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1.
Cell ; 186(13): 2929-2949.e20, 2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37269831

RESUMO

Lifespan varies within and across species, but the general principles of its control remain unclear. Here, we conducted multi-tissue RNA-seq analyses across 41 mammalian species, identifying longevity signatures and examining their relationship with transcriptomic biomarkers of aging and established lifespan-extending interventions. An integrative analysis uncovered shared longevity mechanisms within and across species, including downregulated Igf1 and upregulated mitochondrial translation genes, and unique features, such as distinct regulation of the innate immune response and cellular respiration. Signatures of long-lived species were positively correlated with age-related changes and enriched for evolutionarily ancient essential genes, involved in proteolysis and PI3K-Akt signaling. Conversely, lifespan-extending interventions counteracted aging patterns and affected younger, mutable genes enriched for energy metabolism. The identified biomarkers revealed longevity interventions, including KU0063794, which extended mouse lifespan and healthspan. Overall, this study uncovers universal and distinct strategies of lifespan regulation within and across species and provides tools for discovering longevity interventions.


Assuntos
Longevidade , Fosfatidilinositol 3-Quinases , Animais , Camundongos , Longevidade/genética , Fosfatidilinositol 3-Quinases/genética , Envelhecimento/genética , Mamíferos/genética , Perfilação da Expressão Gênica
2.
Ageing Res Rev ; 92: 102122, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37956927

RESUMO

Vascular ageing, characterized by structural and functional changes in blood vessels of which arterial stiffness and endothelial dysfunction are key components, is associated with increased risk of cardiovascular and other age-related diseases. As the global population continues to age, understanding the underlying mechanisms and developing effective therapeutic interventions to mitigate vascular ageing becomes crucial for improving cardiovascular health outcomes. Therefore, this review provides an overview of the current knowledge on pharmacological modulation of vascular ageing, highlighting key strategies and promising therapeutic targets. Several molecular pathways have been identified as central players in vascular ageing, including oxidative stress and inflammation, the renin-angiotensin-aldosterone system, cellular senescence, macroautophagy, extracellular matrix remodelling, calcification, and gasotransmitter-related signalling. Pharmacological and dietary interventions targeting these pathways have shown potential in ameliorating age-related vascular changes. Nevertheless, the development and application of drugs targeting vascular ageing is complicated by various inherent challenges and limitations, such as certain preclinical methodological considerations, interactions with exercise training and sex/gender-related differences, which should be taken into account. Overall, pharmacological modulation of endothelial dysfunction and arterial stiffness as hallmarks of vascular ageing, holds great promise for improving cardiovascular health in the ageing population. Nonetheless, further research is needed to fully elucidate the underlying mechanisms and optimize the efficacy and safety of these interventions for clinical translation.


Assuntos
Envelhecimento , Rigidez Vascular , Humanos , Envelhecimento/metabolismo , Estresse Oxidativo , Senescência Celular , Transdução de Sinais
3.
Front Aging ; 3: 828058, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35821852

RESUMO

Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence (CS), which is characterized by permanent cell-cycle arrest, has recently emerged as a fundamental mechanism in developing aging-related pathologies. During the aging process, senescent cell accumulation results in senescence-associated secretory phenotype (SASP) which plays an essential role in tissue dysfunction. Although discovered very recently, senotherapeutic drugs have been already involved in clinical studies. This review gives a summary of the molecular mechanisms of CS and its role particularly in the development of cardiovascular diseases (CVD) as the leading cause of death. In addition, it addresses alternative research tools including the nonhuman and human models as well as computational techniques for the discovery of novel therapies. Finally, senotherapeutic approaches that are mainly classified as senolytics and senomorphics are discussed.

4.
Biology (Basel) ; 11(9)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36138732

RESUMO

The blind mole rat (BMR), a long-living subterranean rodent, is an exceptional model for both aging and cancer research since they do not display age-related phenotypes or tumor formation. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is a cytokine-stimulated pathway that has a crucial role in immune regulation, proliferation, and cytokine production. Therefore, the pathway has recently attracted interest in cellular senescence studies. Here, by using publicly available data, we report that JAK-STAT signaling was suppressed in the BMR in comparison to the mouse. Interestingly, our experimental results showed upregulated Jak1/2 expressions in BMR fibroblasts during the replicative senescence process. The transcriptomic analysis using publicly available data also demonstrated that various cytokines related to JAK-STAT signaling were upregulated in the late passage cells, while some other cytokines such as MMPs and SERPINs were downregulated, representing a possible balance of senescence-associated secretory phenotypes (SASPs) in the BMR. Finally, our proteomics data also confirmed cytokine-mediated signaling activation in senescent BMR fibroblasts. Together, our findings suggest the critical role of JAK-STAT and cytokine-mediated signaling pathways during cellular senescence, pointing to the possible contribution of divergent inflammatory factors to the superior resistance of aging and cancer in BMRs.

5.
Biofactors ; 46(4): 653-664, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32384218

RESUMO

Formation of atherosclerotic plaques, called atherogenesis, is a complex process affected by genetic and environmental factors. It was proposed that endoplasmic reticulum (ER) stress is an important factor in the pathogenesis of atherosclerosis and that vitamin E affects atherosclerotic plaque formation via its antioxidant properties. Here, we investigated ER stress-related molecular mechanisms in high-cholesterol diet (HCD, 2%)-induced atherosclerosis model and the role of vitamin E supplementation in it, beyond its antioxidant properties. The consequences of HCD and vitamin E supplementation were examined by determining protein levels of ER stress markers in aortic tissues. As vitamin E supplementation acts on several unfolded protein response (UPR) factors, it decreased ER stress induced by HCD. To elucidate the associated pathways, gene expression profiling was performed, revealing differentially expressed genes enriched in ER stress-related pathways such as the proteasome and the apoptosis pathways. We further assessed the proteasomal activity impaired by HCD in the aorta and showed that vitamin E reversed it to that of control animals. Overall, the study characterized the effects of HCD and vitamin E on ER stress-related gene expression, revealing the role of proteolytic systems during atherogenesis.


Assuntos
Antioxidantes/farmacologia , Aterosclerose/genética , Colesterol/administração & dosagem , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipercolesterolemia/genética , Placa Aterosclerótica/genética , Vitamina E/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Aterosclerose/etiologia , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Hipercolesterolemia/etiologia , Hipercolesterolemia/patologia , Hipercolesterolemia/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Anotação de Sequência Molecular , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/patologia , Placa Aterosclerótica/prevenção & controle , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Coelhos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
6.
Oxid Med Cell Longev ; 2020: 9369524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190179

RESUMO

Aging has been characterized with the accumulation of oxidized proteins, as a consequence of progressive decline in proteostasis capacity. Among others, proteasomal system is an efficient protein turnover complex to avoid aggregation of oxidized proteins. Heat shock protein 70 (HSP70) is another critical player that is involved in some key processes including the correct folding of misfolded proteins and targeting aggregated proteins to the proteasome for rapid degradation. The aim of this study was to determine the role of proteasomal system and heat shock proteins to maintain proteome balance during replicative senescence in mild hyperthermia conditions. Our results demonstrated that HSP40/70 machinery is induced by mild hyperthermia conditions independent from senescence conditions. Since HSP70 is largely responsible for the rapidly inducible cell protection following hyperthermia, the activation of "heat shock response" resulted in the elevation of HSP40/70 expressions as well as the proteasome activity. Interestingly, when HSP70 expression was inhibited, increased proteasomal activation was shown to be responsive to mild hyperthermia. Since HSP70 is involved in various stress-related pathways such as oxidative and endoplasmic reticulum stress, depletion of HSP70 expression may induce proteasomal degradation to maintain proteome balance of the cell. Thus, our data suggests that in mild heat stress conditions, molecular chaperone HSP70 plays an important role to avoid protein oxidation and aggregation; however, activities of proteasomal system are induced when HSP70 expression is depleted.


Assuntos
Senescência Celular , Fibroblastos/citologia , Fibroblastos/metabolismo , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Hipertermia Induzida , Complexo de Endopeptidases do Proteassoma/metabolismo , Compostos Benzidrílicos/farmacologia , Senescência Celular/genética , Inativação Gênica , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Resposta ao Choque Térmico/genética , Humanos , Masculino , Proteostase , Pirrolidinonas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
7.
Cell Metab ; 30(3): 573-593.e8, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31353263

RESUMO

Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but general principles of lifespan extension remain unclear. Here, we performed RNA sequencing (RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences. Expanding this analysis to 17 interventions with public data, we observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues. We further applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794, and ascorbyl-palmitate. Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.


Assuntos
Envelhecimento/genética , Longevidade/genética , Transcriptoma , Envelhecimento/efeitos dos fármacos , Animais , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/farmacologia , Restrição Calórica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Hipóxia/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Expectativa de Vida , Fígado/metabolismo , Longevidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Pirimidinas/farmacologia , Sirolimo/farmacologia
8.
Redox Biol ; 8: 323-32, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26966891

RESUMO

Nrf2 pathway has been known to be protective against cancer progression however recent studies have revealed that the antioxidant activity of Nrf2 contributes to chemotherapy resistance. For many years, hyperthermia has been used as an additional therapy to increase the efficiency of chemotherapy and radiotherapy. Besides the positive effects of hyperthermia during treatment procedure, thermotolerance has been found to develop against heat treatment. Although the involved molecular mechanisms have not been fully clarified, heat shock proteins (HSP) and proteasome activity are known to be involved in the acquisition of thermotolerance. The aim of this study was to investigate the potential beneficial effects of combining hyperthermia with Nrf2 silencing to inhibit molecular mechanisms leading to induction of defense mechanisms in transcription level. Following heat treatment of HT22 cells, HSP70 and the proteasome levels and as well as proteasome activity were found to be elevated in the nucleus. Our results demonstrated that Nrf2 silencing reduced defense mechanisms against heat treatment both in antioxidant and proteolytic manner and Nrf2 may be a potential target for therapeutic approach in order to improve the beneficial effects of hyperthermia in cancer therapy.


Assuntos
Hipertermia Induzida , Fator 2 Relacionado a NF-E2/genética , Neoplasias/terapia , Complexo de Endopeptidases do Proteassoma/genética , Animais , Linhagem Celular , Inativação Gênica , Proteínas de Choque Térmico HSP70/genética , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Neoplasias/genética , Transdução de Sinais , Termotolerância/genética
9.
Mech Ageing Dev ; 157: 17-29, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27393639

RESUMO

Nonalcoholic steatohepatitis (NASH) is considered to be a common health problem since the incidence of nonalcoholic fatty liver disease (NAFLD) has increased in recent years. Disturbed hepatic cholesterol homeostasis and free cholesterol accumulation in liver results in increased oxidative stress leading to the endoplasmic reticulum (ER) stress. Activated ER stress maintains protein homeostasis however, delayed or inadequate ER stress responses may induce fat accumulation, insulin resistance, inflammation, apoptosis, and autophagy, all of which increase with age and play crucial roles in the pathogenesis of NASH. In aging research, there is a growing interest for the role of ER stress in the progression of NASH since aging seems to favor NAFLD according to its pathogenesis. On the other hand, specific microRNAs (miRNAs) expression profiles are strongly related with ER stress as well as NASH progresses. This review highlights molecular mechanisms related to ER stress in the pathogenesis of NASH and miRNAs for the progression and treatment of the disease.


Assuntos
Apoptose , Autofagia , Colesterol/metabolismo , Estresse do Retículo Endoplasmático , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/terapia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia
10.
Free Radic Biol Med ; 77: 195-209, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25236750

RESUMO

Protein turnover reflects the balance between synthesis and degradation of proteins, and it is a crucial process for the maintenance of the cellular protein pool. The folding of proteins, refolding of misfolded proteins, and also degradation of misfolded and damaged proteins are involved in the protein quality control (PQC) system. Correct protein folding and degradation are controlled by many different factors, one of the most important of which is the heat shock protein family. Heat shock proteins (HSPs) are in the class of molecular chaperones, which may prevent the inappropriate interaction of proteins and induce correct folding. On the other hand, these proteins play significant roles in the degradation pathways, including endoplasmic reticulum-associated degradation (ERAD), the ubiquitin-proteasome system, and autophagy. This review focuses on the emerging role of HSPs in the regulation of protein turnover; the effects of HSPs on the degradation machineries ERAD, autophagy, and proteasome; as well as the role of posttranslational modifications in the PQC system.


Assuntos
Proteínas de Choque Térmico/fisiologia , Proteínas/metabolismo , Degradação Associada com o Retículo Endoplasmático , Humanos , Lisossomos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Biossíntese de Proteínas , Proteólise , Ubiquitinação
11.
Free Radic Biol Med ; 75 Suppl 1: S35, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26461349

RESUMO

Proteasomal degradation of oxidized proteins is a crucial mechanism to prevent the accumulation of cellular damage. The removal of the damage is generally a required process for healthy organisms to keep the integrity while in cancer cells the situation may be different. In normal conditions, cancer cells have higher proteasome activity compared to normal cells. During cancer treatment, cellular damage by chemotherapy is an expected process to be able to kill the tumor cells. And the accumulation of this damage accompanied by the decrease in protein repair and removal systems may increase the efficacy of the cancer therapy. Heat shock proteins (Hsp) as molecular chaperones are involved in the folding, activation and assembly of a variety of proteins. Among these Hsp40, Hsp70 and Hsp90 are believed to act as a chaperone system to regulate the proteasomal degradation. In this study, we tested the role of heat stress response on the proteasomal degradation of oxidized proteins. We used two different cell lines to observe the difference in normal and tumor cells. First the effect of heat stress (42°C, 1h) were tested in terms of protein oxidation tested by protein carbonyl formation and proteasomal degradation. The results were extremely different in normal fibroblast cells and hippocampal tumor cells. In the same direction, the expressions of Hsp40, Hsp70 and Hsp90 were affected in a different manner in two cell lines, will be discussed in detail. Supported by TUBITAK COST-CM1001-110S281.

12.
Redox Biol ; 2: 732-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25009774

RESUMO

Atherosclerosis and its complications are major causes of death all over the world. One of the major risks of atherosclerosis is hypercholesterolemia. During atherosclerosis, oxidized low density lipoprotein (oxLDL) regulates CD36-mediated activation of c-jun amino terminal kinase-1 (JNK1) and modulates matrix metalloproteinase (MMP) induction which stimulates inflammation with an invasion of monocytes. Additionally, inhibition of proteasome leads to an accumulation of c-jun and phosphorylated c-jun and activation of activator protein-1 (AP-1) related increase of MMP expression. We have previously reported a significant increase in cluster of differentiation 36 (CD36) mRNA levels in hypercholesterolemic rabbits and shown that vitamin E treatment prevented the cholesterol induced increase in CD36 mRNA expression. In the present study, our aim is to identify the signaling molecules/transcription factors involved in the progression of atherosclerosis following CD36 activation in an in vivo model of hypercholesterolemic (induced by 2% cholesterol containing diet) rabbits. In this direction, proteasomal activities by fluorometry and c-jun, phospo c-jun, JNK1, MMP-9 expressions by quantitative RT-PCR and immunoblotting were tested in aortic tissues. The effects of vitamin E on these changes were also investigated in this model. As a result, c-jun was phosphorylated following decreased proteasomal degradation in hypercholesterolemic group. MMP-9 expression was also increased in cholesterol group rabbits contributing to the development of atherosclerosis. In addition, vitamin E showed its effect by decreasing MMP-9 levels and phosphorylation of c-jun.


Assuntos
Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Colesterol/sangue , Colesterol na Dieta , Expressão Gênica/efeitos dos fármacos , Hipercolesterolemia/complicações , Hipercolesterolemia/metabolismo , Masculino , Malondialdeído/sangue , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/genética , Fosforilação/efeitos dos fármacos , RNA Mensageiro/metabolismo , Coelhos , Transdução de Sinais/efeitos dos fármacos , Vitamina E/sangue , Vitamina E/farmacologia
13.
Free Radic Biol Med ; 75 Suppl 1: S24, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26461313

RESUMO

Hypercholesterolemia is the major risk factor for the development of atherosclerosis and vitamin E is suggested to have a preventive role in this process (1), although the mechanism of action still remains unclear.The ubiquitin-proteasome system (UPS) may in?uence atherosclerosis by affecting disease-relevant cellular processes such as apoptosis, proliferation, and differentiation, or by affecting cellular stress responses and/or adaptive phenomena, such as ER stress, in?ammation, and redox homeostasis (2). NF-E2-related factor 2 (Nrf2) is a transcription factor that controls the expression of phase II detoxi?cation and antioxidant genes. Nrf2 signaling has additionally been shown to upregulate the expression of the proteasome catalytic subunits (3). In the present study, we investigated the role of Nrf2 pathway on oxidative and ER stress conditions induced by cholesterol diet and the effects of vitamin E on related signaling pathways in in vivo model of atherosclerosis. All experimental procedures were approved by the Marmara University Ethics Committee. Twenty-one male albino rabbits (23 months old) were assigned randomly to four groups fed for 8 weeks: (i) vitamin E deficient diet, (ii) vitamin E deficient diet containing 2% cholesterol, and (iii) vitamin E deficient diet containing 2% cholesterol with daily intramuscular injections of vitamin E (50mg/kg), (iv) vitamin E deficient diet with daily intramuscular injections of vitamin E (50mg/kg). In order to elucidate in vivo role of oxidative stress and ER stress in cardiovascular system of hypercholesterolemic rabbits, we investigated serum levels of cholesterol, MDA and vitamin E and Nrf2, GST-1, GRP78, GRP94, PERK, IRE1 protein levels and the proteasomal activity in aortic tissues will be discussed.

14.
Free Radic Biol Med ; 75 Suppl 1: S16, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26461295

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a global health problem and lead to subacute liver failure, cirrhosis and/or hepatocellular carcinoma. An increased generation of reactive oxygen species (ROS) and antioxidant depletion is found in the liver of obese patients with NAFLD. Irisin is a recently identified exercise-induced myokine. It increases total energy consumption, reduces body weight, and insulin resistance. It was shown that irisin levels were significantly lower in patients with NAFLD. The aim of the present study was to investigate the effect of irisin on prooxidant-antioxidant balance in liver. In the first phase; AML12 liver cells were divided into 4 groups: control, hydrogen peroxide (H2O2)-treated, 10nM irisin-treated and 50nM irisin-treated groups. ROS accumulation in these groups was analyzed by FACS. In the second phase; to see if there is any protective role of irisin on ROS production in the liver, AML12 liver cells were divided into 4 groups: control, H2O2 -treated, H2O2+10nM irisin-treated and H2O2+50nM-irisin treated groups. After measuring ROS accumulation again in these groups, the levels of enzymes related with prooxidant-antioxidant balance via oxidative stress in liver were measured by western blotting. In H2O2 treatment groups, ROS production was increased in AML12 liver cells, on the other hand in irisin treatment groups ROS production was slightly changed. Irisin might be a potential target for metabolic diseases like NAFLD.

15.
Free Radic Biol Med ; 70: 174-81, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24583459

RESUMO

Atherosclerosis and associated cardiovascular complications such as stroke and myocardial infarction are major causes of morbidity and mortality. We have previously reported a significant increase in mRNA levels of the scavenger receptor CD36 in aortae of cholesterol-fed rabbits and shown that vitamin E treatment attenuated increased CD36 mRNA expression. In the present study, we further investigated the redox signaling pathways associated with protection against atherogenesis induced by high dietary cholesterol and correlated these with CD36 expression and the effects of vitamin E supplementation in a rabbit model. Male albino rabbits were assigned to either a control group fed with a low vitamin E diet alone or a test group fed with a low vitamin E diet containing 2% cholesterol in the absence or presence of daily intramuscular injections of vitamin E (50mg/kg). To elucidate the mechanisms by which vitamin E supplementation alters the effects of hypercholesterolemia in rabbit aortae, we measured peroxisome proliferator-activated receptor γ (PPARγ), ATP-binding cassette transporter A1 (ABCA1), and matrix metalloproteinase-1 (MMP-1) mRNA levels by quantitative RT-PCR and the expression of MMP-1, nuclear factor-erythroid 2-related factor 2 (Nrf2), and glutathione S-transferase α (GSTα) protein by immunoblotting. The increased MMP-1 and decreased GSTα expression observed suggests that a cholesterol-rich diet contributes to the development of atherosclerosis, whereas vitamin E supplementation affords protection by decreasing MMP-1 and increasing PPARγ, GSTα, and ABCA1 levels in aortae of rabbits fed a cholesterol-rich diet. Notably, protein expression of Nrf2, the antioxidant transcription factor, was increased in both the cholesterol-fed and the vitamin E-supplemented groups. Although Nrf2 activation can promote CD36-mediated cholesterol uptake by macrophages, the increased induction of Nrf2-mediated antioxidant genes is likely to contribute to decreased lesion progression. Thus, our study demonstrates that Nrf2 can mediate both pro- and antiatherosclerotic effects.


Assuntos
Aterosclerose/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , PPAR gama/metabolismo , Vitamina E/administração & dosagem , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Aterosclerose/patologia , Colesterol na Dieta/administração & dosagem , Dieta Hiperlipídica , Regulação da Expressão Gênica , Glutationa Transferase/biossíntese , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/patologia , Isoenzimas/biossíntese , Masculino , Metaloproteinase 1 da Matriz/biossíntese , Coelhos , Transdução de Sinais/efeitos dos fármacos
16.
J Proteomics ; 89: 238-54, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23811050

RESUMO

Since the proteins are involved in many physiological processes in the organisms, modifications of proteins have important outcomes. Protein modifications are classified in several ways and oxidative stress related ones take a wide place. Aging is characterized by the accumulation of oxidized proteins and decreased degradation of these proteins. On the other hand protein turnover is an important regulatory mechanism for the control of protein homeostasis. Heat shock proteins are a highly conserved family of proteins in the various cells and organisms whose expressions are highly inducible during stress conditions. These proteins participate in protein assembly, trafficking, degradation and therefore play important role in protein turnover. Although the entire functions of each heat shock protein are still not completely investigated, these proteins have been implicated in the processes of protection and repair of stress-induced protein damage. This study has focused on the heat stress related carbonylated proteins, as a marker of oxidative protein modification, in young and senescent fibroblasts. The results are discussed with reference to potential involvement of induced heat shock proteins. This article is part of a Special Issue entitled: Protein Modifications. BIOLOGICAL SIGNIFICANCE: Age-related protein modifications, especially protein carbonylation take a wide place in the literature. In this direction, to highlight the role of heat shock proteins in the oxidative modifications may bring a new aspect to the literature. On the other hand, identified carbonylated proteins in this study confirm the importance of folding process in the mitochondria which will be further analyzed in detail.


Assuntos
Senescência Celular/fisiologia , Fibroblastos/metabolismo , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico/fisiologia , Carbonilação Proteica/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Células Cultivadas , Fibroblastos/citologia , Humanos , Masculino
17.
Free Radic Biol Med ; 50(1): 86-92, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20977936

RESUMO

Changes in protein turnover are among the dominant metabolic changes during aging. Of special importance is the maintenance of nuclear protein homeostasis to ensure a coordinated cellular metabolism. Therefore, in the nucleus a special PARP-1-mediated mechanism of proteasomal activation exists to ensure a rapid degradation of oxidized nuclear proteins. It was already demonstrated earlier that the cytosolic proteasomal system declines dramatically with aging, whereas the nuclear proteasome remains less affected. We demonstrate here that the stress-mediated proteasomal activation in the nucleus declines during replicative senescence of human fibroblasts. Furthermore, we clearly show that this decline in the PARP-1-mediated proteasomal activation is due to a decline in the expression and activity of PARP-1 in senescent fibroblasts. In a final study we show that this process also happens in vivo, because the protein expression level of PARP-1 is significantly lower in the skin of aged donors compared to that of young ones. Therefore, we conclude that the rate-limiting factor in poly(ADP-ribose)-mediated proteasomal activation in oxidative stress is PARP-1 and not the nuclear proteasome itself.


Assuntos
Núcleo Celular/metabolismo , Senescência Celular/fisiologia , Estresse Oxidativo/fisiologia , Poli(ADP-Ribose) Polimerases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Envelhecimento/fisiologia , Benzamidas/farmacologia , Biópsia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Poli(ADP-Ribose) Polimerase-1 , Poli Adenosina Difosfato Ribose/metabolismo , Poli Adenosina Difosfato Ribose/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/farmacologia
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