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  • 1
    Online Resource
    Online Resource
    Pharmacogenetics of Atremorine-Induced Neuroprotection and Dopamine Response in Parkinsonʼs Disease
    Georg Thieme Verlag KG ; 2019
    In:  Planta Medica Vol. 85, No. 17 ( 2019-11), p. 1351-1362
    Details
    In: Planta Medica, Georg Thieme Verlag KG, Vol. 85, No. 17 ( 2019-11), p. 1351-1362
    Abstract: Atremorine is a novel bioproduct with neuroprotective effects on dopaminergic neurons and a natural L-DOPA donor in Parkinsonʼs disease (PD). In the present study, we show the effects of a single dose of Atremorine (5 g, p. o.) on plasma dopamine (DA) response and brain function in PD (n = 183) and the influence that pathogenic (LRRK2), metabolic (CYP2D5, CYP2C9, CYP2C19, CYP3A5, NAT2), transporter (ABCB1), pleiotropic (APOE), and detoxifying genes (CYP1B1, GSTT1, GSTP1, GSTM1, SOD2) involved in the pharmacogenetic network exerts on Atremorine-induced DA response. Over 90% of PD patients at diagnosis show plasma DA levels below 20 pg/mL. Atremorine induces DA synthesis causing a significant increase in plasma DA levels 1 h after administration in practically 100% of patients. Females tend to show lower basal DA levels than males and the response of DA to Atremorine is stronger in males than in females. Atremorine-induced DA response is pharmacogenotype-specific and lasts from 6 – 12 h depending upon the pharmacogenetic profile of each patient. Genetic variants in pathogenic genes, metabolic genes, and genes involved in the detoxification processes affect the response of DA to Atremorine in a genotype-specific manner. Atremorine or any of its bioactive components can cross the blood-brain barrier and improve brain function and motor function, as revealed by the reduction in slow wave activity in brain mapping and psychometric assessment, respectively. Atremorine is a selective neuroprotective agent for dopaminergic neurons with prophylactic and therapeutic potential in PD.
    Type of Medium: Online Resource
    ISSN: 0032-0943 , 1439-0221
    URL: Article
    DOI: 10.1055/a-1013-7686
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2019
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  • 2
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    Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics
    Wiley ; 2021
    In:  Medicinal Research Reviews Vol. 41, No. 5 ( 2021-09), p. 2841-2886
    Details
    In: Medicinal Research Reviews, Wiley, Vol. 41, No. 5 ( 2021-09), p. 2841-2886
    Abstract: Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba . Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender‐, time‐, dose‐, and genotype‐dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug‐free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti‐PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti‐PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine‐induced DA response is highly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic ( SNCA, NUCKS1, ITGA8, GPNMB, GCH1, BCKDK, APOE, LRRK2, ACMSD ), mechanistic ( DRD2 ), metabolic ( CYP2D6, CYP2C9, CYP2C19, CYP3A4/5, NAT2 ), transporter ( ABCB1, SLC6A2, SLC6A3, SLC6A4 ) and pleiotropic genes ( APOE ) influence the DA response to Atremorine and its psychomotor and brain effects. Atremorine enhances DNA methylation and displays epigenetic activity via modulation of the pharmacoepigenetic network. Atremorine is a novel neuroprotective agent for dopaminergic neurons with potential prophylactic and therapeutic activity in PD.
    Type of Medium: Online Resource
    ISSN: 0198-6325 , 1098-1128
    URL: Issue
    URL: Article
    DOI: 10.1002/med.v41.5
    DOI: 10.1002/med.21838
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2001841-1
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  • 3
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    AtreMorine Treatment Regulates DNA Methylation in Neurodegenerative Disorders: Epigenetic and Pharmacogenetic Studies
    Bentham Science Publishers Ltd. ; 2021
    In:  Current Pharmacogenomics and Personalized Medicine Vol. 17, No. 3 ( 2021-02-01), p. 159-171
    Details
    In: Current Pharmacogenomics and Personalized Medicine, Bentham Science Publishers Ltd., Vol. 17, No. 3 ( 2021-02-01), p. 159-171
    Abstract: Neurodegenerative disorders are one of the major health problems in Western countries. Genetic and epigenetic mechanisms play crucial roles in the origin and progression of these disorders. DNA methylation is the most widely studied epigenetic mark and is an important regulator of gene expression. Objective: Little is known about the influence of bioactive dietary components on epigenetic mechanisms in neurodegenerative diseases. In this study, we investigated the effects of E-PodoFavalin-15999 (AtreMorine®), a bioproduct with potent neuroprotective and dopamine enhancing capabilities, on DNA methylation patterns in Alzheimer’s (AD) and Parkinson’s Disease (PD). We also aimed to assess, in patients with PD, the effects that genetic variation across candidate pharmacogenes may have on dopamine synthesis and release in response to treatment with AtreMorine. Methods: We analyzed global DNA methylation and de novo DNA methyltransferase (DNMT) expression in a transgenic (3xTg) mouse model of AD, and further examined global DNA methylation in blood samples from patients with PD. Results: AtreMorine treatment increased global DNA methylation in 3xTg mice and in patients with Parkinson´s disease, and produced high DNMT3a expression in AD mice. We observed varied responses to AtreMorine across the following pharmacogenetic genophenotypes analyzed, cytochrome P450 oxidases (CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, CYP1A2), human arylamine N-acetyltransferase 2 (NAT2), the vitamin K epoxide reductase complex subunit 1 (VKORC1), ATP-binding cassette subfamily B member 1 (ABCB1), and solute carrier organic anion transporter family member 1B1 (SLCOB1). Conclusion: Our results suggest that AtreMorine regulates DNA methylation in neurodegenerative disorders and may constitute a new therapeutic option for the treatment of these pathologies.
    Type of Medium: Online Resource
    ISSN: 1875-6921
    URL: Article
    DOI: 10.2174/1875692117999201231152800
    Language: English
    Publisher: Bentham Science Publishers Ltd.
    Publication Date: 2021
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  • 4
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    Influence of Pathogenic and Metabolic Genes on the Pharmacogenetics of Mood Disorders in Alzheimer’s Disease
    MDPI AG ; 2021
    In:  Pharmaceuticals Vol. 14, No. 4 ( 2021-04-15), p. 366-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 14, No. 4 ( 2021-04-15), p. 366-
    Abstract: Background: Mood disorders represent a risk factor for dementia and are present in over 60% of cases with Alzheimer’s disease (AD). More than 80% variability in drug pharmacokinetics and pharmacodynamics is associated with pharmacogenetics. Methods: Anxiety and depression symptoms were assessed in 1006 patients with dementia (591 females, 415 males) and the influence of pathogenic (APOE) and metabolic (CYP2D6, CYP2C19, and CYP2C9) gene variants on the therapeutic outcome were analyzed after treatment with a multifactorial regime in a natural setting. Results and Conclusions: (i) Biochemical, hematological, and metabolic differences may contribute to changes in drug efficacy and safety; (ii) anxiety and depression are more frequent and severe in females than males; (iii) both females and males respond similarly to treatment, showing significant improvements in anxiety and depression; (iv) APOE-3 carriers are the best responders and APOE-4 carriers tend to be the worst responders to conventional treatments; and (v) among CYP2D6, CYP2C19, and CYP2C9 genophenotypes, normal metabolizers (NMs) and intermediate metabolizers (IMs) are significantly better responders than poor metabolizers (PMs) and ultra-rapid metabolizers (UMs) to therapeutic interventions that modify anxiety and depression phenotypes in dementia. APOE-4 carriers and CYP-related PMs and UMs deserve special attention for their vulnerability and poor response to current treatments.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph14040366
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2193542-7
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  • 5
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    Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics
    MDPI AG ; 2019
    In:  International Journal of Molecular Sciences Vol. 20, No. 5 ( 2019-03-12), p. 1249-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 20, No. 5 ( 2019-03-12), p. 1249-
    Abstract: Sirtuins (SIRT1-7) are NAD+-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T 〉 SIRT2-C/T 〉 SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms20051249
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2019364-6
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  • 6
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    Epigenetic Biomarkers as Diagnostic Tools for Neurodegenerative Disorders
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 23, No. 1 ( 2021-12-21), p. 13-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 1 ( 2021-12-21), p. 13-
    Abstract: Epigenetics is the study of heritable changes in gene expression that occur without alterations to the DNA sequence, linking the genome to its surroundings. The accumulation of epigenetic alterations over the lifespan may contribute to neurodegeneration. The aim of the present study was to identify epigenetic biomarkers for improving diagnostic efficacy in patients with neurodegenerative diseases. We analyzed global DNA methylation, chromatin remodeling/histone modifications, sirtuin (SIRT) expression and activity, and the expression of several important neurodegeneration-related genes. DNA methylation, SIRT expression and activity and neuregulin 1 (NRG1), microtubule-associated protein tau (MAPT) and brain-derived neurotrophic factor (BDNF) expression were reduced in buffy coat samples from patients with neurodegenerative disorders. Our data suggest that these epigenetic biomarkers may be useful in clinical practical for the diagnosis, surveillance, and prognosis of disease activity in patients with neurodegenerative diseases.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms23010013
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 7
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    Influence of Metabolic, Transporter, and Pathogenic Genes on Pharmacogenetics and DNA Methylation in Neurological Disorders
    MDPI AG ; 2023
    In:  Biology Vol. 12, No. 9 ( 2023-08-22), p. 1156-
    Details
    In: Biology, MDPI AG, Vol. 12, No. 9 ( 2023-08-22), p. 1156-
    Abstract: Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including CYP1A2, CYP2C9, CYP4F2, GSTP1, and NAT2, that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolizers compared to patients in Group A, did not show an improvement in 5mC levels during follow-up. Furthermore, there were significant differences in phenotype distribution between patient Groups A and B for several SNPs associated with transporter genes (ABCB1, ABCC2, SLC2A9, SLC39A8, and SLCO1B1) and pathogenic genes (APOE, NBEA, and PTGS2). These findings appear to suggest that the interplay between pharmacogenomics and DNA methylation has important implications for improving treatment outcomes in patients with brain-related disorders.
    Type of Medium: Online Resource
    ISSN: 2079-7737
    URL: Article
    DOI: 10.3390/biology12091156
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2661517-4
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  • 8
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    Proteomic and Global DNA Methylation Modulation in Lipid Metabolism Disorders with a Marine-Derived Bioproduct
    MDPI AG ; 2023
    In:  Biology Vol. 12, No. 6 ( 2023-06-02), p. 806-
    Details
    In: Biology, MDPI AG, Vol. 12, No. 6 ( 2023-06-02), p. 806-
    Abstract: Dyslipidemia is a significant risk factor for cardiovascular disease and stroke. Our recent findings showed that RCI-1502, a bioproduct derived from the muscle of the European S. pilchardus, has lipid-lowering effects in the liver and heart in high-fat diet (HFD) fed mice. In the present follow-up study, we investigated the therapeutic potential of RCI-1502 on gene expression and DNA methylation in HFD-fed mice and in patients with dyslipidemia. Using LC-MS/MS, we identified 75 proteins in RCI-1502 that are primarily involved in binding and catalytic activity and which regulate pathways implicated in cardiovascular diseases. In HFD-fed mice, RCI-1502 treatment significantly reduced the expression of cardiovascular disease-related genes, including vascular cell adhesion molecule and angiotensin. RCI-1502 also decreased DNA methylation levels, which were elevated in HFD-fed mice, to levels similar to those in control animals. Furthermore, peripheral blood leukocyte DNA from dyslipidemic patients exhibited higher DNA methylation levels than healthy individuals, suggesting a potential association with cardiovascular risk. Serum analysis also revealed that RCI-1502 treatment regulated cholesterol and triglyceride levels in patients with dyslipidemia. Our findings appear to suggest that RCI-1502 is an epigenetic modulator for the treatment of cardiovascular diseases, specifically in individuals with dyslipidemia.
    Type of Medium: Online Resource
    ISSN: 2079-7737
    URL: Article
    DOI: 10.3390/biology12060806
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
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  • 9
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    Pharmacogenetics of anxiety and depression in Alzheimer's disease
    Future Medicine Ltd ; 2023
    In:  Pharmacogenomics Vol. 24, No. 1 ( 2023-01), p. 27-57
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 24, No. 1 ( 2023-01), p. 27-57
    Abstract: Anxiety and depression coexist with cognitive impairment in Alzheimer's disease along with other concomitant disorders ( 〉 60%), which require multipurpose treatments. Polypharmaceutical regimens cause drug–drug interactions and adverse drug reactions, potentially avoidable in number and severity with the implementation of pharmacogenetic procedures. The accumulation of defective variants ( 〉 30 genes per patient in more than 50% of cases) in pharmagenes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) influences the therapeutic response to antidementia, antidepressant and anxiolytic drugs in polyvalent regimens. APOE, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, COMT, MAOB, CHAT, GSTP1, NAT2, SLC30A8, SLCO1B1, ADRA2A, ADRB2, BCHE, GABRA1, HMGCR, HTR2C, IFNL3, NBEA, UGT1A1, ABCB1, ABCC2, ABCG2, SLC6A2, SLC6A3, SLC6A4, MTHFR and OPRM1 variants affect anxiety and depression in Alzheimer's disease.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/pgs-2022-0137
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2023
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  • 10
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    Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 24 ( 2021-12-10), p. 13302-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 24 ( 2021-12-10), p. 13302-
    Abstract: Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug–drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and insufficient regulation for the generalized use of PGx in the clinical setting. The implementation of PGx requires: (i) education of physicians and all other parties involved in the use and benefits of PGx; (ii) prospective studies to demonstrate the benefits of PGx genotyping; (iii) standardization of PGx procedures and development of clinical guidelines; (iv) NGS and microarrays to cover genes with high PGx potential; and (v) new regulations for PGx-related drug development and PGx drug labelling.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms222413302
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
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