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1.
Nat Commun ; 11(1): 4549, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917889

RESUMO

Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease.


Assuntos
Artérias/citologia , Arterite/imunologia , Diferenciação Celular/fisiologia , Homeostase/fisiologia , Macrófagos/fisiologia , Envelhecimento/fisiologia , Angiotensina II/administração & dosagem , Angiotensina II/imunologia , Animais , Artérias/fisiologia , Medula Óssea/fisiologia , Transplante de Medula Óssea , Linhagem da Célula , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , RNA-Seq , Regeneração/fisiologia , Análise de Célula Única , Quimeras de Transplante
2.
Nat Commun ; 11(1): 4222, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839436

RESUMO

Our understanding of Na+ homeostasis has recently been reshaped by the notion of skin as a depot for Na+ accumulation in multiple cardiovascular diseases and risk factors. The proposed water-independent nature of tissue Na+ could induce local pathogenic changes, but lacks firm demonstration. Here, we show that tissue Na+ excess upon high Na+ intake is a systemic, rather than skin-specific, phenomenon reflecting architectural changes, i.e. a shift in the extracellular-to-intracellular compartments, due to a reduction of the intracellular or accumulation of water-paralleled Na+ in the extracellular space. We also demonstrate that this accumulation is unlikely to justify the observed development of experimental hypertension if it were water-independent. Finally, we show that this isotonic skin Na+ excess, reflecting subclinical oedema, occurs in hypertensive patients and in association with aging. The implications of our findings, questioning previous assumptions but also reinforcing the importance of tissue Na+ excess, are both mechanistic and clinical.


Assuntos
Edema/metabolismo , Homeostase/fisiologia , Sódio/metabolismo , Equilíbrio Hidroeletrolítico/fisiologia , Envelhecimento/metabolismo , Animais , Edema/diagnóstico , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Miocárdio/metabolismo , Especificidade de Órgãos , Concentração Osmolar , Potássio/metabolismo , Ratos Endogâmicos WKY , Pele/metabolismo , Fatores de Transcrição/metabolismo
3.
Nat Commun ; 11(1): 4071, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792491

RESUMO

Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.


Assuntos
Glutationa Transferase/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Caspase 8/genética , Caspase 8/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glutationa Transferase/genética , Homeostase/genética , Homeostase/fisiologia , Imuno-Histoquímica , Masculino , Microglia/citologia , Microglia/metabolismo , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Fagocitose/genética , Fagocitose/fisiologia , Processamento de Proteína Pós-Traducional , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Remielinização/genética , Remielinização/fisiologia
4.
Am J Physiol Regul Integr Comp Physiol ; 319(3): R347-R357, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32755463

RESUMO

How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies; however, findings are contradictory. We test whether low-level stress and Western diet (WD) feeding synergistically influence homeostasis, mood, and myocardial ischemic tolerance. Male C57BL6/J mice were fed a control diet or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 12 wk, with subgroups restrained for 30 min/day over the final 3 wk. Metabolism, behavior, tolerance of perfused hearts to ischemia-reperfusion (I/R), and cardiac "death proteins" were assessed. The WD resulted in insignificant trends toward increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%), and cholesterol (+20%) and reduced leptin (-20%) while significantly reducing insulin sensitivity [100% rise in homeostasis model assessment of insulin resistance (HOMA-IR), P < 0.05]. Restraint did not independently influence metabolism while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60-90% above control) in WD mice (P < 0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was nonadditive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippocampal TNF-α, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, whereas the combination worsened dysfunction and oncosis [lactate dehydrogenase (LDH) efflux]. Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3, and PARP) were unchanged. We conclude that mild, anxiogenic yet cardio-metabolically "benign" stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).


Assuntos
Dieta Hiperlipídica , Ingestão de Energia/fisiologia , Homeostase/fisiologia , Isquemia Miocárdica/fisiopatologia , Miocárdio/metabolismo , Animais , Coração/fisiopatologia , Resistência à Insulina/fisiologia , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/metabolismo , Obesidade/fisiopatologia
5.
PLoS Comput Biol ; 16(8): e1007790, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841234

RESUMO

The impairment of cognitive function in Alzheimer's disease is clearly correlated to synapse loss. However, the mechanisms underlying this correlation are only poorly understood. Here, we investigate how the loss of excitatory synapses in sparsely connected random networks of spiking excitatory and inhibitory neurons alters their dynamical characteristics. Beyond the effects on the activity statistics, we find that the loss of excitatory synapses on excitatory neurons reduces the network's sensitivity to small perturbations. This decrease in sensitivity can be considered as an indication of a reduction of computational capacity. A full recovery of the network's dynamical characteristics and sensitivity can be achieved by firing rate homeostasis, here implemented by an up-scaling of the remaining excitatory-excitatory synapses. Mean-field analysis reveals that the stability of the linearised network dynamics is, in good approximation, uniquely determined by the firing rate, and thereby explains why firing rate homeostasis preserves not only the firing rate but also the network's sensitivity to small perturbations.


Assuntos
Doença de Alzheimer/fisiopatologia , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Sinapses/fisiologia , Homeostase/fisiologia , Humanos
6.
Clin Auton Res ; 30(4): 299-315, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32700055

RESUMO

The pandemic viral illness COVID-19 is especially life-threatening in the elderly and in those with any of a variety of chronic medical conditions. This essay explores the possibility that the heightened risk may involve activation of the "extended autonomic system" (EAS). Traditionally, the autonomic nervous system has been viewed as consisting of the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. Over the past century, however, neuroendocrine and neuroimmune systems have come to the fore, justifying expansion of the meaning of "autonomic." Additional facets include the sympathetic adrenergic system, for which adrenaline is the key effector; the hypothalamic-pituitary-adrenocortical axis; arginine vasopressin (synonymous with anti-diuretic hormone); the renin-angiotensin-aldosterone system, with angiotensin II and aldosterone the main effectors; and cholinergic anti-inflammatory and sympathetic inflammasomal pathways. A hierarchical brain network-the "central autonomic network"-regulates these systems; embedded within it are components of the Chrousos/Gold "stress system." Acute, coordinated alterations in homeostatic settings (allostasis) can be crucial for surviving stressors such as traumatic hemorrhage, asphyxiation, and sepsis, which throughout human evolution have threatened homeostasis; however, intense or long-term EAS activation may cause harm. While required for appropriate responses in emergencies, EAS activation in the setting of chronically decreased homeostatic efficiencies (dyshomeostasis) may reduce thresholds for induction of destabilizing, lethal vicious cycles. Testable hypotheses derived from these concepts are that biomarkers of EAS activation correlate with clinical and pathophysiologic data and predict outcome in COVID-19 and that treatments targeting specific abnormalities identified in individual patients may be beneficial.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Homeostase/fisiologia , Pneumonia Viral/fisiopatologia , Estresse Fisiológico/fisiologia , Infecções por Coronavirus/diagnóstico , Humanos , Pandemias , Pneumonia Viral/diagnóstico
7.
Anesthesiology ; 133(2): 364-376, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32665491

RESUMO

BACKGROUND: Until recently, the mechanism for the malignant hyperthermia crisis has been attributed solely to sustained massive Ca release from the sarcoplasmic reticulum on exposure to triggering agents. This study tested the hypothesis that transient receptor potential cation (TRPC) channels are important contributors to the Ca dyshomeostasis in a mouse model relevant to malignant hyperthermia. METHODS: This study examined the mechanisms responsible for Ca dyshomeostasis in RYR1-p.G2435R mouse muscles and muscle cells using calcium and sodium ion selective microelectrodes, manganese quench of Fura2 fluorescence, and Western blots. RESULTS: RYR1-p.G2435R mouse muscle cells have chronically elevated intracellular resting calcium and sodium and rate of manganese quench (homozygous greater than heterozygous) compared with wild-type muscles. After exposure to 1-oleoyl-2-acetyl-sn-glycerol, a TRPC3/6 activator, increases in intracellular resting calcium/sodium were significantly greater in RYR1-p.G2435R muscles (from 153 ± 11 nM/10 ± 0.5 mM to 304 ± 45 nM/14.2 ± 0.7 mM in heterozygotes P < 0.001] and from 251 ± 25 nM/13.9 ± 0.5 mM to 534 ± 64 nM/20.9 ± 1.5 mM in homozygotes [P < 0.001] compared with 123 ± 3 nM/8 ± 0.1 mM to 196 ± 27 nM/9.4 ± 0.7 mM in wild type). These increases were inhibited both by simply removing extracellular Ca and by exposure to either a nonspecific (gadolinium) or a newly available, more specific pharmacologic agent (SAR7334) to block TRPC6- and TRPC3-mediated cation influx into cells. Furthermore, local pretreatment with SAR7334 partially decreased the elevation of intracellular resting calcium that is seen in RYR1-p.G2435R muscles during exposure to halothane. Western blot analysis showed that expression of TRPC3 and TRPC6 were significantly increased in RYR1-p.G2435R muscles in a gene-dose-dependent manner, supporting their being a primary molecular basis for increased sarcolemmal cation influx. CONCLUSIONS: Muscle cells in knock-in mice expressing the RYR1-p.G2435R mutation are hypersensitive to TRPC3/6 activators. This hypersensitivity can be negated with pharmacologic agents that block TRPC3/6 activity. This reinforces the working hypothesis that transient receptor potential cation channels play a critical role in causing intracellular calcium and sodium overload in malignant hyperthermia-susceptible muscle, both at rest and during the malignant hyperthermia crisis.


Assuntos
Cálcio/metabolismo , Modelos Animais de Doenças , Hipertermia Maligna/metabolismo , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6/metabolismo , Animais , Feminino , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Indanos/farmacologia , Masculino , Hipertermia Maligna/genética , Hipertermia Maligna/patologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/biossíntese , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/genética , Canal de Cátion TRPC6/antagonistas & inibidores , Canal de Cátion TRPC6/genética
8.
Am J Physiol Cell Physiol ; 319(3): C510-C532, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32667864

RESUMO

Neutrophils are polymorphonuclear leukocytes that play a central role in host defense against infection and tissue injury. They are rapidly recruited to the inflamed site and execute a variety of functions to clear invading pathogens and damaged cells. However, many of their defense mechanisms are capable of inflicting collateral tissue damage. Neutrophil-driven inflammation is a unifying mechanism underlying many common diseases. Efficient removal of neutrophils from inflammatory loci is critical for timely resolution of inflammation and return to homeostasis. Accumulating evidence challenges the classical view that neutrophils represent a homogeneous population and that halting neutrophil influx is sufficient to explain their rapid decline within inflamed loci during the resolution of protective inflammation. Hence, understanding the mechanisms that govern neutrophil functions and their removal from the inflammatory locus is critical for minimizing damage to the surrounding tissue and for return to homeostasis. In this review, we briefly address recent advances in characterizing neutrophil phenotypic and functional heterogeneity and the molecular mechanisms that determine the fate of neutrophils within inflammatory loci and the outcome of the inflammatory response. We also discuss how these mechanisms may be harnessed as potential therapeutic targets to facilitate resolution of inflammation.


Assuntos
Apoptose/fisiologia , Homeostase/fisiologia , Inflamação/metabolismo , Neutrófilos/citologia , Animais , Fatores Celulares Derivados do Hospedeiro/metabolismo , Humanos , Fenótipo
9.
Proc Natl Acad Sci U S A ; 117(26): 15343-15353, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32546525

RESUMO

Ion transporters are key players of cellular processes. The mechanistic properties of ion transporters have been well elucidated by biophysical methods. Meanwhile, the understanding of their exact functions in cellular homeostasis is limited by the difficulty of monitoring their activity in vivo. The development of biosensors to track subtle changes in intracellular parameters provides invaluable tools to tackle this challenging issue. AtCLCa (Arabidopsis thaliana Chloride Channel a) is a vacuolar NO3 -/H+ exchanger regulating stomata aperture in A thaliana Here, we used a genetically encoded biosensor, ClopHensor, reporting the dynamics of cytosolic anion concentration and pH to monitor the activity of AtCLCa in vivo in Arabidopsis guard cells. We first found that ClopHensor is not only a Cl- but also, an NO3 - sensor. We were then able to quantify the variations of NO3 - and pH in the cytosol. Our data showed that AtCLCa activity modifies cytosolic pH and NO3 - In an AtCLCa loss of function mutant, the cytosolic acidification triggered by extracellular NO3 - and the recovery of pH upon treatment with fusicoccin (a fungal toxin that activates the plasma membrane proton pump) are impaired, demonstrating that the transport activity of this vacuolar exchanger has a profound impact on cytosolic homeostasis. This opens a perspective on the function of intracellular transporters of the Chloride Channel (CLC) family in eukaryotes: not only controlling the intraorganelle lumen but also, actively modifying cytosolic conditions.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Canais de Cloreto/metabolismo , Citosol/química , Homeostase/fisiologia , Nitratos/química , Proteínas de Arabidopsis/genética , Canais de Cloreto/genética , Citosol/metabolismo , Regulação da Expressão Gênica de Plantas/fisiologia , Concentração de Íons de Hidrogênio , Nitratos/metabolismo
10.
Nat Commun ; 11(1): 3097, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555194

RESUMO

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness. We therefore tested these functions in mice and humans using positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose. This revealed that BMAT resists insulin- and cold-stimulated glucose uptake, while further in vivo studies showed that, compared to WAT, BMAT resists insulin-stimulated Akt phosphorylation. Thus, BMAT is functionally distinct from WAT and BAT. However, in humans basal glucose uptake in BMAT is greater than in axial bones or subcutaneous WAT and can be greater than that in skeletal muscle, underscoring the potential of BMAT to influence systemic glucose homeostasis. These PET/CT studies characterise BMAT function in vivo, establish new methods for BMAT analysis, and identify BMAT as a distinct, major adipose tissue subtype.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Medula Óssea/metabolismo , Glucose/metabolismo , Animais , Western Blotting , Feminino , Homeostase/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons , Ratos , Esqueleto/metabolismo
11.
Int J Oral Sci ; 12(1): 17, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532966

RESUMO

Homoeostasis depends on the close connection and intimate molecular exchange between extracellular, intracellular and intercellular networks. Intercellular communication is largely mediated by gap junctions (GJs), a type of specialized membrane contact composed of variable number of channels that enable direct communication between cells by allowing small molecules to pass directly into the cytoplasm of neighbouring cells. Although considerable evidence indicates that gap junctions contribute to the functions of many organs, such as the bone, intestine, kidney, heart, brain and nerve, less is known about their role in oral development and disease. In this review, the current progress in understanding the background of connexins and the functions of gap junctions in oral development and diseases is discussed. The homoeostasis of tooth and periodontal tissues, normal tooth and maxillofacial development, saliva secretion and the integrity of the oral mucosa depend on the proper function of gap junctions. Knowledge of this pattern of cell-cell communication is required for a better understanding of oral diseases. With the ever-increasing understanding of connexins in oral diseases, therapeutic strategies could be developed to target these membrane channels in various oral diseases and maxillofacial dysplasia.


Assuntos
Comunicação Celular , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Doenças da Boca , Osso e Ossos , Conexinas/fisiologia , Junções Comunicantes/patologia , Homeostase/fisiologia , Humanos , Fosforilação
12.
Arch Biochem Biophys ; 690: 108416, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32502471

RESUMO

Alkaptonuria (AKU) is a rare metabolic disease correlated with the deficiency of homogentisate 1,2-dioxygenase and leading to an accumulation of the metabolite homogentisic acid (HGA) which can be subjected to oxidation and polymerization reactions. These events are considered a trigger for the induction of oxidative stress in AKU but, despite the large description of an altered redox status, the underlying pathogenetic processes are still unstudied. In the present study, we investigated the molecular mechanisms responsible for the oxidative damage present in an osteoblast-based cellular model of AKU. Bone, in fact, is largely affected in AKU patients: severe osteoclastic resorption, osteoporosis, even for pediatric cases, and an altered rate of remodeling biomarkers have been reported. In our AKU osteoblast cell model, we found a clear altered redox homeostasis, determined by elevated hydrogen peroxide (H2O2) levels and 4HNE protein adducts formation. These findings were correlated with increased NADPH oxidase (NOX) activity and altered mitochondrial respiration. In addition, we observed a decreased activity of superoxide dismutase (SOD) and reduced levels of thioredoxin (TRX) that parallel the decreased Nrf2-DNA binding. Overall, our results reveal that HGA is able to alter the cellular redox homeostasis by modulating the endogenous ROS production via NOX activation and mitochondrial dysfunctions and impair the cellular response mechanism. These findings can be useful for understanding the pathophysiology of AKU, not yet well studied in bones, but which is an important source of comorbidities that affect the life quality of the patients.


Assuntos
Alcaptonúria/metabolismo , Homeostase/fisiologia , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Ácido Homogentísico/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , NADPH Oxidases/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Osteoblastos/citologia , Oxirredução , Estresse Oxidativo/fisiologia , Transdução de Sinais , Superóxido Dismutase/metabolismo , Tiorredoxinas/metabolismo
13.
Am J Med Sci ; 360(3): 222-228, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32591091

RESUMO

The present review aimed to present the research highlights on C1q/TNF-related protein 1 (CTRP1), a member of the recently discovered family of highly conserved adiponectin paralog proteins, C1q tumor necrosis factor-related proteins. CTRP1 plays an important role in regulating body energy homeostasis and sensitivity to insulin. Studies on animal models have shown that it lowers the concentration of glucose. Elevated concentrations of CTRP1 reduce weight gain and diet-induced insulin resistance. CTRP1 limits the extent of ischemia-reperfusion injury in acute myocardial infarction. It inhibits platelet aggregation by blocking von Willebrand factor binding to collagen. In patients with chronic kidney disease, an increase in CTRP1 levels is associated with a lesser degree of disease progression. CTRP1 stimulates aldosterone synthesis in the adrenal cortex by affecting aldosterone synthase expression. In dehydration, an increase in CTRP1 concentration helps to maintain normotension. It participates in processes related to the proliferation and maturation of chondrocytes. It also promotes atherosclerosis, and a surge in its concentration is correlated with a higher cardiovascular risk in patients with coronary atherosclerosis. In vascular smooth muscle cells, it induces the expression of proinflammatory cytokines. An increase in CTRP1 levels is correlated with the progression of the neoplastic process in patients with glioblastoma.


Assuntos
Adipocinas/fisiologia , Proteínas/fisiologia , Animais , Doenças Cardiovasculares , Condrogênese/fisiologia , Metabolismo Energético , Glucose/metabolismo , Homeostase/fisiologia , Humanos , Inflamação , Resistência à Insulina/fisiologia , Nefropatias , Metabolismo dos Lipídeos/fisiologia , MEDLINE , Neoplasias , PubMed
14.
Ann Biol Clin (Paris) ; 78(3): 231-242, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32540812

RESUMO

The identification of leptin allowed the discovery of a new endocrine system. This major adipokine controlling energy homeostasis is also involved in the regulation of neuroendocrine function and fertility. Unfortunately, leptin is not able to treat common obesity, which associates hyperleptinemia and resistance to the hormone. Conversely, treatment with recombinant leptin is effective in situations of leptin deficiency. Several pathophysiological situations associated with adipose tissue dysfunctions and abnormal regulation of leptin secretion are discussed in this review. The advantage of the potential use of the leptin assay in some pathophysiological conditions is proposed.


Assuntos
Leptina/fisiologia , Adipocinas/fisiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Homeostase/fisiologia , Humanos , Obesidade/metabolismo , Obesidade/fisiopatologia , Via Secretória/fisiologia
15.
Nat Rev Endocrinol ; 16(8): 421-436, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32493980

RESUMO

Perturbations in metabolic processes are associated with diseases such as obesity, type 2 diabetes mellitus, certain infections and some cancers. A resurgence of interest in creatine biology is developing, with new insights into a diverse set of regulatory functions for creatine. This resurgence is primarily driven by technological advances in genetic engineering and metabolism as well as by the realization that this metabolite has key roles in cells beyond the muscle and brain. Herein, we highlight the latest advances in creatine biology in tissues and cell types that have historically received little attention in the field. In adipose tissue, creatine controls thermogenic respiration and loss of this metabolite impairs whole-body energy expenditure, leading to obesity. We also cover the various roles that creatine metabolism has in cancer cell survival and the function of the immune system. Renewed interest in this area has begun to showcase the therapeutic potential that lies in understanding how changes in creatine metabolism lead to metabolic disease.


Assuntos
Creatina/metabolismo , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Imunidade/fisiologia , Neoplasias/metabolismo , Tecido Adiposo/metabolismo , Animais , Creatina/fisiologia , Creatina Quinase/genética , Expressão Gênica , Humanos , Macrófagos , Doenças Metabólicas , Obesidade/metabolismo , Linfócitos T , Termogênese/fisiologia , Proteína Desacopladora 1
16.
Proc Natl Acad Sci U S A ; 117(19): 10547-10553, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32350140

RESUMO

The activity-regulated cytoskeleton-associated protein (Arc) gene is a neural immediate early gene that is involved in synaptic downscaling and is robustly induced by prolonged wakefulness in rodent brains. Converging evidence has led to the hypothesis that wakefulness potentiates, and sleep reduces, synaptic strengthening. This suggests a potential role for Arc in these and other sleep-related processes. However, the role of Arc in sleep remains unknown. Here, we demonstrated that Arc is important for the induction of multiple behavioral and molecular responses associated with sleep homeostasis. Arc knockout (KO) mice displayed increased time spent in rapid eye movement (REM) sleep under baseline conditions and marked attenuation of sleep rebound to both 4 h of total sleep deprivation (SD) and selective REM deprivation. At the molecular level, the following homeostatic sleep responses to 4-h SD were all blunted in Arc KO mice: increase of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 and its phosphorylation in synaptoneurosomes; induction of a subset of SD-response genes; and suppression of the GluA1 messenger RNA in the cortex. In wild-type brains, SD increased Arc protein expression in multiple subcellular locations, including the nucleus, cytoplasm, and synapse, which is reversed in part by recovery sleep. Arc is critical for these behavioral and multiple molecular responses to SD, thus providing a multifunctional role for Arc in the maintenance of sleep homeostasis, which may be attributed by the sleep/wake-associated changes in subcellular location of Arc.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sono/fisiologia , Animais , Encéfalo/fisiologia , Núcleo Celular/metabolismo , Córtex Cerebral/fisiologia , Citoplasma/metabolismo , Proteínas do Citoesqueleto/genética , Eletroencefalografia/métodos , Homeostase/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Receptores de AMPA/metabolismo , Sono/genética , Privação do Sono/fisiopatologia , Sono REM/fisiologia , Vigília/genética , Vigília/fisiologia
17.
Life Sci ; 255: 117838, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450168

RESUMO

AIMS: Dysregulation of iron homeostasis in the body causes a variety of diseases. Iron deficiency leads to anemia, whereas iron overload aggravates cellular oxidative stress. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein that is activated in the nucleus and turns on the production of antioxidant enzymes, protecting cell against oxidative damage. This study aimed to investigate whether Nrf2 gene knockout influences iron homeostasis in aging mice. MATERIALS AND METHODS: Iron content and iron metabolism-related proteins were assessed in different organs and blood serum of the 18 month-old Nrf2 knockout (Nrf2-/-) mice in comparison with the wild-type (WT) mice. KEY FINDINGS: Results showed that the iron contents in spleen and liver all increased, and expression levels of iron transporters were altered in Nrf2-/- mice. In particularly, we found that the expression of iron export protein ferroportin 1 (Fpn1) in liver, spleen and small intestine all decreased in Nrf2-/- mice, which might account for the deposition of iron in different organs and the increased ROS. Surprisingly, we found that the serum iron level of Nrf2-/- mice did not decrease, but increased significantly even when the iron absorption at small intestine decreased. Our further investigation revealed that the increase of serum iron was due to the release of iron from the hemolysis of erythrocytes, which caused by the increased ROS level in red blood cells of the Nrf2-/- mice. SIGNIFICANCE: These findings provide a more comprehensive understanding of the important role of Nrf2 in the regulation of systemic iron metabolism.


Assuntos
Hemólise/fisiologia , Ferro/metabolismo , Fator 2 Relacionado a NF-E2/genética , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento/fisiologia , Animais , Eritrócitos/citologia , Homeostase/fisiologia , Intestino Delgado/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/metabolismo
18.
Chemosphere ; 256: 127096, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32447113

RESUMO

Global change and anthropogenic activities have driven marine environment changes dramatically during the past century, and hypoxia, acidification and warming have received much attention recently. Yet, the interactive effects among these stressors on marine organisms are extremely complex and not accurately clarified. Here, we evaluated the combined effects of low dissolved oxygen (DO), low pH and warming on the digestive enzyme activities of the mussel Mytilus coruscus. In this experiment, mussels were exposed to eight treatments, including two degrees of pH (8.1, 7.7), DO (6, 2 mg/l) and temperature (30 °C and 20 °C) for 30 days. Amylase (AMS), lipase (LPS), trypsin (TRY), trehalase (TREH) and lysozyme (LZM) activities were measured in the digestive glands of mussels. All the tested stress conditions showed significant effects on the enzymatic activities. AMS, LPS, TRY, TREH showed throughout decreased trend in their activities due to low pH, low DO, increased temperature and different combinations of these three stressors with time but LZM showed increased and then decreased trend in their activities. Hypoxia and warming showed almost similar effects on the enzymatic activities. PCA showed a positive correlation among all measured biochemical parameters. Therefore, the fitness of mussel is likely impaired by such marine environmental changes and their population may be affected under the global change scenarios.


Assuntos
Aquecimento Global , Mytilus/fisiologia , Amilases , Animais , Digestão , Homeostase/fisiologia , Concentração de Íons de Hidrogênio , Hipóxia , Mytilus/efeitos dos fármacos , Oxigênio/farmacologia , Alimentos Marinhos , Água do Mar/química
19.
Proc Natl Acad Sci U S A ; 117(21): 11648-11657, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32398370

RESUMO

The intestinal mucosa exists in dynamic balance with trillions of luminal microbes. Disruption of the intestinal epithelial barrier, commonly observed in mucosal inflammation and diseases such as inflammatory bowel diseases (IBDs), is often associated with dysbiosis, particularly decreases in species producing short-chain fatty acids (SCFAs), such as butyrate. It remains unclear to what extent microbiota-derived factors contribute to the overall maintenance of intestinal homeostasis. Initial studies revealed that butyrate selectively promotes epithelial barrier function and wound healing. We aimed to define the specific mechanism(s) through which butyrate contributes to these epithelial responses. Guided by an unbiased profiling approach, we identified the dominant regulation of the actin-binding protein synaptopodin (SYNPO). Extensions of this work revealed a role for SYNPO in intestinal epithelial barrier function and wound healing. SYNPO was localized to the intestinal epithelial tight junction and within F-actin stress fibers where it is critical for barrier integrity and cell motility. Butyrate, but not other SCFAs, induced SYNPO in epithelial cell lines and murine colonic enteroids through mechanisms possibly involving histone deacetylase inhibition. Moreover, depletion of the microbiota abrogated expression of SYNPO in the mouse colon, which was rescued with butyrate repletion. Studies in Synpo-deficient mice demonstrated exacerbated disease susceptibility and increased intestinal permeability in a dextran sulfate sodium colitis model. These findings establish a critical role for the microbiota and their products, specifically butyrate, in the regulated expression of SYNPO for intestinal homeostasis and reveal a direct mechanistic link between microbiota-derived butyrate and barrier restoration.


Assuntos
Butiratos/metabolismo , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/metabolismo , Proteínas dos Microfilamentos , Animais , Linhagem Celular , Homeostase/fisiologia , Humanos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Junções Íntimas/metabolismo
20.
BMC Neurol ; 20(1): 189, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32414382

RESUMO

BACKGROUND: Endovascular therapy (EVT) is increasingly used to improve cerebral reperfusion after moderate-to-severe acute ischemic stroke (AIS). However, the influence of hemodynamic factors on clinical outcome is still unclear after EVT. Dynamic cerebral autoregulation (dCA) is an important brain reserve mechanism and is impaired after AIS. This study aimed to explore the role of dCA in predicting the outcome of AIS patients after EVT. METHODS: AIS patients with severe stenosis/occlusion of unilateral middle cerebral artery (MCA) or internal carotid and treatment with EVT were enrolled to receive dCA examinations at the 24 h, 72 h and 7th day after stroke onset. Healthy volunteers were also recruited as controls. DCA was recorded from spontaneous fluctuations of blood pressure and MCA flow velocity. Transfer function analysis was used to derive dCA parameters, including phase difference (PD) and coherence in the low-frequency range (0.06-0.12 Hz). The clinical outcome was measured using the modified Rankin Scale (mRS) at 90 days after onset. Multivariate logistic regression was performed to reveal the correlation between dCA and clinical outcomes. The receiver operation characteristics (ROC) curve was performed to determine the cut-off point of PD. RESULTS: A total of 62 AIS patients and 77 healthy controls were included. Compared with controls, dCA were impaired bilaterally till to 7th day after onset in patients, presenting as much lower PD value on the ipsilateral side. During follow-up, we found that PD on the ipsilateral side at 24 h after onset was significantly lower in patients with unfavourable outcome (n = 41) than those with favourable outcome (n = 21), even after adjustment of confounding factors (p = 0.009). ROC curve analysis revealed that PD < 26.93° was an independent predictor of unfavourable-outcome. CONCLUSION: In AIS patients after EVT, dCA was impaired on both sides over the first 7 days. PD on the ipsilateral side at 24 h after onset is an independent unfavourable-outcome predictor for AIS after EVT.


Assuntos
Procedimentos Endovasculares/métodos , Homeostase/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/cirurgia , Adulto , Idoso , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/cirurgia , Circulação Cerebrovascular/fisiologia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
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