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1.
Int J Mol Sci ; 20(24)2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817798

RESUMO

Gestational diabetes mellitus (GDM), a metabolic disease that develops with the increase in insulin resistance during late pregnancy, is currently one of the most common complications affecting pregnancy. The polygenic nature of GDM, together with the interplay between different genetic variants with nutritional and environmental factors has hindered the full understanding of the etiology of this disease. However, an important genetic overlap has been found with type 2 diabetes mellitus (T2DM) and, as in the case of T2DM, most of the identified loci are associated with ß-cell function. Early detection of GDM and adequate interventions to control the maternal glycemia are necessary to avoid the adverse outcomes for both the mother and the offspring. The in utero exposure to the diabetic milieu predispose these children for future diseases, among them T2DM, originating a vicious circle implicated in the increased prevalence of both GDM and T2DM. The involvement of inflammatory processes in the development of GDM highlights the importance of pancreatic ß-cell factors able to favor the adaptation processes required during gestation, concomitantly with the protection of the islets from an inflammatory milieu. In this regard, two members of the Pax family of transcription factors, PAX4 and PAX8, together with the chromatin remodeler factor HMG20A, have gained great relevance due to their involvement in ß-cell mass adaptation together with their anti-inflammatory properties. Mutations in these factors have been associated with GDM, highlighting these as novel candidates for genetic screening analysis in the identification of women at risk of developing GDM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/fisiopatologia , Ilhotas Pancreáticas/fisiologia , Glicemia/metabolismo , Feminino , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Fator de Transcrição PAX8/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Gravidez
2.
Aging (Albany NY) ; 11(18): 7746-7779, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31518338

RESUMO

An inverse correlation between thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness. However, hypothyroidism is a medical condition associated with compromised health and reduced life expectancy. Herein, we show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan. Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan. These pathophysiological conditions were precipitated by hepatic mitochondrial dysfunction and oxidative damage accumulation. These findings indicate that individuals carrying mutations on PAX8 may be susceptible to develop liver cancer and/or diabetes and raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan in mammals.

3.
Front Cell Neurosci ; 13: 204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156392

RESUMO

Radiotherapy is a highly effective tool for the treatment of brain cancer. However, radiation also causes detrimental effects in the healthy tissue, leading to neurocognitive sequelae that compromise the quality of life of brain cancer patients. Despite the recognition of this serious complication, no satisfactory solutions exist at present. Here we investigated the effects of intranasal administration of human mesenchymal stem cells (hMSCs) as a neuroprotective strategy for cranial radiation in mice. Our results demonstrated that intranasally delivered hMSCs promote radiation-induced brain injury repair, improving neurological function. This intervention confers protection against inflammation, oxidative stress, and neuronal loss. hMSC administration reduces persistent activation of damage-induced c-AMP response element-binding signaling in irradiated brains. Furthermore, hMSC treatment did not compromise the survival of glioma-bearing mice. Our findings encourage the therapeutic use of hMSCs as a non-invasive approach to prevent neurological complications of radiotherapy, improving the quality of life of brain tumor patients.

4.
Genes (Basel) ; 10(5)2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072002

RESUMO

The high prevalence of type 2 diabetes mellitus (T2DM), together with the fact that current treatments are only palliative and do not avoid major secondary complications, reveals the need for novel approaches to treat the cause of this disease. Efforts are currently underway to identify therapeutic targets implicated in either the regeneration or re-differentiation of a functional pancreatic islet ß-cell mass to restore insulin levels and normoglycemia. However, T2DM is not only caused by failures in ß-cells but also by dysfunctions in the central nervous system (CNS), especially in the hypothalamus and brainstem. Herein, we review the physiological contribution of hypothalamic neuronal and glial populations, particularly astrocytes, in the control of the systemic response that regulates blood glucose levels. The glucosensing capacity of hypothalamic astrocytes, together with their regulation by metabolic hormones, highlights the relevance of these cells in the control of glucose homeostasis. Moreover, the critical role of astrocytes in the response to inflammation, a process associated with obesity and T2DM, further emphasizes the importance of these cells as novel targets to stimulate the CNS in response to metabesity (over-nutrition-derived metabolic dysfunctions). We suggest that novel T2DM therapies should aim at stimulating the CNS astrocytic response, as well as recovering the functional pancreatic ß-cell mass. Whether or not a common factor expressed in both cell types can be feasibly targeted is also discussed.


Assuntos
Encéfalo/metabolismo , Glucose/metabolismo , Ilhotas Pancreáticas/metabolismo , Doenças Metabólicas/metabolismo , Animais , Astrócitos/metabolismo , Metabolismo Energético , Homeostase , Humanos
5.
Proc Natl Acad Sci U S A ; 116(20): 10103-10112, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31010925

RESUMO

Physical exercise has positive effects on cognition, but very little is known about the inheritance of these effects to sedentary offspring and the mechanisms involved. Here, we use a patrilineal design in mice to test the transmission of effects from the same father (before or after training) and from different fathers to compare sedentary- and runner-father progenies. Behavioral, stereological, and whole-genome sequence analyses reveal that paternal cognition improvement is inherited by the offspring, along with increased adult neurogenesis, greater mitochondrial citrate synthase activity, and modulation of the adult hippocampal gene expression profile. These results demonstrate the inheritance of exercise-induced cognition enhancement through the germline, pointing to paternal physical activity as a direct factor driving offspring's brain physiology and cognitive behavior.


Assuntos
Encéfalo/fisiologia , Cognição/fisiologia , Pai/psicologia , Herança Paterna , Corrida/fisiologia , Animais , Feminino , Expressão Gênica , Masculino , Camundongos , Gravidez
6.
Diabetes ; 68(1): 109-118, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352879

RESUMO

Transient Pax8 expression was reported in mouse islets during gestation, whereas a genome-wide linkage and admixture mapping study highlighted PAX8 as a candidate gene for diabetes mellitus (DM). We sought the significance of PAX8 expression in mouse and human islet biology. PAX8 was induced in gestating mouse islets and in human islets treated with recombinant prolactin. Global gene expression profiling of human and mouse islets overexpressing the corresponding species-specific PAX8 revealed the modulation of distinct genetic pathways that converge on cell survival. Accordingly, apoptosis was reduced in PAX8-overexpressing islets. These findings support that PAX8 could be a candidate gene for the study of gestational DM (GDM). PAX8 was genotyped in patients with GDM and gestational thyroid dysfunction (GTD), a pathology commonly found in patients with mutations on PAX8 A novel missense PAX8 mutation (p.T356M, c.1067C>T) was identified in a female diagnosed with GDM and GTD as well as in her father with type 2 DM but was absent in control patients. The p.T356M variant did not alter protein stability or cellular localization, whereas its transactivation activity was hindered. In parallel, a retrospective clinical analysis uncovered that a pregnant female harboring a second PAX8 mutation (p.P25R, c.74C>G) previously reported to cause congenital hypothyroidism also developed GDM. These data indicate that increased expression of PAX8 affects islet viability and that PAX8 could be considered as a candidate gene for the study of GDM.


Assuntos
Diabetes Gestacional/metabolismo , Fator de Transcrição PAX8/metabolismo , Animais , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Diabetes Gestacional/genética , Feminino , Genótipo , Teste de Tolerância a Glucose , Humanos , Imuno-Histoquímica , Camundongos Endogâmicos C57BL , Mutação/genética , Mutação de Sentido Incorreto/genética , Fator de Transcrição PAX8/genética , Linhagem , Gravidez , Estudos Retrospectivos
7.
Aging (Albany NY) ; 10(11): 3079-3088, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30425188

RESUMO

Multiple interventions in the aging process have been discovered to extend the healthspan of model organisms. Both industry and academia are therefore exploring possible transformative molecules that target aging and age-associated diseases. In this overview, we summarize the presented talks and discussion points of the 5th Annual Aging and Drug Discovery Forum 2018 in Basel, Switzerland. Here academia and industry came together, to discuss the latest progress and issues in aging research. The meeting covered talks about the mechanistic cause of aging, how longevity signatures may be highly conserved, emerging biomarkers of aging, possible interventions in the aging process and the use of artificial intelligence for aging research and drug discovery. Importantly, a consensus is emerging both in industry and academia, that molecules able to intervene in the aging process may contain the potential to transform both societies and healthcare.

8.
Biochim Biophys Acta Bioenerg ; 1859(11): 1235-1248, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30267671

RESUMO

Coenzyme Q10 (CoQ10) is a redox molecule critical for the proper function of energy metabolism and antioxidant defenses. Despite its essential role in cellular metabolism, the regulation of CoQ10 biosynthesis in humans remains mostly unknown. Herein, we determined that PPTC7 is a regulatory protein of CoQ10 biosynthesis required for human cell survival. We demonstrated by in vitro approaches that PPTC7 is a bona fide protein phosphatase that dephosphorylates the human COQ7. Expression modulation experiments determined that human PPTC7 dictates cellular CoQ10 content. Using two different approaches (PPTC7 over-expression and caloric restriction), we demonstrated that PPTC7 facilitates and improves the human cell adaptation to respiratory conditions. Moreover, we determined that the physiological role of PPTC7 takes place in the adaptation to starvation and pro-oxidant conditions, facilitating the induction of mitochondrial metabolism while preventing the accumulation of ROS. Here we unveil the first post-translational mechanism regulating CoQ10 biosynthesis in humans and propose targeting the induction of PPTC7 activity/expression for the treatment of CoQ10-related mitochondrial diseases.


Assuntos
Mitocôndrias/enzimologia , Monoéster Fosfórico Hidrolases/metabolismo , Ubiquinona/análogos & derivados , Animais , Restrição Calórica , Linhagem Celular , Sistema Enzimático do Citocromo P-450/metabolismo , Drosophila , Inativação Gênica , Teste de Complementação Genética , Humanos , Mutação/genética , Estresse Oxidativo , Fosforilação , Saccharomyces cerevisiae/metabolismo , Homologia de Sequência de Aminoácidos , Ubiquinona/biossíntese
9.
Aging Cell ; 17(4): e12767, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29706024

RESUMO

Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+ /sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.


Assuntos
Restrição Calórica , Citocromo-B(5) Redutase/genética , Regulação Enzimológica da Expressão Gênica , NAD(P)H Desidrogenase (Quinona)/genética , Animais , Citocromo-B(5) Redutase/metabolismo , Metabolismo Energético , Longevidade , Masculino , Camundongos , Camundongos Transgênicos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Ratos
10.
Nat Commun ; 9(1): 1488, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29662071

RESUMO

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.


Assuntos
Comunicação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/terapia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Fenalenos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Transplante das Ilhotas Pancreáticas , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/imunologia , Estreptozocina , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Transplante Heterólogo
11.
Cell Death Dis ; 9(3): 279, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29449530

RESUMO

HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the HMG20A gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that HMG20A is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased HMG20A transcript levels, a result also observed in islets of gestating mice. In contrast, HMG20A expression was not altered in islets from diet-induced obese and pre-diabetic mice. The T2DM-associated rs7119 SNP, located in the 3' UTR of the HMG20A transcript reduced the luciferase activity of a reporter construct in the human beta 1.1E7 cell line. Depletion of Hmg20a in the rat INS-1E cell line resulted in decreased expression levels of its neuronal target gene NeuroD whereas Rest and Pax4 were increased. Chromatin immunoprecipitation confirmed the interaction of HMG20A with the Pax4 gene promoter. Expression levels of Mafa, Glucokinase, and Insulin were also inhibited. Furthermore, glucose-induced insulin secretion was blunted in HMG20A-depleted islets. In summary, our data demonstrate that HMG20A expression in islet is essential for metabolism-insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as NeuroD and Mafa and that depletion induces expression of genes such as Pax4 and Rest implicated in beta cell de-differentiation. More importantly we assign to the T2DM-linked rs7119 SNP the functional consequence of reducing HMG20A expression likely translating to impaired beta cell mature function.


Assuntos
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Células Secretoras de Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Glicemia/metabolismo , Linhagem Celular Tumoral , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Predisposição Genética para Doença , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Células Secretoras de Insulina/patologia , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Fenótipo , Ratos
12.
Br J Pharmacol ; 174(21): 3795-3810, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28800677

RESUMO

BACKGROUND AND PURPOSE: Thyroid hormones induce several changes in whole body metabolism that are known to improve metabolic homeostasis. However, adverse side effects have prevented its use in the clinic. In view of the promising effects of thyroid hormones, we investigated the effects of levothyroxine supplementation on glucose homeostasis. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with levothyroxine from birth to 24 weeks of age, when mice were killed. The effects of levothyroxine supplementation on metabolic health were determined. C57BL/6 mice treated with levothyroxine for 2 weeks and then challenged with streptozotocin to monitor survival. Mechanistic experiments were conducted in the pancreas, liver and skeletal muscle. RIP-B7.1 mice were treated with levothyroxine for 2 weeks and were subsequently immunized to trigger experimental autoimmune diabetes (EAD). Metabolic tests were performed. Mice were killed and metabolic tissues were extracted for immunohistological analyses. KEY RESULTS: Long-term levothyroxine supplementation enhanced glucose clearance and reduced circulating glucose in C57BL/6 mice. Levothyroxine increased simultaneously the proliferation and apoptosis of pancreatic beta cells, promoting the maintenance of a highly insulin-expressing beta cell population. Levothyroxine increased circulating insulin levels, inducing sustained activation of IRS1-AKT signalling in insulin-target tissues. Levothyroxine-treated C57BL/6 mice challenged with streptozotocin exhibited extended survival. Levothyroxine blunted the onset of EAD in RIP-B7.1 mice by inducing beta cell proliferation and preservation of insulin-expressing cells. CONCLUSIONS AND IMPLICATIONS: Interventions based on the use of thyroid hormones or thyromimetics could be explored to provide therapeutic benefit in patients with type 1 diabetes mellitus.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucose/metabolismo , Tiroxina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina , Tiroxina/administração & dosagem
13.
NPJ Aging Mech Dis ; 3: 8, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28649426

RESUMO

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process.

14.
Microb Cell ; 4(2): 38-51, 2017 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-28357388

RESUMO

Coenzyme Q is an essential lipid with redox capacity that is present in all organisms. In yeast its biosynthesis depends on a multiprotein complex in which Coq7 protein has both catalytic and regulatory functions. Coq7 modulates CoQ6 levels through a phosphorylation cycle, where dephosphorylation of three amino acids (Ser/Thr) by the mitochondrial phosphatase Ptc7 increases the levels of CoQ6. Here we analyzed the role of Ptc7 and the phosphorylation state of Coq7 in yeast mitochondrial function. The conversion of the three Ser/Thr to alanine led to a permanently active form of Coq7 that caused a 2.5-fold increase of CoQ6 levels, albeit decreased mitochondrial respiratory chain activity and oxidative stress resistance capacity. This resulted in an increase in endogenous ROS production and shortened the chronological life span (CLS) compared to wild type. The null PTC7 mutant (ptc7∆) strain showed a lower biosynthesis rate of CoQ6 and a significant shortening of the CLS. The reduced CLS observed in ptc7Δ was restored by the overexpression of PTC7 but not by the addition of exogenous CoQ6. Overexpression of PTC7 increased mitophagy in a wild type strain. This finding suggests an additional Ptc7 function beyond the regulation of CoQ biosynthesis. Genetic disruption of PTC7 prevented mitophagy activation in conditions of nitrogen deprivation. In brief, we show that, in yeast, Ptc7 modulates the adaptation to respiratory metabolism by dephosphorylating Coq7 to supply newly synthesized CoQ6, and by activating mitophagy to remove defective mitochondria at stationary phase, guaranteeing a proper CLS in yeast.

15.
Expert Opin Ther Targets ; 21(1): 77-89, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27841034

RESUMO

INTRODUCTION: Four members of the PAX family, PAX2, PAX4, PAX6 and PAX8 are known to be expressed in the pancreas. Accumulated evidences indicate that several pancreatic expressed PAX genes play a significant role in pancreatic development/functionality and alterations in these genes are involved in the pathogenesis of pancreatic diseases. Areas covered: In this review, we summarize the ongoing research related to pancreatic PAX genes in diabetes mellitus and pancreatic neuroendocrine tumors. We dissect the current knowledge at different levels; from mechanistic studies in cell lines performed to understand the molecular processes controlled by pancreatic PAX genes, to in vivo studies using rodent models that over-express or lack specific PAX genes. Finally, we describe human studies associating variants on pancreatic-expressed PAX genes with pancreatic diseases. Expert opinion: Based on the current literature, we propose that future interventions to treat pancreatic neuroendocrine tumors and diabetes mellitus could be developed via the modulation of PAX4 and/or PAX6 regulated pathways.


Assuntos
Diabetes Mellitus/genética , Tumores Neuroendócrinos/genética , Fatores de Transcrição Box Pareados/genética , Neoplasias Pancreáticas/genética , Animais , Linhagem Celular , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/terapia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Pâncreas/fisiopatologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia
16.
Cancer Cell ; 30(1): 136-146, 2016 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-27411588

RESUMO

Immune-based interventions are promising strategies to achieve long-term cancer-free survival. Fasting was previously shown to differentially sensitize tumors to chemotherapy while protecting normal cells, including hematopoietic stem and immune cells, from its toxic side effects. Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8(+) tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8(+)-dependent tumor cytotoxicity.


Assuntos
Neoplasias da Mama/dietoterapia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Heme Oxigenase-1/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Progressão da Doença , Regulação para Baixo , Doxorrubicina/farmacologia , Jejum , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Células MCF-7 , Camundongos , Transplante de Neoplasias , Linfócitos T Citotóxicos/efeitos dos fármacos
17.
Aging Cell ; 15(3): 572-81, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26990999

RESUMO

Metformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age-related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA-processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post-transcriptional mechanism involving the RNA-binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life-extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR-20a, miR-34a, miR-130a, miR-106b, miR-125, and let-7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1-dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence-associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age-related disease.


Assuntos
Senescência Celular/genética , RNA Helicases DEAD-box/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Metformina/farmacologia , MicroRNAs/genética , Ribonuclease III/genética , Adulto , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Restrição Calórica , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Senescência Celular/efeitos dos fármacos , RNA Helicases DEAD-box/metabolismo , Demografia , Feminino , Ribonucleoproteína Nuclear Heterogênea D0 , Ribonucleoproteínas Nucleares Heterogêneas Grupo D/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonuclease III/metabolismo
18.
Diabetologia ; 59(4): 755-65, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26813254

RESUMO

AIMS/HYPOTHESIS: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. METHODS: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. RESULTS: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. CONCLUSIONS/INTERPRETATION: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Homeodomínio/metabolismo , Células Secretoras de Insulina/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Animais , Apoptose/fisiologia , Proliferação de Células/fisiologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Mutantes
19.
NPJ Aging Mech Dis ; 2: 16006, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28721264

RESUMO

Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan.

20.
Sci Rep ; 5: 15672, 2015 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-26503027

RESUMO

PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects ß-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes ß-cell dedifferentiation and hyperglycemia, mimicking ß-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable ß-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched ß-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4(+) progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP(+) subpopulation expanded during pregnancy, a state of active ß-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP(+) cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP(+) cells were more resistant to apoptosis than their GFP(-) counterparts. Our data suggest PAX4 defines an expandable ß-cell sub population within adult islets.


Assuntos
Apoptose/fisiologia , Regulação da Expressão Gênica/fisiologia , Proteínas de Homeodomínio/metabolismo , Células Secretoras de Insulina/citologia , Fatores de Transcrição Box Pareados/metabolismo , Animais , Desdiferenciação Celular/fisiologia , Linhagem da Célula , Proliferação de Células/fisiologia , Diabetes Mellitus/patologia , Proteínas de Fluorescência Verde/genética , Proteínas de Homeodomínio/genética , Hiperglicemia/patologia , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/classificação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Transcrição Box Pareados/genética , Regiões Promotoras Genéticas/genética
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