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1.
Nat Commun ; 11(1): 3822, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732898

RESUMO

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.


Assuntos
Histona Desacetilases/genética , Homeostase/genética , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Apoptose/genética , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Histona Desacetilases/deficiência , Histona Desacetilases/metabolismo , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Macrófagos Alveolares/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
2.
Nat Commun ; 11(1): 4071, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792491

RESUMO

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


Assuntos
Glutationa Transferase/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Caspase 8/genética , Caspase 8/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glutationa Transferase/genética , Homeostase/genética , Homeostase/fisiologia , Imuno-Histoquímica , Masculino , Microglia/citologia , Microglia/metabolismo , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Fagocitose/genética , Fagocitose/fisiologia , Processamento de Proteína Pós-Traducional , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Remielinização/genética , Remielinização/fisiologia
3.
PLoS One ; 15(8): e0237400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780768

RESUMO

Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c ≥ 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log2FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.


Assuntos
Análise Química do Sangue , Perfilação da Expressão Gênica , Metformina/farmacologia , Idoso , Colesterol/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Masculino , Pessoa de Meia-Idade
4.
PLoS Genet ; 16(8): e1008989, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810129

RESUMO

Drosophila Myc (dMyc), as a broad-spectrum transcription factor, can regulate the expression of a large number of genes to control diverse cellular processes, such as cell cycle progression, cell growth, proliferation and apoptosis. However, it remains largely unknown about whether dMyc can be involved in Drosophila innate immune response. Here, we have identified dMyc to be a negative regulator of Drosophila Imd pathway via the loss- and gain-of-function screening. We demonstrate that dMyc inhibits Drosophila Imd immune response via directly activating miR-277 transcription, which further inhibit the expression of imd and Tab2-Ra/b. Importantly, dMyc can improve the survival of flies upon infection, suggesting inhibiting Drosophila Imd pathway by dMyc is vital to restore immune homeostasis that is essential for survival. Taken together, our study not only reports a new dMyc-miR-277-imd/Tab2 axis involved in the negative regulation of Drosophila Imd pathway, and provides a new insight into the complex regulatory mechanism of Drosophila innate immune homeostasis maintenance.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Imunidade Inata/genética , MicroRNAs/genética , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Divisão Celular/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/genética , Humanos , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , Transcrição Genética/genética
5.
Med Sci (Paris) ; 36(6-7): 616-625, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32614313

RESUMO

Iron has a fundamental role for cell physiology and especially in retina as a cofactor of many pathways of the visual transduction. A tightly regulated homeostasis avoids the accumulation of prooxidant and proinflammatory free iron. A dysfunction of iron retinal homeostasis is associated with many genetic or age-related degenerative diseases such as age-related macular degeneration (AMD). Here, we describe various mechanisms reported during AMD, enhanced by iron accumulation and its homeostasis dysregulation. We have investigated a local treatment with transferrin, the natural iron carrier, to control these pathological pathways and iron dysfunction, without side effects. Iron has a central role in pathogenesis of AMD and is a target for futures therapies.


Assuntos
Ferro/fisiologia , Degeneração Macular/etiologia , Homeostase/genética , Humanos , Ferro/metabolismo , Degeneração Macular/genética , Degeneração Macular/metabolismo , Degeneração Macular/terapia , Redes e Vias Metabólicas/genética , Retina/metabolismo , Retina/patologia , Terapias em Estudo/métodos , Terapias em Estudo/tendências , Transferrina/genética , Transferrina/fisiologia
6.
Life Sci ; 256: 118007, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32598934

RESUMO

AIMS: In hepatocytes, the retinoic acid receptor-related orphan receptor α (RORα) regulates the transcription of diverse genes encoding lipogenic enzymes, antioxidant enzymes, and mitochondrial factors via the regulation of the transcriptional activity of their promoters. The coordination of the expression of RORα by driving its transcription would provide better aspects for managing liver homeostasis. MAIN METHODS: The transcriptional expression of RORα was measured after treatment of RORα agonists on primary hepatocytes and liver. The histone status of Rora gene bodies was examined by analyzing ChIP-seq database. To elucidate molecular mechanism for RORα autoregulation, broad ChIP assays for promoters and enhancers with histone and RORα antibodies were performed. KEY FINDINGS: We report that natural and synthetic RORα agonists, cholesterol sulfate and JC1-40, respectively, increased the transcriptional expression of RORα in primary hepatocytes. An analysis of histone status around the Rora gene body identified promoter and enhancer regions of RORα. We found that RORα indirectly increased histone acetylation of H3K9 at the promoter region and directly enhanced histone monomethylation of H3K4 by binding to enhancer regions. Interestingly, disturbance of mixed-lineage leukemia 4 (MLL4), a histone methyltransferase for enhancers, abolished the JC1-40-induced activation of RORα via a decrease in H3K4me1. Finally, we observed that the MLL4-mediated autoregulation of RORα also occurred in human liver cancer cell lines. SIGNIFICANCE: The ability of RORα to modulate its own transcription is crucial for liver homeostasis, and ligand-dependent autoregulation could amplify the therapeutic effects of RORα in fatty liver diseases.


Assuntos
Hepatócitos/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Fígado/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Animais , Linhagem Celular Tumoral , Histonas/metabolismo , Homeostase/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Regiões Promotoras Genéticas , Transcrição Genética
7.
Nucleic Acids Res ; 48(12): 6889-6905, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32479602

RESUMO

Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterized, as most disease models have been based on overexpressing mutant FUS, which will alter RNA processing due to FUS autoregulation. We and others have recently created knockin models that overcome the overexpression problem, and have generated high depth RNA-sequencing on FUS mutants in parallel to FUS knockout, allowing us to compare mutation-induced changes to genuine loss of function. We find that FUS-ALS mutations induce a widespread loss of function on expression and splicing. Specifically, we find that mutant FUS directly alters intron retention levels in RNA-binding proteins. Moreover, we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS levels have been linked to disease, and we show here that this novel autoregulation mechanism is altered by FUS mutations. Crucially, we also observe this phenomenon in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.


Assuntos
Esclerose Amiotrófica Lateral/genética , Homeostase/genética , Proteína FUS de Ligação a RNA/genética , Animais , Citoplasma/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Íntrons/genética , Mutação com Perda de Função , Camundongos , Camundongos Knockout , Mutação/genética , Processamento de RNA/genética , Superóxido Dismutase-1/genética , Proteína com Valosina/genética
8.
Nat Commun ; 11(1): 2995, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532984

RESUMO

Adipocyte dysfunction links obesity to insulin resistance and type 2 diabetes. Adipocyte function is regulated by receptor-mediated activation of heterotrimeric G proteins. Little is known about the potential in vivo metabolic roles of Gi-type G proteins expressed by adipocytes, primarily due to the lack of suitable animal models. To address this question, we generated mice lacking functional Gi proteins selectively in adipocytes. Here we report that these mutant mice displayed significantly impaired glucose tolerance and reduced insulin sensitivity when maintained on an obesogenic diet. In contrast, using a chemogenetic strategy, we demonstrated that activation of Gi signaling selectively in adipocytes greatly improved glucose homeostasis and insulin signaling. We also elucidated the cellular mechanisms underlying the observed metabolic phenotypes. Our data support the concept that adipocyte Gi signaling is essential for maintaining euglycemia. Drug-mediated activation of adipocyte Gi signaling may prove beneficial for restoring proper glucose homeostasis in type 2 diabetes.


Assuntos
Adipócitos/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Resistência à Insulina/genética , Transdução de Sinais/genética , Adipócitos/citologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Perfilação da Expressão Gênica/métodos , Intolerância à Glucose/genética , Homeostase/genética , Insulina/sangue , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Obesidade/sangue , Obesidade/genética , Obesidade/metabolismo
9.
RNA ; 26(9): 1160-1169, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32414857

RESUMO

DEAD-box proteins (DBPs) are RNA remodeling factors associated with RNA helicase activity that are found in nearly all organisms. Despite extensive studies on the mechanisms used by DBPs to regulate RNA function, very little is known about how DBPs themselves are regulated. In this work, we have analyzed the expression and regulation of DeaD/CsdA, the largest of the DBPs in Escherichia coli (E. coli). We show that deaD transcription initiates 838 nt upstream of the start of the coding region. We have also found that DeaD is autoregulated through a negative feedback mechanism that operates both at the level of deaD mRNA stability and Rho-dependent transcription termination, and this regulation is dependent upon its mRNA 5' untranslated region (5' UTR). These findings suggest that DeaD might be regulating the conformation of its own mRNA through its RNA helicase activity to facilitate ribonuclease and Rho access to its 5' UTR.


Assuntos
RNA Helicases DEAD-box/genética , Escherichia coli/genética , Homeostase/genética , Estabilidade de RNA/genética , RNA Mensageiro/genética , Transcrição Genética/genética , Regiões 5' não Traduzidas/genética , Proteínas de Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica/genética , RNA Bacteriano/genética
10.
DNA Cell Biol ; 39(6): 926-937, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32352840

RESUMO

Increasing evidence has announced the emerging roles of long noncoding RNAs (lncRNAs) in modulating bone homeostasis due to their potential regulating effects on bone-related cells' proliferation, migration, differentiation and apoptosis. Thus, lncRNAs have been considered as a promising gene tool to facilitate the bone regeneration process and then to predict and cure bone-related diseases such as osteosarcoma, osteoporosis, and osteoarthritis. In this review, we first enumerated several kinds of dysregulated lncRNAs and concisely summarized their regulating role in bone formation as well as resorption process. The related mechanisms were also discussed, respectively. Then, the positive or negative behavior of these lncRNAs in bone-related diseases was elucidated. This review provides an in-depth sight about the lncRNA's clinical values and limitations, which is conducive to explore new gene targets and further establish new therapeutic strategies for bone-related disease.


Assuntos
Doenças Ósseas/genética , Osso e Ossos/metabolismo , Homeostase/genética , RNA Longo não Codificante/genética , Animais , Humanos
11.
PLoS One ; 15(5): e0227786, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32433703

RESUMO

Homeostasis is an essential concept to understand the stability of organisms and their adaptive behaviors when coping with external and internal assaults. Many hormones that take part in homeostatic control come in antagonistic pairs, such as glucagon and insulin reflecting the inflow and outflow compensatory mechanisms to control a certain internal variable, such as blood sugar levels. By including negative feedback loops homeostatic controllers can exhibit oscillations with characteristic frequencies. In this paper we demonstrate the associated frequency changes in homeostatic systems when individual controllers -in a set of interlocked feedback loops- gain control in response to environmental changes. Taking p53 as an example, we show how Per2, ATM and Mdm2 feedback loops -interlocked with p53- gain individual control in dependence to the level of DNA damage, and how each of these controllers provide certain functionalities in their regulation of p53. In unstressed cells, the circadian regulator Per2 ensures a basic p53 level to allow its rapid up-regulation in case of DNA damage. When DNA damage occurs the ATM controller increases the level of p53 and defends it towards uncontrolled degradation, which despite DNA damage, would drive p53 to lower values and p53 dysfunction. Mdm2 on its side keeps p53 at a high but sub-apoptotic level to avoid premature apoptosis. However, with on-going DNA damage the Mdm2 set-point is increased by HSP90 and other p53 stabilizers leading finally to apoptosis. An emergent aspect of p53 upregulation during cell stress is the coordinated inhibition of ubiquitin-independent and ubiquitin-dependent degradation reactions. Whether oscillations serve a function or are merely a by-product of the controllers are discussed in view of the finding that homeostatic control of p53, as indicated above, does in principle not require oscillatory homeostats.


Assuntos
Retroalimentação Fisiológica , Homeostase/genética , Modelos Teóricos , Proteína Supressora de Tumor p53/genética , Apoptose/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Ritmo Circadiano/genética , Dano ao DNA/genética , Regulação da Expressão Gênica/genética , Humanos , Proteínas Circadianas Period/genética , Fosforilação/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Ubiquitina/genética
14.
Biochim Biophys Acta Mol Cell Res ; 1867(8): 118722, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32302667

RESUMO

Dermal fibroblasts seem critical for epidermal maturation and differentiation and recent work demonstrated that diseased fibroblasts may drive pathophysiological processes. Nevertheless, still very little is known about the actual crosstalk between epidermal keratinocytes and dermal fibroblasts and the impact of dermal fibroblasts on epidermal maturation and differentiation. Aiming for a more fundamental understanding of the impact of the cellular crosstalk between keratinocytes and fibroblasts on the skin homeostasis, we generated full-thickness skin equivalents with and without fibroblasts and subsequently analysed them for the expression of skin differentiation markers, their barrier function, skin lipid content and epidermal cell signalling. Skin equivalents without fibroblasts consistently showed an impaired differentiation and dysregulated expression of skin barrier and tight junction proteins, increased skin permeability, and a decreased skin lipid/protein ratio. Most interestingly, impaired Ras/Raf/ERK/MEK signalling was evident in skin equivalents without fibroblasts. Our data clearly indicate that the epidermal-dermal crosstalk between keratinocytes and fibroblasts is critical for adequate skin differentiation and that fibroblasts orchestrate epidermal differentiation processes.


Assuntos
Células Epidérmicas/metabolismo , Fibroblastos/metabolismo , Homeostase/fisiologia , Queratinócitos/metabolismo , Pele/metabolismo , Diferenciação Celular , Células Epidérmicas/patologia , Epiderme/metabolismo , Homeostase/genética , Humanos , Queratinócitos/patologia , Permeabilidade , Pele/patologia , Absorção Cutânea
15.
Nat Rev Rheumatol ; 16(5): 268-281, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32273577

RESUMO

Research into the molecular genetics of osteoarthritis (OA) has been substantially bolstered in the past few years by the implementation of powerful genome-wide scans that have revealed a large number of novel risk loci associated with the disease. This refreshing wave of discovery has occurred concurrently with epigenetic studies of joint tissues that have examined DNA methylation, histone modifications and regulatory RNAs. These epigenetic analyses have involved investigations of joint development, homeostasis and disease and have used both human samples and animal models. What has become apparent from a comparison of these two complementary approaches is that many OA genetic risk signals interact with, map to or correlate with epigenetic mediators. This discovery implies that epigenetic mechanisms, and their effect on gene expression, are a major conduit through which OA genetic risk polymorphisms exert their functional effects. This observation is particularly exciting as it provides mechanistic insight into OA susceptibility. Furthermore, this knowledge reveals avenues for attenuating the negative effect of risk-conferring alleles by exposing the epigenome as an exploitable target for therapeutic intervention in OA.


Assuntos
Epigenômica/métodos , Estudo de Associação Genômica Ampla/métodos , Articulações/metabolismo , Osteoartrite/genética , Alelos , Animais , Condrócitos/metabolismo , Metilação de DNA/genética , Expressão Gênica , Código das Histonas/genética , Homeostase/genética , Homeostase/fisiologia , Humanos , Articulações/crescimento & desenvolvimento , Camundongos , Modelos Animais , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Ribonucleico/genética , Fatores de Risco
16.
PLoS One ; 15(4): e0231072, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275684

RESUMO

A high prevalence of intermediate cardiometabolic risk factors and obesity in chronic obstructive pulmonary disease (COPD) has suggested the existence of pathophysiological links between hypertriglyceridemia, insulin resistance, visceral adiposity, and hypoxia or impaired pulmonary function. However, whether COPD contributes independently to the development of these cardiometabolic risk factors remains unclear. Our objective was to compare ectopic fat and metabolic profiles among representative individuals with COPD and control subjects and to evaluate whether the presence of COPD alters the metabolic risk profile. Study participants were randomly selected from the general population and prospectively classified as non-COPD controls and COPD, according to the Global Initiative for Chronic Obstructive Lung Disease classification. The metabolic phenotype, which consisted of visceral adipose tissue area, metabolic markers including homeostasis model assessment of insulin resistance (HOMA-IR), and blood lipid profile, was obtained in 144 subjects with COPD and 119 non-COPD controls. The metabolic phenotype was similar in COPD and controls. The odds ratios for having pathologic values for HOMA-IR, lipids and visceral adipose tissue area were similar in individuals with COPD and control subjects in multivariate analyses that took into account age, sex, body mass index, tobacco status and current medications. In a population-based cohort, no difference was found in the metabolic phenotype, including visceral adipose tissue accumulation, between COPD and controls. Discrepancies between the present and previous studies as to whether or not COPD is a risk factor for metabolic abnormalities could be related to differences in COPD phenotype or disease severity of the study populations.


Assuntos
Hipertrigliceridemia/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Índice de Massa Corporal , Colesterol/sangue , Feminino , Homeostase/genética , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/patologia , Insulina/metabolismo , Resistência à Insulina/genética , Gordura Intra-Abdominal/patologia , Lipídeos/sangue , Pulmão/metabolismo , Pulmão/patologia , Masculino , Metaboloma/genética , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/patologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Risco
17.
BMC Med Genet ; 21(1): 75, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32268883

RESUMO

BACKGROUND: ß Thalassemia is one of the most common groups of hereditary haemoglobinopathies. Affected people with thalassemia major are dependent on regular blood transfusion which on the long term leads to iron overload. Hepcidin is a peptide hormone and an important regulator of iron homeostasis, especially in thalassemia. Expression of this hormone is influenced by polymorphisms within the hepcidin gene, HAMP. Several studies emphasized the role of single nucleotide polymorphisms (SNPs) located in the promoter region of the gene. This study aimed to analyze the association between three SNPs in promoter of HAMP, c.-582A > G, c.-443C > T, and c.-153C > T, with iron overload in ß-thalassemia major patients. METHODS: A total of 102 samples from ß thalassemia major patients were collected. Genomic DNA was extracted and segments of DNA encompassing rs10421768 and rs142126068 were sequenced. Statistical analysis was performed by SPSS Statistics 23 using independent t test and Fisher's exact test. RESULTS: A total of 102 adult ß-thalassemia major patients were genotyped for three SNPs in the promoter region of HAMP gene by PCR and direct sequencing. Most of the patients (71.3%) were iron overloaded (based on plasma ferritin > 1000 ng/ml) in spite of receiving regular iron-chelating therapy. Our analysis revealed a statistically significant difference between the level of cardiac iron accumulation and c.-582A > G variant (p = 0.02). For c.-443C > T statistical analysis was on the edge of the significant relationship between the minor allele and serum ferritin (p = 0.058). All samples were homozygous for allele C of c.-153C > T. CONCLUSIONS: Despite chelating therapy, iron overload is still one of the main complications of thalassemia. Our findings and others emphasize the role of hepcidin -582A > G polymorphism as a key component of iron homeostasis in these patients.


Assuntos
Hepcidinas/genética , Quelantes de Ferro/uso terapêutico , Polimorfismo de Nucleotídeo Único , Talassemia beta/tratamento farmacológico , Talassemia beta/genética , Adulto , Estudos de Coortes , Feminino , Homeostase/genética , Humanos , Irã (Geográfico) , Ferro/metabolismo , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/genética , Masculino , Regiões Promotoras Genéticas/genética , Falha de Tratamento , Talassemia beta/sangue
18.
Artigo em Inglês | MEDLINE | ID: mdl-32208989

RESUMO

Tryptophan catabolism through the kynurenine pathway generates a variety of bioactive metabolites. Physical exercise can modulate kynurenine pathway metabolism in skeletal muscle and thus change the concentrations of select compounds in peripheral tissues and in the central nervous system. Here we review recent advances in our understanding of how exercise alters tryptophan-kynurenine metabolism in muscle and its subsequent local and distal effects. We propose that the effects of kynurenine pathway metabolites on skeletal muscle, adipose tissue, immune system, and the brain suggest that some of these compounds could qualify as exercise-induced myokines. Indeed, some of the more recently discovered biological activities for kynurenines include many of the best-known benefits of exercise: improved energy homeostasis, promotion of an anti-inflammatory environment, and neuroprotection. Finally, by considering the tissue expression of the different membrane and cytosolic receptors for kynurenines, we discuss known and potential biological activities for these tryptophan metabolites.


Assuntos
Sistema Nervoso Central/metabolismo , Cinurenina/metabolismo , Redes e Vias Metabólicas/fisiologia , Músculo Esquelético/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Sistema Nervoso Central/fisiologia , Exercício Físico/fisiologia , Homeostase/genética , Homeostase/fisiologia , Humanos , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiologia , Cinurenina/genética , Metabolismo/fisiologia , Músculo Esquelético/fisiologia , PPAR gama/genética , Triptofano/metabolismo
19.
Neuron ; 106(5): 769-777.e4, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32199104

RESUMO

Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.


Assuntos
Homeostase/genética , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Neurônios/efeitos dos fármacos , Córtex Visual/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Autístico/genética , Comportamento Animal/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Técnicas de Silenciamento de Genes , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Asseio Animal/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Compostos de Lítio/farmacologia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/efeitos dos fármacos , Vias Neurais , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Córtex Visual/citologia , Córtex Visual/metabolismo
20.
Nat Commun ; 11(1): 1472, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193376

RESUMO

The Hippo TEAD-transcriptional regulators YAP1 and TAZ are central for cell renewal and cancer growth; however, the specific downstream gene networks involved in their activity are not completely understood. Here we introduce TEADi, a genetically encoded inhibitor of the interaction of YAP1 and TAZ with TEAD, as a tool to characterize the transcriptional networks and biological effects regulated by TEAD transcription factors. Blockage of TEAD activity by TEADi in human keratinocytes and mouse skin leads to reduced proliferation and rapid activation of differentiation programs. Analysis of gene networks affected by TEADi and YAP1/TAZ knockdown identifies KLF4 as a central transcriptional node regulated by YAP1/TAZ-TEAD in keratinocyte differentiation. Moreover, we show that TEAD and KLF4 can regulate the activity of each other, indicating that these factors are part of a transcriptional regulatory loop. Our study establishes TEADi as a resource for studying YAP1/TAZ-TEAD dependent effects.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Redes Reguladoras de Genes , Homeostase , Fatores de Transcrição Kruppel-Like/metabolismo , Pele/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Células HEK293 , Homeostase/genética , Humanos , Inflamação/patologia , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Modelos Animais , Modelos Biológicos , Ligação Proteica , Células-Tronco/citologia , Células-Tronco/metabolismo , Transcrição Genética
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