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1.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360911

RESUMO

Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor models, but the possible mode of its actions remains unclear. Hence, in this study, the possible anti-tumoral impact of Pyri on human chronic myeloid leukemia (CML) was deciphered. Pyri inhibited cell growth in various types of tumor cells and exhibited a marked inhibitory action on CML cells. In addition to apoptosis, Pyri also triggered sustained autophagy. Targeted inhibition of autophagy sensitized the tumor cells to Pyri-induced apoptotic cell death. Moreover, the activation of signal transducer and activator of transcription 5 (STAT5) and its downstream target gene Bcl-2 was attenuated by Pyri. Accordingly, small interfering RNA (siRNA)-mediated STAT5 knockdown augmented Pyri-induced autophagy and apoptosis and promoted the suppressive action of Pyri on cell viability. Moreover, ectopic overexpression of Bcl-2 protected the cells from Pyri-mediated autophagy and apoptosis. Overall, the data indicated that the attenuation of STAT5-Bcl-2 cascade by Pyri can regulate its growth inhibitory properties by simultaneously targeting both apoptosis and autophagy cell death mechanism(s).


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Pirimetamina/farmacologia , Apoptose/genética , Autofagia/genética , Proteína 7 Relacionada à Autofagia/deficiência , Proteína 7 Relacionada à Autofagia/genética , Proteína Beclina-1/deficiência , Proteína Beclina-1/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT5/deficiência , Fator de Transcrição STAT5/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células THP-1 , Transfecção , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética
2.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360779

RESUMO

Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic ß-cells, consequently cell death. Inhibition of ß-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced ß-cells during IL-1ß exposure. Our findings reveal new phosphosites in the IL-1ß-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1ß exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving ß-cell functions upon exposure to IL-1ß. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in ß-cells after DMT1 silencing.


Assuntos
Apoptose/imunologia , Autofagia/imunologia , Proteínas de Transporte de Cátions/deficiência , Técnicas de Silenciamento de Genes , Células Secretoras de Insulina/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Transdução de Sinais/imunologia , Animais , Apoptose/genética , Autofagia/genética , Proteínas de Transporte de Cátions/imunologia , Interleucina-1beta/genética , Interleucina-6/genética , Camundongos , Transdução de Sinais/genética
3.
Gen Physiol Biophys ; 40(4): 257-274, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34350832

RESUMO

Autophagy may provide the source of nutrients for tumor cells. We aim to develop an autophagy-related signature to predict the progression from lower-grade gliomas (LGG) to glioblastoma multiforme (GBM) and prognosis. Totally, 686 differentially expressed genes (DEGs) and 73 long non-coding RNAs (DELs) were identified between GBM and LGG samples from the Chinese Glioma Genome Atlas (CGGA). Of them, 131 DEGs were intersected with autophagy genes from the Human Autophagy Database; while 54 DELs co-expressed with autophagy-related DEGs. Ten autophagy-related genes were associated with overall survival and could distinguish GBM from LGG, with the accuracy of 0.891 using CGGA dataset and 0.790 using The Cancer Genome Atlas (TCGA) dataset. The risk score was established based on these 10 genes. Patients with higher risk score were at an increased risk of developing GBM (49.7% vs. 21.3%; p < 0.001) and worse prognosis than those in low risk group. The prognostic accuracy was 0.840 and 0.744 for CGGA and TCGA dataset, respectively. Age, recurrence, isocitrate dehydrogenase mutation and risk score were independent prognostic factors and thus they were used to build a nomogram which showed the highest prognostic power. This established nomogram may aid the clinical decision making of personalized treatment..


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , RNA Longo não Codificante , Autofagia/genética , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioma/diagnóstico , Glioma/genética , Humanos , RNA Mensageiro
4.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445125

RESUMO

Huntington's disease (HD) is an autosomal-dominant brain disorder caused by mutant huntingtin (mHtt). Although the detailed mechanisms remain unclear, the mutational expansion of polyglutamine in mHtt is proposed to induce protein aggregates and neuronal toxicity. Previous studies have shown that the decreased insulin sensitivity is closely related to mHtt-associated impairments in HD patients. However, how mHtt interferes with insulin signaling in neurons is still unknown. In the present study, we used a HD cell model to demonstrate that the miR-302 cluster, an embryonic stem cell-specific polycistronic miRNA, is significantly downregulated in mHtt-Q74-overexpressing neuronal cells. On the contrary, restoration of miR-302 cluster was shown to attenuate mHtt-induced cytotoxicity by improving insulin sensitivity, leading to a reduction of mHtt aggregates through the enhancement of autophagy. In addition, miR-302 also promoted mitophagy and stimulated Sirt1/AMPK-PGC1α pathway thereby preserving mitochondrial function. Taken together, these results highlight the potential role of miR-302 cluster in neuronal cells, and provide a novel mechanism for mHtt-impaired insulin signaling in the pathogenesis of HD.


Assuntos
Autofagia/genética , Proteína Huntingtina/genética , Doença de Huntington/genética , Resistência à Insulina/genética , Insulina/genética , MicroRNAs/genética , Transdução de Sinais/genética , Células Cultivadas , Regulação para Baixo/genética , Células-Tronco Embrionárias/patologia , Humanos , Mitocôndrias/genética , Mitofagia/genética , Neurônios/patologia
5.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204880

RESUMO

Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders (ASD) to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy, and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1, and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels, pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.


Assuntos
Colesterol/genética , Neurônios/metabolismo , Proteínas Quinases/genética , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Serina-Treonina Quinases TOR/genética , Animais , Autofagia/genética , Fator de Ligação a CCAAT/genética , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Colesterol/biossíntese , Regulação da Expressão Gênica no Desenvolvimento/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Neurogênese/genética , Cultura Primária de Células , Transdução de Sinais/genética , Transcrição Genética/genética
6.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204950

RESUMO

The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of V600EBRAF-positive thyroid tumours.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Apoptose/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/farmacologia , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia
7.
Adv Exp Med Biol ; 1208: 175-190, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34260027

RESUMO

Macroautophagy (referred to as autophagy hereafter) is a highly conserved catabolic process in eukaryotic cells. Autophagy is essential for cellular homeostasis through elimination and recycling of large cytoplasmic components, such as abnormal protein aggregates and damaged organelles, via lysosomal degradation. Since being originally identified by genetic screening in yeast, autophagy-related (ATG) genes have played a central role in autophagy research in different organisms, including plants, worms, flies, and mammals. Mouse models for monitoring autophagic activity or clarifying its biological functions have also been established. These mice are powerful tools to investigate roles of autophagy in vivo. Owing to the rapid technological advances in molecular biology, it is ever more efficient and simpler to manipulate autophagy-associated genes. Herein, we will introduce some commonly used approaches of gene silencing in mammalian cells, including CRIPSR/Cas9-mediated gene knockout and siRNA- and shRNA-mediated gene knockdown. We also summarized the common mouse models used for assessing autophagy. We hope to bring the researchers some useful information as they study autophagy.


Assuntos
Autofagia , Lisossomos , Animais , Autofagia/genética , Mamíferos , Camundongos , Proteínas , Saccharomyces cerevisiae
8.
Adv Exp Med Biol ; 1208: 357-371, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34260033

RESUMO

Autophagy is an important intracellular lysosomal degradation process in cells, which is highly conserved from yeast to mammals. The process of autophagy is roughly divided into the following key steps: the formation of a membrane structure called ISM (isolated membrane) after stimulation, the biogenesis and maturation of autophagosomes, and finally the degradation of autophagosomes. A number of proteins are required to function in the whole process of autophagy. Since the initial genetic screening in yeast cells, multiple genes that play pivotal roles in autophagy have been discovered. These molecules have been named ATG genes (AuTophaGy related genes). The screening for new key molecules involved in autophagy has greatly promoted the characterization of the mechanism of the autophagy machinery and provides multiple targets for the development of autophagy-based regulatory drugs.


Assuntos
Autofagossomos , Autofagia , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Lisossomos , Saccharomyces cerevisiae
9.
Adv Exp Med Biol ; 1208: 387-453, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34260035

RESUMO

Autophagy is an important and dynamic biological process, and provides an ideal application scenario for bioinformatics to develop new data resources, algorithms, tools and computational or mathematic models for a better understanding of complex regulatory mechanisms in cells. In the past decade, great efforts have been taken on the development of numerous bioinformatics technologies in autophagy research, and a comprehensive summarization of these important studies will provide a timely reference for both biologists and bioinformaticians who are working in the field of autophagy. In this book chapter, we first introduce bioinformatics technologies that allow sequence analysis of autophagy genes. We briefly summarize the mainstream algorithms in sequence alignment for the identification of homologous autophagy genes and emphasize the computational identification of potential orthologs and paralogs, as well as the evolutionary analysis of autophagy gene families. Three methods for the recognition of autophagy-related sequence motifs are introduced: regular expression, position-specific scoring matrix (PSSM) and group-based prediction system (GPS). Second, we carefully summarize recent progress in the analysis of autophagy-related omics data. We discuss how two major types of computational methods, enrichment analysis and network analysis can be used to analyze omics data, including transcriptomics, non-coding RNAomics, epigenomics, proteomics, phosphoproteomics and protein lysine modification (PLM) omics data. Finally, we summarize several important autophagy-related data resources, including both autophagy gene databases and autophagy-related RNA databases. We anticipate that more useful bioinformatics technologies will be developed and play an ever-more-important role in the analysis of autophagy.


Assuntos
Biologia Computacional , Proteômica , Algoritmos , Autofagia/genética , Alinhamento de Sequência
10.
Adv Exp Med Biol ; 1208: 191-264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34260028

RESUMO

Social and economic impacts of neurodegenerative diseases (NDs) become more prominent in our constantly aging population. Currently, due to the lack of knowledge about the aetiology of most NDs, only symptomatic treatment is available for patients. Hence, researchers and clinicians are in need of solid studies on pathological mechanisms of NDs. Autophagy promotes degradation of pathogenic proteins in NDs, while microRNAs post-transcriptionally regulate multiple signalling networks including autophagy. This chapter will critically discuss current research advancements in the area of microRNAs regulating autophagy in NDs. Moreover, we will introduce basic strategies and techniques used in microRNA research. Delineation of the mechanisms contributing to NDs will result in development of better approaches for their early diagnosis and effective treatment.


Assuntos
MicroRNAs , Doenças Neurodegenerativas , Idoso , Autofagia/genética , Humanos , MicroRNAs/genética , Doenças Neurodegenerativas/genética , Transdução de Sinais/genética
11.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204176

RESUMO

Age-related bone disorders such as osteoporosis or osteoarthritis are a major public health problem due to the functional disability for millions of people worldwide. Furthermore, fractures are associated with a higher degree of morbidity and mortality in the long term, which generates greater financial and health costs. As the world population becomes older, the incidence of this type of disease increases and this effect seems notably greater in those countries that present a more westernized lifestyle. Thus, increased efforts are directed toward reducing risks that need to focus not only on the prevention of bone diseases, but also on the treatment of persons already afflicted. Evidence is accumulating that dietary lipids play an important role in bone health which results relevant to develop effective interventions for prevent bone diseases or alterations, especially in the elderly segment of the population. This review focuses on evidence about the effects of dietary lipids on bone health and describes possible mechanisms to explain how lipids act on bone metabolism during aging. Little work, however, has been accomplished in humans, so this is a challenge for future research.


Assuntos
Envelhecimento/metabolismo , Osso e Ossos/metabolismo , Gorduras na Dieta/metabolismo , Animais , Autofagia/genética , Biomarcadores , Remodelação Óssea , Dieta , Instabilidade Genômica , Hormônios/metabolismo , Humanos , Osteíte/etiologia , Osteíte/metabolismo , Osteíte/patologia , Estresse Oxidativo
12.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207151

RESUMO

Cardiovascular diseases (CVDs) are the number one cause of debilitation and mortality worldwide, with a need for cost-effective therapeutics. Autophagy is a highly conserved catabolic recycling pathway triggered by various intra- or extracellular stimuli to play an essential role in development and pathologies, including CVDs. Accordingly, there is great interest in identifying mechanisms that govern autophagic regulation. Autophagic regulation is very complex and multifactorial that includes epigenetic pathways, such as histone modifications to regulate autophagy-related gene expression, decapping-associated mRNA degradation, microRNAs, and long non-coding RNAs; pathways are also known to play roles in CVDs. Molecular understanding of epigenetic-based pathways involved in autophagy and CVDs not only will enhance the understanding of CVDs, but may also provide novel therapeutic targets and biomarkers for CVDs.


Assuntos
Autofagia/genética , Doenças Cardiovasculares/etiologia , Sistema Cardiovascular/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Animais , Biomarcadores , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Histonas/metabolismo , Humanos , MicroRNAs/genética , Processamento de Proteína Pós-Traducional , RNA Longo não Codificante/genética , RNA Mensageiro/genética
13.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198826

RESUMO

The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which is involved in diverse cellular events in humans. The most well-characterized function of AHR is its ability to upregulate gene transcription after exposure to its ligands, such as environmental toxicants, dietary antioxidants, drugs, and endogenous ligands. The cellular content of AHR is partly controlled by its degradation via the ubiquitin-proteasome system and the lysosome-dependent autophagy. We used human cervical cancer (HeLa) cells to investigate how AHR undergoes protein degradation and how its activity is modulated. Since the glycogen synthase kinase 3 beta (GSK3ß)-mediated phosphorylation can trigger protein degradation and substrates of GSK3ß contain stretches of serine/threonine residues which can be found in AHR, we examined whether degradation and activity of AHR can be controlled by GSK3ß. We observed that AHR undergoes the GSK3ß-dependent, LC3-mediated lysosomal degradation without ligand treatment. The AHR can be phosphorylated in a GSK3ß-dependent manner at three putative sites (S436/S440/S444, S689/S693/T697, and S723/S727/T731), which leads to lysosomal degradation of the AHR protein. Inhibition of the GSK3ß activity suppresses the ligand-activated transcription of an AHR target gene in HeLa, human liver cancer (Hep3B), and human breast cancer (MCF-7) cells. Collectively, our findings support that phosphorylation of AHR by GSK3ß is essential for the optimal activation of its target gene transcription and this phosphorylation may partake as an "off" switch by subjecting the receptor to lysosomal degradation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Glicogênio Sintase Quinase 3 beta/genética , Neoplasias/genética , Receptores de Hidrocarboneto Arílico/genética , Transcrição Genética , Autofagia/genética , Células HeLa , Humanos , Lisossomos/genética , Células MCF-7 , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/genética , Proteólise , Ubiquitina/genética
14.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204653

RESUMO

Mammals face environmental stressors throughout their lifespan, which may jeopardize cellular homeostasis. Hence, these organisms have acquired mechanisms to cope with stressors by sensing, repairing the damage, and reallocating resources to increase the odds of long-term survival. Autophagy is a pro-survival lysosome-mediated cytoplasm degradation pathway for organelle and macromolecule recycling. Furthermore, autophagy efflux increases, and this pathway becomes idiosyncratic depending upon developmental and environmental contexts. Mammalian germ cells and preimplantation embryos are attractive models for dissecting autophagy due to their metastable phenotypes during differentiation and exposure to varying environmental cues. The aim of this review is to explore autophagy during mammalian gametogenesis, fertilization and preimplantation embryonic development by contemplating its physiological role during development, under key stressors, and within the scope of assisted reproduction technologies.


Assuntos
Autofagia , Desenvolvimento Embrionário , Gametogênese , Animais , Autofagia/genética , Humanos , Modelos Biológicos , Oogênese , Espermatogênese
15.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204710

RESUMO

Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, autoimmune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogenesis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease.


Assuntos
Asma/complicações , Asma/patologia , Autofagia , Hipersensibilidade/complicações , Hipersensibilidade/patologia , Animais , Asma/imunologia , Autofagia/genética , Humanos , Hipersensibilidade/imunologia , Inflamação/patologia , Modelos Biológicos , Transcrição Genética
16.
Nat Commun ; 12(1): 4404, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285225

RESUMO

Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-ß (TGFß) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFß induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFß on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFß-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFß signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.


Assuntos
Autofagia/genética , Epigênese Genética , Histona Acetiltransferases/metabolismo , Escleroderma Sistêmico/patologia , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Biópsia , Estudos de Casos e Controles , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Fibroblastos , Fibrose , Técnicas de Inativação de Genes , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Células NIH 3T3 , Cultura Primária de Células , Receptores de Fatores de Crescimento Transformadores beta , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Proteína Smad3/metabolismo , Adulto Jovem
17.
J Cell Sci ; 134(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34228793

RESUMO

Autophagy is a degradative pathway for cytoplasmic constituents, and is conserved across eukaryotes. Autophagy-related (ATG) genes have undergone extensive multiplications and losses in different eukaryotic lineages, resulting in functional diversification and specialization. Notably, even though bacteria and archaea do not possess an autophagy pathway, they do harbor some remote homologs of Atg proteins, suggesting that preexisting proteins were recruited when the autophagy pathway developed during eukaryogenesis. In this Review, we summarize our current knowledge on the distribution of Atg proteins within eukaryotes and outline the major multiplication and loss events within the eukaryotic tree. We also discuss the potential prokaryotic homologs of Atg proteins identified to date, emphasizing the evolutionary relationships and functional differences between prokaryotic and eukaryotic proteins.


Assuntos
Eucariotos , Células Procarióticas , Archaea/genética , Autofagia/genética , Eucariotos/genética , Células Eucarióticas , Evolução Molecular , Filogenia
18.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299246

RESUMO

Cholangiocarcinoma (CCA), an aggressive malignancy, is typically diagnosed at an advanced stage. It is associated with dismal 5-year postoperative survival rates, generating an urgent need for prognostic and diagnostic biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are associated with cancer regulation, including modulation of cell cycle progression, apoptosis, metastasis, angiogenesis, autophagy, therapy resistance, and epithelial-mesenchymal transition. Several miRNAs have been found to be dysregulated in CCA and are associated with CCA-related risk factors. Accumulating studies have indicated that the expression of altered miRNAs could act as oncogenic or suppressor miRNAs in the development and progression of CCA and contribute to clinical diagnosis and prognosis prediction as potential biomarkers. Furthermore, miRNAs and their target genes also contribute to targeted therapy development and aid in the determination of drug resistance mechanisms. This review aims to summarize the roles of miRNAs in the pathogenesis of CCA, their potential use as biomarkers of diagnosis and prognosis, and their utilization as novel therapeutic targets in CCA.


Assuntos
Colangiocarcinoma/genética , MicroRNAs/genética , Apoptose/genética , Autofagia/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/fisiologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal/genética , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Prognóstico , Transcriptoma/genética
19.
Commun Biol ; 4(1): 831, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215848

RESUMO

Gain of even a single chromosome leads to changes in human cell physiology and uniform perturbations of specific cellular processes, including downregulation of DNA replication pathway, upregulation of autophagy and lysosomal degradation, and constitutive activation of the type I interferon response. Little is known about the molecular mechanisms underlying these changes. We show that the constitutive nuclear localization of TFEB, a transcription factor that activates the expression of autophagy and lysosomal genes, is characteristic of human trisomic cells. Constitutive nuclear localization of TFEB in trisomic cells is independent of mTORC1 signaling, but depends on the cGAS-STING activation. Trisomic cells accumulate cytoplasmic dsDNA, which activates the cGAS-STING signaling cascade, thereby triggering nuclear accumulation of the transcription factor IRF3 and, consequently, upregulation of interferon-stimulated genes. cGAS depletion interferes with TFEB-dependent upregulation of autophagy in model trisomic cells. Importantly, activation of both the innate immune response and autophagy occurs also in primary trisomic embryonic fibroblasts, independent of the identity of the additional chromosome. Our research identifies the cGAS-STING pathway as an upstream regulator responsible for activation of autophagy and inflammatory response in human cells with extra chromosomes, such as in Down syndrome or other aneuploidy-associated pathologies.


Assuntos
Autofagia/genética , Dano ao DNA , Imunidade Inata/genética , Proteínas de Membrana/genética , Nucleotidiltransferases/genética , Trissomia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular , Células Cultivadas , Regulação da Expressão Gênica , Células HCT116 , Humanos , Immunoblotting , Proteínas de Membrana/metabolismo , Microscopia Confocal , Nucleotidiltransferases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética
20.
Mol Med Rep ; 24(4)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34328194

RESUMO

Previous studies have suggested that oxidative stress and autophagy results in acute kidney injury (AKI) during sepsis and microRNA (miR)­214 serves a vital role in the protection of kidneys subjected to oxidative stress. The present study aimed to test whether the renoprotection of miR­214 is related to autophagy in sepsis. The role of autophagy was investigated in a mouse model of cecal ligation and puncture (CLP). Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was used to analyze the expression of miR­214. The structure and function of kidneys harvested from the mice were evaluated. Kidney autophagy levels were detected with immunohistochemical, immunofluorescent and western blotting. It was found that miR­214 could alleviate AKI in septic mice by inhibiting the level of kidney autophagy. Furthermore, miR­214 inhibited autophagy by silencing PTEN expression in the kidney tissues of septic mice. These findings indicated that miR­214 ameliorated CLP­induced AKI by reducing oxidative stress and inhibiting autophagy through the regulation of the PTEN/AKT/mTOR pathway.


Assuntos
Injúria Renal Aguda/genética , Autofagia/genética , MicroRNAs/genética , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Animais , Ceco/lesões , Ceco/microbiologia , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Rim/ultraestrutura , Ligadura , Masculino , Camundongos , Estresse Oxidativo/genética , PTEN Fosfo-Hidrolase/genética , Punções , Sepse/complicações , Transdução de Sinais/genética
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