, metabolism and excretion in cancer, metabolic syndrome, neurodegenerative disorders and hormonal dysfunction.

Molecular Aspects of Medicine, Apr 1, 2017

Dietary habits, lifestyle, medication, and food additives affect the composition and functions of... more Dietary habits, lifestyle, medication, and food additives affect the composition and functions of the GI microbiota. Metabolic syndrome is already known to be associated with an aberrant gut microbiota affecting systemic low-grade inflammation, which is also outlined by differing epigenetic patterns. Thus, structural changes and compositional evaluation of gut microbial differences affecting epigenetic patterns in metabolic syndrome are of research interest. In the present review we focus on the disparities in the gut microbiota composition of metabolic syndrome and the resulting aberrant profile of bioactive microbial metabolites known to affect epigenetic modifications such as G-protein coupled receptors and inflammatory pathways.

Methods in pharmacology and toxicology, Dec 14, 2016

Annals of Hematology, Oct 23, 2001

Expression of cytokines such as tumor necrosis factor-alpha (TNF-alpha) induced by lipopolysaccha... more Expression of cytokines such as tumor necrosis factor-alpha (TNF-alpha) induced by lipopolysaccharide (LPS) has been associated with inflammatory and regulatory immune reactions. Antigen-presenting cells, especially macrophages, play a central role in directing immune responses by synthesizing different cytokines. For the analysis of cytokine synthesis, we compared quantitative changes in mRNA and protein synthesis of TNF-alpha in RAW 264.7 cells stimulated with 0.1 ng/ml LPS. TNF-alpha mRNA was quantified using the LightCycler SYBR Green technology (Idaho Technology, Inc., Salt Lake City, Utah, USA). RAW 264.7 cells showed a basal TNF-alpha mRNA expression which increased approximately sixfold after 2 h of stimulation with LPS. TNF-alpha synthesis was analyzed at the protein level using a mouse-specific sandwich enzyme-linked immunosorbent assay (ELISA) and indicated a 56-fold increase in TNF-alpha protein concentration after 4 h. Thus, real-time polymerase chain reaction (PCR) is a sensitive and rapid method for quantitative determination of LPS-induced TNF-alpha expression. However, it requires extremely robust reaction parameters to be reliable for accurate quantification.

Clinical Epigenetics, Oct 1, 2012

Background: Oxidative stress may lead to an increased level of unrepaired cellular DNA damage, wh... more Background: Oxidative stress may lead to an increased level of unrepaired cellular DNA damage, which is discussed as one risk for tumor initiation. Mismatch repair (MMR) enzymes act as proofreading complexes that maintain the genomic integrity and MMR-deficient cells show an increased mutation rate. One important gene in the MMR complex is the MutL homolog 1 (MLH1) gene. Since a diet rich in antioxidants has the potential to counteract harmful effects by reactive oxygen species (ROS), we investigated the impact of an antioxidant, folate, and vitamin rich diet on the epigenetic pattern of MLH1. These effects were analyzed in individuals with non-insulin depended diabetes mellitus type 2 (NIDDM2) and impaired fasting glucose (IFG). Methods: In this post-hoc analysis of a randomized trial we analyzed DNA methylation of MLH1, MSH2, and MGMT at baseline and after 8 weeks of intervention, consisting of 300 g vegetables and 25 ml plant oil rich in polyunsaturated fatty acids per day. DNA methylation was quantified using combined bisulfite restriction enzyme analysis (COBRA) and pyrosequencing. MLH1 and DNMT1 mRNA expression were investigated by qRT-PCR. DNA damage was assessed by COMET assay. Student's two-tailed paired t test and one-way ANOVA with Scheffé corrected Post hoc test was used to determine significant methylation and expression differences. Two-tailed Pearson test was used to determine correlations between methylation level, gene expression, and DNA strand break amount. Results: The intervention resulted in significantly higher CpG methylation in two particular MLH1 promoter regions and the MGMT promoter. DNA strand breaks and methylation levels correlated significantly. The expression of MLH1, DNMT1, and the promoter methylation of MSH2 remained stable. CpG methylation levels and gene expression did not correlate. Conclusion: This vitamin and antioxidant rich diet affected the CpG methylation of MLH1. The higher methylation might be a result of the ROS scavenging antioxidant rich diet, leading to lower activity of DNA demethylating enzymes. Our results suggest the hypothesis of CpG demethylation via DNA repair enzymes under these circumstances. NIDDM2 and IFG patients benefit from this simple dietary intervention involving epigenetic and DNA repair mechanisms.

Beneficial Microbes, Aug 1, 2015

The obese gut microbiota is associated with less bacterial diversity, phylum-and genus-level chan... more The obese gut microbiota is associated with less bacterial diversity, phylum-and genus-level changes, and altered representation of bacterial genes and metabolic pathways involved in nutrient harvest. These differences involve members of the Bacteroidetes, Firmicutes, and Actinobacteria (Tremaroli and Backhed, 2012). Firmicutes

Molecular Biology Reports, May 17, 2023

Background Psychological stress, as an important cofactor in the development of many acute and ch... more Background Psychological stress, as an important cofactor in the development of many acute and chronic diseases, is crucial for general health or well-being, and improved markers are needed to distinguish situations of progressive pathological development, such as depression, anxiety, or burnout, to be recognized at an early stage. Epigenetic biomarkers play an important role in the early detection and treatment of complex diseases such as cancer, and metabolic or mental disorders. Therefore, this study aimed to identify so-called miRNAs, which would be suitable as stress-related biomarkers. Methods and Results In this study, 173 participants (36.4% males, and 63.6% females) were interviewed about stress, stress-related diseases, lifestyle, and diet to assess their acute and chronic psychological stress status. Using qPCR analysis, 13 different miRNAs (miR-10a-5p, miR-15a-5p, miR-16-5p, miR-19b-3p, miR-26b-5p, miR-29c-3p, miR-106b-5p, miR-126-3p, miR-142-3p, let-7a-5p, let-7g-5p, miR-21-5p, and miR-877-5p) were analyzed in dried capillary blood samples. Four miRNAs were identified, miR-10a-5p, miR-15a-5p, let-7a-5p, and let-7g-5p (p < 0.05), which could be used as possible candidates for measuring pathological forms of acute or chronic stress. Let-7a-5p, let-7g-5p, and miR-15a-5p (p < 0.05) were also significantly higher in subjects with at least one stress-related disease. Further, correlations were identified between let-7a-5p and meat consumption (p < 0.05) and between miR-15a-5p and coffee consumption (p < 0.05). Conclusion The examination of these four miRNAs as biomarkers using a minimally invasive method offers the possibility of detecting health problems at an early stage and counteracting them to maintain general and mental health.

Acs Symposium Series, Oct 20, 2008

Wiley-VCH Verlag GmbH & Co. KGaA eBooks, Jan 8, 2010