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Cell Rep ; 32(12): 108160, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32966793


The glyoxalase system is a highly conserved and ubiquitously expressed enzyme system, which is responsible for the detoxification of methylglyoxal (MG), a spontaneous by-product of energy metabolism. This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax). Additionally, we observe proteasomal degradation of non-phosphorylated Glo1 via ubiquitination does occur more rapidly as compared with native Glo1. The absence of CamKIIδ is associated with poor detoxification capacity and decreased protein content of Glo1 in a murine CamKIIδ knockout model. Therefore, phosphorylation of T107 in the Glo1 protein by CamKIIδ is a quick and precise mechanism regulating Glo1 activity, which is experimentally linked to an altered Glo1 status in cancer, diabetes, and during aging.

Oncogene ; 39(6): 1378-1387, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31649333


Calcium ion (Ca2+) is a versatile second messenger that regulates various cellular and physiological functions. However, the in vivo molecular mechanisms by which Ca2+ alterations contribute to tumor growth remain poorly explored. Here we show that Emei is a novel ER Ca2+ regulator that synergizes with RasV12 to induce tumor growth via JNK-mediated Hippo signaling. Emei disruption reduces ER Ca2+ level and subsequently leads to JNK activation and Hippo inactivation. Importantly, genetically increasing cytosolic Ca2+ concentration cooperates with RasV12 to drive tumor growth via inactivating the Hippo pathway. Finally, we identify POSH as a crucial link that bridges cytosolic Ca2+ alteration with JNK activation and Hippo-mediated tumor growth. Together, our findings provide a novel mechanism of tumor growth that acts through intracellular Ca2+ levels to modulate JNK-mediated Hippo signaling.

Cálcio/metabolismo , Carcinogênese/patologia , Proliferação de Células , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Retículo Endoplasmático/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais
J Med Life ; 12(1): 43-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123524


This study aimed to assess the masticatory efficiency in patients with a removable dental prosthesis, presenting different systemic, oral and prosthetic states while chewing different foods. The study was conducted on a convenient sample of patients aged 45 and above, with removable prostheses in at least one jaw. Patients were asked to chew samples of digestive biscuits, apple, and carrot, until the sensation of swallowing. The recorded masticatory function parameters were: chewing time, the number of mastication cycles, mean masticatory cycle duration, and chewing frequency. We found out that the masticatory functional parameters registered statistically significant differences according to the chewed food (e.g., generally the highest values were recorded for carrot and lowest for apple), most likely this being in relation to food's consistency, wetting, and adherence. High positive correlations were found between the chewing time and the number of mastication cycles for all three foods taken into consideration. Higher values for chewing time and number of mastication cycles were found for all foods in patients with complete dentures and overdentures, and while chewing carrot in patients with altered general status and of advanced age. Therefore, it that it takes a different time and number of mastication cycles to complete chewing, in relation to individual and food characteristics, to the systemic, oral and prosthetic patient's status. The residual teeth number and the type of prosthetic rehabilitation favor the adaptation and improvement of masticatory parameters and can have marker value for masticatory efficiency.

Prótese Dentária , Prótese Total , Mastigação/fisiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Deglutição/fisiologia , Feminino , Alimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
Artigo em Inglês | MEDLINE | ID: mdl-29693637


Evidence suggests that nutritional status during fetal development and early life leaves an imprint on the genome, which leads to health outcomes not only on a person as an adult but also on his offspring. The purpose of this study is to bring forth an overview of the relevant parameters that need to be collected to assess the long-term and transgenerational health outcomes of famine. A literature search was conducted for the most pertinent articles on the epigenetic effects of famine. The results were compiled, synthesized and discussed with an expert in genetics for critical input and validation. Prenatal and early life exposure to famine was associated with metabolic, cardiovascular, respiratory, reproductive, neuropsychiatric and oncologic diseases. We propose a set of parameters to be collected in disaster settings to assess the long-term outcomes of famine: PALTEM (parameters to assess long-term effects of malnutrition).

Desastres , Epigenômica/organização & administração , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Inanição/complicações , Inanição/fisiopatologia , Adulto , Feminino , Desenvolvimento Fetal/fisiologia , Nível de Saúde , Humanos , Masculino , Estado Nutricional , Gravidez
Cell Metab ; 27(4): 926-934.e8, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29551588


The molecular causes of type 2 diabetes (T2D) are not well understood. Both type 1 diabetes (T1D) and T2D are characterized by impaired insulin signaling and hyperglycemia. From analogy to T1D, insulin resistance and hyperglycemia are thought to also play causal roles in T2D. Recent clinical studies, however, found that T2D patients treated to maintain glycemia below the diabetes definition threshold (HbA1c < 6.5%) still develop diabetic complications. This suggests additional insulin- and glucose-independent mechanisms could be involved in T2D progression and/or initiation. T2D patients have elevated levels of the metabolite methylglyoxal (MG). We show here, using Drosophila glyoxalase 1 knockouts, that animals with elevated methylglyoxal recapitulate several core aspects of T2D: insulin resistance, obesity, and hyperglycemia. Thus elevated MG could constitute one root cause of T2D, suggesting that the molecular causes of elevated MG warrant further study.

Diabetes Mellitus Tipo 2/metabolismo , Aldeído Pirúvico/metabolismo , Animais , Células Cultivadas , Drosophila melanogaster , Hiperglicemia/metabolismo , Resistência à Insulina , Lactoilglutationa Liase/genética , Obesidade/metabolismo
Dev Cell ; 41(1): 72-81.e6, 2017 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-28399403


Human susceptibility to obesity is mainly genetic, yet the underlying evolutionary drivers causing variation from person to person are not clear. One theory rationalizes that populations that have adapted to warmer climates have reduced their metabolic rates, thereby increasing their propensity to store energy. We uncover here the function of a gene that supports this theory. THADA is one of the genes most strongly selected during evolution as humans settled in different climates. We report here that THADA knockout flies are obese, hyperphagic, have reduced energy production, and are sensitive to the cold. THADA binds the sarco/ER Ca2+ ATPase (SERCA) and acts on it as an uncoupler. Reducing SERCA activity in THADA mutant flies rescues their obesity, pinpointing SERCA as a key effector of THADA function. In sum, this identifies THADA as a regulator of the balance between energy consumption and energy storage, which was selected during human evolution.

Proteínas de Transporte/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Metabolismo Energético , Temperatura Alta , Proteínas de Neoplasias/metabolismo , Animais , Sequência Conservada , Retículo Endoplasmático/metabolismo , Feminino , Técnicas de Inativação de Genes , Células HeLa , Humanos , Mutação/genética , Obesidade/metabolismo , Obesidade/patologia , Ligação Proteica , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo