Category Archives: Epigenetics

Blood pressure reduction in telmisartan-treated patients

J Pharm Pharmacogn Res 6(6): 424-432, 2018.

Original Article | Artículo Original

Blood pressure reduction in telmisartan-treated angiotensinogen G-217A polymorphism hypertensive patients: A pilot study

[Reducción de la presión arterial en pacientes hipertensos con polimorfismo de angiotensinógeno G-217A tratados con telmisartán: un estudio piloto]

Mohammad S. Rohman1*, Risa Ramadhiani2, Widodo Widodo3, Valerinna Y.S. Putri1, Mifetika Lukitasari4, Jayarani F. Putri5, Didik H. Utomo3

1Departement of Cardiology and Vascular Medicine, Faculty of Medicine, Brawijaya University, Veteran Street, Malang, 65145, Indonesia.
 2Departement of Biomedical Science, Faculty of Medicine, Brawijaya University, Veteran Street, Malang, 65145, Indonesia.
3Departement of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Veteran Street, Malang, 65145, Indonesia.
4Departement of Nursing, Faculty of Medicine, Brawijaya University, Veteran Street, Malang, 65145, Indonesia.
5Departement of Biological Science, Faculty of Life and Enviromental Science, Tsukuba University, Higashi 1-1-1, Tsukuba, 305-8565, Japan.

*E-mail: ippoenk@ub.ac.id; ippoenk@yahoo.com

Abstract

Context: The angiotensinogen (AGT) G-217A polymorphism has been proved as one factor contributing the susceptibility of hypertension, meanwhile, the effect of this polymorphism to the variability antihypertensive response remains unknown.

Aims: To investigate whether the angiotensinogen (AGT) G-217A polymorphism affects the blood pressure response to telmisartan and valsartan in Indonesian hypertensive patients.

Methods: The blood pressure was measured by ambulatory blood pressure monitoring (ABPM) and plasma angiotensinogen (AGT) levels of telmisartan- and valsartan-treated AGT G-217A polymorphism hypertensive patients (n=46) were analyzed using ELISA at the baseline and 4 months after treatments. Molecular docking was used to predict the interaction between C/EBPα and AGT G-217A polymorphism.

Results: Daytime and 24 hours blood pressure in telmisartan-treated -217 AA/AG patients were significantly lower compared to GG genotype patients. The plasma AGT level in those who had AA/AG genotype and received telmisartan 80 mg was also slightly decreased compared to GG genotype, even these differences were failed to reach statistically significant. The docking results showed that the basic region of C/EBPα transcription factor recognized the partially homologous of its consensus sequences within -217A oligonucleotide, but not in -217G oligonucleotide.

Conclusions: The blood pressure reduction responses in telmisartan-treated angiotensinogen G-217A polymorphism hypertensive patients might correlate with PPARγ agonist effects of telmisartan via C/EBPα and AGT -217A interaction.

Keywords: AGT G-217A polymorphism; hypertension; telmisartan; valsartan.

Resumen

Contexto: El polimorfismo del angiotensinógeno (AGT) G-217A se ha demostrado como un factor que contribuye a la susceptibilidad de la hipertensión, mientras tanto, el efecto de este polimorfismo sobre la variabilidad de la respuesta antihipertensiva permanece desconocido.

Objetivos: Investigar si el polimorfismo angiotensinógeno (AGT) G-217A afecta la respuesta de la presión arterial a telmisartán y valsartán en pacientes hipertensos indonesios.

Métodos: Se realizó la monitorización ambulatoria de la presión arterial (MAPA) y se analizaron los niveles de angiotensinógeno plasmático (AGT) de pacientes hipertensos con polimorfismo AGT G-217A tratados con telmisartán y valsartán (n=46), mediante ELISA, al inicio y 4 meses después de los tratamientos. El acoplamiento molecular se usó para predecir la interacción entre el polimorfismo C/EBPα y AGT G-217A.

Resultados: La presión arterial durante el día y las 24 horas en pacientes -217 AA/AG tratados con telmisartán fueron significativamente menores en comparación con los pacientes con genotipo GG. El nivel de AGT en plasma en aquellos que tenían genotipo AA/AG y recibieron 80 mg de telmisartán también se redujo ligeramente en comparación con el genotipo GG, incluso estas diferencias no fueron estadísticamente significativas. Los resultados de acoplamiento mostraron que la región básica del factor de transcripción C/EBPα reconocía el homólogo parcialmente se su secuencia de consenso en el oligonucleótido -217A, pero no en el oligonucleótido -217G.

Conclusiones: Las respuestas de reducción de la presión arterial en pacientes hipertensos con polimorfismo de angiotensinógeno G-217A tratados con telmisartán podrían correlacionarse con los efectos del agonista de PPARγ de telmisartán via interacción C/EBPα y AGT-217A.

Palabras Clave: hipertensión; polimorfismo AGT G-217A; telmisartán; valsartán.

Download the PDF file .

 

Citation Format: Rohman MS, Ramadhiani R, Widodo W, Putri VYGS, Lukitasari M, Putri JF, Utomo DH (2018) Blood pressure reduction in telmisartan-treated angiotensinogen G-217A polymorphism hypertensive patients: A pilot study. J Pharm Pharmacogn Res 6(6): 424–432.

© 2018 Journal of Pharmacy & Pharmacognosy Research (JPPRes)

C 013: PROMISES & CHALLENGES OF MICRORNAS IN MULTIPLE MYELOMA THERAPY

J Pharm Pharmacogn Res 2(Suppl. 1): S30, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 013: PROMISES & CHALLENGES OF MICRORNAS IN MULTIPLE MYELOMA THERAPY

Palagani A1, Stefan Naulaerts2, Ken Op de Beeck3, Vandesompele J4, Mestdagh F4, Guy Van Camp3, Kris Laukens2,Vanden Berghe W.1

1Laboratory of Protein Chemistry, Proteomics and Epigenetic Signalling,2Department of Mathematics and Computer Science,3Center of Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Belgium.
4Center for Medical Genetics, Ghent University, Belgium.
Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy and is the second most common hematological cancer. It is characterized by complex, recurrent genetic and epigenetic abnormalities. Perturbed transcription of various noncoding miRNAs has been demonstrated in MM and their functional roles in MM pathogenesis and therapy response just starts to be unraveled. miRNAs are about 20 nucleotide, single strand, non-coding RNAs that may act as tumor suppressors or oncogenes and regulate gene expression by mRNA degradation or translational repression of hundreds of genes, often in a tissue-specific manner. As such, miRNA dysregulation can have profound cellular consequences. Whereas the loss of tumour-suppressive miRNAs enhances the expression of target oncogenes, increased expression of oncogenic miRNAs (known as oncomirs) can repress target tumour suppressor genes. This creates complex networks regulating a large variety of cellular processes, including differentiation, development, apoptosis and cell cycle progression. Understanding the molecular biology of myeloma also requires linking the miRNome to genomic, transcriptomic, epigenomic and proteomic features of malignant plasma cells. Integrative analysis based on computational target prediction, quantitative proteomics and miRNA/mRNA profiling revealed various functional miRNA-target regulatory networks supported by expression data. We will discuss convergence of microRNA regulation and nuclear factor-κB (NF-κB) and glucocorticoid pathways in MM therapy response. As such, interfering with microRNAs in myeloma regulatory networks holds promise to overcome drug resistance, which may improve clinical outcome.

C 012: EPIGENETIC REGULATION OF BREAST CANCER METASTASIS BY STEROIDAL LACTONE WITHAFERIN A

J Pharm Pharmacogn Res 2(Suppl. 1): S30, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 012: EPIGENETIC REGULATION OF BREAST CANCER METASTASIS BY STEROIDAL LACTONE WITHAFERIN A

Szarcvel Szic K1, Scherf D2, Beck IM3, Bracke M3, De Meyer T4, Gerhauser C2, Vanden Berghe W.1

1Laboratory of Protein Chemistry, Proteomics and Epigenetic Signalling, Department of Biomedical Sciences, University of Antwerp (UA), Universiteitsplein 1, Campus DrieEiken, 2610, Wilrijk, Belgium.
2Cancer Chemoprevention, Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120, Heidelberg, Germany.
3Laboratory for Experimental Cancer Research, Department of Radiation Therapy & Experimental Cancer Research, De Pintelaan 185, Building 1P7, Ghent University Hospital, B-9000, Gent, Belgium.
4Department of Mathematical Modelling, Ghent University, Ghent, Belgium.
Abstract

Because a vast majority of cancer patients succumb metastatic disease interfering with metastatic cascade remains one of the main challenges in cancer therapy. This dangerous, yet very inefficient process includes several discrete steps: local invasion, intravasation (or dissemination in lymph nodes or body cavities), circulation and survival, extravasation, growth at distinct sites and angiogenesis, all of which occur in a context of tumour promoting microenvironment. It is now becoming apparent that these cell-microenvironment interactions are highly susceptible to epigenetic regulation, both by internal and external cues.

Here we show that several essential components of metastasis, including urokinase plasminogen activator (PLAU), ADAM8 metallopeptidase, and tumour promoting cytokine TNFSF12 are regulated epigenetically by DNA methylation in breast cancer as revealed by 450K IlluminaBeadChipArray and EpiTyper Mass Array. Moreover, Withaferin A, a natural compound derived from Withania somnifera decreases breast cancer invasion by increasing methylation of these genes leading to lowered gene expression as revealed by qPCR.

C 011: EPIGENETIC DEREGULATION IN CANCER: THERAPEUTIC APPLICATIONS

J Pharm Pharmacogn Res 2(Suppl. 1): S29, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 011: EPIGENETIC DEREGULATION IN CANCER: THERAPEUTIC APPLICATIONS

Berdasco M.

Cancer Epigenetics and Biology Program (PEBC), Institut d’ Investigació Biomedica de Bellvitge (IDIBELL), Barcelona, Spain.
Abstract

Initially, cancer was thought to be solely a consequence of genetic changes in key tumor-suppressor genes and oncogenes that regulate cell proliferation, DNA repair, cell differentiation, and other homeostatic functions. However, recent research suggests that these alterations could also be due to epigenetic disruption. The study of epigenetic mechanisms in cancer, such as DNA methylation, histone modification, nucleosome positioning and micro-RNA expression, has provided extensive information about the mechanisms that contribute to the neoplastic phenotype through the regulation of expression of genes critical to transformation pathways. Regarding DNA methylation, the low level of CpG methylation in tumors compared with that in their normal-tissue counterparts and the hypermethylation of the CpG islands in the promoter regions of tumor-suppressor are accepted as being a common feature of human cancer. Due to the complexity of permutations and combinations, less is known about the patterns of histone modification disruption in human tumors. Results have shown that the CpG promoter hypermethylation event in tumor-suppressor genes in cancer cells is associated with a particular combination of histone markers and the opposite of that observed in normal cells. Aberrations in the epigenetic profiles, with respect to DNA methylation and histone modifications, could also be a consequence of genetic disruption of the epigenetic machinery, such as disruption of the histone methyltransferase NSD1 in neuroblastomas or mutations in the histone deacetylase HDAC2 in colon cancer. The deregulation of miRNA expression has also been linked to tumor progression. Changes in miRNA expression in cancer can be achieved through various mechanisms, including impairment of miRNA processing machinery, such as the recently identified mutations of TRBP2 (an essential functional partner of the DICER1 complex) in sporadic and hereditary carcinomas with microsatellite instability or by CpG hypermethylation of miRNAs with tumor-suppressor properties. The possibility of “resetting” the abnormal cancer epigenome by applying pharmacologic or genetic strategies will be also discussed.

C 010: FLAVANOLS MODULATE THE TRANSCRIPTION OF GENES INVOLVED IN ATHEROSCLEROSIS WITH HETEROGENIC EPIGENETIC CHANGES OF THEIR DNA METHYLATION STATE

J Pharm Pharmacogn Res 2(Suppl. 1): S29, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 010: FLAVANOLS MODULATE THE TRANSCRIPTION OF GENES INVOLVED IN ATHEROSCLEROSIS WITH HETEROGENIC EPIGENETIC CHANGES OF THEIR DNA METHYLATION STATE

Weseler AR1, Milenkovic D2, Szarcvel Szic K3, Declerck K3, Heyninck K4, Haegeman G4, Haenen GRMM1, Bast A1, Fuks F5, Gerhauser C6, Vanden Berghe W3,4 .

1Maastricht University, The Netherlands.
2INRA Research Centre Clermont-Ferrand/Theix, France.
3University of Antwerp, Belgium. E-mail: wim.vandenberghe@ua.ac.be
4University of Gent, Belgium.
5Free University of Brussels, Belgium  6DKFZ Heidelberg, Germany.
Abstract

Epidemiological studies show that a flavanol-rich diet (cocoa, grape) is associated with a decreased risk of cardiovascular disease (CVD). In how far biological effects occur in endothelial HUVEC cells exposed to flavanols in vitro or in humans upon flavanol supplementation is yet unclear. In the Flaviola-consortium (www.flaviola.org), potential biological processes modified by flavanols were evaluated at the transcriptomic and epigenomic levelin HUVEC cells exposed to specific flavanol metabolites or in leukocyte samples collected from diet intervention studies. In vitro experiments in HUVEC cells demonstrate that flavanols significantly decrease monocyte cell adhesion, concomitantly with changes in gene expression and DNA methylation in cell adhesion pathways. Furthermore, in a randomized, double-blind, placebo controlled trial, healthy male smokers supplemented for 8 weeks with 200 mg/d oligomeric flavanols, unveiled pleiotropic vascular health benefit by an integrative multi-biomarker approach (PLoS One. 2011;6(12):e28460.).Gene expression analysis via cDNA microarrays (Agilent 4x44Kv2) further revealed significant changes in various cellular processes like chemotaxis, cell adhesion, cell infiltration and cytoskeleton organization. Regarding DNA methylation changes measured by Illumina 450K CpG array, heterogenic responses were observed in gene clusters involved in detoxification, metabolism and cell adhesion. Although the intervention triggered significant changes in DNA methylation levels (>10%) of 0.2-1% of the methylome (450.000 CGI) at the individual level, no common flavanol-specific DNA methylation response of specific target genes involved in CVD could be identified at the cohort level. Interestingly, strong interindividual variability in DNA methylation levels of detoxification and metabolisation genes can be linked to long-term smoking history, which may overrule diet specific effects of an 8 week diet intervention. Altogether, flavanols may elicit cardioprotective effects by decreasing cell adhesion pathways at the transcriptomic and epigenomic level. Furthermore, smoking history may be a confounding factor in epigenetic profiling studies of leucocytes from subjects involved in a flavanol diet intervention.