Linolenic Acid Plus Ethanol Exacerbates Cell Death in Saccharomyces cerevisiae by Promoting Lipid Peroxidation, Cardiolipin Loss, and Necrosis.

Polyunsaturated fatty acids (PUFA) hypersensitize yeast to oxidative stress. Ethanol accumulation during fermentation is another factor that induces oxidative stress via mitochondrial dysfunction and ROS overproduction. Since this microorganism has raised growing interest as a PUFA factory, we have studied if the combination of PUFA plus ethanol enhances yeast death. Respiration, ROS generation, lipid peroxidation, mitochondrial cardiolipin content, and cell death were assessed in yeast grown in the presence of 10% ethanol (ETOH) or linolenic acid (C18:3), or ethanol plus C18:3 (ETOH+C18:3). Lipid peroxidation and cardiolipin loss were several-fold higher in cells with ETOH+C18:3 than with C18:3. On the contrary, ETOH tended to increase cardiolipin content without inducing changes in lipid peroxidation. This was consistent with a remarkable diminution of cell growth and an exacerbated propidium iodide staining in cells with only ETOH+C18:3. The respiration rate decreased with all the treatments to a similar degree, and this was paralleled with similar increments in ROS between all the treatments. These results indicate that PUFA plus ethanol hypersensitize yeast to necrotic cell death by exacerbating membrane damage and mitochondrial cardiolipin loss, independent of mitochondrial dysfunction and ROS generation. The implications of these observations for some biotechnological applications in yeast and its physiology are discussed.

Avocado oil alleviates non-alcoholic fatty liver disease by improving mitochondrial function, oxidative stress and inflammation in rats fed a high fat-High fructose diet.

Non-alcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in hepatocytes, and in advanced stages, by inflammation and fibrosis. Excessive ROS production due to mitochondrial dysfunction contributes to NAFLD development, making the decrease in mitochondrial ROS production an emerging target to alleviate NAFLD. Previously, we have shown that avocado oil, a source of several bioactive compounds with antioxidant effects, decreases oxidative stress by improving the function of the mitochondrial electron transport chain (ETC) and decreasing ROS levels in mitochondria of diabetic and hypertensive rats. Therefore, we tested in this work whether avocado oil alleviates NAFLD by attenuating mitochondrial dysfunction, oxidative stress and inflammation. NAFLD was induced in rats by a high fat-high fructose (HF) diet administered for six (HF6) or twelve (HF12) weeks. Hepatic steatosis, hypertrophy and inflammation were detected in both the HF6 and HF12 groups. Hyperglycemia was observed only in the HF12 group. The HF6 and HF12 groups displayed dyslipidemia, impairments in mitochondrial respiration, complex III activity, and electron transfer in cytochromes in the complex III. This led to an increase in the levels of ROS and lipid peroxidation. The substitution of the HF6 diet by standard chow and avocado oil for 6 weeks (HF6+AVO + D), or supplementation of the HF12 diet with avocado oil (HF12 + AVO), ameliorated NAFLD, hyperglycemia, dyslipidemia, and counteracted mitochondrial dysfunctions and oxidative stress. The substitution of the HF6 diet by standard chow without avocado oil did not correct many of these abnormalities, confirming that the removal of the HF diet is not enough to counteract NAFLD and mitochondrial dysfunction. In summary, avocado oil decreases NAFLD by improving mitochondrial function, oxidative stress, and inflammation.

The 5-HT1A receptor agonist, 8-OH-DPAT, attenuates long-lasting pain in imiquimod-induced psoriasis in mice.

Psoriasis pain is a common symptom underestimated and rarely evaluated in psoriasis clinical trials. This work aimed to investigate whether the development of secondary chronic allodynia and hyperalgesia in the imiquimod (IMQ)-induced psoriasis mice model could be modulated by anti-inflammatory agents and compound 48/80 (C48/80) and to determine whether the activation of 5-HT1A receptor modulates these nociceptive behaviours. C57BL/6 male mice were treated with 5% IMQ for 7 days. The paw withdrawal responses to von Frey filaments (10 and 250 mN) were used to assess the allodynia and hyperalgesia. Nociceptive behaviours were also evaluated using ketorolac 15 mg/kg s.c., adalimumab 10 mg/kg s.c. and C48/80 10 mg/kg i.p. Then, the serum serotonin and the impact of 8-OH-DPAT (1 mg/kg s.c), a 5-HT1A receptor agonist, on long-lasting pain were examined. Mice receiving IMQ showed enhanced nociception, which decreased with all tested compounds. The serum serotonin in the IMQ group showed a significant decrease (947.042 ng/ml) regarding the control group (1143.68 ng/ml). The pretreatment with 8-OH-DPAT alleviated pain-related behaviours. These results suggest that the long-lasting pain resulting from psoriasis inflammation is also associated with the serotonergic system. The 5-HT1A receptor should be further explored as a potential therapeutic target for psoriasis pain modulation.

Avocado Oil Prevents Kidney Injury and Normalizes Renal Vasodilation after Adrenergic Stimulation in Hypertensive Rats: Probable Role of Improvement in Mitochondrial Dysfunction and Oxidative Stress.

Hypertension impairs the function of the kidney and its vasculature. Adrenergic activation is involved in these processes by promoting oxidative stress and mitochondrial dysfunction. Thus, the targeting of mitochondrial function and mitochondrial oxidative stress may be an approach to alleviate hypertensive kidney damage. Avocado oil, a source of oleic acid and antioxidants, improves mitochondrial dysfunction, decreases mitochondrial oxidative stress, and enhances vascular function in hypertensive rats. However, whether avocado oil improves the function of renal vasculature during the adrenergic stimulation, and if this is related to improvement in renal damage and enhancement of mitochondrial activity is unknown. Thus, the effects of avocado oil on renal vascular responses to adrenergic stimulation, mitochondrial dysfunction, oxidative stress, and renal damage were compared with prazosin, an antagonist of α1-adrenoceptors, in hypertensive rats induced by L-NAME. Avocado oil or prazosin decreased blood pressure, improved endothelium-dependent renal vasodilation, prevented mitochondrial dysfunction and kidney damage in hypertensive rats. However, avocado oil, but not prazosin, decreased mitochondrial ROS generation and improved the redox state of mitochondrial glutathione. These results suggest that avocado oil and prazosin prevented hypertensive renal damage due to the improvement in mitochondrial function.

Interplay between NADH oxidation by complex I, glutathione redox state and sirtuin-3, and its role in the development of insulin resistance.

Metabolic diseases are characterized by high NADH/NAD+ ratios due to excessive electron supply, causing defective mitochondrial function and impaired sirtuin-3 (SIRT-3) activity, the latter driving to oxidative stress and altered fatty acid ß-oxidation. NADH is oxidized by the complex I in the electron transport chain, thereby factors inhibiting complex I like acetylation, cardiolipin peroxidation, and glutathionylation by low GSH/GSSG ratios affects SIRT3 function by increasing the NADH/NAD+ ratio. In this review, we summarized the evidence supporting a role of the above events in the development of insulin resistance, which is relevant in the pathogenesis of obesity and diabetes. We propose that maintenance of proper NADH/NAD+ and GSH/GSSG ratios are central to ameliorate insulin resistance, as alterations in these redox couples lead to complex I dysfunction, disruption of SIRT-3 activity, ROS production and impaired ß-oxidation, the latter two being key effectors of insulin resistance.

The severity of rat liver injury by fructose and high fat depends on the degree of respiratory dysfunction and oxidative stress induced in mitochondria.

BACKGROUND: High fat or fructose induces non-alcoholic fatty liver disease (NAFLD) accompanied of mitochondrial dysfunction and oxidative stress. Controversy remains about whether fructose or fat is more deleterious for NAFLD development. To get more insights about this issue and to determine if the severity of liver disease induced by fructose or fat is related to degree of mitochondrial dysfunction, we compared the effects of diets containing high fat (HF), fructose (Fr) or high fat plus fructose (HF + Fr) on NAFLD development, mitochondrial function, ROS production and lipid peroxidation. METHODS: Wistar rats were assigned to four groups: Control, fed with standard rodent chow; High fat (HF), supplemented with lard and hydrogenated vegetable oil; Fructose (Fr), supplemented with 25% fructose in the drinking water; High fat plus fructose group (HF + Fr), fed with both HF and Fr diets. Rats were sacrificed after 6 weeks of diets consumption and the liver was excised for histopathological analysis by hematoxylin and eosin staining and for mitochondria isolation. Mitochondrial function was evaluated by measuring both mitochondrial respiration and complex I activity. Lipid peroxidation and ROS production were evaluated in mitochondria by the thiobarbituric acid method and with the fluorescent ROS probe 2,4-H2DCFDA, respectively. RESULTS: Fr group underwent the lower degree of both liver damage and mitochondrial dysfunction that manifested like less than 20% of hepatocytes with microvesicular steatosis and partial decrease in state 3 respiration, respectively. HF group displayed an intermediate degree of damage as it showed 40% of hepatocytes with microvesicular steatosis and diminution of both state 3 respiration and complex I activity. HF + Fr group displayed more severe damage as showed microvesicular steatosis in 60% of hepatocytes and inflammation, while mitochondria exhibited fully inhibited state 3 respiration, impaired complex I activity and increased ROS generation. Exacerbation of mitochondrial lipid peroxidation was observed in both the Fr and HF + Fr groups. CONCLUSION: Severity of liver injury induced by fructose or fat was related to the degree of dysfunction and oxidative damage in mitochondria. Attention should be paid on the serious effects observed in the HF + Fr group as the typical Western diet is rich in both fat and carbohydrates.

Vasculitis leucocitoclástica (vasculitis por hipersensibilidad) / Leukocytoclastic vasculitis (hypersensitivity vasculitis)

Resumen La vasculitis leucocitoclástica es un trastorno autoinmunitario que afecta pequeños vasos y provoca inflamación, destrucción y necrosis de los mismos; con frecuencia es subdiagnosticada. La causa es multifactorial, la fisiopatología es compleja y los inmunomoduladores son los medicamentos más importantes en su tratamiento. Este artículo tiene por objetivo revisar el estado actual del conocimiento en vasculitis leucocitocástica con insistencia en el diagnóstico y tratamiento. Se revisaron artículos publicados en el periodo comprendido entre 1990 y 2017. Los navegadores fueron Google Crome y Firefox y el motor de búsqueda fue Scholar google. Las bases de datos consultadas fueron: MEDLINE, RIMA Astra-Zeneca y las guías de práctica clínica del sistema de salud mexicano (CENETEC). Se revisaron 108 publicaciones relevantes para el tema, priorizando las pertenecientes a revistas indizadas en MEDLINE y Science Citation Index-JCR. Se requieren estudios para integrar subgrupos clínicos y de tratamiento e investigar los mecanismos de daño tisular en cada subgrupo. La inmunomodulación juega un papel central en el tratamiento.

Abstract Leukocytoclastic vasculitis is an autoimmune disorder that affects small vessels, and causes inflammation, destruction and necrosis of the same. It is often underdiagnosed. The etiology is multifactorial, the pathophysiology is complex and immunomodulators are the most important medications in their treatment. This article aims to review the current state of knowledge in leukocytoclastic vasculitis with emphasis on diagnosis and treatment. Articles published in the period from 1990 to 2017 were reviewed. The browsers were Google Crome and Firefox and the search engine was Scholar google. The database consulted was: MEDLINE, RIMA Astra-Zeneca and the clinical practice guidelines of the Mexican health system (CENETEC); 108 relevant publications to the subject were reviewed, prioritizing those belonging to journals indexed in MEDLINE and Science Citation Index-JCR. Studies are required to integrate clinical and treatment subgroups and investigate the mechanisms of tissue damage in each subgroup. Immunomodulation plays a central role in the treatment.

La psoriasis: de la investigación básica y clínica al desarrollo de nuevos tratamientos.

La psoriasis es una enfermedad cutánea incurable que afecta a 2.9 % de la población mexicana, por lo que es trascendente analizar el impacto de la medicina traslacional en el desarrollo de medicamentos antipsoriásicos. En esta revisión se discuten conceptos etiopatogénicos de la enfermedad y se analizan artículos publicados entre 2005 y 2017 en torno a medicamentos en desarrollo, además, se presenta un análisis crítico sobre las perspectivas futuras en el desarrollo de nuevos tratamientos. El uso de estrategias bidireccionales de la medicina traslacional ha permitido incrementar significativamente el número de tratamientos antipsoriásicos disponibles. Se encontraron 18 nuevos fármacos en exploración. La caracterización de antígenos responsables de la activación inmunológica, la identificación de biomarcadores predictivos de eficacia farmacológica, el desarrollo de modelos más representativos de la enfermedad, así como la integración de aspectos farmacogenómicos a estrategias de medicina traslacional fueron identificados como elementos relevantes que deben ser incorporados en el desarrollo de nuevas opciones terapéuticas.Psoriasis is an incurable cutaneous disease that affects 2.9% of the Mexican population, and it is therefore important for the impact of translational medicine on the development of anti-psoriatic drugs to be analyzed. In this review, current etiopathogenic concepts of the disease are discussed, and articles on drugs under development published between 2005 and 2017 are reviewed; in addition, a critical analysis on future perspectives for the development new treatments is presented. The use of translational medicine bi-directional strategies of has allowed to significantly increase the number of available anti-psoriatic therapies. Eighteen new investigational drugs were found. Characterization of antigens responsible for immune activation, identification of predictive biomarkers with pharmacologic efficacy, and the development of more representative disease models, as well as the integration of pharmacogenomic aspects to translational medicine strategies were identified as relevant aspects that should be incorporated in the development of new therapeutic options.

[Antioxidant vitamins in asthma]. / Vitaminas antioxidantes en asma.

Asthma is a condition of unknown etiology characterized by chronic airway inflammation. Cells that mediate the inflammatory response generate reactive oxygen species that, together with other respiratory tract naturally-occurring oxidant species, produce a rupture of the redox balance, generating oxidative stress. It has been proposed that oxidative stress can be reverted by supplemental or dietary intake of antioxidant vitamins such as vitamin A, C, D and E, and this way relieve, improve or protect people with asthma. In this research, observational and placebo-controlled trials with regard to the role of antioxidant vitamins in the course of asthma, published between 1979 and 2016, were reviewed. The search engines were Google and Google Scholar, whereas consulted databases were PubMed and The Cochrane Library. There were 75 articles relevant to the subject that were found and reviewed, and it was concluded that it is not clear if the intake of supplements of these vitamins has any beneficial clinical effect on asthma control. Further controlled, longer trials are needed to elucidate the role of these nutrients in the course of asthma.

El asma es una enfermedad de etiología desconocida que cursa con inflamación crónica de las vías respiratorias. Las células que median la respuesta inflamatoria generan especies reactivas de oxígeno, que en conjunto con otras especies oxidantes presentes de manera natural en las vías aéreas ocasionan la ruptura del equilibrio redox, generando estrés oxidativo. Se ha propuesto que este puede revertirse mediante la administración de vitaminas antioxidantes como A, C, E y D y de esta forma aliviar, mejorar o proteger a las personas con asma. En esta investigación se revisaron los ensayos observacionales y controlados con placebo relativos al papel de las vitaminas antioxidantes en el curso del asma, publicados entre 1979 y 2016. Los motores de búsqueda fueron Google y Google Scholar; las bases de datos consultadas fueron PubMed y The Cochrane Library. Se encontraron y revisaron 75 artículos relevantes para el tema, de los cuales se concluyó que no está claro si la ingesta de suplementos de estas vitaminas tiene algún efecto clínico benéfico en el control del asma. Son necesarios más ensayos controlados y de mayor duración para elucidar el papel de estos nutrientes en el curso del asma.

Comparative effects of avocado oil and losartan on blood pressure, renal vascular function, and mitochondrial oxidative stress in hypertensive rats.

OBJECTIVE: Angiotensin II (Ang-II) antagonism alleviates hypertensive kidney damage by improving mitochondrial function and decreasing oxidative stress. This condition also is associated with altered renal vascular tone due to enhanced constriction by Ang-II. Thus, approaches ameliorating these events are desirable to alleviate kidney damage. Avocado oil, a source of antioxidants and oleic acid, is known to improve mitochondrial function, while oleic acid has antihypertensive effects. Therefore, the aim of this study was to test whether avocado oil counteracts, to a similar degree as the Ang-II blocker losartan, the deleterious effects of hypertension on blood pressure, renal vascular performance, kidney mitochondrial function, and oxidative stress. METHODS: Hypertensive rats induced with Nω-nitro-l-arginine methyl ester (L-NAME) were supplemented during 45 d with avocado oil or losartan. Vascular responses were analyzed in perfused kidney. Membrane potential, reactive oxygen species levels, and glutathione were analyzed in isolated kidney mitochondria. RESULTS: In hypertensive rats, avocado oil decreased 21.2% and 15.5% diastolic and systolic blood pressures, respectively, and alleviated impaired renal vasodilation. Hypertension decreased membrane potential by 83.7% and augmented reactive oxygen species levels by 51% in mitochondria fueled with a complex I substrate, whereas it augmented the levels of oxidized glutathione in 48%. These alterations were normalized by avocado oil at a comparable degree to losartan. CONCLUSIONS: Because avocado oil mimicked the effects of losartan, we propose that the effects of avocado oil might be mediated by decreasing the actions of Ang-II on mitochondria. These results suggest that avocado oil intake might be a nutritional approach to attenuate the deleterious effects of hypertension on kidney.

Characterization of the effects of a polyunsaturated fatty acid (PUFA) on mitochondrial bioenergetics of chronologically aged yeast.

Increased membrane unsaturation has been associated with shorter longevity due to higher sensitivity to lipid peroxidation (LP) leading to enhanced mitochondrial dysfunction and ROS overproduction. However, the role of LP during aging has been put in doubt along with the participation of electron leak at the electron transport chain (ETC) in ROS generation in aged organisms. Thus, to test these hypothesis and gain further information about how minimizing LP preserves ETC function during aging, we studied the effects of α-linolenic acid (C18:3) on in situ mitochondrial ETC function, ROS production and viability of chronologically aged cells of S. cerevisiae, whose membranes are intrinsically resistant to LP due to the lack of PUFA. Increased sensitivity to LP was observed in cells cultured with C18:3 at 6 days of aging. This was associated with higher viability loss, dissipated membrane potential, impaired respiration and increased ROS generation, being these effects more evident at 28 days. However, at this point, lower sensitivity to LP was observed without changes in the membrane content of C18:3, suggesting the activation of a mechanism counteracting LP. The cells without C18:3 display better viability and mitochondrial functionality with lower ROS generation even at 28 days of aging and this was attributed to full preservation of complex III activity. These results indicate that the presence of PUFA in membranes enhances ETC dysfunction and electron leak and suggest that complex III is crucial to preserve membrane potential and to maintain a low rate of ROS production during aging.

[Typology of nosocomial architecture on both sides of the Atlantic Ocean, XVI century. Enrique Egas' model in Spain and Vasco de Quiroga's model in New Spain]. / Tipologías de arquitectura nosocomial a ambos lados del Atlántico, siglo XVI. El modelo de Enrique Egas en España y el de Vasco de Quiroga en Nueva España.

Two visions of the nosocomial architecture are discussed, located in a close time period, 1505-1535, but inserted in two different scenarios. One is in the Renaissance Spain, proposed by the architect E. Egas (born in Toledo, Spain), and the other one in the New Spain, proposed by V. de Quiroga, who chose an architectural style coherent with the Franciscan ideals of humbleness and evangelization, which set aside the ornamentation typical of Spanish medieval hospitals rather than palatial monuments built by E. Egas. The "hospital-village" project by V. de Quiroga allowed the patients and their families to live together, which was accepted by pre-Hispanic families that in the time were extensive. The hospital-village, both in its typology and in its health conception, returns to designs already in disuse of the Spanish Middle Age by picking up the idea of a hospital as a multifunctional space in which sanitary attention, nurseries, and shelters for poor people were combined within the church.

No direct association among respiratory function, disease control and family functioning in a sample of Mexican children with intermittent asthma.

Asthma has been linked to family disfunctioning and poor control of the disease.This study was conducted to analyze the interactions between the level of intermittent asthma control, family functioning and respiratory function and between quality of life of asthmatic patients and their caregivers.7 to 15 years old children with intermittent asthma were included. Asthma Control Test Questionnaire, Pediatric Asthma Quality of Life Questionnaire (PAQLQ) test, and flowmetry were applied to children and Pediatric Asthma Caregiver´s Quatily of Life Questionnaire (PAQCLQ) and the Family Functioning Perception Test (FF-SIL) were applied to their parents.The most affected areas of family functioning in dysfunctional families were adaptability and permeability. A medium to high strength of association was founded between the emotional function of parents and the emotional function of children, R2=0.552. The most remarkable associations were among parents' limitation of activities and parents' emotional function (r=0.837), parents' limitation of activities and child's emotional function (r=0.722), parents' emotional role and limitation of activities (r=0.837), parents' emotional role and emotional functioning of children with asthma (r=0.743) and the limitation of activities of children with asthma and the emotional function of children with asthma (r=0.870).No direct associations were founded among respiratory function, disease control and family functioning in Mexican children with intermittent asthma and emotional function of parents and children were associated in both groups.