Epigenomics of Alzheimer’s Disease

Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, and environmental factors are involved. Epigenetic factors have emerged as important mediators of aging, neurodegeneration, and brain disorders. Epigenomic changes underlying the phenotypic expression of AD, represented by deposits of extracellular Aβ aggregates in senile plaques, intracellular neurofibrillary tangles, neuronal loss, dendritic desarborization, and neurochemical alterations are candidate targets for therapeutic intervention. Changes in DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA dysregulation can affect AD-related gene expression, leading to the multistep process of premature neurodegeneration. Epigenetic modifications are reversible and can be potentially targeted by pharmacological and dietary interventions

Prevention of Chronic Experimental Colitis Induced by Dextran Sulphate Sodium (DSS) in Mice Treated with FR91

One of the main treatments currently used in humans to fight cancer is chemotherapy. A huge number of compounds with antitumor activity are present in nature, and many of their derivatives are produced by microorganisms. However, the search for new drugs still represents a main objective for cancer therapy, due to drug toxicity and resistance to multiple chemotherapeutic drugs. In animal models, a short-time oral administration of dextran sulfate sodium (DSS) induces colitis, which exhibits several clinical and histological features similar to ulcerative colitis (UC). However, the pathogenic factors responsible for DSS-induced colitis and the subsequent colon cancer also remain unclear. We investigated the effect of FR91, a standardized lysate of microbial cells belonging to the Bacillus genus which has been previously shown to have significant immunomodulatory effects, against intestinal inflammation. Colitis was induced in mice during 5 weeks by oral administration 2% (DSS). Morphological changes in the colonic mucosa were evaluated by hematoxylin-eosin staining and immunohistochemistry methods. Adenocarcinoma and cryptal cells of the dysplastic epithelium showed cathenin-β, MLH1, APC, and p53 expression, together with increased production of IFN-γ. In our model, the optimal dose response was the 20% FR91 concentration, where no histological alterations or mild DSS-induced lesions were observed. These results indicate that FR91 may act as a chemopreventive agent against inflammation in mice DSS-induced colitis

Histamine and Immune Biomarkers in CNS Disorders

Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer’s disease, Parkinson’s disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer’s disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death

Histamine and immune biomarkers in CNS disorders

La desregulación neuroinmune es un fenómeno común en diferentes formas de trastornos del sistema nervioso central (SNC). Los enlaces cruzados entre los mecanismos inmunitarios centrales y periféricos parecen estar interrumpidos, como se refleja en una serie de marcadores inmunitarios (CD3, CD4, CD7, HLA-DR, CD25, CD28 y CD56) que muestran variabilidad en trastornos cerebrales como ansiedad, depresión , psicosis, accidente cerebrovascular, enfermedad de Alzheimer, enfermedad de Parkinson, trastorno por déficit de atención con hiperactividad, migraña, epilepsia, demencia vascular, retraso mental, encefalopatía cerebrovascular, esclerosis múltiple, tumores cerebrales, neuropatías del nervio craneal, retraso mental y lesión cerebral postraumática. La histamina (HA) es una monoamina pleiotrópica involucrada en varias funciones neurofisiológicas, regulación neuroinmune y patogénesis del SNC. Los cambios en la HA cerebral muestran un patrón relacionado con la edad y el sexo, y las alteraciones en los niveles de HA cerebral están presentes en diferentes regiones del SNC de pacientes con enfermedad de Alzheimer (EA). La HA cerebral en los compartimentos neuronales y no neuronales desempeña una doble función (neurotrófica versus neurotóxica) de una manera específica del tejido. Los mecanismos patógenos asociados con la desregulación neuroinmune en la AD involucran HA, interleucina-1β , y TNF- α , cuya expresión aberrante contribuye a la neuroinflamación como factor agravante para la neurodegeneración y la muerte neuronal prematura

Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics

Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics

Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

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