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1.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203560

RESUMO

A number of plants used in folk medicine in Thailand and Eastern Asia are attracting interest due to the high bioactivities of their extracts. The aim of this study was to screen the edible leaf extracts of 20 plants found in Thailand and investigate the potential neuroprotective effects of the most bioactive sample. The total phenol and flavonoid content and 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity were determined for all 20 leaf extracts. Based on these assays, Glochidion littorale leaf extract (GLE), which showed a high value in all tested parameters, was used in further experiments to evaluate its effects on neurodegeneration in Caenorhabditis elegans. GLE treatment ameliorated H2O2-induced oxidative stress by attenuating the accumulation of reactive oxygen species and protected the worms against 1-methyl-4-phenylpyridinium-induced neurodegeneration. The neuroprotective effects observed may be associated with the activation of the transcription factor DAF-16. The characterization of this extract by LC-MS identified several phenolic compounds, including myricetin, coumestrin, chlorogenic acid, and hesperidin, which may play a key role in neuroprotection. This study reports the novel neuroprotective activity of GLE, which may be used to develop treatments for neurodegenerative diseases such as Parkinson's syndrome.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fármacos Neuroprotetores , Estresse Oxidativo/efeitos dos fármacos , Phyllanthus/química , Extratos Vegetais , Animais , Peróxido de Hidrogênio/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia
2.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299063

RESUMO

Regulatory T cells (Tregs) suppress immune responses and maintain immunological self-tolerance and homeostasis. We currently investigated relationships between skin barrier condition and Treg behavior using skin barrier-disrupted mice. Skin barrier disruption was induced by repeated topical application of 4% sodium dodecyl sulfate (SDS) on mice. The number of CD4+ forkhead box protein P3 (Foxp3)+ Tregs was higher in 4% SDS-treated skins than in controls. This increasing was correlated with the degree of acanthosis. The numbers of interleukin (IL)-10+ and transforming growth factor (TGF)-ß+ Tregs also increased in 4% SDS-treated skins. Localization of IL-33 in keratinocytes shifted from nucleus to cytoplasm after skin barrier disruption. Notably, IL-33 promoted the migration of Tregs in chemotaxis assay. The skin infiltration of Tregs was cancelled in IL-33 neutralizing antibody-treated mice and IL-33 knockout mice. Thus, keratinocyte-derived IL-33 may induce Treg migration into barrier-disrupted skin to control the phase transition between healthy and inflammatory conditions.


Assuntos
Movimento Celular , Quimiotaxia , Dermatite/patologia , Interleucina-33/fisiologia , Pele/patologia , Linfócitos T Reguladores/imunologia , Animais , Dermatite/imunologia , Dermatite/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pele/metabolismo
3.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299148

RESUMO

During influenza A virus (IAV) infections, CD4+ T cell responses within infected lungs mainly involve T helper 1 (Th1) and regulatory T cells (Tregs). Th1-mediated responses favor the co-expression of T-box transcription factor 21 (T-bet) in Foxp3+ Tregs, enabling the efficient Treg control of Th1 responses in infected tissues. So far, the exact accumulation kinetics of T cell subsets in the lungs and lung-draining lymph nodes (dLN) of IAV-infected mice is incompletely understood, and the epigenetic signature of Tregs accumulating in infected lungs has not been investigated. Here, we report that the total T cell and the two-step Treg accumulation in IAV-infected lungs is transient, whereas the change in the ratio of CD4+ to CD8+ T cells is more durable. Within lungs, the frequency of Tregs co-expressing T-bet is steadily, yet transiently, increasing with a peak at Day 7 post-infection. Interestingly, T-bet+ Tregs accumulating in IAV-infected lungs displayed a strongly demethylated Tbx21 locus, similarly as in T-bet+ conventional T cells, and a fully demethylated Treg-specific demethylated region (TSDR) within the Foxp3 locus. In summary, our data suggest that T-bet+ but not T-bet- Tregs are epigenetically stabilized during IAV-induced infection in the lung.


Assuntos
Linfócitos T CD8-Positivos/virologia , Epigênese Genética , Fatores de Transcrição Forkhead/metabolismo , Pulmão/virologia , Infecções por Orthomyxoviridae/virologia , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Fatores de Transcrição Forkhead/genética , Vírus da Influenza A/fisiologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/patologia , Proteínas com Domínio T/genética
4.
Nat Commun ; 12(1): 4354, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272374

RESUMO

Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. Here we examine the functional and structural consequences of SARS-CoV-2 infection in a reconstructed human bronchial epithelium model. SARS-CoV-2 replication causes a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remains limited. Rather, SARS-CoV-2 replication leads to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. Downregulation of the master regulator of ciliogenesis Foxj1 occurs prior to extensive cilia loss, implicating this transcription factor in the dedifferentiation of ciliated cells. Motile cilia function is compromised by SARS-CoV-2 infection, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramp up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrates the loss of motile cilia in vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma.


Assuntos
COVID-19/patologia , Cílios/ultraestrutura , Depuração Mucociliar/fisiologia , SARS-CoV-2 , Animais , Axonema , Corpos Basais , Cílios/metabolismo , Cílios/patologia , Cricetinae , Citocinas , Células Epiteliais/patologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Pulmão/patologia , Masculino , Mesocricetus , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Replicação Viral
5.
Nat Commun ; 12(1): 3913, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162888

RESUMO

Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve, activated, and effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic and functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional and migratory impairments under aGVHD. These findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease.


Assuntos
Diferenciação Celular/genética , Fatores de Transcrição Forkhead/imunologia , Transdução de Sinais/genética , Análise de Célula Única/métodos , Linfócitos T Reguladores/imunologia , Transcriptoma/genética , Western Blotting , Ensaio de Imunoadsorção Enzimática , Fatores de Transcrição Forkhead/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , RNA-Seq/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
6.
Open Biol ; 11(6): 210069, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34102081

RESUMO

The COVID-19 pandemic has wreaked unprecedented societal havoc worldwide. The infected individuals may present mild to severe symptoms, with nearly 20% of the confirmed patients impaired with significant complications, including multi-organ failure. Acute respiratory distress imposed by SARS-CoV-2 largely results from an aggravated cytokine storm and deregulated immune response. The forkhead box O (FoxO) transcription factors are reported to play a significant role in maintaining normal cell physiology by regulating survival, apoptosis, oxidative stress, development and maturation of T and B lymphocytes, secretion of inflammatory cytokines, etc. We propose a potent anti-inflammatory approach based on activation of the FoxO as an attractive strategy against the novel coronavirus. This regime will be focused on restoring redox and inflammatory homeostasis along with repair of the damaged tissue, activation of lymphocyte effector and memory cells. Repurposing FoxO activators as a means to alleviate the inflammatory burst following SARS-CoV-2 infection can prove immensely valuable in the ongoing pandemic and provide a reliable groundwork for enriching our repertoire of antiviral modalities for any such complication in the future. Altogether, our review highlights the possible efficacy of FoxO activation as a novel arsenal for clinical management of COVID-19.


Assuntos
COVID-19/metabolismo , COVID-19/virologia , Fatores de Transcrição Forkhead/metabolismo , Interações Hospedeiro-Patógeno , SARS-CoV-2/fisiologia , Biomarcadores , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Citocinas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Descoberta de Drogas , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Oxirredução , Transdução de Sinais
7.
Nat Immunol ; 22(6): 735-745, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34017124

RESUMO

Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+ T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+ Treg and eomesodermin homolog (EOMES)+ type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not Treg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1-targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Hematopoiese Clonal/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Proliferação de Células/genética , Quimioterapia Adjuvante/métodos , Quitinases/metabolismo , Colectomia , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Conjuntos de Dados como Assunto , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Granzimas/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA-Seq , Análise de Célula Única , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/metabolismo
8.
Rinsho Ketsueki ; 62(4): 299-304, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33967155

RESUMO

Regulatory T cells (Tregs) are a subset of CD4+ T lymphocytes that suppress the functions of antigen-presenting cells and effector T cells, characterized by the expression of transcription factor forkhead box P3 (FOXP3). Recent studies have reported an increase in the number of Tregs in the bone marrow (BM) of multiple myeloma (MM) patients. However, the role and mechanisms of Treg accumulation in the BM of MM patients remain debatable. Here, we present our data demonstrating the significance of Tregs in the context of MM disease progression. Using the transplantable MM mouse model, we observed a significant increase in Tregs in the BM of MM-injected mice from the early disease stage. We observed extended survival in MM-injected mice with Treg depletion than in mice without Treg depletion, demonstrating direct in vivo evidence that Tregs enhance disease progression in MM. It is noteworthy that type 1 interferon (IFN) signaling is activated in MM-associated Tregs. By using type 1 IFN receptor blocking antibody treatment and type 1 IFN receptor knockout Tregs, we demonstrated a significant decrease in MM-associated Treg proliferation, which was associated with longer survival in MM-injected mice. Thus, we have demonstrated that Tregs play a significant role in MM progression; the function and homeostasis of Tregs are regulated by type 1 IFN secreted in the BM microenvironment.


Assuntos
Mieloma Múltiplo , Linfócitos T Reguladores , Animais , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Humanos , Camundongos , Transdução de Sinais , Microambiente Tumoral
9.
Nat Commun ; 12(1): 2617, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976169

RESUMO

Disruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impairs vocal development in humans and songbirds. The basal ganglia are important for the selection and sequencing of motor actions, but the circuit mechanisms governing accurate sequencing of learned vocalizations are unknown. Here, we show that expression of FoxP2 in the basal ganglia is vital for the fluent initiation and termination of birdsong, as well as the maintenance of song syllable sequencing in adulthood. Knockdown of FoxP2 imbalances dopamine receptor expression across striatal direct-like and indirect-like pathways, suggesting a role of dopaminergic signaling in regulating vocal motor sequencing. Confirming this prediction, we show that phasic dopamine activation, and not inhibition, during singing drives repetition of song syllables, thus also impairing fluent initiation and termination of birdsong. These findings demonstrate discrete circuit origins for the dysfluent repetition of vocal elements in songbirds, with implications for speech disorders.


Assuntos
Corpo Estriado/metabolismo , Tentilhões/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/fisiologia , Vocalização Animal/fisiologia , Adulto , Animais , Animais Geneticamente Modificados , Dopamina/metabolismo , Técnicas de Silenciamento de Genes , Centro Vocal Superior , Humanos , Masculino , Modelos Animais , Vias Neurais/fisiologia , Optogenética , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Fala/fisiologia , Técnicas Estereotáxicas
10.
Fish Shellfish Immunol ; 114: 82-89, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33878427

RESUMO

Oxidative stress is considered as the toxicity mechanism of environmental stressors on aquatic organisms. This study aims to explore the effects of oxidative stress on physiological responses, DNA damage and transcriptional profiles of the mud crabs Scylla paramamosain. In the present study, mud crabs were injected with 0.1% and 1% hydrogen peroxide (H2O2) for 72 h. The results showed that superoxide dismutase and catalase activities significantly decreased after H2O2 injection. Malondialdehyde content, H2O2 content, aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase activity significantly increased after H2O2 injection. Moreover, DNA damage occurred after H2O2 injection. Transcriptome analysis showed that 531 and 372 differentially expressed genes (DEGs) were identified after 0.1% and 1% H2O2 injection, respectively. These DEGs were mainly involved in the oxidative stress response and immune functions. All these results indicated that oxidative stress could impair both antioxidant defense systems and immune systems. Transcriptome analysis provided valuable information on gene functions associated with the response to oxidative stress in the mud crab.


Assuntos
Braquiúros , Dano ao DNA/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Transcriptoma
11.
Int J Mol Sci ; 22(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800594

RESUMO

Activation of trimethylation of histone 3 lysine 27 (H3K27me3) by EZH2, a component of the Polycomb repressive complex 2 (PRC2), is suggested to play a role in endometriosis. However, the mechanism by which this complex is dysregulated in endometriosis is not completely understood. Here, using eutopic and ectopic tissues, as well as peritoneal fluid (PF) from IRB-approved and consented patients with and without endometriosis, the expression of PRC2 complex components, JARID2, miR-155 (known regulators of EZH2), and a key inflammatory modulator, FOXP3, was measured. A higher expression of EZH2, H3K27me3, JARID2, and FOXP3 as well as miR-155 was noted in both the patient tissues and in endometrial PF treated cells. Gain-or-loss of function of miR-155 showed an effect on the PRC2 complex but had little effect on JARID2 expression, suggesting alternate pathways. Chromatin immunoprecipitation followed by qPCR showed differential expression of PRC2 complex proteins and its associated binding partners in JARID2 vs. EZH2 pull down assays. In particular, endometriotic PF treatment increased the expression of PHF19 (p = 0.0474), a gene silencer and co-factor that promotes PRC2 interaction with its targets. Thus, these studies have identified the potential novel crosstalk between miR-155-PRC2 complex-JARID2 and PHF19 in endometriosis, providing an opportunity to test other epigenetic targets in endometriosis.


Assuntos
Líquido Ascítico/metabolismo , Endometriose/metabolismo , Endométrio/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Adolescente , Adulto , Metilação de DNA , Feminino , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Humanos , Metilação , Pessoa de Meia-Idade , Peritônio/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , Adulto Jovem
12.
Biochem Biophys Res Commun ; 556: 106-113, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33839405

RESUMO

Among all lung cancer cases, lung adenocarcinoma (LAC) represents nearly 40% and remains the leading cause of cancer deaths worldwide. Although the combination therapy of surgical treatment with radiotherapy, chemotherapy, and immunotherapy, has been used to treat LAC, unfortunately, high recurrence rates and poor survival remain. Therefore, novel prognostic markers and new targets for molecular targeted therapy in LAC is urgently needed. Fork-head box R2 (FOXR2) plays a key role in a wide range of cellular processes, including cellular proliferation, invasion, differentiation, and apoptosis, and it has been reported to be implicated in progression of LAC, thus inhibition of FOXR2 may be a novel targeting therapy for lung cancer. This current study found that E3 ligase PJA1 regulates ubiquitin-mediated degradation of FOXR2 and predicts good outcome of patients with LAC. In addition, it was showed force expression of PJA1 significantly inhibited LAC cells invasion and induced apoptosis in vitro through inactivating Wnt/ß-catenin signaling pathway. In short, our findings reveal that PJA1 could be a potential diagnostic and prognostic biomarkers and the PJA1- FOXR2 axis could be served as a promising target for LAC therapy.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Apoptose , Fatores de Transcrição Forkhead/metabolismo , Invasividade Neoplásica , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/genética , Animais , Apoptose/genética , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/química , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Invasividade Neoplásica/genética , Prognóstico , Ubiquitina-Proteína Ligases/biossíntese , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Via de Sinalização Wnt , beta Catenina/metabolismo
13.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804729

RESUMO

Obesity or overweight are not superficial problems, constituting a pressing issue. The obesity index has almost tripled since 1975, which is an alarming state. Most of the individuals are currently becoming overweight or have inappropriate body mass index (BMI) conditions. Obesity is characterized by increased fat accumulation and thus poses a higher health risk. There is increased size and volume of fat cells in the body, which usually accounts for obesity. Many investigations have been carried out in this area, such as behavioral improvements, dietary changes, chemical involvements, etc., but presently no such goals are established to manage these health concerns. Based on previous literature reports and our interpretation, the current review indicates the involvement of various transcriptional and transporter functions in modifying the above-mentioned health conditions. Various transcriptional factors such as Forkhead box O1 (FoxO1) impart a significant effect on the physiology and pathology of metabolic dysfunction such as obesity. FoxO1 plays a dual role whether in the progression or suppression of metabolic processes depending on its targets. Thus, in the current study, will be discussed the dual role of FoxO1 in metabolic conditions (such as obesity), also summarizing the role of various other transcriptional factors involved in obesity.


Assuntos
Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Predisposição Genética para Doença , Obesidade/etiologia , Obesidade/metabolismo , Adipogenia , Animais , Metabolismo Energético , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Insulina/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Obesidade/patologia , Especificidade de Órgãos , Estresse Oxidativo/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
14.
Nat Commun ; 12(1): 2277, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859189

RESUMO

Determining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response. Here, we profile open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We reveal key cell type-specific transcription factors and major gene-regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrates that podocyte commitment occurs early and is associated with sustained Foxl1 expression. Renal tubule cells follow a more complex differentiation, where Hfn4a is associated with proximal and Tfap2b with distal fate. Mapping single nucleotide variants associated with human kidney disease implicates critical cell types, developmental stages, genes, and regulatory mechanisms. The single cell multi-omics atlas reveals key chromatin remodeling events and gene expression dynamics associated with kidney development.


Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Néfrons/crescimento & desenvolvimento , Organogênese/genética , Insuficiência Renal Crônica/genética , Animais , Comunicação Celular , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Epigenômica , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Camundongos , Néfrons/citologia , Podócitos/fisiologia , Polimorfismo de Nucleotídeo Único , RNA-Seq , Insuficiência Renal Crônica/patologia , Análise de Célula Única , Fator de Transcrição AP-2/genética , Fator de Transcrição AP-2/metabolismo
15.
Nutrients ; 13(3)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802038

RESUMO

Many studies have highlighted the relationship between food and health status, with the aim of improving both disease prevention and life expectancy. Among the different food groups, fermented foods a have huge microbial biodiversity, making them an interesting source of metabolites that could exhibit health benefits. Our previous study highlighted the capacity of raw goat milk cheese, and some of the extracts recovered by the means of chemical fractionation, to increase the longevity of the nematode Caenorhabditis elegans. In this article, we pursued the investigation with a view toward understanding the biological mechanisms involved in this phenomenon. Using mutant nematode strains, we evaluated the implication of the insulin-like DAF-2/DAF-16 and the p38 MAPK pathways in the phenomenon of increased longevity and oxidative-stress resistance mechanisms. Our results demonstrated that freeze-dried raw goat milk cheese, and its extracts, induced the activation of the DAF-2/DAF-16 pathway, increasing longevity. Concerning oxidative-stress resistance, all the extracts increased the survival of the worms, but no evidence of the implication of both of the pathways was highlighted, except for the cheese-lipid extract that did seem to require both pathways to improve the survival rate. Simultaneously, the cheese-lipid extract and the dried extract W70, obtained with water, were able to reduce the reactive oxygen species (ROS) production in human leukocytes. This result is in good correlation with the results obtained with the nematode.


Assuntos
Caenorhabditis elegans/fisiologia , Queijo , Leucócitos/fisiologia , Estresse Oxidativo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Núcleo Celular/metabolismo , Sobrevivência Celular , Alimentos em Conserva , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Liofilização , Regulação da Expressão Gênica , Longevidade , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases , Leite , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Acetato de Tetradecanoilforbol/farmacologia
16.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918672

RESUMO

Huntington's disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (HTT). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although HTT is expressed ubiquitously, most of our knowledge has been obtained on neurons. More recently, the impact of mutant huntingtin (mHTT) on other cell types, including glial cells, has received growing interest. It is currently unclear whether new pathological pathways could be identified in these cells compared to neurons. To address this question, we performed an in vivo screen for modifiers of mutant huntingtin (HTT-548-128Q) induced pathology in Drosophila adult glial cells and identified several putative therapeutic targets. Among them, we discovered that partial nej/dCBP depletion in these cells was protective, as revealed by strongly increased lifespan and restored locomotor activity. Thus, dCBP promotes the HD pathology in glial cells, in contrast to previous opposite findings in neurons. Further investigations implicated the transcriptional activator Foxo as a critical downstream player in this glial protective pathway. Our data suggest that combinatorial approaches combined to specific tissue targeting may be required to uncover efficient therapies in HD.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/genética , Drosophila/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Neuroglia/metabolismo , Transdução de Sinais , Fatores de Transcrição de p300-CBP/metabolismo , Animais , Biomarcadores , Cálcio/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Metabolismo Energético , Testes Genéticos , Doença de Huntington/diagnóstico , Doença de Huntington/etiologia , Doença de Huntington/metabolismo , Neurônios/metabolismo
17.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924155

RESUMO

Ferulic acid (FA) is a naturally-occurring well-known potent antioxidant and free radical scavenger. FA supplementation is an effective strategy to delay aging, but the underlying mechanism remains unknown. In the present study, we examined the effects of FA on lifespan extension and its mechanism of FA in Caenorhabditis elegans (C. elegans). Results suggested that FA increased the lifespan of C. elegans, rather than altering the growth of E. coli OP50. Meanwhile, FA promoted the healthspan of C. elegans by improving locomotion and reducing fat accumulation and polyQ aggregation. FA increased the resistance to heat and oxidative stress through reducing ROS. The upregulating of the expression of the hlh-30, skn-1, and hsf-1 were involved in the FA-mediated lifespan extension. Furthermore, FA treatment had no impact on the lifespan of daf-2, hlh-30, skn-1, and hsf-1 mutants, confirming that insulin/IGF-1 signaling pathway and multiple longevity mechanisms were associated with the longevity mechanism of FA. We further found that mitochondrial signaling pathway was modulation involved in FA-mediated lifespan extension. With the results from RNA-seq results and mutants lifespan assay. These findings contribute to our knowledge of the lifespan extension and underlying mechanism of action of FA in C. elegans.


Assuntos
Ácidos Cumáricos/administração & dosagem , Suplementos Nutricionais , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismo , Longevidade , Transdução de Sinais , Estresse Fisiológico , Animais , Autofagia , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33649850

RESUMO

Colorectal cancer (CRC) is a lethal and common malignancy worldwide. Non­coding (nc)RNAs have been shown to modulate tumor progression in several types of cancer. The present study aimed to investigate the role of hsa_circ_0000212 in CRC, as a sponge of microRNA (miR)­491. The expression levels of miR­491 and forkhead box P4 (FOXP4) were analyzed using data from The Cancer Genome Atlas. The association between miR­491 and FOXP4 and the clinicopathological characteristics were also analyzed. A novel circular (circ)RNA, hsa_circ_0000212, was found to sponge miR­491 based on bioinformatics analysis. The potential binding site between miR­491 and FOXP4 or circ­0000212 was validated using luciferase and RNA immunoprecipitation assays. The expression levels and distribution of circ­0000212 was also determined. Cell Counting Kit­8 and colony formation assays were performed to determine the role of miR­491 or circ­0000212 on the proliferation of the CRC cells. Decreased miR­491 or increased FOXP4 expression levels were associated with the pathological stage in patients with CRC. In addition, miR­491 inhibited cell proliferation by targeting FOXP4. circ­0000212 was increased in CRC tissues and was predominantly localized in the cytoplasm. Furthermore, circ­0000212 augmented viability of the CRC cells by sponging miR­491 and modulating FOXP4. In conclusion, circ­0000212 may serve as a novel tumor­promoter and drug target in CRC.


Assuntos
Proliferação de Células/genética , Neoplasias Colorretais/genética , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Circular/genética , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade
19.
Nat Immunol ; 22(4): 471-484, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664518

RESUMO

The diversity of regulatory T (Treg) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt+ Treg cells with elevated expression of ß-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt+ Treg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt-ß-catenin signaling in human and murine Treg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt+ Treg cells coexpressing multiple pro-inflammatory cytokines. Binding of the ß-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt-ß-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Treg cells. Activation of ß-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.


Assuntos
Proliferação de Células , Reprogramação Celular , Colite Ulcerativa/metabolismo , Neoplasias Associadas a Colite/metabolismo , Doença de Crohn/metabolismo , Epigênese Genética , Ativação Linfocitária , Linfócitos T Reguladores/metabolismo , Via de Sinalização Wnt , Animais , Estudos de Casos e Controles , Células Cultivadas , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Neoplasias Associadas a Colite/genética , Neoplasias Associadas a Colite/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fenótipo , Fator 1 de Transcrição de Linfócitos T , Linfócitos T Reguladores/imunologia
20.
Mol Immunol ; 133: 128-134, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33657462

RESUMO

Systemic lupus erythematosus (SLE, lupus) is a chronic autoimmune disease characterized by loss of peripheral tolerance to nuclear self-antigens. It is increasingly recognized that aberrant T cell metabolism is a critical mediator of SLE immunopathology. Hypoxia inducible factor 1⍺ (HIF-1α) is a key transcription factor that regulates T cell metabolism in response to immune stimuli. T cell activation induces HIF-1α expression and transcriptional activation of HIF-responsive genes. HypoxamiRs are a group of microRNAs sensitive to HIF-1α transcriptional regulation that function to fine-tune the HIF-driven transcriptional program. The 'master' hypoxamiR, miR-210 is transcriptionally regulated by HIF-1α and negatively regulates HIF-1α activity. Although a key role for HIF-1α in has been described in a number of autoimmune and inflammatory diseases and abnormal microRNA expression profiles correlate with poor clinical outcome in a number of rheumatologic diseases, the expression and function of HIF-1α and miR-210 in lupus remains largely uncharacterized. Here we report HIF-1α and miR-210 differential and lineage-specific expression in systemic lupus erythematosus. We show that HIF-1α mRNA and protein is overexpressed in human lupus CD4+ cells but not in CD8+ or CD19+ cells. RORγt, was upregulated in human lupus lymphocytes while FoxP3 expression remained unchanged. We show that miR-210 expression in lupus-prone mice correlates with disease activity and is robustly and selectively upregulated in CD4+ cells from both human lupus patients and lupus-prone mice. Our results suggest that abnormal HIF-1α and miR-210 expression contributes to SLE immune pathology and that HIF-1α/miR-210 may represent a novel and important regulatory axis in SLE.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo
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