Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42.382
Filtrar
1.
World J Gastroenterol ; 28(26): 3063-3070, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-36051337

RESUMO

Crohn's disease (CD) is driven by the loss of tolerance to intestinal microbiota and excessive production of pro-inflammatory cytokines. These pro-inflammatory cytokines are produced by macrophages and dendritic cells (DCs) upon sensing the intestinal microbiota by the pattern recognition receptors (PRRs). Impaired activation of PRR-mediated signaling pathways is associated with chronic gastrointestinal inflammation, as shown by the fact that loss-of-function mutations in the nucleotide-binding oligomerization domain 2 gene increase the risk of CD development. Autophagy is an intracellular degradation process, during which cytoplasmic nutrients and intracellular pathogens are digested. Given that impaired reaction to intestinal microbiota alters signaling pathways mediated by PRRs, it is likely that dysfunction of the autophagic machinery is involved in the development of CD. Indeed, the loss-of-function mutation T300A in the autophagy related 16 like 1 (ATG16L1) protein, a critical regulator of autophagy, increases susceptibility to CD. Recent studies have provided evidence that ATG16L1 is involved not only in autophagy, but also in PRR-mediated signaling pathways. ATG16L1 negatively regulates pro-inflammatory cytokine responses of macrophages and DCs after these cells sense the intestinal microbiota by PRRs. Here, we discuss the molecular mechanisms underlying the development of CD in the T300A ATG16L1 mutation by focusing on PRR-mediated signaling pathways.


Assuntos
Proteínas Relacionadas à Autofagia , Doença de Crohn , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Doença de Crohn/genética , Doença de Crohn/imunologia , Citocinas/metabolismo , Humanos , Imunidade Inata , Inflamação , Mutação , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/metabolismo
2.
Nat Commun ; 13(1): 5204, 2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36057605

RESUMO

In addition to investigating the virology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), discovering the host-virus dependencies are essential to identify and design effective antiviral therapy strategy. Here, we report that the SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) and provide evidence indicating that prevention of ACE2 SUMOylation can block SARS-CoV-2 infection. E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. TOLLIP deficiency results in the stabilization of ACE2 and elevated SARS-CoV-2 infection. In conclusion, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination as a potential way to combat SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Autofagia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Sumoilação , Ubiquitina-Proteína Ligases/metabolismo
3.
Oxid Med Cell Longev ; 2022: 5142381, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36062192

RESUMO

Background: It is well-known that dysfunctions of vascular smooth muscle cells (VSMCs) act an essential part in vascular complications of diabetes. Studies have shown that circular RNAs (circRNAs) and microRNAs (miRNAs) play a crucial role in regulating cell functions. However, their influence on the proliferation, calcification, and autophagy of VSMCs remains to be further explored. Therefore, this study elucidates the role and mechanism of hsa_circRNA_0008028 in high glucose- (HG-, 30 mM) treated VSMCs in vitro. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was chosen to detect the levels of hsa_circRNA_0008028, miR-182-5p, and tribble 3 (TRIB3). Then, dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to predict and verify the binding relationship between miR-182-5p and hsa_circRNA_0008028 or TRIB3. Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, corresponding commercial kits, and western blotting were used to measure indexes reflecting cell viability, proliferation, calcification, and autophagy of VSMCs, respectively. Results: In HG-induced VSMCs, hsa_circRNA_0008028 and TRIB3 were highly expressed, whereas miR-182-5p decreased. Meanwhile, cell proliferation, calcification, and autophagy could be repressed by silencing of hsa_circRNA_0008028. However, these effects can be eliminated by miR-182-5p inhibition. Furthermore, it was demonstrated that hsa_circRNA_0008028 could promote the expression of TRIB3, a target of miR-182-5p, by directly sponging miR-182-5p. The expression of TRIB3 was suppressed by hsa_circRNA_0008028 knockout, which was rescued by miR-182-5p inhibition. Conclusion: This study reveals that hsa_circRNA_0008028 can act as a sponge of miR-182-5p and promote HG-induced proliferation, calcification, and autophagy of VSMCs partly by regulating TRIB3.


Assuntos
Calcinose , Proteínas de Ciclo Celular , MicroRNAs , Proteínas Serina-Treonina Quinases , RNA Circular , Proteínas Repressoras , Autofagia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Glucose/farmacologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Circular/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
4.
J Cell Biol ; 221(10)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36066504

RESUMO

A ferritin particle consists of 24 ferritin proteins (FTH1 and FTL) and stores iron ions within it. During iron deficiency, ferritin particles are transported to lysosomes to release iron ions. Two transport pathways have been reported: macroautophagy and ESCRT-dependent endosomal microautophagy. Although the membrane dynamics of these pathways differ, both require NCOA4, which is thought to be an autophagy receptor for ferritin. However, it is unclear whether NCOA4 only acts as an autophagy receptor in ferritin degradation. Here, we found that ferritin particles form liquid-like condensates in a NCOA4-dependent manner. Homodimerization of NCOA4 and interaction between FTH1 and NCOA4 (i.e., multivalent interactions between ferritin particles and NCOA4) were required for the formation of ferritin condensates. Disruption of these interactions impaired ferritin degradation. Time-lapse imaging and three-dimensional correlative light and electron microscopy revealed that these ferritin-NCOA4 condensates were directly engulfed by autophagosomes and endosomes. In contrast, TAX1BP1 was not required for the formation of ferritin-NCOA4 condensates but was required for their incorporation into autophagosomes and endosomes. These results suggest that NCOA4 acts not only as a canonical autophagy receptor but also as a driver to form ferritin condensates to facilitate the degradation of these condensates by macroautophagy (i.e., macroferritinophagy) and endosomal microautophagy (i.e., microferritinophagy).


Assuntos
Autofagia , Ferritinas , Coativadores de Receptor Nuclear , Endossomos/metabolismo , Ferritinas/genética , Ferritinas/metabolismo , Ferro/metabolismo , Lisossomos/metabolismo , Coativadores de Receptor Nuclear/genética , Coativadores de Receptor Nuclear/metabolismo , Fagossomos/metabolismo , Fatores de Transcrição/metabolismo
5.
J Craniofac Surg ; 33(6): 1693-1697, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36054886

RESUMO

ABSTRACT: This study was aimed to observe the effects of skull defects on the brain in rats and further to investigate its underlying pathophysiological. Three different sizes of skull were removed in rats to produce models of skull defect, and then the behavioral changes were detected using a grip strength meter and neurobehavioral severity scale scores. The authors further examined the levels of cell apoptosis and autophagy, the cerebral blood flow with immunoblotting, and immunofluorescence micro-ultrasound system, respectively. The authors found that the sensory function but not the grip was impaired on the 6th day after a 5 × 10 mm defect while the motor function was on the 2nd day. In addition, the authors found an increment in B-cell lymphoma-2/BCL2-Associated X (Bcl2/Bax) and LC3 II/I expression, a maker of apoptosis and autophagy, respectively, in the defective hemisphere especially at the edge of the defective area. Importantly, the blood flow of internal carotid artery began to decline at 2 hours, and reached minimum on the 4th day, but began to recover on the 6th day in the hemi-defect group. In conclusion, a larger skull defect could impair the cognitive function but not the motor function and its underlying pathophysiology were mainly related to a decrease in cerebral flow.


Assuntos
Apoptose , Autofagia , Animais , Encéfalo , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos , Crânio/diagnóstico por imagem , Crânio/metabolismo
6.
Sci Rep ; 12(1): 15030, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056063

RESUMO

Dilated cardiomyopathy (DCM) is a condition of impaired ventricular remodeling and systolic diastole that is often complicated by arrhythmias and heart failure with a poor prognosis. This study attempted to identify autophagy-related genes (ARGs) with diagnostic biomarkers of DCM using machine learning and bioinformatics approaches. Differential analysis of whole gene microarray data of DCM from the Gene Expression Omnibus (GEO) database was performed using the NetworkAnalyst 3.0 platform. Differentially expressed genes (DEGs) matching (|log2FoldChange ≥ 0.8, p value < 0.05|) were obtained in the GSE4172 dataset by merging ARGs from the autophagy gene libraries, HADb and HAMdb, to obtain autophagy-related differentially expressed genes (AR-DEGs) in DCM. The correlation analysis of AR-DEGs and their visualization were performed using R language. Gene Ontology (GO) enrichment analysis and combined multi-database pathway analysis were served by the Enrichr online enrichment analysis platform. We used machine learning to screen the diagnostic biomarkers of DCM. The transcription factors gene regulatory network was constructed by the JASPAR database of the NetworkAnalyst 3.0 platform. We also used the drug Signatures database (DSigDB) drug database of the Enrichr platform to screen the gene target drugs for DCM. Finally, we used the DisGeNET database to analyze the comorbidities associated with DCM. In the present study, we identified 23 AR-DEGs of DCM. Eight (PLEKHF1, HSPG2, HSF1, TRIM65, DICER1, VDAC1, BAD, TFEB) molecular markers of DCM were obtained by two machine learning algorithms. Transcription factors gene regulatory network was established. Finally, 10 gene-targeted drugs and complications for DCM were identified.


Assuntos
Cardiomiopatia Dilatada , Redes Reguladoras de Genes , Autofagia/genética , Biomarcadores , Cardiomiopatia Dilatada/genética , Biologia Computacional , RNA Helicases DEAD-box/genética , Perfilação da Expressão Gênica , Humanos , Aprendizado de Máquina , Ribonuclease III/genética , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética
7.
Cell Mol Life Sci ; 79(9): 505, 2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36057892

RESUMO

In multiple cancers, autophagy promotes tumor development by recycling intracellular components into metabolic pathways. Autophagy-induced metabolic reprogramming and plasticity lead to cancer cell survival and resistance to anticancer therapy. We investigated the role of small leucine zipper protein (sLZIP) in autophagy and cell survival under nutrient-deficient conditions in colorectal cancer (CRC). sLZIP was induced by nutrient stress and increased the transcription of microtubule-associated protein 1A/1B-light chain 3 (LC3), by directly binding to its promoter. Under nutrient stress conditions, sLZIP activated autophagy and promoted the survival of CRC cells. sLZIP induced metabolic reprogramming of CRC cells, to activate glutaminolysis and the tricarboxylic acid cycle. sLZIP also enhanced the autophagic degradation of Keap1 and the nuclear accumulation of Nrf2, leading to NQO1 expression, for maintenance of redox homeostasis. sLZIP-knockout CRC cells exhibited impaired autophagy induction in the glycolytic inhibition state. Xenograft mice lacking sLZIP showed decreased tumor growth, by rendering CRC cells sensitive to glycolysis inhibition. The expression of sLZIP and LC3B was highly elevated in tumors of CRC patients compared to that in normal tissues, and correlated with the progression of CRC. These findings suggest that sLZIP drives autophagy and metabolic reprogramming to promote colorectal tumorigenesis.


Assuntos
Neoplasias Colorretais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Animais , Autofagia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Zíper de Leucina , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Nutrientes
8.
Front Cell Infect Microbiol ; 12: 989451, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36061869

RESUMO

Salmonella enterica is capable of invading different host cell types including epithelial cells and M cells during local infection, and immune cells and fibroblasts during the subsequent systemic spread. The intracellular lifestyles of Salmonella inside different cell types are remarkable for their distinct residential niches, and their varying replication rates. To study this, researchers have employed different cell models, such as various epithelial cells, immune cells, and fibroblasts. In epithelial cells, S. Typhimurium dwells within modified endolysosomes or gains access to the host cytoplasm. In the cytoplasm, the pathogen is exposed to the host autophagy machinery or poised for rapid multiplication, whereas it grows at a slower rate or remains dormant within the endomembrane-bound compartments. The swift bimodal lifestyle is not observed in fibroblasts and immune cells, and it emerges that these cells handle intracellular S. Typhimurium through different clearance machineries. Moreover, in these cell types S. Typhimurium grows withing modified phagosomes of distinct functional composition by adopting targeted molecular countermeasures. The preference for one or the other intracellular niche and the diverse cell type-specific Salmonella lifestyles are determined by the complex interactions between a myriad of bacterial effectors and host factors. It is important to understand how this communication is differentially regulated dependent on the host cell type and on the distinct intracellular growth rate. To support the efforts in deciphering Salmonella invasion across the different infection models, we provide a systematic comparison of the findings yielded from cell culture models. We also outline the future directions towards a better understanding of these differential Salmonella intracellular lifestyles.


Assuntos
Infecções por Salmonella , Salmonella typhimurium , Autofagia , Proteínas de Bactérias/metabolismo , Células Epiteliais/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Fagossomos/metabolismo , Infecções por Salmonella/microbiologia
9.
Curr Cancer Drug Targets ; 22(9): 749-756, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36062863

RESUMO

Basal autophagy plays a crucial role in maintaining intracellular homeostasis and prevents the cell from escaping the cell cycle regulation mechanisms and being cancerous. Mitophagy and nucleophagy are essential for cell health. Autophagy plays a pivotal role in cancer cell transformation, where upregulated precancerous autophagy induces apoptosis. Impaired autophagy has been shown to upregulate cancer cell transformation. However, tumor cells upregulate autophagy to escape elimination and survive the unfavorable conditions and resistance to chemotherapy. Cancer cells promote autophagy through modulation of autophagy regulation mechanisms and increase expression of the autophagyrelated genes. Whereas, autophagy regulation mechanisms involved microRNAs, transcription factors, and the internalized signaling pathways such as AMPK, mTOR, III PI3K, and ULK-1. Disrupted regulatory mechanisms are various as the cancer cell polymorphism. Targeting a higher level of autophagy regulation is more effective, such as gene expression, transcription factors, or epigenetic modification that are responsible for the up-regulation of autophagy in cancer cells. Currently, the CRISPR-CAS9 technique is available and can be applied to demonstrate the potential effects of autophagy in cancerous cells.


Assuntos
Autofagia , Neoplasias , Apoptose , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Transdução de Sinais , Fatores de Transcrição
10.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 44(4): 709-716, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36065706

RESUMO

Sarcopenia,an age-related disease caused by the imbalance in protein synthesis and degradation,can result in significant decreases in skeletal muscle mass and strength.Skeletal muscle loss during aging is inevitable and can affect the life quality of the elderly.Moreover,it may increase the risks of other age-related diseases in the elderly.However,the underlying molecular mechanism remains unclear in age-related skeletal muscle loss.Autophagy is a degradation pathway for the removal of dysfunctional organelles and damaged macromolecules during aging.Mitochondria also play a key role in skeletal muscle function.To maintain skeletal muscle mass,we should pay attention to autophagy and improve mitochondrial homeostasis through autophagy or other means.This paper summarizes the research progress of autophagy and mitochondrial quality control in sarcopenia,aiming to provide reference for exploring new therapies.


Assuntos
Sarcopenia , Idoso , Autofagia , Homeostase , Humanos , Mitocôndrias , Músculo Esquelético
11.
Biomed Pharmacother ; 149: 112916, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-36068776

RESUMO

During placentation, cytotrophoblasts differentiate and fuse to form multinucleated cells (syncytiotrophoblasts) in a process that involves autophagy. Appropriate syncytial differentiation is essential for establishing a healthy pregnancy. In this study, we evaluated the effect of two chloroquine compounds, hydroxychloroquine (HCQ) and chloroquine (CQ), on syncytial differentiation and autophagy in cultured primary human trophoblasts (PHTs). PHT cells were isolated from the human term placenta. Bafilomycin, a well-known autophagy inhibitor, was used as a positive control. Biochemical and morphological differentiation was assessed in syncytiotrophoblasts, and autophagy-related proteins and genes were evaluated. Affymetrix Human Gene 2.0 ST Array profiling was used to identify genes affected by HCQ during syncytial differentiation. Chloroquine compounds lowered the production of beta-human chorionic gonadotropin (ß-hCG) and the fusion index in PHTs. Syncytial differentiation in PHT was associated with the increased expression of ATG4C mRNA (autophagy-related gene), and this expression was affected by CQ but not by HCQ. Microarray analysis revealed that HCQ or CQ affected several genes (MMP15, GPC3, CXCL10, TET-1, and S100A7) during syncytial differentiation, which were different from that of the syncytial differentiation suppression (Ham's/Waymouth media) or autophagy inhibition (bafilomycin treatment). Using Kyoto Encyclopedia of Genes and Genomes analysis we identified that HCQ might affect JAK2 signaling in the syncytial differentiation of PHT. In conclusion, chloroquine compounds could mitigate biochemical and morphological syncytial trophoblast differentiation in cultured PHT cells through the JAK signaling pathway rather than the inhibition of autophagic activity.


Assuntos
Cloroquina , Hidroxicloroquina , Autofagia , Diferenciação Celular , Cloroquina/farmacologia , Feminino , Glipicanas/metabolismo , Glipicanas/farmacologia , Humanos , Hidroxicloroquina/farmacologia , Gravidez , Trofoblastos/metabolismo
12.
Oxid Med Cell Longev ; 2022: 1898844, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046681

RESUMO

Platelet transfusion is a life-saving therapy to prevent bleeding; however, the availability of platelets for transfusion is limited by the markedly short shelf life owing to the development of platelet storage lesions (PSLs). The mechanism of PSLs remains obscure. Dissection of the intracellular biological changes in stored platelets may help to reduce PSLs and improve platelet transfusion efficiency. In the present study, we explore the changes of stored platelets at room temperature under constant agitation. We found that platelets during storage showed an increased reactive oxygen species (ROS) generation accompanied with receptor shedding, apoptosis, and diminished platelet aggregation. ROS scavenger reduced platelet shedding but also impaired platelet aggregation. Autophagy is a conserved catabolic process that sequesters protein aggregates and damaged organelles into lysosomes for degradation and platelets' own intact autophagic system. We revealed that there exist a stable autophagic flux in platelets at the early stage of storage, and the autophagic flux in platelets perished after long-term storage. Treatment stored platelets with rapamycin, which stimulates autophagy in eukaryotic cells, markedly ameliorated PSLs, and improved platelet aggregation in response to extracellular stimuli.


Assuntos
Plaquetas , Agregação Plaquetária , Autofagia , Plaquetas/metabolismo , Transfusão de Plaquetas , Espécies Reativas de Oxigênio/metabolismo
13.
Oxid Med Cell Longev ; 2022: 6483582, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046683

RESUMO

Background: Astrocytes can be involved in motor neuron toxicity in amyotrophic lateral sclerosis (ALS) induced by noncell autonomous effects, and inflammatory cytokines may play the main role in mediating this process. However, the etiology of aberrant cytokine secretion is unclear. The present study assessed possible involvement of the mTOR-autophagy pathway in aberrant cytokine secretion by ALS patient iPSC-derived astrocytes. Method and Results. PBMCs from sporadic ALS patients and control subjects were reprogrammed into iPSCs, which were then differentiated into astrocytes and/or motor neurons. Comparison with control astrocytes indicated that conditioned medium of ALS astrocytes reduced the viability of the control motor neurons (p < 0.05) assessed using the MTT assay. The results of ELISA showed that the concentrations of TNFα, IL1ß, and IL6 in cell culture medium of ALS astrocytes were increased (p < 0.05). ALS astrocytes had higher p62 and mTOR levels and lower LC3BII/LC3BI ratio and ULK1 and p-Beclin-1 (Ser15) levels (p < 0.05), indicating defective autophagy. Exogenous inhibition of the mTOR-autophagy pathway, but not the activation of the pathway in control subject astrocytes, increased the levels of p62 and mTOR and concentration of IL-1ß, TNF-α, and IL-6 in cell culture medium and decreased the LC3BII/LC3BI ratio and levels of ULK1 and p-Beclin-1 (Ser15), and these changes were comparable to those in ALS astrocytes. After 48 h of rapamycin (autophagy activator) and 3-methyladenine (autophagy inhibitor) treatments, the exogenous activation of the mTOR-autophagy pathway, but not inhibition of the pathway, in ALS astrocytes significantly reduced the concentrations of TNFα, IL1ß, and IL6 in cell culture medium and reduced the levels of p62, while increasing the levels of LC3B-II/LC3B-I, ULK1, and p-Beclin-1 (Ser15), and these changes were comparable to those in control subject astrocytes. Conclusion: Alteration in the mTOR/ULK1/Beclin-1 pathway regulated cytokine secretion in ALS astrocytes, which was able to lead to noncell autonomous toxicity. Autophagy activation mitigated cytokine secretion by ALS astrocytes.


Assuntos
Esclerose Amiotrófica Lateral , Células-Tronco Pluripotentes Induzidas , Esclerose Amiotrófica Lateral/metabolismo , Astrócitos/metabolismo , Autofagia , Proteína Beclina-1/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Interleucina-6/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Zhongguo Zhen Jiu ; 42(9): 1011-6, 2022 Sep 12.
Artigo em Chinês | MEDLINE | ID: mdl-36075597

RESUMO

OBJECTIVE: To investigate the effect of moxibustion on autophagy and amyloid ß-peptide1-42 (Aß1-42) protein expression in amyloid precursor protein/presenilin 1 (APP/PS1) double-transgenic mice with Alzheimer's disease (AD). METHODS: After 2-month adaptive feeding, fifty-six 6-month-old APP/PS1 double transgenic AD mice were randomly divided into a model group, a moxibustion group, a rapamycin group and an inhibitor group, 14 mice in each group. Another 14 C57BL/6J mice with the same age were used as a normal group. The mice in the moxibustion group were treated with monkshood cake-separated moxibustion at "Baihui"(GV 20), "Fengfu" (GV 16) and "Dazhui" (GV 14) for 20 min; the mice in the rapamycin group were intraperitoneally injected with rapamycin (2 mg/kg); the mice in the inhibitor group were treated with moxibustion and injection of 1.5 mg/kg 3-methyladenine (3-MA). All the treatments were given once a day for consecutive 2 weeks. The morphology of hippocampal tissue was observed by HE staining; the ultrastructure of hippocampal tissue was observed by transmission electron microscopy; the expression of Aß1-42 protein in frontal cortex and hippocampal tissue was detected by immunohistochemistry; the expressions of mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR), p70 ribosomal protein S6 kinase (p70S6K) and phosphorylated p70S6K (p-p70S6K) protein in hippocampus were detected by Western blot method. RESULTS: Compared with the normal group, the number of neuron cells was decreased, cells were necrotic and deformed, and autophagy vesicle and lysosome were decreased in the model group. Compared with the model group, the number of neuron cells was increased, cell necrosis was decreased, and autophagy vesicle and lysosome were increased in the moxibustion group and the rapamycin group. Compared with the normal group, the protein expressions of Aß1-42, mTOR, p-mTOR, p70S6K and p-p70S6K in the model group were increased (P<0.05); compared with the model group, the protein expressions of Aß1-42, mTOR, p-mTOR, p70S6K and p-p70S6K in the moxibustion group, rapamycin group and inhibitor group were decreased (P<0.05); compared with the inhibitor group, the protein expressions of Aß1-42, mTOR, p-mTOR, p70S6K and p-p70S6K in the moxibustion group and rapamycin group were decreased (P<0.05); compared with the rapamycin group, the protein expressions of mTOR, p-mTOR, p70S6K and p-p70S6K in the moxibustion group were decreased (P<0.05). CONCLUSION: Moxibustion could enhance autophagy in hippocampal tissue of APP/PS1 double transgenic AD mice and reduce abnormal Aß aggregation in brain tissue, the mechanism may be related to the inhibition of mTOR/p70S6K signaling pathway.


Assuntos
Doença de Alzheimer , Moxibustão , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/genética , Animais , Autofagia , Modelos Animais de Doenças , Hipocampo/metabolismo , Mamíferos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/farmacologia , Transdução de Sinais , Sirolimo/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
15.
Biomed Pharmacother ; 153: 113424, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076545

RESUMO

Diabetic nephropathy (DN) is one of the most serious microvascular complications following diabetes mellitus (DM). Ferulic acid (FA), a phenolic acid widely found in plants, has multiple pharmacological effects such as anti-oxidation, anti-inflammation and anti-tumor. However, the current research on FA in the field of DN is insufficient. The present study aimed to explore the nephroprotective effect of FA on DN in mice and reveal its underlying mechanism. DN was induced by high-fat diet (HFD) combined with streptozotocin (STZ) injection in male C57BL/6J mice. Animals were randomly divided into four groups (n = 8): Control group, DN group, FA group (200 mg/kg FA, i.g.) and valsartan (VAL) group (12 mg/kg VAL, i.g.). The drug was administered once a day for 8 weeks. Treated with FA, the body weight and fasting blood glucose (FBG) of DN mice were reduced and the renal organ coefficient was significantly optimized. Meanwhile, FA decreased levels of 24-h urine protein excretion (24-h UP) in urine and blood urea nitrogen (BUN), creatinine (Cr) in serum, reduced levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in serum. In addition, FA promoted light chain 3 (LC3) expression markedly, and inhibited the expressions of p62, NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1ß (IL-1ß) in renal tissues. In conclusion, FA played a positive role in alleviating renal injury in HFD/STZ-induced DN mice by enhancing autophagy and suppressing excessive inflammation.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Autofagia , Colesterol/metabolismo , Ácidos Cumáricos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Inflamação/metabolismo , Rim , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina/farmacologia
16.
Biomed Pharmacother ; 153: 113443, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076558

RESUMO

16-hydroxycleroda-3,13-dien-15,16-olide (HCD) has antitumor activity reported in numerous types of cancers. However, the efficacy of HCD treatment in non-small-cell lung cancer (NSCLC) cells and doxorubicin-resistant (Dox-R)-NSCLC cells remains to be unraveled. The underlying anti-cancer mechanism of HCD on Dox-R and Dox-sensitive (Dox-S) of A549 cells was also investigated. Cytotoxicity of HCD against two cell lines (Dox-S and Dox-R) were determined via MTT assay, flow cytometry, and Western blot. A further examination of its anti-cancer efficacy was performed in A549-bearing xenograft mice via orthotopic intratrachea (IT) inoculation, which showed that HCD could arrest both Dox-S and Dox-R cells at G2/M phase without altering the sub-G1 cycle along with increasing of cleaved-PARP. HCD downregulated the mTOR/Akt/PI3K-p85 and PI3K-ClassIII/Beclin-1 signals and upregulated p62/LC3-I/II expressions to further confirm that the cell autophagy of NSCLC cells after being HCD-induced. Morphological observations of mouse lung sections illustrated that fewer cancer cells accumulated close to the trachea while less neoplastic activities were found in HCD orthotopic treated mice without liver, kidney, and spleen toxicity. Lastly, Dox, HCD, and target therapy medicines of EGFR and ALK were nicely docked with EGFR, ALK, and mTOR. Conclusively, HCD was demonstrated the chemotherapeutic potential regardless of Dox-R and Dox-S cells, suggesting natural autophagic inducer HCD provides a promising lead compound for new drug discovery and development of lung cancer therapies.


Assuntos
Morte Celular Autofágica , Carcinoma Pulmonar de Células não Pequenas , Diterpenos , Neoplasias Pulmonares , Animais , Apoptose , Autofagia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Receptores ErbB , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Fosfatidilinositol 3-Quinases , Receptores Proteína Tirosina Quinases , Serina-Treonina Quinases TOR/metabolismo
17.
Biomed Pharmacother ; 153: 113549, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076613

RESUMO

Microglial activation in the spinal cord contributes to the development of inflammatory pain. Monocyte chemotactic protein 3 (MCP3) can induce microglial activation, resulting in increased pain sensitivity; however, the underlying mechanism remains poorly understood. 3,5-dicaffeoylquinic acid (3,5-DCQA) has shown protective effects against inflammation-related diseases, but the effect of 3,5-DCQA on microglial activation and inflammatory pain is not evaluated. This study aimed to investigate the effects of 3,5-DCQA on microglial activation-induced inflammatory pain. Furthermore, the underlying mechanism inhibited by 3,5-DCQA via MCP3 suppression was studied. To induce microglial activation, LPS was treated in BV2 microglial cells. The LPS-induced microglial activation and pro-inflammatory cytokines production were significantly reduced by 3,5-DCQA treatment in BV2 cells. Moreover, 3,5-DCQA suppressed LPS-induced MCP3 expression, resulting in reduced phosphorylation of JAK2/STAT3. Interestingly, the suppressed JAK2/STAT3 signaling enhanced autophagy induction in BV2 cells. The increased autophagy by 3,5-DCQA and knockout of MCP3 inhibited LPS-induced inflammatory response in BV2 cells. To establish the inflammatory pain, CFA was injected into the right paw of mice. The CFA-induced pain hypersensitivity and foot swelling were attenuated by the oral administration of 3,5-DCQA. Moreover, CFA-induced microglial activation was reduced and the autophagy markers were recovered in the spinal cord of 3,5-DCQA-administered mice. Similar results were observed in cultured primary microglia. Our findings indicate that 3,5-DCQA attenuates inflammation-mediated pain hypersensitivity by enhancing autophagy through inhibition of MCP3-induced JAK2/STAT3 signaling. Therefore, 3,5-DCQA could be a potential therapeutic agent for alleviating inflammatory pain.


Assuntos
Lipopolissacarídeos , Microglia , Animais , Autofagia , Quimiocina CCL7/metabolismo , Ácido Clorogênico/análogos & derivados , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Dor/tratamento farmacológico , Dor/metabolismo
18.
Biomed Pharmacother ; 153: 113547, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076620

RESUMO

Autophagy is a well-conserved biological process that maintains homeostasis. Accumulating evidence has revealed that autophagy plays an important role in various cardiovascular diseases, such as aneurysm, aortic dissection, atherosclerosis, and myocardial ischemia-reperfusion injury. Here, we summarize the current experimental evidence on the function of autophagy and autophagy proteins in aortic aneurysm and dissection (AAD). AAD is a very serious aortic disease, and there are currently no effective drug treatment options. Studies have shown that autophagy is activated during AAD. However, the role of autophagy in AAD is still controversial. For example, knocking out autophagy related 5 (ATG5) or ATG7 to inhibit autophagy and excessive autophagy activation can promote the occurrence of AAD. Recently, multiple studies have demonstrated that rapamycin and metformin, which are autophagy activators, can delay the progression of AAD. Thus, targeting autophagy has the potential to become a new therapeutic strategy for AAD. In addition, we discuss the recent research progress on AAD from the perspective of single-cell RNA sequencing. Moreover, we offer our perspective on current challenges and barriers in this research field.


Assuntos
Aneurisma Dissecante , Aneurisma Aórtico , Aneurisma Dissecante/tratamento farmacológico , Aneurisma Aórtico/tratamento farmacológico , Autofagia , Humanos , Resultado do Tratamento
19.
Neurol India ; 70(4): 1643-1648, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36076674

RESUMO

X-linked myopathy with excessive autophagy (XMEA) is a rare, recently characterized type of autophagic vacuolar myopathy caused by mutations in the VMA21 gene. It is characterized by slowly progressive weakness restricted to proximal limb muscles and generally has a favorable outcome. The characteristic histological and ultrastructural features distinguish this entity from other mimics, notably Danon disease. XMEA is an under recognized disease and should be considered in the differentials of slowly progressive myopathy in children. Awareness of this rare entity is also important for the pathologists in order to distinguish it from other causes of vacuolar myopathy in view of its favourable prognosis. We report the first genetically confirmed case of XMEA from India in an 8-year-old boy which was diagnosed based on the characteristic light microscopic and ultrastructural findings on muscle biopsy and subsequently confirmed by mutation analysis. The differential diagnostic considerations are also discussed.


Assuntos
Doenças Musculares , ATPases Vacuolares Próton-Translocadoras , Autofagia/genética , Criança , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Doenças por Armazenamento dos Lisossomos , Masculino , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/patologia , ATPases Vacuolares Próton-Translocadoras/genética
20.
Int J Mol Sci ; 23(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36076926

RESUMO

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient's fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients' cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients' cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling.


Assuntos
Ferroptose , Autofagia/genética , Encéfalo/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Feminino , Ferroptose/genética , Humanos , Ferro/metabolismo , Imageamento por Ressonância Magnética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...