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1.
Nutrients ; 14(7)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35406143

RESUMO

Radiation therapy damages and depletes total bone marrow (BM) cellularity, compromising safety and limiting effective dosing. Aging also strains total BM and BM hematopoietic stem and progenitor cell (HSPC) renewal and function, resulting in multi-system defects. Interventions that preserve BM and BM HSPC homeostasis thus have potential clinical significance. Here, we report that 50% calorie restriction (CR) for 7-days or fasting for 3-days prior to irradiation improved mouse BM regrowth in the days and weeks post irradiation. Specifically, one week of 50% CR ameliorated loss of total BM cellularity post irradiation compared to ad libitum-fed controls. CR-mediated BM protection was abrogated by dietary sulfur amino acid (i.e., cysteine, methionine) supplementation or pharmacological inhibition of sulfur amino acid metabolizing and hydrogen sulfide (H2S) producing enzymes. Up to 2-fold increased proliferative capacity of ex vivo-irradiated BM isolated from food restricted mice relative to control mice indicates cell autonomy of the protective effect. Pretreatment with H2S in vitro was sufficient to preserve proliferative capacity by over 50% compared to non-treated cells in ex vivo-irradiated BM and BM HSPCs. The exogenous addition of H2S inhibited Ten eleven translocation 2 (TET2) activity in vitro, thus providing a potential mechanism of action. Short-term CR or fasting therefore offers BM radioprotection and promotes regrowth in part via altered sulfur amino acid metabolism and H2S generation, with translational implications for radiation treatment and aging.


Assuntos
Sulfeto de Hidrogênio , Lesões por Radiação , Animais , Medula Óssea/metabolismo , Restrição Calórica , Suplementos Nutricionais , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Metionina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Radiação Ionizante
2.
JCI Insight ; 3(21)2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30385734

RESUMO

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase in Apoa5 expression was controlled by the transcription factor CREBH, which coordinately regulated hepatic expression of fatty acid oxidation-related genes, including Fgf21 and Ppara. The CREBH-APOA5 axis activation upon PR was intact in mice lacking the GCN2-dependent amino acid-sensing arm of the integrated stress response. However, constitutive hepatic activation of the amino acid-responsive kinase mTORC1 compromised CREBH activation, leading to blunted APOA5 expression and PR-recalcitrant hypertriglyceridemia. PR also contributed to hypotriglyceridemia by reducing the rate of VLDL-TG secretion, independently of activation of the CREBH-APOA5 axis. Finally, a randomized controlled clinical trial revealed that 4-6 weeks of reduced protein intake (7%-9% of calories) decreased VLDL particle number, increased VLDL-bound APOA5 expression, and lowered plasma TGs, consistent with mechanistic conservation of PR-mediated hypotriglyceridemia in humans with translational potential as a nutraceutical intervention for dyslipidemia.


Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Lipoproteínas VLDL/sangue , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Triglicerídeos/sangue , Animais , Apolipoproteína A-V , Apolipoproteínas/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Dieta com Restrição de Proteínas/métodos , Feminino , Humanos , Hidrólise , Hipertrigliceridemia/complicações , Hipertrigliceridemia/epidemiologia , Metabolismo dos Lipídeos , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Proteínas Serina-Treonina Quinases/deficiência , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Triglicerídeos/metabolismo
3.
Cell Metab ; 25(6): 1320-1333.e5, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28591635

RESUMO

Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Fígado/metabolismo , Animais , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Dextrotireoxina/metabolismo , Feminino , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Knockout
4.
Ageing Res Rev ; 39: 68-77, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28216454

RESUMO

Reduced caloric intake including fasting, as well as the dietary composition or the timing of food intake, impact longevity, likely through a modification in the onset or the severity of chronic aging-related diseases such as cancer. As with pre- and post-operative dietary recommendations, evidence-based nutritional advice from healthcare professionals during and after cancer treatment is often vague or conflicting. We hypothesize that preventive dietary recommendations can help in the context of both chronic cancer treatment efficacy and the avoidance of development of secondary malignancies, as well as in the context of protection from the acute stress of surgery. In this perspective review, we will discuss the latest findings on the potential role of short-term dietary restriction in cancer treatment and improvement of surgical outcome.


Assuntos
Restrição Calórica , Jejum/fisiologia , Neoplasias/prevenção & controle , Cuidados Pré-Operatórios , Estresse Fisiológico , Animais , Dieta , Ingestão de Energia , Humanos , Longevidade , Transdução de Sinais
5.
Gerontology ; 63(3): 228-237, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28052287

RESUMO

Dietary restriction (DR) is best known for extending lifespan in experimental model organisms, but also increases resistance to a variety of clinically relevant stressors, including those associated with surgery. Extended periods of DR, lasting months to years, are required for optimal longevity benefits in rodents, but short-term dietary preconditioning (less than 1 week) remarkably protects from acute injury. Here, we discuss recent advances in our understanding of the mechanistic basis of short-term DR and fasting in the context of surgical stress resistance, including upstream amino acid sensing by the GCN2 and mTORC1 pathways, and downstream effector mechanisms including increased insulin-dependent prosurvival signaling and elevated endogenous hydrogen sulfide production. We also review the current trend in preoperative nutrition away from preoperative fasting and towards carbohydrate loading. Finally, we discuss the rationale for the nonmutually exclusive use of brief DR or pharmacological DR mimetics to precondition against the stress and potential complications of surgery.


Assuntos
Jejum , Cuidados Pré-Operatórios/métodos , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/fisiologia , Animais , Restrição Calórica/efeitos adversos , Restrição Calórica/métodos , Carboidratos da Dieta/administração & dosagem , Jejum/efeitos adversos , Humanos , Sulfeto de Hidrogênio/metabolismo , Insulina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos/metabolismo , Fenômenos Fisiológicos da Nutrição , Cuidados Pré-Operatórios/efeitos adversos , Proteínas Serina-Treonina Quinases/metabolismo , Sirtuína 1/metabolismo , Estresse Fisiológico , Serina-Treonina Quinases TOR/metabolismo , Pesquisa Translacional Biomédica
6.
J Nutr ; 145(8): 1717-27, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26041674

RESUMO

BACKGROUND: Short-term dietary restriction (DR) without malnutrition preconditions against surgical stress in rodents; however, the nutritional basis and underlying nutrient/energy-sensing pathways remain poorly understood. OBJECTIVES: We investigated the relative contribution of protein restriction (PR) vs. calorie restriction (CR) to protection from renal ischemia reperfusion injury (IRI) and changes in organ-autonomous nutrient/energy-sensing pathways and hormones underlying beneficial effects. METHODS: Mice were preconditioned on experimental diets lacking total calories (0-50% CR) or protein/essential amino acids (EAAs) vs. complete diets consumed ad libitum (AL) for 1 wk before IRI. Renal outcome was assessed by serum markers and histology and integrated over a 2-dimensional protein/energy landscape by geometric framework analysis. Changes in renal nutrient/energy-sensing signal transduction and systemic hormones leptin and adiponectin were also measured. The genetic requirement for amino acid sensing via general control non-derepressible 2 (GCN2) was tested with knockout vs. control mice. The involvement of the hormone leptin was tested by injection of recombinant protein vs. vehicle during the preconditioning period. RESULTS: CR-mediated protection was dose dependent up to 50% with maximal 2-fold effect sizes. PR benefits were abrogated by EAA re-addition and additive with CR, with maximal benefits at any given amount of CR occurring with a protein-free diet. GCN2 was not required for functional benefits of PR. Activation and repression of nutrient/energy-sensing kinases, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1), respectively, on PR reflected a state of negative energy balance, paralleled by 13% weight loss and an 87% decrease in leptin, independent of calorie intake. Recombinant leptin administration partially abrogated benefits of dietary preconditioning against renal IRI. CONCLUSIONS: In male mice, PR and CR both contributed to the benefits of short-term DR against renal IRI independent of GCN2 but partially dependent on reduced circulating leptin and coincident with AMPK activation and mTORC1 repression.


Assuntos
Injúria Renal Aguda/prevenção & controle , Restrição Calórica , Proteínas Alimentares/administração & dosagem , Leptina/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Área Sob a Curva , Leptina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ureia/sangue
7.
Nat Commun ; 6: 6050, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25636003

RESUMO

Host nutrition can affect the outcome of parasitic diseases through metabolic effects on host immunity and/or the parasite. Here we show that modulation of mouse immunometabolism through brief restriction of food intake (dietary restriction, DR) prevents neuropathology in experimental cerebral malaria (ECM). While no effects are detected on parasite growth, DR reduces parasite accumulation in peripheral tissues including the brain, and increases clearance in the spleen. Leptin, a host-derived adipokine linking appetite, energy balance and immune function, is required for ECM pathology and its levels are reduced upon DR. Recombinant leptin abrogates DR benefits, while pharmacological or genetic inhibition of leptin signalling protects against ECM. DR reduces mTORC1 activity in T cells, and this effect is abrogated upon leptin administration. Furthermore, mTORC1 inhibition with rapamycin prevents ECM pathology. Our results suggest that leptin and mTORC1 provide a novel mechanistic link between nutrition, immunometabolism and ECM pathology, with potential therapeutic implications for cerebral malaria.


Assuntos
Restrição Calórica , Leptina/metabolismo , Malária Cerebral/metabolismo , Malária Cerebral/prevenção & controle , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Feminino , Leptina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Sirolimo/farmacologia
8.
Cell ; 160(1-2): 132-44, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25542313

RESUMO

Dietary restriction (DR) without malnutrition encompasses numerous regimens with overlapping benefits including longevity and stress resistance, but unifying nutritional and molecular mechanisms remain elusive. In a mouse model of DR-mediated stress resistance, we found that sulfur amino acid (SAA) restriction increased expression of the transsulfuration pathway (TSP) enzyme cystathionine γ-lyase (CGL), resulting in increased hydrogen sulfide (H2S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H2S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H2S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H2S production was observed in yeast, worm, fruit fly, and rodent models of DR-mediated longevity. Together, these data are consistent with evolutionary conservation of TSP-mediated H2S as a mediator of DR benefits with broad implications for clinical translation. PAPERFLICK:


Assuntos
Dieta , Sulfeto de Hidrogênio/metabolismo , Animais , Evolução Biológica , Caenorhabditis elegans/fisiologia , Restrição Calórica , Cistationina gama-Liase/metabolismo , Cisteína/metabolismo , Drosophila melanogaster/fisiologia , Feminino , Rim/irrigação sanguínea , Rim/lesões , Expectativa de Vida , Fígado/irrigação sanguínea , Fígado/lesões , Masculino , Metionina/metabolismo , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismo por Reperfusão , Transdução de Sinais , Estresse Fisiológico , Transcriptoma , Leveduras/fisiologia
9.
Cell Rep ; 8(4): 1160-70, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25131199

RESUMO

Protein restriction (PR) is important for the benefits of dietary restriction on longevity and stress resistance, but relevant nutrient sensors and downstream effectors in mammals remain poorly defined. We used PR-mediated protection from hepatic ischemia reperfusion injury to probe genetic requirements for the evolutionarily conserved nutrient sensors GCN2 and mTORC1 in stress resistance. One week of PR reduced free amino acids and circulating growth factors, activating GCN2 and mTORC1 repressor tuberous sclerosis complex (TSC). However, although GCN2 was dispensable for PR-induced protection, hepatic TSC1 was required. PR improved hepatic insulin sensitivity in a TSC1-dependent manner prior to ischemia, facilitating increased prosurvival signaling and reduced apoptosis after reperfusion. These benefits were partially abrogated by pharmacological PI3K inhibition or genetic deletion of the insulin receptor in hepatocytes. In conclusion, improved insulin sensitivity upon short-term PR required TSC1, facilitated increased prosurvival signaling after injury, and contributed partially to PR-mediated resistance to clinically relevant ischemia reperfusion injury.


Assuntos
Fígado/metabolismo , Traumatismo por Reperfusão/metabolismo , Proteínas Supressoras de Tumor/fisiologia , Aminoácidos Essenciais/metabolismo , Animais , Células Cultivadas , Dieta com Restrição de Proteínas , Técnicas de Inativação de Genes , Resistência à Insulina , Isquemia/metabolismo , Fígado/irrigação sanguínea , Fígado/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Complexos Multiproteicos/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Traumatismo por Reperfusão/dietoterapia , Estresse Fisiológico , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa
10.
Biochem J ; 449(1): 1-10, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23216249

RESUMO

DR (dietary restriction), or reduced food intake without malnutrition, is associated with extended longevity, improved metabolic fitness and increased stress resistance in a wide range of organisms. DR is often referred to as calorie restriction, implying that reduced energy intake is responsible for its widespread and evolutionarily conserved benefits. However, recent data indicate dietary amino acid restriction as a key mediator of DR benefits. In fruitflies, an imbalance in essential amino acid intake is thought to underlie longevity benefits of DR. In mammals, reduced dietary protein or essential amino acid intake can extend longevity, improve metabolic fitness and increase stress resistance. In the present paper we review two evolutionarily conserved signal transduction pathways responsible for sensing amino acid levels. The eIF2α (eukaryotic initiation factor 2α) kinase GCN2 (general amino acid control non-derepressible 2) senses the absence of one or more amino acids by virtue of direct binding to uncharged cognate tRNAs. The presence of certain amino acids, such as leucine, permits activation of the master growth regulating kinase TOR (target of rapamycin). These two signal transduction pathways react to amino acid deprivation by inhibiting general protein translation while at the same time increasing translation of specific mRNAs involved in restoring homoeostasis. Together, these pathways may contribute to the regulation of longevity, metabolic fitness and stress resistance.


Assuntos
Aminoácidos/fisiologia , Restrição Calórica , Longevidade/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Restrição Calórica/métodos , Humanos , Ligação Proteica/fisiologia
11.
Sci Signal ; 5(217): ra24, 2012 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-22457330

RESUMO

The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient-sensitive protein kinase that is aberrantly activated in many human cancers. Whether dysregulation of mTORC1 signaling in normal tissues increases the risk for cancer, however, is unknown. We focused on hepatocellular carcinoma, which has been linked to environmental factors that affect mTORC1 activity, including diet. Ablation of the gene encoding TSC1 (tuberous sclerosis complex 1), which as part of the TSC1-TSC2 complex is an upstream inhibitor of mTORC1, results in constitutively increased mTORC1 signaling, an effect on this pathway similar to that of obesity. We found that mice with liver-specific knockout of Tsc1 developed sporadic hepatocellular carcinoma with heterogeneous histological and biochemical features. The spontaneous development of hepatocellular carcinoma in this mouse model was preceded by a series of pathological changes that accompany the primary etiologies of this cancer in humans, including liver damage, inflammation, necrosis, and regeneration. Chronic mTORC1 signaling led to unresolved endoplasmic reticulum stress and defects in autophagy, factors that contributed to hepatocyte damage and hepatocellular carcinoma development. Therefore, we conclude that increased activation of mTORC1 can promote carcinogenesis and may thus represent a key molecular link between cancer risk and environmental factors, such as diet.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Células Cultivadas , Progressão da Doença , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Hepatócitos/metabolismo , Hepatócitos/patologia , Immunoblotting , Imuno-Histoquímica , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
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