Luis Javier Flores-Alvarado

Immunology and Oxidative Stress in Multiple Sclerosis: Clinical and Basic Approach

Multiple sclerosis (MS) exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB), the recruitment of lymphocytes, microglia, and macrophages to lesion sites, the presence of multiple lesions, generally being more pronounced in the brain stem and spinal cord, the predominantly perivascular location of lesions, the temporal maturation of lesions from inflammation through demyelination, to gliosis and partial remyelination, and the presence of immunoglobulin in the central nervous system and cerebrospinal fluid. Lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Pro-inflammatory cytokines amplify the inflammatory cascade by compromising the BBB, recruiting immune cells from the periphery, and activating resident microglia. inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in the demyelination and free radical-mediated tissue injury in the pathogenesis of MS. The inflammatory environment in demyelinating lesions leads to the generation of oxygen- and nitrogen-free radicals as well as proinflammatory cytokines which contribute to the development and progression of the disease. Inflammation can lead to oxidative stress and vice versa. Thus, oxidative stress and inflammation are involved in a self-perpetuating cycle.

Role of the Blood–Brain Barrier in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with demyelination and axonal loss eventually leading to neurodegeneration. MS exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB). The BBB is a complex organization of cerebral endothelial cells, pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. In pathological conditions, lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Cytotoxic factors including pro-inflammatory cytokines, proteases, and reactive oxygen and nitrogen species accumulate and may contribute to myelin destruction. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in MS brains and parallel the release of inflammatory cytokines. In this review we establish the importance of the role of the BBB in MS. Improvements in our understanding of molecular mechanism of BBB functioning in physiological and pathological conditions could lead to improvement in the quality of life of MS patients.

Chapter One - Oxidative Stress: Love and Hate History in Central Nervous System

Molecular oxygen is essential for aerobic organisms in order to synthesize large amounts of energy during the process of oxidative phosphorylation and it is harnessed in the form of adenosine triphosphate, the chemical energy of the cell. Oxygen is toxic for anaerobic organisms but it is also less obvious that oxygen is poisonous to aerobic organisms at higher concentrations of oxygen. For instance, oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen at increased partial pressures. Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen that are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, in pathological conditions ROS levels can increase dramatically. This may result in significant damage to cell structures. Living organisms have been adapted to the ROS in two ways: they can mitigate the unwanted effects through removal by the antioxidant systems and can advantageously use them as messengers in cell signaling and regulation of body functions. Some other physiological functions of ROS include the regulation of vascular tone, detection, and adaptation to hypoxia. In this review, we describe the mechanisms of oxidative damage and its relationship with the most highly studied neurodegenerative diseases.

Molecular Heterogeneity of Type 2 Diabetes Mellitus in Mexican Populationand its Impact of the Public Health on Policies in Primary Care

Type 2 diabetes mellitus is a complex disease and a global health problem; hence the first level of health care should handle the approaches of medical genetics to reduce its incidence. In this manuscript we present perspectives of the study of genomic medicine carried out in Mexican population, which show a molecular heterogeneity according to the studied population. Genes currently associated to diabetes are fifty, including ABCA1, APOE, BGLAP, LRP2, CYP19A1, hIAPP, SCARB1, TCF7L2, TNFA. Up to date there are no variants related to diabetes mellitus in the HNF1β, INS, and NEUROD1 among other genes. In relation to chronic complications of DM2, the genes ACE, ADRB3, APOE, CUBN, hANP, LRP2 and HPSE are analyzed.

Alzheimer Disease and Metabolism: Role of Cholesterol and Membrane Fluidity

Alzheimers disease (AD) is an age-related disorder characterized by deposition of amyloid β-peptide (Aβ) and degeneration of neurons in brain regions such as the hippocampus, re‐ sulting in progressive cognitive dysfunction. The causes of Alzheimers disease (AD) have not been fully discovered, there are three main hypotheses to explain the phenomenon: a) The deficit of acetylcholine; b) The accumulation of beta-amyloid (Aβ and / or tau protein; and c) Metabolic disorders.

Tight Junction Protein 1 Gene in Neurodegenerative Disease, New Frontier

Submit Manuscript | http://medcraveonline.com amino acid p.Gln791Glu in the domain guanylate kinase (Location residue 682-861). The domain ZU5 (Location residue 1701-1799) has 33 polymorphisms leading to conformational changes (Table 1). Polymorphisms that affect gene expression, by nucleotide changes at the cryptic sites of the alternative splicing, such as rs781148827, rs5478300017, rs78014403 and rs1020739943 in acceptor region, and rs1029122894 in the donor region. None of these polymorphisms have been explored for their pathogenic effect, which is why they are a new frontier of research in neurodegenerative disease related to aging, due to their effect on ZO-1 expression. Volume 3 Issue 3 2018

Multiple Sclerosis and Its Relationship with Oxidative Stress, Glutathione Redox System, ATPase System, and Membrane Fluidity

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with a focus on inflammation, demyelination, and damage to axons leading to neurological deficits. MS pathology is associated with excessive reactive oxygen species (ROS) and generation of reactive nitrogen species (RNS), causing oxidative/nitrosa‐ tive stress. Deregulation of glutathione homeostasis and alterations in glutathione‐ dependent enzymes are implicated in MS. Reactive oxygen species enhance both monocyte adhesion and migration across brain endothelial cells. In addition, ROS can activate the expression of the nuclear transcription factor‐kappa, which upregulates the expression of many genes involved in MS, such as tumor necrosis factor‐α and nitric oxide synthase, among others, leading to mitochondrial dysfunction and energy deficits that result in mitochondrial and cellular calcium overload. Loss of mitochondrial membrane potential can increase the release of cytochrome c, one pathway that leads to neuronal apoptosis. Clinical studies suggest that omega‐3 long‐chain polyunsaturat‐ ed fatty acids (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti‐inflammatory, antioxidant, and neuroprotective effects in MS and animal models of MS. Here, we review the relationship of oxidative stress, the

Cross-talk between glial cells and neurons: Relationship in Multiple Sclerosis.

Laboratorio Desarrollo-Envejecimiento; Enfermedades Neurodegenerativas. Division de Neurociencias. Centro de Investigacion Biomedica de Occidente (CIBO). Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jal. Mexico Departamento de Biologia molecular y genomica. Centro Universitario de Ciencias de la Salud (CUCS). Universidad de Guadalajara. Guadalajara, Jal. Mexico Departamento de Quimica. Centro Universitario de Ciencias Exactas e Ingenierias. Universidad de Guadalajara. Guadalajara, Jal. Mexico Departamento de Neurologia. Unidad Medica de Alta Especialidad (UMAE). Hospital de Especialidades (HE). Centro Medico Nacional de Occidente (CMNO), IMSS, Guadalajara, Jal. Mexico. Departamento de Investigacion, Centro Universitario de Los Altos, Universidad de Guadalajara.

Alta frecuencia del alelo ancestral del polimorfismo rs2291166 de TJP1 en población mexicana, efecto conformacional así como las aplicaciones en cirugía y medicina

BACKGROUND TJP1 gene encodes a ZO-1 protein that is required for the recruitment of occludins and claudins in tight junction, and is involved in cell polarisation. It has different variations, the frequency of which has been studied in different populations. In Mexico there are no studies of this gene. These are required because their polymorphisms can be used in studies associated with medicine and surgery. Therefore, the aim of this study was to estimate the frequency of alleles and genotypes of rs2291166 gene polymorphism TJP1 in Mexico Mestizos population, and to estimate the conformational effect of an amino acid change. MATERIAL AND METHODS A total of 473 individuals were included. The rs2291166 polymorphism was identified PASA PCR-7% PAGE, and stained with silver nitrate. The conformational effect of amino acid change was performed in silico, and was carried out with servers ProtPraram Tool and Search Database with Fasta. RESULTS The most frequent allele in the two populations is the ancestral allele (T). A genotype distribution similar to other populations was found. The polymorphism is in Hardy-Weinberg, p>0.05. Changing aspartate to alanine produced a conformational change. CONCLUSIONS The study reveals a high frequency of the ancestral allele at rs2291166 polymorphism in the Mexican population.

Mitochondrial DNA Haplogroups in Patients with Alzheimer Probable in Guadalajara, México

Background and aims. It has been suggested that mitochondrial dysfunction is relevant to Alzheimer disease (AD) and some mitochondrial haplogroups could be related to the risk of AD. Therefore, in this work we have genotyped mtDNA haplogroups in Mexican patients with AD and their respective matched controls. Methods: Haplotyping of 33 AD patients and 49 healthy control subjects was performed using polymerase chain reaction/digest identification of key polymorphic sites in the mitochondrial genome. Results: Mitochondrial haplogroup A is the most frequent in AD patients and controls followed by haplogroup B. The haplogroup C was the least frequent in the control group and it was absent in the AD group. The frequency of haplogroup D was significantly higher in the AD group than in the control group (p = 0.03). Conclusion: There is clear association between the frequency of haplogroup D and Alzheimer disease in the analyzed population from Guadalajara, Mexico. Interestingly the haplogroup C was absent in the AD group. These data requires further study in a larger population to identify these differences more clearly.