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1.
Cell Metab ; 34(10): 1532-1547.e6, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36198294

RESUMO

The hypothalamus is key in the control of energy balance. However, strategies targeting hypothalamic neurons have failed to provide viable options to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here, we show that obesity promotes anatomically restricted remodeling of hypothalamic astrocyte activity. In the paraventricular nucleus (PVN) of the hypothalamus, chemogenetic manipulation of astrocytes results in bidirectional control of neighboring neuron activity, autonomic outflow, glucose metabolism, and energy balance. This process recruits a mechanism involving the astrocytic control of ambient glutamate levels, which becomes defective in obesity. Positive or negative chemogenetic manipulation of PVN astrocyte Ca2+ signals, respectively, worsens or improves metabolic status of diet-induced obese mice. Collectively, these findings highlight a yet unappreciated role for astrocytes in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy.


Assuntos
Astrócitos , Hipotálamo , Animais , Astrócitos/metabolismo , Metabolismo Energético/fisiologia , Glucose/metabolismo , Ácido Glutâmico/metabolismo , Hipotálamo/metabolismo , Camundongos , Obesidade/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo
2.
Free Radic Biol Med ; 162: 27-37, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33278510

RESUMO

Etoposide is an extensively prescribed anticancer drug that, unfortunately, causes therapy-related leukemia. The mechanisms by which etoposide induces secondary hematopoietic malignancies are poorly documented. However, etoposide-related leukemogenesis is known to depend on oxidative metabolites of etoposide, notably etoposide quinone, that can react with protein cysteine residues such as in topoisomerases II. CREBBP is a major histone acetyltransferase that functions mainly as a transcriptional co-activator. This epigenetic enzyme is considered as a tumor suppressor that plays a major role in hematopoiesis. Genetic alterations affecting CREBBP activity are highly common in hematopoietic malignancies. We report here that CREBBP is impaired by etoposide quinone. Molecular and kinetic analyses show that this inhibition occurs through the rapid and covalent (kinhib = 16.102 M-1. s-1) adduction of etoposide quinone with redox sensitive cysteine residues within the RING and PHD Zn2+-fingers of CREBBP catalytic core leading to subsequent release of Zn2+. In agreement with these findings, experiments conducted in cells and in mice treated with etoposide showed irreversible inhibition of endogenous CREBBP activity and decreased H3K18 and H3K27 acetylation. As shown for topoisomerases II, our work thus suggests that the leukemogenic metabolite etoposide quinone can impair the epigenetic CREBBP acetyltransferase through reaction with redox sensitive cysteine residues.


Assuntos
Antineoplásicos , Cisteína , Animais , Proteína de Ligação a CREB/metabolismo , Etoposídeo , Humanos , Camundongos , Oxirredução , Estresse Oxidativo , Quinonas , Zinco
3.
Org Biomol Chem ; 18(12): 2219-2222, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32159577

RESUMO

More than 500 siderophores are known to date, but only three were identified to be aryl-containing hydroxamate siderophores, legonoxamines A and B from Streptomyces sp. MA37, and aryl ferrioxamine 2 from Micrococcus luteus KLE1011. Siderophores are produced by microorganisms to scavenge iron from the environment, thereby making this essential metal nutrient available to the microbe. We demonstrate here that LgoC from MA37 is responsible for the key aryl-hydroxamate forming step in legonoxamine biosynthesis. Biochemical characterization established that LgoC displays considerable promiscuity for the acylation between N-hydroxy-cadaverine and SNAC (N-acetylcysteamines) thioester derivatives.


Assuntos
Coenzima A-Transferases/metabolismo , Sideróforos/metabolismo , Acilação , Proteínas de Bactérias/metabolismo , Ácidos Hidroxâmicos/química , Ferro/metabolismo , Micrococcus luteus/química , Sideróforos/biossíntese , Sideróforos/isolamento & purificação , Streptomyces/química , Streptomyces/enzimologia
4.
Biochim Biophys Acta Proteins Proteom ; 1868(2): 140318, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31740411

RESUMO

Human cathepsin K (hCatK), which is highly expressed in osteoclasts, has the noteworthy ability to cleave type I and II collagens in their helical domain. Its collagenase potency depends strictly on the formation of an oligomeric complex with chondroitin 4-sulfate (C4-S). Accordingly, hCatK is a pivotal protease involved in bone resorption and is an attractive target for the treatment of osteoporosis. As rat is a common animal model for the evaluation of hCatK inhibitors, we conducted a comparative analysis of rat CatK (rCatK) and hCatK, which share a high degree of identity (88%) and similarity (93%). The pH activity profile of both enzymes displayed a similar bell-shaped curve (optimal pH: 6.4). Presence of Ser134 and Val160 in the S2 pocket of rCatK instead of Ala and Leu residues, respectively, in hCatK, led to a weaker peptidase activity, as observed for mouse CatK. Also, regardless of the presence of C4-S, rCatK cleaved in the nonhelical telopeptide regions of both type I (tail) and type II (articular joint) rat collagens. Structure-based computational analyses (electrostatic potential, molecular docking, molecular dynamics, free energy calculations) sustained that the C4-S mediated collagenolytic activity of rCatK obeys distinct molecular interactions from those of hCatK. Additionally, T-kininogen (a.k.a. thiostatin), a unique rat serum acute phase molecule, acted as a tight-binding inhibitor of hCatK (Ki = 0.11 ± 0.05 nM). Taken into account the increase of T-Kininogen level in inflamed rat sera, this may raise the question of the appropriateness to evaluate pharmacological hCatK inhibitors in this peculiar animal model.


Assuntos
Catepsina K/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Catepsina K/antagonistas & inibidores , Colágeno Tipo I/metabolismo , Colágeno Tipo II/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Ratos Wistar , Alinhamento de Sequência , Especificidade por Substrato , Termodinâmica
5.
Am J Physiol Lung Cell Mol Physiol ; 317(5): L625-L638, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553637

RESUMO

Cigarette smoking has marked effects on lung tissue, including induction of oxidative stress, inflammatory cell recruitment, and a protease/antiprotease imbalance. These effects contribute to tissue remodeling and destruction resulting in loss of lung function in chronic obstructive pulmonary disease (COPD) patients. Cathepsin S (CatS) is a cysteine protease that is involved in the remodeling/degradation of connective tissue and basement membrane. Aberrant expression or activity of CatS has been implicated in a variety of diseases, including arthritis, cancer, cardiovascular, and lung diseases. However, little is known about the effect of cigarette smoking on both CatS expression and activity, as well as its role in smoking-related lung diseases. Here, we evaluated the expression and activity of human CatS in lung tissues from never-smokers and smokers with or without COPD. Despite the presence of an oxidizing environment, CatS expression and activity were significantly higher in current smokers (both non-COPD and COPD) compared with never-smokers, and correlated positively with smoking history. Moreover, we found that the exposure of primary human bronchial epithelial cells to cigarette smoke extract triggered the activation of P2X7 receptors, which in turns drives CatS upregulation. The present data suggest that excessive CatS expression and activity contribute, beside other proteases, to the deleterious effects of cigarette smoke on pulmonary homeostasis.


Assuntos
Catepsinas/metabolismo , Fumar Cigarros/efeitos adversos , Células Epiteliais/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/enzimologia , Mucosa Respiratória/enzimologia , Fumantes/estatística & dados numéricos , Idoso , Estudos de Casos e Controles , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Mucosa Respiratória/efeitos dos fármacos
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