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1.
Mater Sci Eng C Mater Biol Appl ; 127: 112214, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34225866

RESUMO

In recent times, the development of functionalized nanoparticle methodology for biomedical applications has become a major challenge. In the present study, we prepared a novel gold nanoparticle (AuNP), named Curto-Cumin AuNP (CC-AuNP), using the biosynthetic process involving Nigella sativa (black cumin) seed extract and membrane vesicles isolated from the novel probiotic strain, Curtobacterium proimmune K3. Various spectrometric and microscopic analyses were performed to characterize the physicochemical properties of the nanoparticles. CC-AuNP exhibited significant cytotoxicity against human gastric adenocarcinoma (AGS) cells but not against normal cells. The toxic effects of the nanoparticles were associated with the excessive production of reactive oxygen species (ROS) in damaged mitochondria. Further, we investigated the molecular mechanisms underlying the cytotoxic effect of CC-AuNP. Results showed that except for B cell lymphoma 2 (Bcl-2), the intracellular apoptotic signaling molecules, such as p53, Bcl-associated X protein (Bax), and Caspase 9/Caspase 3 were significantly upregulated in AGS cells. ROS production and alterations in mitochondrial membrane potential were observed in AGS cells treated with CC-AuNP. The activation of autophagy flux-related biomarkers, such as LC3b/a, Beclin-1, p62, and Caspase 8, was confirmed by qPCR and western blotting. Autophagy pathway was suppressed in CC-AuNP-treated AGS cells and could not proceed further to the mature state. This was confirmed by the evaluation of both apoptosis and autophagy signaling pathways using autophagy-induced AGS cells treated with rapamycin, a well-studied autophagy activator. Overall, our results showed that CC-AuNP upregulates apoptotic signaling and suppresses the autophagy-related signaling pathway, and thus has potential as an anticancer agent. To our knowledge, the present study is the first to demonstrate that CC-AuNP may serve as novel therapeutic agent against gastric cancer. Furthermore, our study provides preliminary data which can be used to develop novel anticancer candidates and understand their anticancer mechanisms, and seems to be a good starting point for the development of alternative medications based on CC-AuNP.


Assuntos
Nanopartículas Metálicas , Nigella sativa , Apoptose , Autofagia , Linhagem Celular Tumoral , Ouro , Humanos , Espécies Reativas de Oxigênio
2.
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
3.
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
4.
Adv Exp Med Biol ; 1332: 51-66, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34251638

RESUMO

Autophagy is a dynamic process in which the eukaryotic cells break down intracellular components by lysosomal degradation. Under the normal condition, the basal level of autophagy removes damaged organelles, misfolded proteins, or protein aggregates to keep cells in a homeostatic condition. Deprivation of nutrients (e.g., removal of amino acids) stimulates autophagy activity, promoting lysosomal degradation and the recycling of cellular components for cell survival. Importantly, insulin and amino acids are two main inhibitors of autophagy. They both activate the mTOR complex 1 (mTORC1) signaling pathway to inhibit the autophagy upstream of the uncoordinated-51 like kinase 1/2 (ULK1/2) complex that triggers autophagosome formation. In particular, insulin activates mTORC1 via the PI3K class I-AKT pathway; while amino acids activate mTORC1 either through the PI3K class III (hVps34) pathway or through a variety of amino acid sensors located in the cytosol or lysosomal membrane. These amino acid sensors control the translocation of mTORC1 from the cytosol to the lysosomal surface where mTORC1 is activated by Rheb GTPase, therefore regulating autophagy and the lysosomal protein degradation.


Assuntos
Aminoácidos , Serina-Treonina Quinases TOR , Autofagia , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
5.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201121

RESUMO

Eva-1 homolog A (EVA1A) is regarded as TMEM166 (transmembrane protein 166) or FAM176A (family with sequence similarity 176) and a lysosome and endoplasmic reticulum-associated protein involved in regulating autophagy and apoptosis. EVA1A regulates embryonic neurogenesis, cardiac remodeling, islet alpha-cell functions, acute liver failure, and hepatitis B virus replication. However, the related mechanisms are not fully clear. Autophagy is a process in which cells transfer pathogens, abnormal proteins and organelles to lysosomes for degradation. It plays an important role in various physiological and pathological processes, including cancer, aging, neurodegeneration, infection, heart disease, development, cell differentiation and nutritional starvation. Recently, there are many studies on the important role of EVA1A in many physiological and pathological processes by regulating autophagy. However, the related molecular mechanisms need further study. Therefore, we summarize the above-mentioned researches about the role of EVA1A in physiological and pathological processes through regulating autophagy in order to provide theoretical basis for future researches.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Doença/etiologia , Homeostase , Proteínas de Membrana/metabolismo , Animais , Humanos
6.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200718

RESUMO

Euterpe oleracea Mart. (açai) is a native palm from the Amazon region. There are various chemical constituents of açai with bioactive properties. This study aimed to evaluate the chemical composition and cytotoxic effects of açai seed extract on breast cancer cell line (MCF-7). Global Natural Products Social Molecular Networking (GNPS) was applied to identify chemical compounds present in açai seed extract. LC-MS/MS and molecular networking were employed to detect the phenolic compounds of açai. The antioxidant activity of açai seed extract was measured by DPPH assay. MCF-7 breast cancer cell line viability was evaluated by MTT assay. Cell death was evaluated by flow cytometry and time-lapse microscopy. Autophagy was evaluated by orange acridin immunofluorescence assay. Reactive oxygen species (ROS) production was evaluated by DAF assay. From the molecular networking, fifteen compounds were identified, mainly phenolic compounds. The açai seed extract showed cytotoxic effects against MCF-7, induced morphologic changes in the cell line by autophagy and increased the ROS production pathway. The present study suggests that açai seed extract has a high cytotoxic capacity and may induce autophagy by increasing ROS production in breast cancer. Apart from its antioxidant activity, flavonoids with high radical scavenging activity present in açai also generated NO (nitric oxide), contributing to its cytotoxic effect and autophagy induction.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Euterpe/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sementes/química , Antioxidantes/química , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Líquida/métodos , Feminino , Flavonoides/química , Flavonoides/farmacologia , Frutas/química , Humanos , Células MCF-7 , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Polifenóis/química , Polifenóis/farmacologia , Espectrometria de Massas em Tandem/métodos
7.
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
8.
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
9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(6): 601-608, 2021 Jun 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34275928

RESUMO

OBJECTIVES: To explore the relationship between autophagy and epithelial-to-mesenchymal transition (EMT), and to evaluate whether autophagy can affect the progression of renal fibrosis in obstructive nephropathy by regulating the EMT process. METHODS: Unilateral ureteral obstruction (UUO) renal fibrosis model of rat was constructed, and the animals were divided into a sham group, an UUO group, an UUO+low-dose rapamycin group, and an UUO+high-dose rapamycin group. HE staining was used to observe the structure of the kidney, and Masson staining was used to observe renal interstitial collagen deposition. The expressions of E-cadherin, alpha-smooth muscle actin (α-SMA), Snail 1, and microtubule-associated protein-1 light chain 3II (LC3II) were detected by Western blotting, reflecting cellular EMT and autophagy. Transforming growth factor ß1 (TGF-ß1) induced-NRK52E cells model was constructed, and the cells were divided into a control group, a TGF-ß1 group, and a TGF-ß1+ Snail 1 siRNA group. To explore the effect of autophagy on EMT, the cells were also divided into a control group, a rapamycin group, and a Beclin 1 siRNA group. Western blotting was used to detect the expressions of E-cadherin, α-SMA, Snail 1, LC3II, collagen I, and fibronectin. RESULTS: Compared with the sham group, the kidney damage in the UUO group was significantly worse; compared with the sham group, the collagen deposition in the kidney tissues in the UUO group was significantly increased, which were significantly reduced in the UUO+high-dose rapamycin group and the UUO+low-dose rapamycin group compared with the UUO group; compared with the sham group, the E-cadherin level in the kidney of the UUO group was significantly reduced, and the expression levels of α-SMA and LC3II were significantly increased (all P<0.05). Compared with the UUO group, the expression levels of E-cadherin and LC3II in the UUO+high-dose rapamycin group and the UUO+low-dose rapamycin group were significantly increased (P<0.01 and P<0.05, respectively), and the expression level of α-SMA was significantly decreased (P<0.01 and P<0.05, respectively). The expression levels of Snail 1, α-SMA, collagen I and fibronectin were significantly higher, and the E-cadherin level was significantly lower in the TGF-ß1 group than those in the control group (all P<0.05). Compared with the TGF-ß1 group, the expression of E-cadherin was increased significantly, and the expressions of α-SMA, collagen I and fibronectin were decreased significantly in the TGF-ß1+Snail 1 siRNA group (all P<0.05). Compared with the control group, the expression levels of LC3II and E-cadherin were significantly elevated, and the expression levels of α-SMA and Snail 1 in the rapamycin group were significantly reduced (all P<0.05); the expression levels of LC3II and E-cadherin were significantly reduced, and the expression levels of α-SMA and Snail 1 were significantly increased in the Beclin 1 siRNA group (all P<0.05). CONCLUSIONS: Autophagy plays an essential role in the regulation of EMT in obstructive nephropathy fibrosis. Autophagy can alleviate renal fibrosis by inhibiting EMT.


Assuntos
Nefropatias , Obstrução Ureteral , Animais , Autofagia , Transição Epitelial-Mesenquimal , Fibrose , Rim/patologia , Nefropatias/patologia , Ratos , Fator de Crescimento Transformador beta1/genética
10.
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
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(7): 1012-1021, 2021 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-34308850

RESUMO

OBJECTIVE: To determine whether miR-424 affects cancer cell proliferation and autophagy through ATG14 in hepatocellular carcinoma (HCC) cells. METHODS: We detected miR-424-5p and ATG14 expression levels in surgical specimens of HCC and adjacent tissues and in different HCC cell lines (HepG2, SMMC-7721, Huh-7, MHCC97H, and HCCLM3) and normal human hepatocyte LO2 cells using qRT-PCR and Western blotting. In the cell transfection experiments, we observed the effects of miR-424-5p knockdown in Huh-7 cells and the effects of overexpression miR-424-5p and ATG14 in HCCLM3 cells on the proliferation, cell cycle, apoptosis and expression levels of autophagy-related proteins (LC3, Beclin1 and p62). Dual luciferase reporter assay was used to verify the possible interaction between miR-424-5p and ATG14. RESULTS: In HCC tissues and cells, ATG14 was highly expressed and miR-424-5p expression was downregulated. In HCC cells, overexpression of miR-424-5p obviously suppressed cell proliferation and promoted cell apoptosis (P < 0.05), while inhibiting miR-424-5p or overexpressing ATG14 significantly promoted cell proliferation and inhibited cell apoptosis (P < 0.05). Dual luciferase reporter assay indicated that miR-424-5p inhibits HCC cells by targeting ATG14. In addition, inhibition of miR-424-5p and overexpression of ATG14 both enhanced the expressions of LC3-ΙΙ/LC3-Ι and Beclin1 and decreased p62 expression (P < 0.05), but miR-424-5p overexpression reduced the expressions of LC3-ΙΙ/LC3-Ι and Beclin1 and increased p62 expression (P < 0.05). CONCLUSION: MiR-424 inhibits HCC cell autophagy and proliferation through regulating ATG14.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Apoptose , Autofagia , Proteínas Relacionadas à Autofagia/genética , Carcinoma Hepatocelular/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(7): 1073-1078, 2021 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-34308859

RESUMO

OBJECTIVE: To investigate the effect of exendin-4 on lipid deposition in hepatocytes and explore its possible mechanism for treatment of nonalcoholic fatty liver disease (NAFLD). METHODS: Human normal hepatocyte line LO2 and hepatoma cell line HepG2 were treated with palmitic acid (PA) to mimic hepatocyte steatosis or with combined treatments with PA+exendin-4 or PA+exendin-4+3BDO. Lipid deposition and proliferation of the two cell lines following treatment with PA or PA+exendin-4 were detected using Oil Red O staining and CCK8 assay, and the expression of p-mTOR, m-TOR, p-AKT, AKT and autophagy-related proteins LC3-Ⅰ/Ⅱ and p62 were detected with Western blotting; the expression of GLP-1R was detected with both Western blotting and immunofluorescence assay. The expression of LC3-Ⅰ/Ⅱ and p62 in the cells following treatment with PA+exendin-4 and PA+exendin-4+3BDO was detected with Western blotting. RESULTS: Lipid deposition in the two cell lines increased significantly after PA treatment, but was alleviated by co-treatment with exendin-4. PA treatment significantly inhibited the proliferation of the two cell lines (P < 0.01), and this inhibitory effect was obviously attenuated by exendin-4 (P < 0.05). Immunofluorescence assay showed that both LO2 and HepG2 cells expressed GLP-1R. The expression of p-mTOR was significantly lower and that of p-AKT was higher in cells treated with PA+exendin-4 than in PA-treated cells. Exendin-4 also down-regulated the autophagy-associated protein p62 and up-regulated the expression of LC3-Ⅱ in PA-treated cells, and this effect was obviously reversed by 3BDO. CONCLUSION: Exendin-4 may activate the AKT-mTOR signal pathway to promote autophagy via its direct action on GLP-1R. Exendin-4 can also alleviate lipid deposition and promote proliferation of PA-treated hepatocytes, suggesting its important role in PA-induced lipid deposition in hepatocytes.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Autofagia , Exenatida/farmacologia , Humanos , Ácido Palmítico/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
13.
Cardiovasc Ther ; 2021: 5554569, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34257705

RESUMO

Ginkgolide B (GB) is an active ingredient extracted from Ginkgo biloba leaves. However, the effects of GB on cardiac hypertrophy remain unclear. The study is aimed at determining whether GB could alleviate cardiac hypertrophy and exploring its underlying molecular mechanism. Rat cardiomyocyte cell line H9c2 cells were pretreated with GB and incubated with angiotensin II (Ang II) to simulate an in vitro cardiac hypertrophy model. Cell viability, cell size, hypertrophy markers, and autophagy were determined in H9c2 cells after Ang II treatment. Proteins involved in autophagy and the SIRT1 pathway were determined by western blot. Our data demonstrated that GB attenuated Ang II-induced cardiac hypertrophy and reduced the mRNA expressions of hypertrophy marker, atrial natriuretic peptide (ANP), and ß-myosin heavy chain (ß-MHC). GB further increased Ang II-induced autophagy in H9c2 cells and modulated expressions of autophagy-related proteins Beclin1 and P62. Modulation of autophagy using autophagy inhibitor 3-methyladenine (3-MA) could abrogate GB-downregulated transcription of NPPA. We then showed that GB attenuated Ang II-induced oxidative stress and reduction in SIRT1 and FoxO1 protein expression. Finally, the effect of GB on autophagy and cardiac hypertrophy could be reversed by SIRT1 inhibitor EX-527. GB inhibits Ang II-induced cardiac hypertrophy by enhancing autophagy via the SIRT1-FoxO1 signaling pathway and might be a potential agent in treating pathological cardiac hypertrophy.


Assuntos
Angiotensina II/toxicidade , Autofagia/efeitos dos fármacos , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Sirtuína 1/metabolismo , Animais , Fator Natriurético Atrial/genética , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Linhagem Celular , Miócitos Cardíacos/patologia , Substâncias Protetoras/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Miosinas Ventriculares/genética
14.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281243

RESUMO

BACKGROUND: Bisphenol A (BPA) is a ubiquitous environmental toxin that accumulates in chronic kidney disease (CKD). Our aim was to explore the effect of chronic exposition of BPA in healthy and injured kidney investigating potential mechanisms involved. METHODS: In C57Bl/6 mice, administration of BPA (120 mg/kg/day, i.p for 5 days/week) was done for 2 and 5 weeks. To study BPA effect on CKD, a model of subtotal nephrectomy (SNX) combined with BPA administration for 5 weeks was employed. In vitro studies were done in human proximal tubular epithelial cells (HK-2 line). RESULTS: Chronic BPA administration to healthy mice induces inflammatory infiltration in the kidney, tubular injury and renal fibrosis (assessed by increased collagen deposition). Moreover, in SNX mice BPA exposure exacerbates renal lesions, including overexpression of the tubular damage biomarker Hepatitis A virus cellular receptor 1 (Havcr-1/KIM-1). BPA upregulated several proinflammatory genes and increased the antioxidant response [Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme Oxygenase-1 (Ho-1) and NAD(P)H dehydrogenase quinone 1 (Nqo-1)] both in healthy and SNX mice. The autophagy process was modulated by BPA, through elevated autophagy-related gene 5 (Atg5), autophagy-related gene 7 (Atg7), Microtubule-associated proteins 1A/1B light chain 3B (Map1lc3b/Lc3b) and Beclin-1 gene levels and blockaded the autophagosome maturation and flux (p62 levels). This autophagy deregulation was confirmed in vitro. CONCLUSIONS: BPA deregulates autophagy flux and redox protective mechanisms, suggesting a potential mechanism of BPA deleterious effects in the kidney.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/farmacologia , Fenóis/efeitos adversos , Fenóis/farmacologia , Insuficiência Renal Crônica/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos Benzidrílicos/metabolismo , Linhagem Celular , Feminino , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Túbulos Renais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Fenóis/metabolismo , Insuficiência Renal Crônica/fisiopatologia
15.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281248

RESUMO

Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) may directly interact with proteins important for senescence, DNA damage response, and autophagy, which are impaired in AMD. hTERT interaction with mTORC1 (mTOR (mechanistic target of rapamycin) complex 1) and PINK1 (PTEN-induced kinase 1) activates macroautophagy and mitophagy, respectively, and removes cellular debris accumulated over AMD progression. Ectopic expression of telomerase in retinal pigment epithelium (RPE) cells lengthened telomeres, reduced senescence, and extended their lifespan. These effects provide evidence for the potential of telomerase in AMD therapy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be involved in AMD pathogenesis through decreasing oxidative stress and senescence, regulation of vascular endothelial growth factor (VEGF), and improving autophagy. PGC-1α and TERT form an inhibitory positive feedback loop. In conclusion, telomerase activation and its ectopic expression in RPE cells, as well as controlled clinical trials on the effects of telomerase activation in AMD patients, are justified and should be assisted by PGC-1α modulators to increase the therapeutic potential of telomerase in AMD.


Assuntos
Degeneração Macular/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Telomerase/metabolismo , Envelhecimento/metabolismo , Autofagia/fisiologia , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Humanos , Degeneração Macular/fisiopatologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais , Telomerase/fisiologia , Telômero/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Nat Commun ; 12(1): 4258, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253734

RESUMO

The maintenance of constant karyoplasmic ratios suggests that nuclear size has physiological significance. Nuclear size anomalies have been linked to malignant transformation, although the mechanism remains unclear. By expressing dominant-negative TER94 mutants in Drosophila photoreceptors, here we show disruption of VCP (valosin-containing protein, human TER94 ortholog), a ubiquitin-dependent segregase, causes progressive nuclear size increase. Loss of VCP function leads to accumulations of MDC1 (mediator of DNA damage checkpoint protein 1), connecting DNA damage or associated responses to enlarged nuclei. TER94 can interact with MDC1 and decreases MDC1 levels, suggesting that MDC1 is a VCP substrate. Our evidence indicates that MDC1 accumulation stabilizes p53A, leading to TER94K2A-associated nuclear size increase. Together with a previous report that p53A disrupts autophagic flux, we propose that the stabilization of p53A in TER94K2A-expressing cells likely hinders the removal of nuclear content, resulting in aberrant nuclear size increase.


Assuntos
Autofagia , Tamanho do Núcleo Celular , Núcleo Celular/metabolismo , Dano ao DNA , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína com Valosina/metabolismo , Animais , Biomarcadores/metabolismo , Olho Composto de Artrópodes , Reparo do DNA , Mitose , Transdução de Sinais , Fatores de Tempo , Proteínas Ubiquitinadas/metabolismo
17.
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
18.
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
19.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208589

RESUMO

There is mounting evidence that type 2 diabetes mellitus (T2DM) is related with increased risk for the development of cancer. Apart from shared common risk factors typical for both diseases, diabetes driven factors including hyperinsulinemia, insulin resistance, hyperglycemia and low grade chronic inflammation are of great importance. Recently, vitamin D deficiency was reported to be associated with the pathogenesis of numerous diseases, including T2DM and cancer. However, little is known whether vitamin D deficiency may be responsible for elevated cancer risk development in T2DM patients. Therefore, the aim of the current review is to identify the molecular mechanisms by which vitamin D deficiency may contribute to cancer development in T2DM patients. Vitamin D via alleviation of insulin resistance, hyperglycemia, oxidative stress and inflammation reduces diabetes driven cancer risk factors. Moreover, vitamin D strengthens the DNA repair process, and regulates apoptosis and autophagy of cancer cells as well as signaling pathways involved in tumorigenesis i.e., tumor growth factor ß (TGFß), insulin-like growth factor (IGF) and Wnt-ß-Cathenin. It should also be underlined that many types of cancer cells present alterations in vitamin D metabolism and action as a result of Vitamin D Receptor (VDR) and CYP27B1 expression dysregulation. Although, numerous studies revealed that adequate vitamin D concentration prevents or delays T2DM and cancer development, little is known how the vitamin affects cancer risk among T2DM patients. There is a pressing need for randomized clinical trials to clarify whether vitamin D deficiency may be a factor responsible for increased risk of cancer in T2DM patients, and whether the use of the vitamin by patients with diabetes and cancer may improve cancer prognosis and metabolic control of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Neoplasias/etiologia , Deficiência de Vitamina D/complicações , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Redes e Vias Metabólicas , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Neoplasias/terapia , Prognóstico , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/metabolismo
20.
Aging (Albany NY) ; 13(13): 17462-17472, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253689

RESUMO

Propose: Autophagy plays a complicated role in cancer progression. This study aims at assessing the function of ATG5-induced autophagy in progression of lung squamous cell carcinoma and its upstream mechanism. METHOD: TCGA database of lung squamous cell carcinoma was analyzed to explore the differentially expressed miRNAs and mRNAs and relative prognosis. RT-PCR and Western blot were performed to evaluate autophagy relative gene expression level in human lung squamous cell carcinoma cell Lines. Autophagy flux was observed using transmission electron microscopy and immunofluorescence. Meanwhile, binding relationship of potential target miRNA and mRNAs were also confirmed using Dual-luciferase reporter gene assay. Lung metastatic model was established to evaluated the effect of targeting protein and miRNA. RESULT: High level expression of ATG5 was detected in LUSC patients. Relative experiments confirmed that ATG5 silencing could decrease the autophagy flux in LUSC. In addition, our research revealed that there is a binding sites between hsa-mir-30a-5p and 3'-UTR of ATG5. Mimic miR-30a-5p suppresses ATG5-mediated autophagy in lung squamous cell carcinoma cells. The in vivo experiments confirmed that miR-30a-5p could attenuate lung squamous cell carcinoma progression through the autophagy pathway. CONCLUSION: Accordingly, the in vivo and in vitro study in our research have demonstrated that miR-30a-5p inhibits lung squamous cell carcinoma progression via ATG5-mediated autophagy.


Assuntos
Proteína 5 Relacionada à Autofagia/genética , Autofagia/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Animais , Sítios de Ligação , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Biologia Computacional , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/genética , Prognóstico , RNA Mensageiro/genética , Transdução de Sinais/genética
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