RESUMEN
Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.
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Proteína BRCA2 , Neoplasias de la Mama , Glucólisis , Piruvaldehído , Animales , Proteína BRCA2/metabolismo , Proteína BRCA2/genética , Ratones , Humanos , Femenino , Piruvaldehído/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Haploinsuficiencia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Mutación , Daño del ADN , Reparación del ADN , Línea Celular TumoralRESUMEN
Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.
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Inflamación/inmunología , Activación de Macrófagos , Macrófagos/inmunología , Mitocondrias/enzimología , Succinato Deshidrogenasa/metabolismo , Ácido Succínico/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Ciclo del Ácido Cítrico , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/genética , Interleucina-10/metabolismo , Lipopolisacáridos/inmunología , Macrófagos/metabolismo , Malonatos/farmacología , Potencial de la Membrana Mitocondrial , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Oxidación-Reducción/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Oxidorreductasas/metabolismo , Proteínas de Plantas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Análisis de Secuencia de ARN , Succinato Deshidrogenasa/genética , TranscriptomaRESUMEN
Several classes of antibiotics have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here, we report that tetracycline antibiotics, which target the mitoribosome, protected against sepsis without affecting the pathogen load. Mechanistically, we found that mitochondrial inhibition of protein synthesis perturbed the electron transport chain (ETC) decreasing tissue damage in the lung and increasing fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a liver-specific partial and acute deletion of Crif1, a critical mitoribosomal component for protein synthesis, we found that mice were protected against sepsis, an observation that was phenocopied by the transient inhibition of complex I of the ETC by phenformin. Together, we demonstrate that mitoribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a mechanism for the induction of disease tolerance.
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Antibacterianos/uso terapéutico , Doxiciclina/uso terapéutico , Hígado/inmunología , Pulmón/inmunología , Mitocondrias/metabolismo , Sepsis/tratamiento farmacológico , Tetraciclina/uso terapéutico , Animales , Proteínas de Ciclo Celular/genética , Modelos Animales de Enfermedad , Transporte de Electrón , Células Hep G2 , Humanos , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.
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ADN Mitocondrial , Fumaratos , Inmunidad Innata , Mitocondrias , Animales , Ratones , ADN Mitocondrial/metabolismo , Fumarato Hidratasa/genética , Fumarato Hidratasa/metabolismo , Fumaratos/metabolismo , Mitocondrias/enzimología , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Riñón/enzimología , Riñón/metabolismo , Riñón/patología , Citosol/metabolismoRESUMEN
Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-ß production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.
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Fumarato Hidratasa , Interferón beta , Macrófagos , Mitocondrias , ARN Mitocondrial , Humanos , Argininosuccinato Sintasa/metabolismo , Ácido Argininosuccínico/metabolismo , Ácido Aspártico/metabolismo , Respiración de la Célula , Citosol/metabolismo , Fumarato Hidratasa/antagonistas & inhibidores , Fumarato Hidratasa/genética , Fumarato Hidratasa/metabolismo , Fumaratos/metabolismo , Interferón beta/biosíntesis , Interferón beta/inmunología , Lipopolisacáridos/farmacología , Lipopolisacáridos/metabolismo , Lupus Eritematoso Sistémico/enzimología , Macrófagos/enzimología , Macrófagos/inmunología , Macrófagos/metabolismo , Potencial de la Membrana Mitocondrial , Metabolómica , Mitocondrias/genética , Mitocondrias/metabolismo , ARN Mitocondrial/metabolismoRESUMEN
Glycolysis is linked to the rapid response of memory CD8+ T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3ß (GSK3ß) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria. Binding of HK-I to VDAC promoted respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of interferon-γ (IFN-γ) in memory T cells. Subcellular organization of mTORC2-AKT-GSK3ß at mitochondria-ER contact sites, promoting HK-I recruitment to VDAC, thus underpins the metabolic reprogramming needed for memory CD8+ T cells to rapidly acquire effector function.
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Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Retículo Endoplásmico/metabolismo , Metabolismo Energético , Memoria Inmunológica , Mitocondrias/metabolismo , Transducción de Señal , Respiración de la Célula , Retículo Endoplásmico/ultraestructura , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucólisis , Membranas Intracelulares/metabolismo , Activación de Linfocitos , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Mitocondrias/ultraestructura , Modelos Biológicos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/deficienciaRESUMEN
Prokaryotes adapt to challenges from mobile genetic elements by integrating spacers derived from foreign DNA in the CRISPR array1. Spacer insertion is carried out by the Cas1-Cas2 integrase complex2-4. A substantial fraction of CRISPR-Cas systems use a Fe-S cluster containing Cas4 nuclease to ensure that spacers are acquired from DNA flanked by a protospacer adjacent motif (PAM)5,6 and inserted into the CRISPR array unidirectionally, so that the transcribed CRISPR RNA can guide target searching in a PAM-dependent manner. Here we provide a high-resolution mechanistic explanation for the Cas4-assisted PAM selection, spacer biogenesis and directional integration by type I-G CRISPR in Geobacter sulfurreducens, in which Cas4 is naturally fused with Cas1, forming Cas4/Cas1. During biogenesis, only DNA duplexes possessing a PAM-embedded 3'-overhang trigger Cas4/Cas1-Cas2 assembly. During this process, the PAM overhang is specifically recognized and sequestered, but is not cleaved by Cas4. This 'molecular constipation' prevents the PAM-side prespacer from participating in integration. Lacking such sequestration, the non-PAM overhang is trimmed by host nucleases and integrated to the leader-side CRISPR repeat. Half-integration subsequently triggers PAM cleavage and Cas4 dissociation, allowing spacer-side integration. Overall, the intricate molecular interaction between Cas4 and Cas1-Cas2 selects PAM-containing prespacers for integration and couples the timing of PAM processing with the stepwise integration to establish directionality.
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Proteínas Asociadas a CRISPR/metabolismo , Sistemas CRISPR-Cas , Endonucleasas/metabolismo , Geobacter/enzimología , Bases de Datos Genéticas , Modelos Moleculares , Conformación Molecular , Motivos de NucleótidosRESUMEN
Mammalian voltage-activated L-type Ca2+ channels, such as Ca(v)1.2, control transmembrane Ca2+ fluxes in numerous excitable tissues. Here, we report that the pore-forming α1C subunit of Ca(v)1.2 is reversibly palmitoylated in rat, rabbit, and human ventricular myocytes. We map the palmitoylation sites to two regions of the channel: The N terminus and the linker between domains I and II. Whole-cell voltage clamping revealed a rightward shift of the Ca(v)1.2 current-voltage relationship when α1C was not palmitoylated. To examine function, we expressed dihydropyridine-resistant α1C in human induced pluripotent stem cell-derived cardiomyocytes and measured Ca2+ transients in the presence of nifedipine to block the endogenous channels. The transients generated by unpalmitoylatable channels displayed a similar activation time course but significantly reduced amplitude compared to those generated by wild-type channels. We thus conclude that palmitoylation controls the voltage sensitivity of Ca(v)1.2. Given that the identified Ca(v)1.2 palmitoylation sites are also conserved in most Ca(v)1 isoforms, we propose that palmitoylation of the pore-forming α1C subunit provides a means to regulate the voltage sensitivity of voltage-activated Ca2+ channels in excitable cells.
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Células Madre Pluripotentes Inducidas , Miocitos Cardíacos , Ratas , Humanos , Conejos , Animales , Miocitos Cardíacos/metabolismo , Calcio/metabolismo , Lipoilación , Canales de Calcio Tipo L/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Calcio de la Dieta , Mamíferos/metabolismoRESUMEN
Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn's disease and Parkinson's disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.
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Predisposición Genética a la Enfermedad , Lepra , Niño , Humanos , Alelos , Genotipo , Lepra/genética , Mutación , Proteína Adaptadora de Señalización NOD2/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genéticaRESUMEN
OBJECTIVES: Autoimmune hepatitis (AIH) is a necroinflammatory disease that occurs when genetically susceptible individuals are exposed to an environmental trigger. It is a rare disease, and its epidemiological aspects are nearly unknown in Northeast Brazil. In the literature, the activation of components of the inflammatory cascade pathways, including interleukins such as TNF-α and signaling factors like MAPK-p38 and NFκB, in the pathogenesis of AIH is well described in animal models. This study evaluated, for the first time, the immunostaining of TNF-α, MAPK-p38, and NFκB in immunohistochemical analysis of liver biopsies from AIH patients. The activation of the MAPK-p38 pathway was also studied through immunoassay analysis in the peripheral blood of AIH patients. METHODS AND RESULTS: Data from medical records of 25 AIH patients were analyzed. Histological and immunohistochemical analysis of liver tissue obtained from biopsies was performed to detect NFκB, MAPK-p38, and TNF-α. Immunoassay analysis of the MAPK-p38 pathway was performed in peripheral blood from 18 AIH patients and 8 healthy volunteers. Medical record analysis showed an average age of 33.3 years, with a female predominance in a ratio of 7.3:1. Concomitance with other autoimmune diseases was observed in 36 % of patients, with thyroid disorders being the most prominent among them, and an 8 % indication for liver transplantation. In the evaluation of autoantibodies, ANA was detected in 52 %, followed by SMA at 20 %, and Anti-LKM-1 at 16 %. Liver biopsy findings were like the global literature, with interface hepatitis and lymphoplasmacytic infiltration observed. Immunohistochemical analysis showed immunostaining for NFκB, MAPK-p38, and TNF-α, corroborating the inflammatory and immunological characteristics of the disease. Immunoassay analysis in peripheral blood confirmed the activation of the MAPK-p38 signaling pathway, with a statistically significant difference between AIH patients and healthy controls. CONCLUSIONS: The epidemiological and histological findings of AIH in this study in Northeast Brazil were like global population data. Immunohistochemical analysis of liver tissue and immunoassay analysis in peripheral blood confirmed the activation of TNF-α and the NFκB and MAPK-p38 signaling pathways in AIH patients.
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Hepatitis Autoinmune , Trasplante de Hígado , Animales , Humanos , Femenino , Adulto , Masculino , Factor de Necrosis Tumoral alfa , Hígado/patología , Autoanticuerpos , Transducción de SeñalRESUMEN
Autism is more frequently diagnosed in males, with evidence suggesting that females are more likely to be misdiagnosed or underdiagnosed. Possibly, the male/female ratio imbalance relates to phenotypic and camouflaging differences between genders. Here, we performed a comprehensive approach to phenotypic and camouflaging research in autism addressed in two studies. First (Study 1 - Phenotypic Differences in Autism), we conducted a systematic review and meta-analysis of gender differences in autism phenotype. The electronic datasets Pubmed, Scopus, Web of Science, and PsychInfo were searched. We included 67 articles that compared females and males in autism core symptoms, and in cognitive, socioemotional, and behavioural phenotypes. Autistic males exhibited more severe symptoms and social interaction difficulties on standard clinical measures than females, who, in turn, exhibited more cognitive and behavioural difficulties. Considering the hypothesis of camouflaging possibly underlying these differences, we then conducted a meta-analysis of gender differences in camouflaging (Study 2 - Camouflaging Differences in Autism). The same datasets as the first study were searched. Ten studies were included. Females used more compensation and masking camouflage strategies than males. The results support the argument of a bias in clinical procedures towards males and the importance of considering a 'female autism phenotype'-potentially involving camouflaging-in the diagnostic process.
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The mitochondrial outer membrane protein porin 1 (Por1), the yeast orthologue of mammalian voltage-dependent anion channel (VDAC), is the major permeability pathway for the flux of metabolites and ions between cytosol and mitochondria. In yeast, several Por1 phosphorylation sites have been identified. Protein phosphorylation is a major modification regulating a variety of biological activities, but the potential biological roles of Por1 phosphorylation remains unaddressed. In this work, we analysed 10 experimentally observed phosphorylation sites in yeast Por1 using bioinformatics tools. Two of the residues, T100 and S133, predicted to reduce and increase pore permeability, respectively, were validated using biological assays. In accordance, Por1T100D reduced mitochondrial respiration, while Por1S133E phosphomimetic mutant increased it. Por1T100A expression also improved respiratory growth, while Por1S133A caused defects in all growth conditions tested, notably in fermenting media. In conclusion, we found phosphorylation has the potential to modulate Por1, causing a marked effect on mitochondrial function. It can also impact on cell morphology and growth both in respiratory and, unpredictably, also in fermenting conditions, expanding our knowledge on the role of Por1 in cell physiology.
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Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Animales , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Fosforilación , Canales Aniónicos Dependientes del Voltaje/metabolismo , Mitocondrias/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Mamíferos/metabolismoRESUMEN
BACKGROUND: POLE mutated endometrial carcinomas may represent a subspecific type of tumors harboring a more favorable prognosis. Grade 3 (G3 or high-grade) endometrioid endometrial carcinomas remain a clinical dilemma, with some tumors behaving as the low-grade counterparts and others presenting a more aggressive behavior. OBJECTIVES: To determine the association between POLE mutational status and the overall-survival (OS) and progression-free-survival (PFS) of patients with G3 endometrioid endometrial cancer (EC). We also aimed to determine the prevalence of POLE mutations in G3 endometrioid EC. METHODS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO No: CRD4202340008). We searched the following electronic databases: PubMed/Medline, EMBASE, Cochrane Library, Scopus, and Web of Science. For time-to-event data, the effect of POLE mutation in G3 EC was described using hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Individual patient data for each study was investigated if available from the study authors. If individual patient data were not available, information regarding time-to-event outcomes was extracted using an appropriate methodology. OS and PFS were analyzed using both one-stage and two-stage approaches, the Kaplan-Meier method, and Cox-proportional hazards models. RESULTS: This systematic review and meta-analysis included 19 studies with 3092 patients who had high-grade endometrioid EC. Patients with POLE mutations had lower risks of death (HR = 0.36, 95% CI 0.26 to 0.50, I2 = 0%, 10 trials) and disease progression (HR = 0.31, 95% CI 0.17 to 0.57, I2 = 33%, 10 trials). The pooled prevalence of POLE mutation was 11% (95% CI 9 to 13, I2 = 68%, 18 studies). CONCLUSION: POLE mutations in high-grade endometrioid EC are associated with a more favorable prognosis with increased OS and PFS.
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Carcinoma Endometrioide , ADN Polimerasa II , Neoplasias Endometriales , Mutación , Clasificación del Tumor , Proteínas de Unión a Poli-ADP-Ribosa , Humanos , Femenino , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Neoplasias Endometriales/mortalidad , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , ADN Polimerasa II/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Pronóstico , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Cluster headache is a primary headache disorder characterized by bouts with circadian and circannual patterns. The CLOCK gene has a central role in regulating circadian rhythms. Here, we investigate the circannual CLOCK expression in a population of cluster headache patients in comparison to matched controls. METHODS: Patients with cluster headache were sampled two to four times over at least one year, both in or outside bouts, one week after each solstice and equinox. The expression of CLOCK was measured by quantitative real-time polymerase chain reaction (RT-PCR) in the peripheral blood. RESULTS: This study included 50 patients and 58 matched controls. Among the patient population, composed of 42/50 males (84%) with an average age of 44.6 years, 45/50 (90%) suffered from episodic cluster headache. Two to four samples were collected from each patient adding up to 161 samples, 36 (22.3%) of which were collected within a bout. CLOCK expression for cluster headache patients was considerably different from that of the control population in winter (p-value mean = 0.006283), spring (p-value mean = 0.000006) and summer (p-value mean = 0.000064), but not in autumn (p-value mean = 0.262272). For each season transition, the variations in CLOCK expression were more pronounced in the control group than in the cluster headache population. No statistically significant differences were found between bout and non-bout samples. No individual factors (age, sex, circadian chronotype, smoking and coffee habits or history of migraine) were related to CLOCK expression. CONCLUSIONS: We observed that CLOCK expression in cluster headache patients fluctuates less throughout the year than in the control population. Bout activity and lifestyle factors do not seem to influence CLOCK expression.
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Proteínas CLOCK , Cefalalgia Histamínica , Humanos , Cefalalgia Histamínica/genética , Masculino , Femenino , Adulto , Proteínas CLOCK/genética , Proteínas CLOCK/biosíntesis , Persona de Mediana Edad , Ritmo Circadiano , Estaciones del AñoRESUMEN
This cross-sectional study aims to describe and compare energy, nutrient intake and food consumption according to eating location and by age groups using data from the National Food, Nutrition and Physical Activity Survey (IAN-AF 2015/2016). Dietary intake was estimated by two non-consecutive days of food diaries (children)/24-h recalls (other age groups), and four eating location categories were defined according to the proportion of meals consumed at out-of-home locations: Home (at least 80 % of meals at home), Other Homes, School or Work and Restaurants and Other Places. The majority of meals (69·1 %) were consumed at home. Meals were also often taken at school by children and adolescents and in restaurants and similar outlets by adults and elderly. Children and adolescents in the School or Work category ate more fruit, vegetables and pulses and cereals and starchy tubers, whereas adults in this category ate more red and processed meats, sugar-sweetened beverages and sweets. Compared with Home category, Restaurants and Other Places was associated with worse diet adequacies among children (ß = -1·0; 95 % CI = -2·0, -0·04), adolescents: (ß = -2·4; 95 % CI = -3·2, -1·5) and adults (ß = -1·3; 95 % CI = -1·6, -1·0) reflecting higher intakes of energy, fat, trans-fatty acids and SFA, and Na. The elderly consumed more free sugars and fat when eating out of home in general. Overall, findings reflect important variation in nutrient profiles by eating location, with meals taken at school or work contributing to higher consumption of nutrient-dense foods and those taken in restaurants and other similar settings implying higher consumption of energy-dense foods.
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The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.
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Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/química , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/agonistas , Factor 2 Relacionado con NF-E2/metabolismo , Succinatos/metabolismo , Alquilación , Animales , Carboxiliasas , Bovinos , Cisteína/química , Cisteína/metabolismo , Citocinas/biosíntesis , Citocinas/inmunología , Retroalimentación Fisiológica , Femenino , Células HEK293 , Humanos , Hidroliasas/biosíntesis , Interferón beta/inmunología , Interferón beta/farmacología , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Proteínas/metabolismo , Ratas , Ratas Wistar , Succinatos/químicaRESUMEN
To evaluate the influence of early nutritional intake on the growth pattern of very preterm infants. This was an observational study including 109 newborns (< 32 weeks gestational age). Perinatal morbidities, nutritional therapy (first four weeks of life), and weight, length, and head circumference (HC) growth at term-equivalent age were evaluated. Growth restriction was defined as a difference > 1.2 SD between the birth and term age measurements. Growth restriction at term-equivalent age: 52.3% (weight), 42.9% (length), and 22% (HC). Morbidities were positively correlated with nutrition therapy and negatively correlated with the total energy provision: protein ratio. The duration of parenteral nutrition, the time to reach full enteral feedings, and the total energy provision: protein ratio were significantly correlated. Nutrient intake influenced weight, length, and HC growth, and cumulative energy deficit was significantly associated with HC growth restriction. Conclusion: Perinatal morbidities interfere with nutritional therapy and early nutrient intake, leading to insufficient energy and energy provision: protein ratio for growth. What is Known: ⢠The intake of macronutrients early in life, mainly protein, is important for the optimal growth of pretem infants. ⢠The severity of morbidities and low gestational ages impact the nutritional management of preterm infants. What is New: ⢠The number of morbidities, reflecting the severity of the neonatal clinical course, had a detrimental effect on the nutritional therapy and nutrients intake. ⢠The inadequate energy provision per gram of protein ratio was significantly associated with growth restriction in all growth measures at the second week of life, persisting for head circumference up to the fourth week, highlighting the importance of its measurement, as it could be a precocious sign of development risk.
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Proteínas en la Dieta , Ingestión de Energía , Humanos , Recién Nacido , Femenino , Masculino , Proteínas en la Dieta/administración & dosificación , Nutrición Parenteral/métodos , Fenómenos Fisiológicos Nutricionales del Lactante , Recien Nacido Prematuro/crecimiento & desarrollo , Edad Gestacional , Enfermedades del Prematuro/etiologíaRESUMEN
Many women seek treatment to improve menopausal vasomotor symptoms (VMS). The selection of women most likely to benefit from menopause hormone therapy (MHT) is crucial in clinical practice. There is general agreement that women younger than 60 years or who initiate MHT within the first 10 years of menopause, with no contraindications, have greater benefits considering symptomatic relief and additional advantages. This group may have the advantage of protection from osteoporosis and from other chronic diseases that affect postmenopausal women, namely cardiovascular disease (CVD). Cumulating evidence supports MHT for symptomatic women. However, inadequate use according to the needs of symptomatic women led to a burden of suffering worldwide. In recent years, the emergent use of non-regulated body-identical hormones (non-rBHT) can expose patients to potential harms. These hormone preparations are not regulated through the same tests of safety, efficacy or dosing consistency as regulated-BHT (r-BHT). The POESIT (Portugal + Spain + Italy) recommendations highlight the use of 17ß-estradiol (E2) and micronized progesterone (P4) as the real r-BHT. In addition, the group emphasizes as an example the data from the REPLENISH study with 1 mg E2/100 mg P4. The combination of the two hormones in one convenient pill showed a clear reduction or elimination of hot flashes and an improvement in sleep quality and, consequently, quality of life. At the same time, this combination has shown high rates of amenorrhea and no significant impact on lipid, glucose or coagulation parameters. Both the REPLENISH study and a real-life retrospective study pointed to the possibility of a lower risk of venous thromboembolism (VTE) with this formulation than with other combinations.
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Estradiol , Terapia de Reemplazo de Estrógeno , Sofocos , Menopausia , Progesterona , Humanos , Femenino , Sofocos/tratamiento farmacológico , Estradiol/administración & dosificación , Progesterona/administración & dosificación , Progesterona/uso terapéutico , Terapia de Reemplazo de Estrógeno/métodos , Persona de Mediana Edad , Calidad de Vida , España , ItaliaRESUMEN
Most instruments measuring nutrition literacy evaluate theoretical knowledge, not necessarily reflecting skills relevant to food choices. We aimed to develop and validate a photograph-based instrument to assess nutrition literacy (NUTLY) among adults in Portugal. NUTLY assesses the ability to distinguish foods with different nutritional profiles; from each of several combinations of three photographs (two foods with similar contents and one with higher content) participants are asked to identify the food with the highest energy/sodium content. The NUTLY version with 79 combinations, obtained after experts/lay people evaluations, was applied to a sample representing different age, gender and education groups (n = 329). Dimensionality was evaluated through latent trait models. Combinations with negative or with positive small factor loadings were excluded after critical assessment. Internal consistency was measured using Cronbach's alpha and construct validity by comparing NUTLY scores with those obtained in the Medical Term Recognition Test and the Newest Vital Sign (NVS), and across education and training in nutrition/health groups. The cut-off to distinguish adequate/inadequate nutrition literacy was defined through ROC analysis using the Youden index criterion, after performing a Latent class analysis which identified a two-class model to have the best goodness of fit. Test-retest reliability was assessed after one month (n = 158). The final NUTLY scale was unidimensional and included 48 combinations (energy: 33; sodium: 15; α = 0.74). Mean scores (±standard deviation) were highest among nutritionists (39.9 ± 4.4), followed by health professionals (38.5 ± 4.1) and declined with decreasing education (p < 0.001). Those with adequate nutrition literacy according to NVS showed higher NUTLY scores (37.9 ± 4.3 vs. 33.9 ± 6.9, p < 0.001). Adequate nutrition literacy was defined as a NUTLY score≥35 (sensitivity: 89.3%; specificity: 93.7%). Test-retest reliability was high (ICC = 0.77). NUTLY is a valid and reliable nutrition literacy measurement tool.
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Alfabetización en Salud , Fotograbar , Humanos , Femenino , Masculino , Adulto , Reproducibilidad de los Resultados , Portugal , Persona de Mediana Edad , Adulto Joven , Conocimientos, Actitudes y Práctica en Salud , Anciano , Encuestas y Cuestionarios/normas , AdolescenteRESUMEN
OBJECTIVES: There is limited evidence regarding the impact of race/racism and its intersection with socioeconomic status (SES) on breast and cervical cancer, the two most common female cancers globally. We investigated racial inequalities in breast and cervical cancer mortality and whether SES (education and household conditions) interacted with race/ethnicity. DESIGN: The 100 Million Brazilian Cohort data were linked to the Brazilian Mortality Database, 2004-2015 (n = 20,665,005 adult women). We analysed the association between self-reported race/ethnicity (White/'Parda'(Brown)/Black/Asian/Indigenous) and cancer mortality using Poisson regression, adjusting for age, calendar year, education, household conditions and area of residence. Additive and multiplicative interactions were assessed. RESULTS: Cervical cancer mortality rates were higher among Indigenous (adjusted Mortality rate ratio = 1.80, 95%CI 1.39-2.33), Asian (1.63, 1.20-2.22), 'Parda'(Brown) (1.27, 1.21-1.33) and Black (1.18, 1.09-1.28) women vs White women. Breast cancer mortality rates were higher among Black (1.10, 1.04-1.17) vs White women. Racial inequalities in cervical cancer mortality were larger among women of poor household conditions, and low education (P for multiplicative interaction <0.001, and 0.02, respectively). Compared to White women living in completely adequate (3-4) household conditions, the risk of cervical cancer mortality in Black women with 3-4, 1-2, and none adequate conditions was 1.10 (1.01-1.21), 1.48 (1.28-1.71), and 2.03 (1.56-2.63), respectively (Relative excess risk due to interaction-RERI = 0.78, 0.18-1.38). Among 'Parda'(Brown) women the risk was 1.18 (1.11-1.25), 1.68 (1.56-1.81), and 1.84 (1.63-2.08), respectively (RERI = 0.52, 0.16-0.87). Compared to high-educated White women, the risk in high-, middle- and low-educated Black women was 1.14 (0.83-1.55), 1.93 (1.57-2.38) and 2.75 (2.33-3.25), respectively (RERI = 0.36, -0.05-0.77). Among 'Parda'(Brown) women the risk was 1.09 (0.91-1.31), 1.99 (1.70-2.33) and 3.03 (2.61-3.52), respectively (RERI = 0.68, 0.48-0.88). No interactions were found for breast cancer. CONCLUSION: Low SES magnified racial inequalities in cervical cancer mortality. The intersection between race/ethnicity, SES and gender needs to be addressed to reduce racial health inequalities.