Open Access
Pharmacogenetics of vascular risk factors in Alzheimer's disease
(MDPI, 2018-01-03) Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan Carlos; Cacabelos, Pablo; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.
Open Access
Pharmacogenomics of Alzheimer's disease: genetic determinants of phenotypic variation and therapeutic outcome
(SciTech Central, 2016-11-16) Cacabelos, Ramón; Carril, Juan Carlos; Cacabelos, Pablo; Teijido Hermida, Óscar; Goldgaber, Dmitry; Ciencias de la Salud; Osasun Zientziak
Alzheimer's disease is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Conventional anti-dementia drugs are not cost-effective, and pharmacological breakthroughs have not been achieved for the past 10 years. Major determinants of therapeutic outcome in Alzheimer's disease (AD) include age- and sex-related factors, pathogenic phenotype, concomitant disorders, treatment modality and polypharmacy, and pharmacogenetics. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety. Pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes represent the major genetic determinants of response to treatment in AD. In pharmacogenetic studies, APOE-4 carriers are the worst responders and APOE-3 carriers are the best responders to conventional treatments. Patients harboring a large (L) number of poly T repeats in intrón 6 of the TOMM40 gene (L/L or S/L genotypes) in haplotypes associated with APOE-4 are the worst responders whereas patients with short (S) TOMM40 poly T variants (S/S genotype), and to a lesser extent S/VL and VL/VL carriers, in haplotypes with APOE-3 are the best responders to treatment. Only 25% of the Caucasian population are extensive metabolizers for trigenic haplotypes integrating CYP2D6- CYP2C19-CYP2C9 variants. Patients harboring CYP-related por (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG- AG-CC) exhibit the lowest cholesterol levels and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Epigenetic aberrations (DNA methylation, histone modifications, miRNA dysregulation) in genes configuring the pharmacoepigenetic cascade also influence the response/resistance to drugs. Consequently, novel strategies in drug development, either preventive or therapeutic, for AD should take into consideration these pharmacogenetic determinants for treatment optimization.
Open Access
Biochemistry, cytogenetics and DMD gene mutations in south indian patients with Duchenne muscular dystrophy
(Kamla-Raj Enterprises, 2017) Meyyazhagan, Arun; Raman, N. M.; Easwaran, M.; Balasubramanian, B.; Alagamuthu, K.; Kuchi Bhotla, H.; Shanmugam, S.; Inbaraj, K.; Ramesh Kumar, M.; Kumar, P.; Thangamani, L.; Piramanayagam, S.; Anand, V.; Mohd, Y.; Park, S.; Teijido Hermida, Óscar; Carril, Juan Carlos; Cacabelos, Pablo; Keshavarao, S.; Cacabelos, Ramón; Ciencias de la Salud; Osasun Zientziak
Thirty children aged 3-10 years with clinically confirmed or suspected Duchenne Muscular Dystrophy (DMD) were analyzed for chromosomal aberrations using cytological preparations, biochemical changes using enzyme kit protocol, and deletions in the 26 exons of the DMD gene by targeting the mutations at the proximal and distal ‘hot spot’ regions of the dystrophin gene in South Indian patients with DMD. The frequency of chromosomal aberrations (both chromosomal and chromatid-type) and serum enzyme levels were significantly elevated in DMD subjects as compared to controls. Multiplex PCR assays revealed 27 patients having deletions in the DMD gene located at the distal ‘hot spot’ region. This study suggests that disease progression is directly associated with higher incidence of the deletions at the distal ‘hot spot’ of the DMD gene.
Open Access
Basic and clinical studies with marine lipofishins and vegetal favalins in neurodegeneration in age-related disorders
(Elsevier, 2018) Cacabelos, Ramón; Lombardi, Valter; Fernández-Novoa, Lucía; Carrera, Iván; Cacabelos, Pablo; Corzo, Lola; Carril, Juan Carlos; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Over the past 30 years, many different types of nutraceuticals have been produced for the natural management of diverse health conditions. Nutraceuticals are vegetal, marine, or animal bioderivatives in nature. A novel category of nutraceutical compounds is represented by the ProteoLipins, a series of complex lipoproteins derived from natural sources. Among ProteoLipins, LipoFishins (LFs) are a new class of lipoproteins obtained from the muscle of different fish species. Examples of LFs obtained from biomarine sources by means of nondenaturing biotechnological procedures include the following: E-JUR-94013 (DefenVid®), E-CAB-94011 (CabyMar®), E-Congerine-10423 (AntiGan®), E-SAR-94010 (LipoEsar®), and E-MHK-0103 (MineraXin®). Specifically, these compounds show immune-enhancing, cell growth and maturation, antitumoral, hypolipemic, and hormone-modulating properties, respectively. Favalins are a novel category of nutraceuticals extracted from the structural components of the Vicia faba plant. E-PodoFavalin-15999 is a powerful antiparkinsonian agent with procatecholaminergic properties and neuroprotective activity on dopaminergic neurons. Clinical studies with some of these products in different clinical conditions (cardiovascular disorders, dyslipidemia, cancer, Alzheimer's disease, Parkinson's disease, menopause) have revealed that most of the effects of these novel bioproducts are genotype-dependent, showing specific nutrigenomic and pharmacogenomic profiles.

Teijido Hermida, Óscar

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