Dolphin leukocytes exhibit an attenuated cytokine response and increase heme oxygenase activity upon exposure to lipopolysaccharides.

Cetaceans exhibit physiological adaptations that allowed the transition to aquatic life, including a robust antioxidant defense system that prevents injury from repeated exposure to ischemia/reperfusion events associated with breath-hold diving. The signaling cascades that characterize ischemic inflammation in humans are well characterized. In contrast, cetaceans' molecular and biochemical mechanisms that confer tolerance to inflammatory events are poorly understood. Heme oxygenase (HO) is a cytoprotective protein with anti-inflammatory properties. HO catalyzes the first step in the oxidative degradation of heme. The inducible HO-1 isoform is regulated by various stimuli, including hypoxia, oxidant stress, and inflammatory cytokines. The objective of this study was to compare the response of HO-1 and cytokines to a proinflammatory challenge in leukocytes isolated from humans and bottlenose dolphins (Tursiops truncatus). We measured changes in HO activity, and abundance and expression of interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and heme oxygenase 1 (HMOX1) in leukocytes treated with lipopolysaccharide (LPS) for 24 and 48 h. HO activity increased (p < 0.05) in dolphin (48 h) but not human cells. TNF-α expression increased in human (24 h, 48 h), but not dolphin cells following LPS stimulation. LPS-induced cytokine expression was lower in dolphin than in human leukocytes, suggesting a blunted cytokine response in bottlenose dolphin leukocytes treated with LPS. Results suggest species-specific regulation of inflammatory cytokines in leukocytes treated with LPS, which may lead to differential responses to a pro-inflammatory challenge between marine and terrestrial mammals.

Neurocognitive Psychiatric and Neuropsychological Alterations in Parkinson's Disease: A Basic and Clinical Approach.

The main histopathological hallmarks of Parkinson's disease (PD) are the degeneration of the dopaminergic neurons of the substantia nigra pars compacta and the loss of neuromelanin as a consequence of decreased dopamine synthesis. The destruction of the striatal dopaminergic pathway and blocking of striatal dopamine receptors cause motor deficits in humans and experimental animal models induced by some environmental agents. In addition, neuropsychiatric symptoms such as mood and anxiety disorders, hallucinations, psychosis, cognitive impairment, and dementia are common in PD. These alterations may precede the appearance of motor symptoms and are correlated with neurochemical and structural changes in the brain. This paper reviews the most crucial pathophysiology of neuropsychiatric alterations in PD. It is worth noting that PD patients have global task learning deficits, and cognitive functions are compromised in a way is associated with hypoactivation within the striatum, anterior cingulate cortex, and inferior frontal sulcus regions. An appropriate and extensive neuropsychological screening battery in PD must accurately assess at least five cognitive domains with some tests for each cognitive domain. This neuropsychological screening should consider the pathophysiological and clinical heterogeneity of cognitive dysfunction in PD.

In silico Characterization of the Heme Oxygenase 1 From Bottlenose Dolphin (Tursiops truncatus): Evidence of Changes in the Active Site and Purifying Selection.

Cetacea is a clade well-adapted to the aquatic lifestyle, with diverse adaptations and physiological responses, as well as a robust antioxidant defense system. Serious injuries caused by boats and fishing nets are common in bottlenose dolphins (Tursiops truncatus); however, these animals do not show signs of serious infections. Evidence suggests an adaptive response to tissue damage and associated infections in cetaceans. Heme oxygenase (HO) is a cytoprotective protein that participates in the anti-inflammatory response. HO catalyzes the first step in the oxidative degradation of the heme group. Various stimuli, including inflammatory mediators, regulate the inducible HO-1 isoform. This study aims to characterize HO-1 of the bottlenose dolphin in silico and compare its structure to the terrestrial mammal protein. Upstream HO-1 sequence of the bottlenose dolphin was obtained from NCBI and Ensemble databases, and the gene structure was determined using bioinformatics tools. Five exons and four introns were identified, and proximal regulatory elements were detected in the upstream region. The presence of 10 α-helices, three 310 helices, the heme group lodged between the proximal and distal helices, and a histidine-25 in the proximal helix serving as a ligand to the heme group were inferred for T. truncatus. Amino acid sequence alignment suggests HO-1 is a conserved protein. The HO-1 "fingerprint" and histidine-25 appear to be fully conserved among all species analyzed. Evidence of positive selection within an α-helix configuration without changes in protein configuration and evidence of purifying selection were found, indicating evolutionary conservation of the coding sequence structure.

Antioxidant response to cadmium exposure in primary skeletal muscle cells isolated from humans and elephant seals.

Cadmium (Cd) occurs naturally; however, its concentration can increase with anthropogenic activities. Excess Cd increases reactive oxygen species (ROS) production and oxidative damage, which can lead to pathological conditions. Marine mammals accumulate Cd in the liver and the kidney; yet, there are no reports of Cd-associated tissue damage in whales, seals or dolphins. Response to Cd exposure (0-5.0 µM CdCl2 for 1-12 h) was analyzed and compared in primary skeletal muscle cells isolated from northern elephant seals (Mirounga angustirostris) and humans (Homo sapiens). Antioxidant enzyme activities (glutathione S-transferase, glutathione reductase, glutathione peroxidase), glutathione concentration, and protein carbonyl levels (an indicator of oxidative damage) were quantified. Glutathione levels were higher in northern elephant seal than in human cells. Protein carbonyl content in cells exposed to Cd was lower and had a smaller variability range in elephant seals than in humans. Generalized linear models (GLIM) identified Cd exposure and antioxidant defenses as significant contributors to protein carbonyl variability in human but not in elephant seal cells. These results suggest that the previously observed differences in circulating and tissue glutathione levels between marine and terrestrial mammals are maintained under cell culture conditions and that northern elephant seal and human muscle cells respond differently to Cd exposure. The results also suggest that the observed differences could potentially be associated with the protective mechanisms that allow northern elephant seals to tolerate extreme conditions that result in increased ROS generation (e.g. diving, sleep apnea, fasting) with no oxidative damage.

Cytokines and nervous system: relationship with schizophrenia / Citocinas y sistema nervioso: relación con la esquizofrenia

Schizophrenia is a heterogeneous disorder of mental symptoms and alterations, characterized by presenting abnormal ideas and perceptions, in which the individual loses contact with reality as a result of a complex neuropsychological disorganization, which affects the affective, intellectual and behavioral functioning; as well as inducing a significant social dysfunction. The etiology of schizophrenia is extremely complex, and is not very clear yet; it is believed to be the result of the combination of genetic factors and the environment. Numerous neurotransmitters have been implicated in this disease, as is the case of dopamine, serotonin and glutamate. The role of the inflammatory process in the pathogenesis of schizophrenia has been postulated, where a prenatal immune "challenge" during the second trimester of pregnancy can be key to the development of the disease. Some of the pro-inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) play a key role in the processes of modulation of the nervous system functions related to affective, emotional and social alterations in subjects with schizophrenia. The mechanisms associated with inflammation and the anti-inflammatory defense system that may be associated with the development of schizophrenia are still unknown. This review was intended to address schizophrenia, in regards to the mechanisms associated with inflammation and the anti-inflammatory defense system in its development.

La esquizofrenia es un trastorno heterogéneo de síntomas y alteraciones mentales, caracterizadas por presentar ideas y percepciones anormales, en el que el individuo pierde contacto con la realidad a consecuencia de una compleja desorganización neuropsicológica, lo cual afecta el funcionamiento afectivo, intelectual y de comportamiento; asimismo, conlleva una disfunción social significativa. La etiología de la esquizofrenia aún no está establecida con claridad. Numerosos neurotransmisores han sido implicados en esta enfermedad, como es el caso de la dopamina, la serotonina y el glutamato. Se ha postulado el papel del proceso inflamatorio en la patogenia de la esquizofrenia, donde un "desafío" inmune prenatal durante el segundo trimestre de la gestación puede ser clave para el desarrollo de la enfermedad. Algunas de las citocinas proinflamatorias (TNF-alfa, IL-1beta e IL-6) juegan un papel clave en los procesos de modulación de las funciones del sistema nervioso relacionadas con alteraciones afectivas, emocionales y sociales en los sujetos con esquizofrenia. Aún se desconocen los mecanismos asociados con la inflamación y el sistema de defensa antiinflamatorio que pudieran intervenir en el desarrollo de la esquizofrenia. Esta revisión tuvo el propósito de tratar sobre la esquizofrenia, en lo que respecta a los mecanismos asociados con la inflamación y el sistema de defensa antiinflamatorio en su desarrollo.

The Neuroprotective Effect of Erythropoietin in Rat Hippocampus in an Endotoxic Shock Model.

BACKGROUND: Sepsis is characterized by an early systemic inflammation in response to infection. In the brain, inflammation is associated with expression of pro-inflammatory cytokines (e.g. tumor necrosis factor-α, interleukin-1ß and interleukin-6, among others) that may induce an overproduction of reactive oxygen and nitrogen species. The constitutive expression of cytokines in the brain is low, but may be induced by various stimuli, including lipopolysaccharide, which causes neuronal damage. Erythropoietin, among other effects, acts as a multifunctional neurotrophic factor implicated in neurogenesis, angiogenesis, vascular permeability, and immune regulation in the central nervous system. In an experimental model of endotoxic shock, we studied the neuroprotective capacity of erythropoietin in the rat hippocampus and compared with melatonin, a neurohormone with an important antioxidant and immunomodulatory effect. METHODS: In 21-day-old male Wistar rats divided into eight groups, we administered by intraperitoneal injection lipopolysaccharide, erythropoietin, melatonin, or combinations thereof. The hippocampus was dissected and morphological (histological analysis) and biochemical (cytokine levels) studies were conducted. RESULTS: The number of dead neuronal cells in histological sections in groups treated with lipopolysaccharide was higher compared to the erythropoietin group. There was a greater decrease (70%) in interleukin-1ß concentrations in rats with endotoxic shock that received erythropoietin compared to the lipopolysaccharide group. CONCLUSIONS: The neuronal cell loss caused by endotoxic shock and interleukin-1ß levels were reduced by the administration of the hematopoietic cytokine erythropoietin in this experimental model.

Peroxidación de lípidos y la respuesta del sistema de defensa antioxidante en el diabético tipo 2 obeso en comparación al diabético tipo 2 sin obesidad / Lipid peroxidation and the response of the antioxidant defense system in the obese type 2 diabetic compared with the non-obese type 2 diabetic

Introducción: La diabetes se asocia a un incremento en la peroxidación de lípidos, cuantificada a partir del nivel de sustancias reactivas al ácido tiobarbitúrico (TBARS). En paralelo, se activa el sistema de defensa antioxidante (SDA) para delimitar el daño. Objetivo: Determinar el grado de peroxidación de lípidos en individuos obesos diabéticos tipo 2 (DM2) y la respuesta del SDA en comparación con individuos con DM2 sin obesidad. Método: Se evaluó el daño a lípidos a través de la medición de las TBARS en dos grupos de 30 individuos. Se evaluó la respuesta del SDA por medio de la medición de la actividad de las enzimas catalasa (CAT), superóxido dismutasa (SOD) y glutatión peroxidasa (GPx). Resultados: El grupo de DM2 obesos presentó un índice de masa corporal (IMC) promedio de 38,6 ± 3,5 kg m2 en comparación con el grupo control 24,7 ± 3,6 kg m2 (p < 0,01). Los niveles de TBARS en el grupo en estudio fueron más altos en comparación al grupo control (p < 0.01). En un análisis de regresión lineal múltiple la actividad de SOD y CAT explicó los niveles de TBARS en el obeso con DM2. Conclusión: Los niveles de TBARS sugieren mayor daño por estrés oxidativo en DM2 obesos por un exceso en la producción de radicales libres (RL), así como incapacidad del SDA para delimitar el daño (AU)

Introduction: Diabetes is associated with increased lipid peroxidation, quantified as the levels of thiobarbituric acid reactive substances (TBARS). In parallel, the antioxidant defense system (ADS) reacts to diminish the oxidative damage. Objective: To determine the levels of lipid peroxidation and the activity of antioxidant enzymes in obese type 2 diabetic (DM2) individuals compared to non-obese DM2 individuals. Methods: Lipid peroxidation was quantified by measuring TBARS and the ADS response by measuring the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Results: Two groups of 30 subjects were studied. The obese DM2 group had a mean body mass index (BMI) 38.6 ± 3.5 kg m-2 compared to the control group 24.7 ± 3.6 kg m-2 (p<0.01). TBARS levels in the study group were higher compared to the control group (p <0.01). Multiple linear regression analysis suggested that activities of SOD and CAT adjusted to lipid peroxidation (TBARS) in the obese DM2 individuals. Conclusion: TBARS levels suggest greater oxidative damage in obese DM2 subjects with a diminished response of ADS (AU)

[Lipid peroxidation and the response of the antioxidant defense system in the obese type 2 diabetic compared with the non-obese type 2 diabetic]. / Peroxidación de lípidos y la respuesta del sistema de defensa antioxidante en el diabético tipo 2 obeso en comparación al diabético tipo 2 sin obesidad.

INTRODUCTION: Diabetes is associated with increased lipid peroxidation, quantified as the levels of thiobarbituric acid reactive substances (TBARS). In parallel, the antioxidant defense system (ADS) reacts to diminish the oxidative damage. OBJECTIVE: To determine the levels of lipid peroxidation and the activity of antioxidant enzymes in obese type 2 diabetic (DM2) individuals compared to non-obese DM2 individuals. METHODS: Lipid peroxidation was quantified by measuring TBARS and the ADS response by measuring the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). RESULTS: Two groups of 30 subjects were studied. The obese DM2 group had a mean body mass index (BMI) 38.6 ± 3.5 kg m(-2) compared to the control group 24.7 ± 3.6 kg m(-2) (p<0.01). TBARS levels in the study group were higher compared to the control group (p <0.01). Multiple linear regression analysis suggested that activities of SOD and CAT adjusted to lipid peroxidation (TBARS) in the obese DM2 individuals. CONCLUSION: TBARS levels suggest greater oxidative damage in obese DM2 subjects with a diminished response of ADS.

Introducción: La diabetes se asocia a un incremento en la peroxidación de lípidos, cuantificada a partir del nivel de sustancias reactivas al ácido tiobarbitúrico (TBARS). En paralelo, se activa el sistema de defensa antioxidante (SDA) para delimitar el daño. Objetivo: Determinar el grado de peroxidación de lípidos en individuos obesos diabéticos tipo 2 (DM2) y la respuesta del SDA en comparación con individuos con DM2 sin obesidad. Método: Se evaluó el daño a lípidos a través de la medición de las TBARS en dos grupos de 30 individuos. Se evaluó la respuesta del SDA por medio de la medición de la actividad de las enzimas catalasa (CAT), superóxido dismutasa (SOD) y glutatión peroxidasa (GPx). Resultados: El grupo de DM2 obesos presentó un índice de masa corporal (IMC) promedio de 38.6 ± 3.5 kg m-2 en comparación con el grupo control 24.7 ± 3.6 kg m-2 (p.