Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis

Peer reviewedPublisher PD

The NLRP3 inflammasome: contributions to inflammation‑related diseases

The NOD-like receptor protein 3 (NLRP3) inflammasome is a protein complex that regulates innate immune responses by activating caspase-1 and the inflammatory cytokines interleukin (IL)-1β and IL-18. Multiple studies have demonstrated the importance of the NLRP3 inflammasome in the development of immune and inflammation-related diseases, including arthritis, Alzheimer’s disease, inflammatory bowel disease, and other autoimmune and autoinflammatory diseases. This review first explains the activation and regulatory mechanism of the NLRP3 inflammasome. Secondly, we focus on the role of the NLRP3 inflammasome in various inflammation-related diseases. Finally, we look forward to new methods for targeting the NLRP3 inflammasome to treat inflammation-related diseases, and provide new ideas for clinical treatment.National Natural Science Foundation of China, 82200330, 82070422, 81871607Youth Science and Technology Rising Star Project of Shaanxi Province2020KJXX-036, Innovation Capability Strong Foundation Plan of Xi’an City, 21YXYJ003

Estado nutricional, hábitos alimentarios y prácticas deportivas según turno escolar en niños de CABA 2014

Introducción: los cambios en el estilo de vida y los malos hábitos alimentarios en los últimos años han traído consecuencias de sobrepeso y obesidad en los niños en edad escolar. Objetivo: identificar si el turno escolar en los niños se relaciona con su estado nutricional, los hábitos alimentarios y las prácticas deportivas. Material y métodos: se realizó un estudio transversal, descriptivo. Se analizaron las encuestas de consumo en las cuatro comidas principales, el picoteo entre ingestas, la realización de colaciones y de actividad física extraescolar. Resultados: se pudo observar un leve desequilibrio en los niños que asisten al turno tarde, en comparación a los niños que asisten al turno mañana, ya que los niños que asisten al TT tienen a padecer mayor sobrepeso y obesidad, mayor consumo de las cuatro comidas principales (desayuno, almuerzo, merienda y cena), al consumo elevado de colaciones y picoteos, gaseosas con azúcar, mayor gasto de plata en el kiosco escolar, menor realización de actividad física y frecuencia semanal extraescolar. Conclusiones: la problemática de la urbanización y modernación afecta notablemente el modo de vida de los niños, el entorno en donde se emergen desalienta la actividad física y posibilitan más fácil el acceso a una amplia variedad de alimentos que generalmente son de baja calidad nutricional. Estos cambios determinan que la ingesta de energía resulta superior a la recomendada, sumado a la poca actividad física conducen a un aumento en la prevalencia de sobrepeso y obesidad.Tutora: Lic. Celeste ConcilioTutora: Lic. Eleonora Zumme

Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma

Supplementary Materials The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cells11213467/s1, Figure S1: Metabolic baseline characterization, treatments with melatonin agonists, and combina-tion treatments of melatonin (aMT) and the standard of care for GBM; Figure S2: Seahorse com-plementary analyses; Figure S3: pH fluctuations; Figure S4: In vivo results after melatonin intra-tumoral treatment.Funding This research was funded by the Distinguished Mayo Clinic Investigator Award (A.Q.-H.) and the William J. and Charles H. Mayo Professor (A.Q.-H.); the Uihlein Neuro-oncology Research Fund (A.Q.-H.) and R01CA200399 (A.Q.-H.).Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM).We analyzed melatonin’s functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin’s cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.Distinguished Mayo Clinic Investigator Award (A.Q.-H.)William J. and Charles H. Mayo Professor (A.Q.-H.)Uihlein Neuro-oncology Research Fund (A.Q.-H.)R01CA200399 (A.Q.-H.

VALORES, ACTITUDES Y HABILIDADES EN LA EDUCACIÓN PARA LA SALUD

El presente artículo parte de la concepción de la salud como "la capacidad de realizar el propio potencial personal y responder positivamente a los retos del ambiente". La adquisición por los estudiantes de competencias en valores, actitudes y habilidades que hagan operativa tal capacidad es una de las funciones de la Educación para la Salud. Los valores que se proponen al aprendizaje de los estudiantes son: la dignidad humana, la responsabilidad y la solidaridad. Entre las actitudes: la autenticidad, la fortaleza de la voluntad, la autoestima, la calidad de vida, el cuidado del otro, el desarrollo sostenible, la conservación de la Naturaleza y la austeridad. Entre las habilidades: el autocontrol, las referidas al diálogo y ponerse en lugar del otro. Palabras clave: Salud, Educación para la salud, valores, actitudes, habilidades.ABSTRACTThe present article starts from a concept ofhealth uderstood as «capacity to develop the own personal potential and to answer positively to the environments defies». The students achievement of competencies on values, altitudes and abilities which will ease such capacity is one ofthe goals of Health Education. The proposed values for the students' education are: human dignity, responsability and solidarity. Among the altitudes we find: genuine stance, strong will, self-steem, quality of life, concern for others, sustainable development, nature preservation and austerity. Among the abilities: self-control, and those referred to dialogue and empathy. Key words: Health, health education, valúes, attitudes, ábilitie

CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9R239X mice, the deficit in SQR induces an increase in thiosulfate sulfurtransferase and sulfite oxidase, as well as modifications in the levels of thiols. As a result, biosynthetic pathways of glutamate, serotonin, and catecholamines were altered in the cerebrum, and the blood pressure was reduced. Therefore, this study reveals the reduction in SQR activity as one of the pathomechanisms associated with CoQ deficiency syndrome.Ministerio de Economía y CompetitividadERDF/SAF2013-47761-RERDF/SAF2014-55523-RERDF/RD12/0042/0011ERDF/SAF2015-65786-RJunta de AndalucíaNIH/P01HD08064

Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic miceIts relation with mitochondrial dysfunction and prevention by melatonin

Producción CientíficaSepsis provokes an induction of inducible nitric oxide synthase (iNOS) and melatonin down-regulates its expression and activity. Looking for an inducible mtNOS isoform, we induced sepsis by cecal ligation and puncture in both normal and iNOS knockout mice and studied the changes in mtNOS activity. We also studied the effects of mtNOS induction in mitochondrial function, and the role of melatonin against induced mtNOS and mitochondrial dysfunction. The activity of mtNOS and nitrite levels significantly increased after sepsis in iNOS+/+ mice. These animals showed a significant inhibition of the respiratory chain activity and an increase in mitochondrial oxidative stress, reflected in the disulfide/glutathione ratio, glutathione redox cycling enzymes activity and lipid peroxidation levels. Interestingly, mtNOS activity remained unchanged in iNOS-/- septic mice, and mitochondria of these animals were unaffected by sepsis. Melatonin administration to iNOS+/+ mice counteracted mtNOS induction and respiratory chain failure, restoring the redox status. The results support the existence of an inducible mtNOS that is likely coded by the same gene as iNOS. The results also suggest that sepsis-induced mtNOS is responsible for the increase of mitochondrial impairment due to oxidative stress in sepsis, perhaps due to the high production of NO. Melatonin treatment prevents mitochondrial failure at the same extend as the lack of iNOS gene

Oncostatic effect of melatonin in head and neck cancer cells: clonogenic assay

Background: The oncostatic effect of melatonin has been previously described among different neoplastic types. One of these is head and neck squamous cell cancer (HNSCC) with a high rate of mortality and morbidity. Melatonin (aMT) could cause cell death in this neoplastic cell type. To determine this, we performed a clonogenic assay with CAL-27 cells treated with melatonin and/or radiation. Methods: Cells were plated in a 6-well plate, with 800 cells per well. Assays were performed at least twice and each time in triplicates. Cells were allowed to grow 15 days to form colonies of at least 50 cells each one. Cells were treated with melatonin (100, 500, 1000, 1500 and 2000 µM) alone or in combination with irradiation (8 Gy). To visualize colonies, cells were fixed in 100 % ethanol on days 12, 13, 14 and 15 after they were plated and stained with crystal violet solution. Colonies were scored with Image J Software. Results: The results clearly show that melatonin inhibits colony growth of CAL-27 cells in a dosedependent manner in the groups treated with melatonin alone 1500 µM or in combination with irradiation. Conclusion: The results show the capability of aMT to prevent colony growth and causing cell death on CAL-27 cancer cells, especially when combined with radiation. This is consistent with previous studies on aMT oncostatic effects and suggests that usage of aMT in vivo should have future clinical application

Is there a role for melatonin in fibromyalgia?

Fibromyalgia, characterised by persistent pain, fatigue, sleep disturbance and cognitive dysfunction, is a central sensitivity syndrome that also involves abnormality in peripheral generators and in the hypothalamic pituitary adrenal axis. Heterogeneity of clinical expression of fibromyalgia with a multifactorial aetiology has made the development of effective therapeutic strategies challenging. Physiological properties of the neurohormone melatonin appear related to the symptom profile exhibited by patients with fibromyalgia and thus disturbance of it’s production would be compatible with the pathophysiology. Altered levels of melatonin have been observed in patients with fibromyalgia which are associated with lower secretion during dark hours and higher secretion during daytime. However, inconsistencies of available clinical evidence limit conclusion of a relationship between levels of melatonin and symptom profiles in patients with fibromyalgia. Administration of melatonin to patients with fibromyalgia has demonstrated suppression of many symptoms and an improved quality of life consistent with benefit as a therapy for the management of this condition. Further studies with larger samples, however, are required to explore the potential role of melatonin in the pathophysiology of fibromyalgia and determine the optimal dosing regimen of melatonin for the management of fibromyalgia

Melatonin and Other Tryptophan Metabolites Produced by Yeasts: Implications in Cardiovascular and Neurodegenerative Diseases

Yeast metabolism produces compounds derived from tryptophan, which are found in fermented beverages, such as wine and beer. Melatonin and serotonin, in particular, may play a significant role due to their bioactivity in humans. Indeed, the former is a neurohormone related to circadiam rhythms, which also has a putative protective effect against degenerative diseases. Serotonin, on the other hand, is a neurotransmitter itself, in addition to being a precursor of melatonin synthesis. This paper summarizes data reported on fermented beverages, to evaluate dietary intake. Additionally, the article reviews observed effects of yeast amino acid metabolites on the prevention of neurodegenerative diseases (Alzheimer’s and Parkinson’s) and angiogenesis, focusing on evidence of the molecular mechanism involved and identification of molecular target