RESUMO
Age-related chronic inflammation is characterized as the unresolved low-grade inflammatory process underlying the ageing process and various age-related diseases. In this chapter, we review the age-related changes in the oxidative stress-sensitive pro-inflammatory NF-κB signaling pathways causally linked with chronic inflammation during ageing based on senoinflammation schema. We describe various age-related dysregulated pro- and anti-inflammatory cytokines, chemokines, and senescence-associated secretory phenotype (SASP), and alterations of inflammasome, specialized pro-resolving lipid mediators (SPM), and autophagy as major players in the chronic inflammatory intracellular signaling network. A better understanding of the molecular, cellular, and systemic mechanisms involved in chronic inflammation in the ageing process would provide further insights into the potential anti-inflammatory strategies.
Assuntos
Senescência Celular , Transdução de Sinais , Humanos , Estresse Oxidativo , Inflamação/metabolismo , NF-kappa B/metabolismoRESUMO
BACKGROUND: Converging evidence indicates prolactin (PRL) and diabetes play an important role in the pathophysiology of cognitive impairment. However, little is known about the mechanisms responsible for the effects of PRL and diabetes on cognitive impairment. SUMMARY: We summarize and review the available literature and current knowledge of the association between PRL and diabetes on aspects of cognitive impairment. KEY MESSAGES: The phosphatidylinositol 3-kinase/protein kinase B pathway is central to the molecular mechanisms underlying how PRL and diabetes interact in cognitive impairment. Further work is needed to identify the interaction between PRL and diabetes, especially in the molecular aspects of cognitive impairment, which can suggest novel strategies for cognitive dysfunction treatment.
Assuntos
Disfunção Cognitiva , Diabetes Mellitus , Prolactina , Disfunção Cognitiva/etiologia , Diabetes Mellitus/metabolismo , Humanos , Prolactina/metabolismo , Receptores da Prolactina/metabolismoRESUMO
BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress is one of the major causes of hepatic insulin resistance through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signalling to glucose and lipid metabolism, therefore, dysregulated FoxO6 is involved in hepatic insulin resistance. In this study, we elucidated the role of FoxO6 in ER stress-induced hepatic lipogenesis. METHODS: Hepatic ER stress responses and lipogenesis were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. In the in vitro study, HepG2 cells overexpressing constitutively active FoxO6 were treated with palmitate, and then alterations in ER stress and lipid metabolism were measured. RESULTS: FoxO6 activation induced hepatic lipogenesis and the expression of ER stress-inducible genes. The expression and transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ) were significantly increased in constitutively active FoxO6 allele. Interestingly, we found that the active FoxO6 physically interacted with C/EBP homologous protein (CHOP), an ER stress-inducible transcription factor, which was responsible for PPARγ expression. Palmitate treatment caused the expression of ER stress-inducible genes, which was deteriorated by FoxO6 activation in HepG2 cells. Palmitate-induced ER stress led to PPARγ expression through interactions between CHOP and FoxO6 corresponding to findings in the in vivo study. On the other hand, the expression of PPARα and ß-oxidation were decreased in constitutively active FoxO6 allele which implied that lipid catabolism is also regulated by FoxO6. CONCLUSION: Our data present significant evidence demonstrating that CHOP and FoxO6 interact to induce hepatic lipid accumulation through PPARγ expression during ER stress.
Assuntos
Fígado Gorduroso , Metabolismo dos Lipídeos , Animais , Estresse do Retículo Endoplasmático , Fatores de Transcrição Forkhead , Células Hep G2 , Humanos , Lipídeos , Camundongos , Fator de Transcrição CHOPRESUMO
Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator-activated receptor α (PPARα) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPARα and the FAO pathway-associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPARα protein expression associated with increased expression of PPARα-targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPARα expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF-ß-induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPARα-/- mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPARα signaling during aging aggravates renal fibrosis development, and targeting PPARα is useful for preventing age-associated CKD.
Assuntos
Envelhecimento/metabolismo , Ácidos Graxos/metabolismo , Rim/patologia , PPAR alfa/metabolismo , Envelhecimento/patologia , Animais , Restrição Calórica , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Proteínas da Matriz Extracelular/biossíntese , Proteínas da Matriz Extracelular/genética , Fibrose , Regulação da Expressão Gênica , Rim/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/farmacologia , Ácido Oleico/farmacologia , Oxirredução , PPAR alfa/deficiência , PPAR alfa/genética , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta/fisiologiaRESUMO
Nonalcoholic fatty liver disease (NAFLD) is frequently observed in obese and aged individuals. Peroxisome proliferator-activated receptors (PPARs) play a role in regulating hepatic lipid accumulation, a hallmark of NAFLD development. A PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) has been shown to prevent fatty liver formation and insulin resistance in obese mice (db/db) model. However, the beneficial effects of MHY2013 in aged model remain unknown. In this study, we investigated whether MHY2013 alleviates hepatic lipid accumulation in aged Sprague-Dawley (SD) rats. We confirmed that MHY2013 increased the activities of three PPAR subtypes in HepG2 cells using luciferase assay. When administered orally in aged SD rats, MHY2013 markedly decreased the hepatic triglyceride levels without changes in body weight. Regarding underlying mechanisms, MHY2013 increased the mRNA levels of lipid oxidation-related genes, including carnitine palmitoyltransferase 1 (CPT1) and peroxisomal acyl-CoA oxidase 1 (ACOX1), without apparent change in the mRNA expression of lipogenesis-related genes. Furthermore, MHY2013 significantly increased systemic fibroblast growth factor 21 (FGF21) and adiponectin levels and suppressed inflammatory mRNA expression in the liver. In conclusion, MHY2013 alleviated age-related hepatic lipid accumulation, in part by upregulating ß-oxidation signaling and suppressing inflammation in the liver. Therefore, MHY2013 is a potential pharmaceutical agent for treating age-related hepatic lipid accumulation.
Assuntos
Envelhecimento/metabolismo , Benzotiazóis/farmacologia , Citocinas/genética , Ácidos Graxos/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Propionatos/farmacologia , Triglicerídeos/metabolismo , Administração Oral , Animais , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/sangue , Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Inflamação , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Masculino , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oxirredução , Ratos Sprague-Dawley , Triglicerídeos/sangueRESUMO
FoxO activity and modifications, such as its phosphorylation, acetylation, and methylation, may help drive the expression of genes involved in combating oxidative stress by causing the epigenetic modifications, and thus, preserve cellular function during aging and age-related diseases, such as diabetes, cancer, and Alzheimer disease. Insulin signaling has been postulated to influence the aging process by increasing resistance to oxidative stress, and slowing the accumulation of oxidative damage. Some antioxidative effects are mediated by a conserved family of forkhead box transcription factors (FoxOs), which in the absence of insulin signaling freely bind to promoters of antioxidant enzymes, superoxide dismutase, and catalase. On the other hand, calorie restriction (CR) extends the lifespans of several species via the insulin pathway, and extends longevity and healthspan in diverse species via a conserved mechanism. CR enhances adaptive stress responses at the cellular and organism levels and extends lifespan in a FoxO-independent manner. Thus, increased modification of FoxO is modulated via the hyperinsulinemia-induced PI3K/Akt pathway during aging, and CR reverses this process. Accordingly, FoxO plays an important role in maintenance of metabolic homeostasis and removal of oxidative stress in the aging process and in the effect of CR on lifespan.
Assuntos
Envelhecimento/fisiologia , Restrição Calórica , Fatores de Transcrição Forkhead/fisiologia , Homeostase/fisiologia , Humanos , Insulina/fisiologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologiaRESUMO
This study investigated the agonistic activity of magnesium lithospermate B (1), isolated from Salvia miltiorrhiza, on peroxisome proliferator-activated receptor (PPARß/δ) and the expressions of collagen genes (COL1A1 and COL3A1) and transforming growth factor-ß1 (TGF-ß1) in models of skin aging. The action of compound 1 as a PPARß/δ agonist was determined by reporter gene assay, immunostaining, and Western blotting. To determine the antiaging effects of compound 1 on skin, aged Sprague-Dawley rat skin and ultraviolet B (UVB)-irradiated human skin fibroblasts were used. The results show that 1 presented a marked enhancement of both nuclear protein levels and activity of PPARß/δ in fibroblasts. In addition, 1 prevented downregulation of PPARß/δ activity in aged rat skin and UVB-induced fibroblasts. Furthermore, 1 increased the expressions of COL1A1, COL3A1, and TGF-ß1 in vivo and in a cell culture system. Therefore, the present study shows that compound 1 prevents collagen degradation in aged rat skin and UVB-exposed fibroblasts through PPARß/δ activation. The therapeutic and cosmetic applications of compound 1 need further investigation.
Assuntos
Colágeno/metabolismo , PPAR delta/metabolismo , PPAR beta/metabolismo , Salvia miltiorrhiza/química , Pele/efeitos dos fármacos , Idoso , Animais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Magnésio/metabolismo , Masculino , Estrutura Molecular , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Ativação Transcricional , Regulação para CimaRESUMO
Resveratrol is a phytoalexin and natural phenol that is present at relatively high concentrations in peanuts and red grapes and wine. Based upon studies of yeast and invertebrate models, it has been proposed that ingestion of resveratrol may also have anti-aging actions in mammals including humans. It has been suggested that resveratrol exerts its beneficial effects on health by activating the same cellular signaling pathways that are activated by dietary energy restriction (DR). Some studies have reported therapeutic actions of resveratrol in animal models of metabolic and neurodegenerative disorders. However, the effects of resveratrol on cell, tissue and organ function in healthy subjects are largely unknown. In the present study, we evaluated the potential effects of resveratrol on the proliferation and survival of neural progenitor cells (NPCs) in culture, and in the hippocampus of healthy young adult mice. Resveratrol reduced the proliferation of cultured mouse multi-potent NPCs, and activated AMP-activated protein kinase (AMPK), in a concentration-dependent manner. Administration of resveratrol to mice (1-10 mg/kg) resulted in activation of AMPK, and reduced the proliferation and survival of NPCs in the dentate gyrus of the hippocampus. Resveratrol down-regulated the levels of the phosphorylated form of cyclic AMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Finally, resveratrol-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that resveratrol, unlike DR, adversely affects hippocampal neurogenesis and cognitive function by a mechanism involving activation of AMPK and suppression of CREB and BDNF signaling.
Assuntos
Hipocampo/citologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estilbenos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Giro Denteado/citologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Hipocampo/embriologia , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/enzimologia , Fosforilação/efeitos dos fármacos , Resveratrol , Estilbenos/administração & dosagemRESUMO
Epithelial barrier function is determined by both transcellular and paracellular permeability, the latter of which is mainly influenced by tight junctions (TJs) and apoptotic leaks within the epithelium. We investigated the protective effects of ferulate on epithelial barrier integrity by examining permeability, TJ protein expression, and apoptosis in Caco-2 cells treated with tert-butyl hydroperoxide (t-BHP), a strong reactive species inducer. Caco-2 cells pretreated with ferulate (5 or 15 µM) were exposed to t-BHP (100 µM), and ferulate suppressed the t-BHP-mediated increases in reactive species and epithelial permeability in Caco-2 cells. Moreover, ferulate inhibited epithelial cell leakage induced by t-BHP, which was accompanied by decreased expression of the TJ proteins zonula occludens-1 and occludin. In addition, pretreatment with ferulate markedly protected cells against t-BHP-induced apoptosis, as evidenced by decreased nuclear condensation, cytochrome c release, and caspase-3 cleavage and an increased Bax/Bcl-2 ratio. These results suggest that ferulate protects the epithelial barrier of Caco-2 cells against oxidative stress, which results in increased epithelial permeability, decreased TJ protein expression, and increased apoptosis. The most significant finding of our study is the demonstration of protective, ferulate-mediated antioxidant effects on barrier integrity, with a particular focus on intracellular molecular mechanisms.
Assuntos
Apoptose/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Ocludina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo , Antioxidantes/farmacologia , Células CACO-2 , Caspase 3/metabolismo , Sobrevivência Celular , Citocromos c/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Proteína X Associada a bcl-2/metabolismo , terc-Butil Hidroperóxido/efeitos adversosRESUMO
Baicalin, a herb-derived flavonoid compound, has beneficial activities, including the modulation of oxidative stress and inflammation. Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor that plays an important role in regulating nuclear factor-κB (NF-κB)-induced age-related inflammation. We investigated the anti-inflammatory action of baicalin, which depends on its ability to activate PPARγ, and subsequently to suppress NF-κB. We examined baicalin-treated kidney tissue from 24-month-old Fischer 344 aged rats (10 or 20 mg/kg/day for 10 days) and baicalin-fed mice (10 mg/kg/day for 3 days) for in vivo investigations, and used endothelial YPEN-1 cells for in vitro studies. In the baicalin-fed aged rats, there was a marked enhancement of both nuclear protein levels and DNA binding activity of PPARγ, and a decreased expression of NF-κB target genes (VCAM-1, IL-1ß, and IL-6) compared with non-baicalin-fed aged rats. Furthermore, to confirm the anti-inflammatory action of PPARγ activated by baicalin, we used lipopolysaccharide (LPS)-treated cells and mice. The results showed that baicalin induced PPARγ-selective activation in YPEN-1 cells, and that the effects of baicalin were blocked by the PPARγ receptor antagonist, GW9662. In addition, baicalin treatment prevented RS generation, NF-κB activation and the expression of pro-inflammatory genes, whereas it increased PPARγ expression in LPS-treated cells and mouse kidney. Our data suggest that baicalin-induced PPARγ expression reduced age-related inflammation through blocking pro-inflammatory NF-κB activation. These results indicate that baicalin is a novel PPARγ activator and that this agent may have the potential to minimize inflammation.
Assuntos
Envelhecimento , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Flavonoides/farmacologia , Rim/efeitos dos fármacos , NF-kappa B/metabolismo , Nefrite/prevenção & controle , PPAR gama/agonistas , Fatores Etários , Envelhecimento/imunologia , Envelhecimento/metabolismo , Anilidas/farmacologia , Animais , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Mediadores da Inflamação/metabolismo , Rim/imunologia , Rim/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/genética , Nefrite/induzido quimicamente , Nefrite/genética , Nefrite/imunologia , Nefrite/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Endogâmicos F344 , Transfecção , Regulação para CimaRESUMO
Memory loss is the most common occurrence of dementia in the elderly population. Evidence shows 1,2-Diacetylbenzene (DAB) can exacerbate cerebral dysfunction. The molecular mechanisms involved in DAB actions in the hippocampus have not been well elucidated to date. qPCR, western blot, Morris water maze, and RNAseq analysis were used to identify the association between inflammation and hyperphosphorylated tau in male DAB-treated mice (1 or 5 mg/kg/day), rats (3 mg/kg/day), in vitro BV2 microglial cells (1 or 5 µM), and the hippocampal transcriptome of male DAB-treated rats. We found that DAB induces memory deficits by activating pro-inflammatory cytokines as well as down-regulating memory and learning genes. Several genes involved in learning, memory, and behavior induced by DAB (e.g., PRL, Pit-1, PRLR, Ttr, Notch2, Ntsr1, C5ar2, Cd74) were not changed or downregulated in young rats, but upregulated in old rats. Detoxification pathways were upregulated in young rats treated with DAB, whereas prolactin (PRL) signaling pathways were upregulated in old DAB-treated rats. Further work is needed to gain a better understanding of the roles of PRL during aging.
Assuntos
Citocinas , Prolactina , Acetofenonas/farmacologia , Idoso , Animais , Citocinas/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/metabolismo , Camundongos , Prolactina/metabolismo , Prolactina/farmacologia , Ratos , Receptor da Anafilatoxina C5a/metabolismoRESUMO
The vitamin-C-synthesizing enzyme senescent marker protein 30 (SMP30) is a cold resistance gene in Drosophila, and vitamin C concentration increases in brown adipose tissue post-cold exposure. However, the roles of SMP30 in thermogenesis are unknown. Here, we tested the molecular mechanism of thermogenesis using wild-type (WT) and vitamin C-deficient SMP30-knockout (KO) mice. SMP30-KO mice gained more weight than WT mice without a change in food intake in response to short-term high-fat diet feeding. Indirect calorimetry and cold-challenge experiments indicated that energy expenditure is lower in SMP30-KO mice, which is associated with decreased thermogenesis in adipose tissues. Therefore, SMP30-KO mice do not lose weight during cold exposure, whereas WT mice lose weight markedly. Mechanistically, the levels of serum FGF21 were notably lower in SMP30-KO mice, and vitamin C supplementation in SMP30-KO mice recovered FGF21 expression and thermogenesis, with a marked reduction in body weight during cold exposure. Further experiments revealed that vitamin C activates PPARα to upregulate FGF21. Our findings demonstrate that SMP30-mediated synthesis of vitamin C activates the PPARα/FGF21 axis, contributing to the maintenance of thermogenesis in mice.
Assuntos
Ácido Ascórbico , PPAR alfa , Animais , Camundongos , Tecido Adiposo Marrom/metabolismo , Ácido Ascórbico/farmacologia , Ácido Ascórbico/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR alfa/genética , PPAR alfa/metabolismo , Termogênese/genética , Vitaminas/metabolismoRESUMO
Angiotensin II (Ang II), a main effector of the renin-angiotensin system, is recognized as a pro-inflammatory mediator on age-related vascular inflammation. Ang II is one of the most important oxidative stress inducer, activates the redox-sensitive transcription factor, nuclear factor-κB (NF-κB) during aging. Genistein, a major component found in isoflavone, has anti-inflammatory activities that are often associated with its anti-oxidative activity. The purpose of this study is to document molecular mechanism of altered Ang II-related NF-κB activation during aging and inhibitory molecular events by genistein regarding to age-related Ang II-induced NF-κB activation. At present, we utilized young (6 months old), old (24 months old), and genistein-treated (2 and 4 mg/kg/day for 10 days) old rats. For our current study, we choose to use the kidney and rat endothelial cell line, YPEN-1 because of its vulnerability to age-related oxidative stress and inflammatory responsiveness. The results of the analysis showed that Ang II and AT1 expression increased during aging and that these increases were blunted by treatment with genistein. Furthermore, we investigated the inhibitory effects of genistein on the Ang II-induced redox imbalance in aged rat kidneys. Genistein reduced age-related increases in NF-κB activity and NF-κB-dependent pro-inflammatory genes expression. We also determined genistein attenuated Ang II-induced NF-κB activation through its anti-oxidant activity in YPEN-1 cells. Taken together, our present results show that genistein has potent anti-inflammatory effect resulting in the attenuation of the Ang II-induced NF-κB activation during aging. The most significant new finding from this study is that genistein exerts its anti-Ang II action during aging by suppressive effect of NF-κB activation. Based on these data, genistein may be an anti-Ang II agent that may be used in anti-inflammatory therapies.
Assuntos
Envelhecimento/imunologia , Angiotensina II/metabolismo , Anti-Inflamatórios/farmacologia , Células Endoteliais/efeitos dos fármacos , Genisteína/farmacologia , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , NF-kappa B/metabolismo , Fatores Etários , Animais , Antioxidantes/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Células Endoteliais/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/imunologia , Masculino , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
FoxOs and their post-translational modification by phosphorylation, acetylation, and methylation can affect epigenetic modifications and promote the expression of downstream target genes. Therefore, they ultimately affect cellular and biological functions during aging or occurrence of age-related diseases including cancer, diabetes, and kidney diseases. As known for its key role in aging, FoxOs play various biological roles in the aging process by regulating reactive oxygen species, lipid accumulation, and inflammation. FoxOs regulated by PI3K/Akt pathway modulate the expression of various target genes encoding MnSOD, catalases, PPARγ, and IL-1ß during aging, which are associated with age-related diseases. This review highlights the age-dependent differential regulatory mechanism of Akt/FoxOs axis in metabolic and non-metabolic organs. We demonstrated that age-dependent suppression of Akt increases the activity of FoxOs (Akt/FoxOs axis upregulation) in metabolic organs such as liver and muscle. This Akt/FoxOs axis could be modulated and reversed by antiaging paradigm calorie restriction (CR). In contrast, hyperinsulinemia-mediated PI3K/Akt activation inhibited FoxOs activity (Akt/FoxOs axis downregulation) leading to decrease of antioxidant genes expression in non-metabolic organs such as kidneys and lungs during aging. These phenomena are reversed by CR. The results of studies on the process of aging and CR indicate that the Akt/FoxOs axis plays a critical role in regulating metabolic homeostasis, redox stress, and inflammation in various organs during aging process. The benefical actions of CR on the Akt/FoxOs axis in metabolic and non-metabolic organs provide further insights into the molecular mechanisms of organ-differential roles of Akt/FoxOs axis during aging.
RESUMO
1,2-Diacetylbenzene (DAB) is a metabolite of 1,2-diethylbenzene, which is commonly used in the manufacture of plastics and gasoline. We examined the neurotoxic effects of DAB in young and old rats, particularly its effects on hippocampus. Previously, we reported DAB impairs hippocampal neurogenesis but that the underlying mechanism remained unclear. In this study, we evaluate the toxicities exhibited by DAB in the hippocampi of 6-month-old (young) and 20-month-old (old) male SD rats by treating animals intraperitoneally with DAB at 3 mg/kg/day for 1 week. Hippocampal areas were dissected from brains and RNA was extracted and subjected to RNA-seq analysis. RNA results showed animals exhibited age-dependent sensitivity to the neurotoxic effects of DAB. We observed that inflammatory pathways were up-regulated in old rats but that metabolism- and detoxification-related pathways were up-regulated in young rats. This result in old rats, especially upregulation of the TREM1 signaling pathway (an inflammatory response involved in Alzheimer's disease (AD)) was confirmed by RT-PCR. Our study results provide a better understanding of age-dependent responses to DAB and new insight into the association between DAB and AD.
RESUMO
In searching for new agents with a depigmenting effect, we synthesized a derivative of resveratrol, 5-(6-hydroxy-2-naphthyl)-1,2,3-benzenetriol (5HNB) with a potent tyrosinase inhibitory activity. 5HNB inhibited mushroom tyrosinase with an IC(50) value of 2.95 microM, which is more potent than the well-known anti-tyrosinase activity of kojic acid (IC(50)=38.24). The results of the enzymatic inhibition kinetics by Lineweaver-Burk analysis indicated 5HNB inhibits tyrosinase non-competitively when L-tyrosine was used as the substrate. Based on the strong inhibitory action of 5HNB, it is expected that 5HNB can suppress melanin production in which tyrosinase plays the essential role. Our expectation was confirmed by the experimentations with B16 melanoma cells in which 5HNB inhibited melanin production. We propose that 5HNB might have skin-whitening effects as well as therapeutic potential for treating skin pigmentation disorders.
Assuntos
Inibidores Enzimáticos/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Naftóis/química , Pirogalol/análogos & derivados , Agaricales/enzimologia , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Cinética , Melaninas/biossíntese , Melanoma Experimental/metabolismo , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Naftóis/síntese química , Naftóis/farmacologia , Pirogalol/síntese química , Pirogalol/química , Pirogalol/farmacologia , Pironas/farmacologia , Resveratrol , Estilbenos/farmacologiaRESUMO
5-Hydroxyindole (5HI), a metabolite of tryptophan, is involved in learning and memory, central neuron system regulation, and anti-oxidant activity. However, its protective action in mitochondrial function is not clear. Here, we tested whether 5HI protects against tert-butylhydroperoxide (t-BHP)-induced oxidative damage and mitochondrial dysfunction in human fibroblast cells. 5HI significantly suppressed t-BHP-induced cytotoxicity as determined by intracellular reactive species generation, lipid peroxidation, glutathione depletion, and peroxynitrite (ONOO(-)) generation. In addition, 5HI reduced t-BHP-induced DNA condensation. Pretreatment with 5HI significantly restored mitochondrial membrane potential (Deltapsim), suggesting that it protected cells against t-BHP-induced apoptosis. Western blot analysis also revealed that 5HI markedly inhibited cytochrome c release and caspase-3 activation, but not caspase-9 activation. Our data suggest that 5HI protects cells by attenuating oxidative stress and consequently protects against mitochondrial dysfunction.
Assuntos
Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Indóis/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Fibroblastos/metabolismo , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias/metabolismo , Ácido Peroxinitroso/biossíntese , Espécies Reativas de Oxigênio/metabolismo , terc-Butil Hidroperóxido/efeitos adversosRESUMO
This special issue on the effects of calorie restriction (CR) and intermittent fasting (IF) on health and diseases includes five scholarly reviews and four original articles that provide an insight into the molecular and cellular action mechanisms of epigenetically manipulated dietary paradigms [...].
Assuntos
Restrição Calórica/métodos , Doença , Jejum , Saúde , Dieta , Dietoterapia , Ingestão de Energia , HumanosRESUMO
Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view, as proposed in our previous work. In this review, we discuss the effects of CR on multiple phases of proinflammatory networks and inflammatory signaling pathways to elucidate the basic mechanism underlying aging. Based on studies on senoinflammation and CR, we recognized that senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. These results further support and enhance our understanding of the novel concept of senoinflammation, which is related to the metabolic changes that occur in the aging process. Furthermore, a thorough elucidation of the effect of CR on senoinflammation will reveal key insights and allow possible interventions in aging mechanisms, thus contributing to the development of new therapies focused on improving health and longevity.
Assuntos
Envelhecimento/fisiologia , Restrição Calórica , Senescência Celular/fisiologia , Inflamação , Longevidade/fisiologia , Animais , Quimiocinas/sangue , Citocinas/sangue , Humanos , Transdução de Sinais/fisiologiaRESUMO
Chronic inflammation is a complex and unresolved inflammatory response with low-grade multivariable patterns that aggravate systemic pathophysiological conditions and the aging process. To redefine and delineate these age-related complex inflammatory phenomena at the molecular, cellular, and systemic levels, the concept of "Senoinflammation" was recently formulated. In this review, we describe the accumulated data on both the multiphase systemic inflammatory process and the cellular proinflammatory signaling pathway. We also describe the proinflammatory mechanisms underlying the metabolic molecular pathways in aging. Additionally, we review age-related lipid accumulation, the role of the inflammatory senescence-associated secretory phenotype (SASP), the involvement of cytokine/chemokine secretion, endoplasmic reticulum (ER) stress, insulin resistance, and autophagy. The last section of the review highlights the modulation of the senoinflammatory process by the anti-aging and anti-inflammatory action of calorie restriction (CR). Evidence from aging and CR research strongly suggests that SASP from senescent cells may be the major source of secreted cytokines and chemokines during aging. A better understanding of the mechanisms underpinning the senoinflammatory response and the mitigating role of CR will provide insights into the molecular mechanisms of chronic inflammation and aging for potential interventions.