RESUMO
BACKGROUND: COVID-19, the current global pandemic caused by SARS-CoV-2 infection, can damage the heart and lead to heart failure (HF) and even cardiac death. The 2',5'-oligoadenylate synthetase (OAS) gene family encode interferon (IFN)-induced antiviral proteins which is associated with the antiviral immune responses of COVID-19. While the potential association of OAS gene family with cardiac injury and failure in COVID-19 has not been determined. METHODS: The expression levels and biological functions of OAS gene family in SARS-CoV-2 infected cardiomyocytes dataset (GSE150392) and HF dataset (GSE120852) were determined by comprehensive bioinformatic analysis and experimental validation. The associated microRNAs (miRNAs) were explored from Targetscan and GSE104150. The potential OAS gene family-regulatory chemicals or ingredients were predicted using Comparative Toxicogenomics Database (CTD) and SymMap database. RESULTS: The OAS genes were highly expressed in both SARS-CoV-2 infected cardiomyocytes and failing hearts. The differentially expressed genes (DEGs) in the two datasets were enriched in both cardiovascular disease and COVID-19 related pathways. The miRNAs-target analysis indicated that 10 miRNAs could increase the expression of OAS genes. A variety of chemicals or ingredients were predicted regulating the expression of OAS gene family especially estradiol. CONCLUSION: OAS gene family is an important mediator of HF in COVID-19 and may serve as a potential therapeutic target for cardiac injury and HF in COVID-19.
Assuntos
COVID-19 , Insuficiência Cardíaca , MicroRNAs , Humanos , COVID-19/complicações , COVID-19/genética , SARS-CoV-2 , Insuficiência Cardíaca/genética , Antivirais , MicroRNAs/genéticaRESUMO
The high-throughput production of the eco-friendly MIL-88A(Fe) was achieved under mild reaction conditions with normal pressure and temperature. The as-prepared MIL-88A(Fe) exhibited efficient photo-Fenton catalytic ofloxacin (OFL) degradation upon visible light irradiation with good stability and reusability. The OFL (20.0 mg/L) was completely degraded within 50 min under visible light with the aid of MIL-88A(Fe) (0.25 g/L) and H2O2 (1.0 mL/L) in aqueous solution (pH = 7.0). The hydroxyl radicals (·OH) are the main active species during the photo-Fenton oxidation process. Meanwhile, the degradation intermediates and the corresponding degradation pathways were identified and proposed with the aid of both ultra-high performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and density functional theory (DFT) calculations. Finally, the degradation product library was firstly established to identify intermediate transformation products (TPs) with their variation of concentration, and their corresponding toxicologic activities were assessed via Toxtree and T.E.S.T software as well. Finally, the MIL-88A is efficient and stable with four cycles' catalysis operations, demonstrating good potential for water treatment.
Assuntos
Ofloxacino , Purificação da Água , Catálise , Peróxido de Hidrogênio/química , Ofloxacino/toxicidade , Purificação da Água/métodosRESUMO
Lysine crotonylation (Kcr) is a newly identified protein translational modification and is involved in major biological processes including glycolysis, but its role in colorectal cancer (CRC) is unknown. Here, we found that the Kcr of α enolase (ENO1) was significantly elevated in human CRC tissues compared with the paratumoral tissues. CREB-binding protein (CBP) functioned as a crotonyltranferase of ENO1, and SIRT2 was involved in the decrotonylation of ENO1. Using quantitative mass spectrometry for crotonylomics analysis, we further found that K420 was the main Kcr site of ENO1 and ENO1 K420 Kcr promoted the growth, migration, and invasion of CRC cells in vitro by enhancing the activity of ENO1 and regulating the expression of tumor-associated genes. Our study reveals an important mechanism by which ENO1 regulates CRC through crotonylation.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteína de Ligação a CREB/metabolismo , Neoplasias Colorretais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Lisina/metabolismo , Fosfopiruvato Hidratase/metabolismo , Processamento de Proteína Pós-Traducional , Sirtuína 2/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Biomarcadores Tumorais/genética , Proteína de Ligação a CREB/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Humanos , Espectrometria de Massas , Metástase Neoplásica , Fosfopiruvato Hidratase/genética , Sirtuína 2/genética , Proteínas Supressoras de Tumor/genética , Regulação para CimaRESUMO
To investigate the factors associated with the duration of severe acute respiratory syndrome coronavirus 2 RNA shedding in patients with coronavirus disease 2019 (COVID-19). A retrospective cohort of COVID-19 patients admitted to a designated hospital in Beijing was analyzed to study the factors affecting the duration of viral shedding. The median duration of viral shedding was 11 days (IQR, 8-14.3 days) as measured from illness onset. Univariate regression analysis showed that disease severity, corticosteroid therapy, fever (temperature>38.5°C), and time from onset to hospitalization were associated with prolonged duration of viral shedding (P < .05). Multivariate regression analysis showed that fever (temperature>38.5°C) (OR, 5.1, 95%CI: 1.5-18.1), corticosteroid therapy (OR, 6.3, 95%CI: 1.5-27.8), and time from onset to hospitalization (OR, 1.8, 95%CI: 1.19-2.7) were associated with increased odds of prolonged duration of viral shedding. Corticosteroid treatment, fever (temperature>38.5°C), and longer time from onset to hospitalization were associated with prolonged viral shedding in COVID-19 patients.
Assuntos
COVID-19/virologia , SARS-CoV-2/fisiologia , Eliminação de Partículas Virais/fisiologia , Corticosteroides/uso terapêutico , Adulto , COVID-19/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/isolamento & purificação , Fatores de Risco , Fatores de Tempo , Tratamento Farmacológico da COVID-19RESUMO
Constitutive activation of Hedgehog (Hh) pathway is intimately related with the occurrence and development of several malignancies, such as medulloblastoma (MB) and other tumors. Therefore, small molecular inhibitors of Hh pathway are urgently needed. In this study, three new steroidal alkaloids, â¿5 (20R, 24R) 23-oxo-24-methylsolacongetidine, â¿5 (20S, 24R) 23-oxo-24-methylsolacongetidine and veralinine 3-O-α-l-rhamnopyranosyl-(1 â 2)-ß-D-glucopyranoside, together with six known alkaloids, 20-epi-verazine, verazine, protoverine 15-(l)-2'-methylbutyrate, jervine, veramarine and ß1-chaconine, were isolated and determined from Veratrum grandiflorum Loes. The dual-luciferase bioassay indicated that all compounds exhibited significant inhibitions of Hh pathway with IC50 values of 0.72-14.31 µM against Shh-LIGHT 2 cells. To determine whether these Hh pathway inhibitors act with the Smoothened (Smo) protein, which is an important oncoprotein and target for this pathway, BODIPY-cyclopamine (BC) competitive binding assay was preferentially performed. Compared with BC alone, all compounds obviously reduced the fluorescence intensities of BC binding with Smo in Smo-overexpression HEK293T cells through fluorescence microscope and flow cytometer. By directly interacting with Smo, it revealed that they were actually novel natural Smo inhibitors. Then, their anti-tumor effects were investigated against the human MB cell line DAOY, which is a typical pediatric brain tumor cells line with highly expressed Hh pathway. Interestingly, most of compounds had slight proliferation inhibitions on DAOY cells after treatment for 24 h same as vismodegib, while ß1-chaconine showed the strongest inhibitory effect on the growth of DAOY with IC50 value of 5.35 µM. In conclusion, our studies valuably provide several novel natural Smo inhibitors for potential targeting treatment of Hh-dependent tumors.
Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Proliferação de Células/efeitos dos fármacos , Meduloblastoma/patologia , Receptor Smoothened/antagonistas & inibidores , Esteroides/química , Veratrum/química , Alcaloides/química , Linhagem Celular Tumoral , Células HEK293 , Humanos , Estrutura Molecular , Análise Espectral/métodosRESUMO
Ligustilide is a phenolic compound isolated from Asian plants of Umbelliferae family. This study was aimed at exploring the neuroprotective effects of Ligustilide from the perspective of endoplasmic reticulum stress (ERS) and autophagy. The Alzheimer's disease (AD) cell models were constructed by SH-SY5Y cell line, which was exposed to 20 µM Aß25-35 . CCK-8 was used to evaluate the cell viability of Ligustilide on AD cell model. Hoechst staining and LysoTracker Red were used to test the cell apoptosis and Lysosome function, respectively. ERS in living cells were detected by Thioflavin T. The expression of autophagy-related proteins (LC3B-II/I, P62/SQSTM1, Beclin1, and Atg5), ERS marker proteins (PERK, GRP78, and CHOH), and apoptosis proteins (Bax, Bcl-2, and Caspase-12) were analyzed by Western blot analyses. Aß25-35 could induce ERS and autophagy in a time-dependent manner in SH-SY5Y cells. We demonstrated that Ligustilide significantly decreased the rate of apoptosis, and improved the viability of cells. Simultaneously, Ligustilide effectively modulated ERS via inhibiting the over-activation of GRP78/PERK/CHOP signaling pathway. In addition, Ligustilide alleviated the accumulation of autophagy vacuoles, reduced the ratio of LC3B-II/I and the level of P62/SQSTM1. Ligustilide significantly up-regulated lysosomal acidity and the expression of Cathepsin D (CTSD). Ligustilide could rescue lysosomal function to promote autophagy flux and inhibit the over-activation of ERS. This finding may contribute to the development of new therapeutic strategies for AD.
Assuntos
4-Butirolactona/análogos & derivados , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Apoptose , Chaperona BiP do Retículo Endoplasmático , Humanos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais , TransfecçãoRESUMO
In-depth analysis on the rambling genes of psoriasis may help to identify the pathologic mechanism of this disease. However, this has seldom been performed. Using bioinformatic approaches, we analyzed four gene expression profiles in gene expression omnibus (GEO) database, identified the differentially expressed genes (DEGs), and found out the overlapping DEGs (common DEGs, CDEGs) in the above four profiles. The CDEGs were further subjected to Gene Ontology (GO) enrichment analysis, Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis and protein-protein interaction (PPI) network analysis, and hub genes were ranked. We identified 139 CDEGs associated with a variety of GO processes including keratinization, immune and inflammatory responses, and type 1 interferon signaling pathway. These CDEGs were enriched in a variety of KEGG processes, including cytokine-cytokine receptor interaction and chemokine signaling. PPI analysis showed that seven genes (HERC6, ISG15, MX1, RSAD2, OAS2, OASL, and OAS3) were likely the novel hub genes of psoriasis. RT-qPCR identified that five (ISG15, MX1, OAS2, OASL, and OAS3) of the seven predicted hub genes were overexpressed in TNF-α stimulated HaCaT cell lines, a result quite consistent with the predictions. The study provides new information in exploring the mechanisms and therapeutic targets of psoriasis.
Assuntos
Mapas de Interação de Proteínas , Psoríase , Biologia Computacional , Ontologia Genética , Humanos , Psoríase/genética , TranscriptomaRESUMO
This study aims to investigate the PPARγ agonists isolated from the aqueous extract of Siegesbeckia pubescens( SPA) and their anti-inflammatory activities in vitro. The 293 T cells transfected transiently with PPARγ recombinant plasmid were used as a screening model to guide the isolation of PPARγ activitating components,and then PPARγ activities were measured by double luciferase reporter gene assay. The chemical structures were identified by chromatography or spectroscopic techniques. Furthermore,a UC inflammatory model in vitro was established on HT-29 cells by stimulating with TNF-αï¼ The mRNA levels and secretion of proinflammatory cytokines on HT-29 cells,such as IL-1ß,TNF-α,IL-8,were detected by RT-PCR and ELISA. The results showed that five diterpenoids were obtained from the fraction D_(50) with the strongest PPARγ activity among others in SPA,and determined as kirenol( 1),darutigenol( 2),enantiomeric-2-ketone-15,16,19-three hydroxypinomane-8( 14)-ene-19-O-ß-D-glucoside( 3),darutoside( 4),enantiomeric-2-ß,15,16,19-four hydroxypinomane-8( 14)-ene-19-O-ß-D-glucoside( 5),respectively. All the compounds exhibited active effects on PPARγ in a concentration-dependent manner( P<0. 01). In addition,compound 1 significantly inhibited the expression of IL-1ß mRNA and secretion of IL-8 on HT-29 cells inflammation model( P<0. 001); both compounds 2 and 3 effectively inhibited the expression of IL-1ß,TNF-α,IL-8 mRNA and secretion of IL-8( P<0. 01 or P<0. 001),although at different extent; compound 4 significantly inhibited the expression of IL-1ß and TNF-α mRNA( P<0. 01 or P<0. 001),while compound 5 inhibited the expression of IL-1ß mRNA obviously( P<0. 001). In conclusion,the diterpenoids 1-5 isolated from S. pubescens have the PPARγ activation activities and potential effects of anti-UC in vitro.
Assuntos
Anti-Inflamatórios/farmacologia , Asteraceae/química , Diterpenos/farmacologia , PPAR gama/agonistas , Colite Ulcerativa , Citocinas/imunologia , Células HT29 , Humanos , Fator de Necrose Tumoral alfaRESUMO
The aim of this study was to screen the genes related to the pathogenesis of major depression disorder (MDD) by bioinformatics. Taking GSE98793 chip data from GEO public database of National Biotechnology Information Center (NCBI) website as the research object, 116 differentially expressed genes (DEGs) were screened by R language limma package. Among the 116 DEGs, 66 genes were up-regulated and 50 down-regulated. The results of gene functional annotation analysis of Gene Ontology (GO) showed that the DEGs were mainly distributed in mitochondria intima and mitochondria. They were involved in copper ion binding, cysteine-type endopeptidase activity, the cell response of interleukin-1, protein processing and other biological processes. KEGG pathway enrichment analysis results showed that the DEGs were mainly concentrated in oxidative phosphorylation, Parkinson's disease, non-alcoholic fatty liver disease, Alzheimer's disease and Huntington's disease etc. The results of protein interaction network analysis showed that there were interactions among proteins encoded by 54 DEGs. Combined with the analysis results of the above methods, 11 key genes were screened out, including UQCRC1, GZMB, NDUFB9, NSF, SLC17A5, CTSH, NDUFB10, UQCR10, ATOX1, CST7 and CTSW, which could be used as candidate genes for the diagnosis and treatment of MDD. Taken together, the key genes were obtained by analyzing the microarray and the DEGs of MDD in the present study, which would provide important clues for revealing the molecular mechanism and clinical targeted therapy of depression.
Assuntos
Biologia Computacional , Transtorno Depressivo Maior/genética , Mapas de Interação de Proteínas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Análise de Sequência com Séries de OligonucleotídeosRESUMO
OBJECTIVE: To investigate the clinical effects of aripiprazole on sexual dysfunction induced by amisulpride or risperidone in male patients with schizophrenia. METHODS: This study included 75 male patients with drug-induced secondary sexual dysfunction after treated with amisulpride or risperidone for first-episode schizophrenia between October 2014 and October 2016. We substituted aripiprazole for amisulpride or risperidone, gradually increased the dose from 10 to 30 mg/d within 2 weeks, and maintained 30 mg/d from the 3rd week. At 4 and 8 weeks after medication, we evaluated the sexual function of the patients, measured the levels of serum prolactin (PRL) and testosterone (T), obtained the scores of the Positive and Negative Symptoms Scale (PANSS), recorded adverse reactions, and compared the parameters with those before aripiprazole administration. RESULTS: Compared with pre-aripiprazole administration, the patients showed significant increases after 4 weeks of medication in the sexual function score (24.3 ± 2.1 vs 32.6 ± 3.6, P <0.05) and T level (ï¼»13.3 ± 2.7ï¼½ vs ï¼»17.4±3.0ï¼½ mmol/L, P <0.05) but a decreased level of PRL (ï¼»38.5 ± 10.5ï¼½ vs ï¼»27.9 ± 8.2ï¼½ ng/ml, P <0.05). At 8 weeks, the sexual function score and serum PRL were both restored to the baseline levels at admission, and the erectile function score, ejaculation score, total score, and serum T level even exceeded the baseline, though with no statistically significant differences (P >0.05). In comparison with pre-aripiprazole administration, the PANSS score was significantly decreased at 4 weeks after medication (62.1 ± 4.9 vs 57.2 ± 5.5, P <0.05) and even lower at 8 weeks (51.2 ± 5.2) (P <0.05). The incidence rates of medication-related excitation, dizziness, insomnia, and loss of appetite were 6.7%, 5.3%, 4.0% and 1.3% respectively, and no other serious adverse reactions were observed. CONCLUSIONS: Aripiprazole is effective for the treatment of drug-induced sexual dysfunction in schizophrenic men by continuously alleviating their positive and negative symptoms and meanwhile improving their sexual function and restoring their sexual hormone levels.
Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Aripiprazol/administração & dosagem , Risperidona/efeitos adversos , Esquizofrenia/tratamento farmacológico , Disfunções Sexuais Fisiológicas/induzido quimicamente , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Sulpirida/análogos & derivados , Amissulprida , Esquema de Medicação , Humanos , Masculino , Prolactina/sangue , Esquizofrenia/sangue , Comportamento Sexual , Disfunções Sexuais Fisiológicas/sangue , Sulpirida/efeitos adversos , Testosterona/sangue , Resultado do TratamentoRESUMO
In order to understand the distribution of microorganisms and various antibiotic resistance genes in the aquaculture area of Changli County, Qinhuangdao, high-throughput sequencing technology was used in this study. We utilized 16S rDNA gene sequencing and metagenome sequencing methods to analyze the seawater, sediment, and gut contents of the local fish Synechogobius hasta in the aquaculture area in spring. The results showed that Proteobacteria, Firmicutes, and Bacteroidota were the dominant bacteria in seawater; and Proteobacteria, Crenarchaeota, Acidobacter, and Actinobaciota were rich in the sediment; whereas Proteobacteria, Cyanobacteria, Firmicutes, and Bacteroidota were in relatively high abundance in fish gut contents. The microbial diversity of sediment samples was the most abundant, followed by seawater samples, and the microbial diversity of fish intestinal contents was the lowest. Moreover, the microbial diversity of similar samples was relatively similar, and the microbial diversity of different types of samples was quite different. For samples at different sites, there were significant differences between seawater samples at each site, and there were small differences between sediment samples at each site, and some sediment sample groups did not have significant differences in microbial composition. In all sample groups, five ß-lactam antibiotic resistance genes (blaOXA-325, cepS, blaCARB-20, blaOXA-55, and blaTRU-1) and four aminoglycoside antibiotic resistance genes[aac(6')-IIb, amrA, aac(6')-Ie-aph(2â³)-Ia, and aph(3')-Vc] were detected. There was also a certain correlation between antibiotic resistance genes and microbial communities.
Assuntos
Antibacterianos , Bactérias , Animais , Antibacterianos/análise , Bactérias/genética , Genes Bacterianos , Aquicultura , Resistência Microbiana a Medicamentos/genética , Peixes/genética , RNA Ribossômico 16SRESUMO
BACKGROUND: Blood-based tests have public appeal in screening cancers due to their minimally invasive nature, ability to integrate with other routine blood tests, and high compliance. This study aimed to investigate whether certain epigenetic modulation of peripheral blood mononuclear cells (PBMCs) could be a biomarker of colorectal cancer (CRC). RESULTS: Western blotting of histones in the PBMCs from 40 colorectal cancer patients and 40 healthy controls was performed to identify the crotonylation sites of proteins. The correlation of crotonylation with tumor staging and diagnostic efficacy were analyzed. Crotonylation of H2BK12 (H2BK12cr) was identified significantly upregulated in the PBMCs of CRC patients compared to healthy controls, and were closely related to distant metastasis (P = 0.0478) and late TNM stage (P = 0.0201). Receiver operator characteristic curve (ROC) analysis demonstrated that the area under curve (AUC) of H2BK12cr was 0.8488, the sensitivity was 70%, and the specificity was 92.5%. The H2BK12cr parameter significantly increased the diagnostic effectiveness of CRC compared with the commercial carcinoembryonic antigen assays. CONCLUSIONS: The H2BK12cr level in PBMCs of CRC patients has a potential to be a biomarker for distinguishing CRC patients from healthy controls with the advantages of easy operation and high diagnostic efficacy.
Assuntos
Neoplasias Colorretais , Histonas , Humanos , Leucócitos Mononucleares , Biomarcadores , Epigenômica , Neoplasias Colorretais/diagnósticoRESUMO
Background: Lifestyle habits are vital components of the culture of mental health treatment settings. We examined the bridge connection between depressive and anxiety symptoms and lifestyles from a network perspective using a population-based study. Methods: Face-to-face interviews were conducted with a provincially representative sample of 13,768 inhabitants from the Guangdong Sleep and Psychosomatic Health Survey based on standardized evaluation techniques. We identified the central symptoms by expected influence. The interconnection between depression and anxiety symptoms, as well as the bridge connectivity linking depression-anxiety symptoms and lifestyle factors, were assessed using the bridge centrality index. Network stability and sensibility analyses were performed using a case-dropping bootstrap procedure. Results: The core symptom that exhibited the highest expected influence was fatigue or little energy, followed by uncontrollable worry, trouble relaxing, and sad mood in the depression-anxiety symptoms network, while guilt was the most interconnected symptom and had the highest bridge strength. Surrounding nodes of each node explained an average variance of 57.63%. Additionally, suicidal thoughts were recognized as collective bridging symptoms connecting lifestyle variables in the network integrating depression-anxiety symptoms with lifestyle factors. Current tobacco and alcohol consumption were positively associated with suicidal thoughts and irritability. Habitual diet rhythm and physical exercise frequency were linked to suicidal thoughts, guilt, and poor appetite or overeating. Suicidal thoughts, irritability, and guilt indicated the greatest connectivity with lifestyle factors. All networks had high stability and accuracy. Conclusion: These highlighted core and bridge symptoms could serve as latent targets for the prevention and intervention of comorbid depression and anxiety. It might be crucial for clinical practitioners to design effective and targeted treatment and prevention strategies aiming at specific lifestyles and behaviors.
RESUMO
Background: An imbalance in the redox homeostasis has been reported in multiple cancers and is associated with a poor prognosis of disease. However, the prognostic value of redox-related genes in non-small-cell lung cancer (NSCLC) remains unclear. Methods: RNA sequencing data, DNA methylation data, mutation, and clinical data of NSCLC patients were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Redox-related differentially expressed genes (DEGs) were used to construct the prognostic signature using least absolute shrinkage and selection operator (LASSO) regression analysis. Kaplan-Meier survival curve and receiver operator characteristic (ROC) curve analyses were applied to validate the accuracy of the gene signature. Nomogram and calibration plots of the nomogram were constructed to predict prognosis. Pathway analysis was performed using gene set enrichment analysis. The correlations of risk score with tumor stage, immune infiltration, DNA methylation, tumor mutation burden (TMB), and chemotherapy sensitivity were evaluated. The prognostic signature was validated using GSE31210, GSE26939, and GSE68465 datasets. Real-time polymerase chain reaction (PCR) was used to validate dysregulated genes in NSCLC. Results: A prognostic signature was constructed using the LASSO regression analysis and was represented as a risk score. The high-risk group was significantly correlated with worse overall survival (OS) (p < 0.001). The area under the ROC curve (AUC) at the 5-year stage was 0.657. The risk score was precisely correlated with the tumor stage and was an independent prognostic factor for NSCLC. The constructed nomogram accurately predicted the OS of patients after 1-, 3-, and 5-year periods. DNA replication, cell cycle, and ECM receptor interaction were the main pathways enriched in the high-risk group. In addition, the high-risk score was correlated with higher TMB, lower methylation levels, increased infiltrating macrophages, activated memory CD4+ T cells, and a higher sensitivity to chemotherapy. The signature was validated in GSE31210, GSE26939, and GSE68465 datasets. Real-time PCR validated dysregulated mRNA expression levels in NSCLC. Conclusions: A prognostic redox-related gene signature was successfully established in NSCLC, with potential applications in the clinical setting.
RESUMO
Lysine malonylation, a novel identified protein posttranslational modification (PTM), is conservative and present in both eukaryotic and prokaryotic cells. Previous studies have reported that malonylation plays an important role in inflammation, angiogenesis, and diabetes. However, its potential role in cardiac remodeling remains unknown. Here, we observed a reduced lysine malonylation in hypertrophic mice hearts created by transverse aortic constriction (TAC) for 8 weeks. We also detected a decreased lysine malonylation in hypertrophic H9C2 cardiomyocytes induced by angiotensin II for 48 h. Using a proteomic method based on affinity purification and LC-MS/MS, we identified total 679 malonylated sites in 330 proteins in the hearts of sham mice and TAC mice. Bioinformatic analysis of the proteomic data revealed enrichment of malonylated proteins involved in cardiac structure and contraction, cGMP-PKG pathway, and metabolism. Specifically, we detected a decreased lysine malonylation in myocardial isocitrate dehydrogenase 2 (IDH2) by immunoprecipitation coupled with Western blotting both in vivo and in vitro. Together, our work suggests an important role and implication of protein lysine malonylation in cardiac hypertrophy, especially the IDH2. SIGNIFICANCE: Heart failure is the terminal stage of cardiac hypertrophy, which imposes an enormous clinical and economic burden worldwide. Despite our knowledge on the pathophysiology of the disease, current therapeutic approaches are still largely limited. Cardiac hypertrophy can be regulated at post-translational modifications (PTMs), and several PTMs have been reported in cardiac hypertrrophy and heart failure. In our study, we first reported a novel PTMs, lysine malonylation, in cardiac hypertophy. we found a reduced lysine malonylation in hypertrophic mice hearts in vivo and H9C2 cardiomyocytes after stimulating with angiotensinII for 48 h in vitro. Using affinity purification and LC-MS/MS, we identified 679 malonylated sites in 330 proteins in the hearts of sham and TAC mice. Compared to the sham group, 5 sites in 2 proteins were quantified as downregulated targets using a 2-fold threshold (downregulation <0.5-fold, P < 0.05). Functional analysis showed a significant enrichment in cardiac structure and contraction, cGMP-PKG pathway and metabolism. Notably, we identified a decreased Kmal level in isocitrate dehydrogenase 2 (IDH2), but the protein level of IDH2 has no changed in cardiac hypertrophy, These results highlight that lysine malonylation is associated with cardiac hypertrophy, and may be a new therapeutic target of the disease.
Assuntos
Insuficiência Cardíaca , Lisina , Animais , Cardiomegalia , Cromatografia Líquida , Humanos , Isocitrato Desidrogenase , Lisina/metabolismo , Malonatos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Proteínas/metabolismo , Proteômica/métodos , Espectrometria de Massas em TandemRESUMO
Background: OAS gene family plays an important role in antiviral process, but its role in pancreatic cancer has not yet been studied. Methods: We analyzed the expression, prognostic value and biological function of the OAS gene family in human pancreatic cancer through comprehensive bioinformatic analysis and cellular level validation. Results: OAS family was highly expressed in pancreatic cancer, and this high expression significantly affected the clinical stage and prognosis of the tumor. OAS gene family was closely related to the immune infiltration of pancreatic cancer, especially neutrophils and dendritic cells, and many immune-related factors and pathways are enriched in the tumor, such as type I interferon signaling pathway and NOD-like receptor signaling pathway. Conclusion: Taken together, high expression of OAS family is closely related to poor prognosis of pancreatic cancer. OAS gene family may serve as the biomarker and even therapeutic target of pancreatic cancer.
RESUMO
Objective: This study aimed to address the status, role, and mechanism of sympathetic nerve infiltration in the progression of stomach adenocarcinoma (STAD). Methods: Sympathetic nerve and its neurotransmitter NE, ß-ARs, and associated signaling molecules in the STAD tissues and the adjacent tissues from 46 STAD patients were examined using immunostaining, HPLC, and western blotting. The effects and mechanisms of ß2-AR activation on the proliferation, migration and invasion of AGS and SGC-7901 gastric cancer (GC) cell lines were examined using CCK-8, transwell, and western blotting assays. Correlations between genes and STAD survival were analyzed using bioinformatics. Results: Striking sympathetic nerve infiltration, elevations of NGF, TrkA, GAP43, TH, S100, NE, ß2-AR, YKL-40, syndecan-1, MMP9, CD206, and CD31 were observed in the STAD tissues compared to the adjacent tissues. Activation of ß2-AR in the two GC cell lines significantly amplified the expressions of NGF, YKL-40, MMP9, syndecan-1, p-STAT3 and p-ERK, and increased GC cell proliferation, migration and invasion. Bioinformatic analyses revealed positive correlations of NGF, ß2-AR, syndecan-1, and macrophage infiltration, respectively, with low survival of STAD, of ß2-AR respectively with STAT3, ERK1/2 (MAPK1/3), YKL-40, MMP9, and syndecan-1, and of YKL-40 with MMP9. Conclusion: Sympathetic nerves significantly infiltrated into human STAD tissues as a result of high NGF and TrkA expressions; elevated NE led to overactivation of ß2-AR-STAT3/ERK-YKL-40 signaling pathway, and finally caused cancer cell growth and invasion, M2 macrophage infiltration, angiogenesis, matrix degradation and STAD metastasis and progression.
RESUMO
Autophagy serves an important role in amyloid-ß (Aß) metabolism and τ processing and clearance in Alzheimer's disease. The progression of Aß plaque accumulation and hyperphosphorylation of τ proteins are enhanced by oxidative stress. A hydrogen peroxide (H2O2) injury cell model was established using SH-SY5Y cells. Cells were randomly divided into normal, H2O2 and chlorogenic acid (5-caffeoylquinic acid; CGA) groups. The influence of CGA on cell viability was evaluated using a Cell Counting Kit-8 assay and cell death was assessed using Hoechst 33342 nuclear staining. Autophagy induction and fusion of autophagic vacuoles assays were performed using monodansylcadaverine staining. Additionally, SH-SY5Y cells expressing Ad-mCherry-green fluorescent protein-LC3B were established to detect autophagic flow. LysoTracker Red staining was used to evaluate lysosome function and LysoSensor™ Green staining assays were used to assess lysosomal acidification. The results demonstrated that CGA decreased the apoptosis rate, increased cell viability and improved cell morphology in H2O2-treated SH-SY5Y cells. Furthermore, CGA alleviated the accumulation of autophagic vacuoles, reduced the LC3BII/I ratio and decreased P62 levels, resulting in increased autophagic flux. Additionally, CGA upregulated lysosome acidity and increased the expression levels of cathepsin D. Importantly, these effects of CGA on H2O2-treated SH-SY5Y cells were mediated via the mTOR-transcription factor EB signaling pathway. These results indicated that CGA protected cells against H2O2-induced oxidative damage via the upregulation of autophagosomes, which promoted autophagocytic degradation and increased autophagic flux.
RESUMO
This study investigated whether the mitochondrial-targeted peptide SS-31 can protect against cigarette smoke- (CS-) induced airway inflammation and oxidative stress in vitro and in vivo. Mice were exposed to CS for 4 weeks to establish a CS-induced airway inflammation model, and those in the experimental group were pretreated with SS-31 1 h before CS exposure. Pathologic changes and oxidative stress in lung tissue, inflammatory cell counts, and proinflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. The mechanistic basis for the effects of SS-31 on CS extract- (CSE-) induced airway inflammation and oxidative stress was investigated using BEAS-2B bronchial epithelial cells and by RNA sequencing and western blot analysis of lung tissues. SS-31 attenuated CS-induced inflammatory injury of the airway and reduced total cell, neutrophil, and macrophage counts and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, and matrix metalloproteinase (MMP) 9 levels in BALF. SS-31 also attenuated CS-induced oxidative stress by decreasing malondialdehyde (MDA) and myeloperoxidase (MPO) activities and increasing that of superoxide dismutase (SOD). It also reversed CS-induced changes in the expression of mitochondrial fission protein (MFF) and optic atrophy (OPA) 1 and reduced the amount of cytochrome c released into the cytosol. Pretreatment with SS-31 normalized TNF-α, IL-6, and MMP9 expression, MDA and SOD activities, and ROS generation in CSE-treated BEAS-2B cells and reversed the changes in MFF and OPA1 expression. RNA sequencing and western blot analysis showed that SS-31 inhibited CS-induced activation of the mitogen-activated protein kinase (MAPK) signaling pathway in vitro and in vivo. Thus, SS-31 alleviates CS-induced airway inflammation and oxidative stress via modulation of mitochondrial function and regulation of MAPK signaling and thus has therapeutic potential for the treatment of airway disorders caused by smoking.
Assuntos
Antioxidantes/uso terapêutico , Mediadores da Inflamação/uso terapêutico , Inflamação/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Pulmão/patologia , Oligopeptídeos/uso terapêutico , Fumaça/efeitos adversos , Animais , Antioxidantes/farmacologia , Humanos , Pneumopatias/patologia , Masculino , Camundongos , Oligopeptídeos/farmacologia , Estresse OxidativoRESUMO
The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to the world in many aspects. Effective therapeutic and preventive approaches including drugs and vaccines are still unavailable although they are in development. Comprehensive understandings on the life logic of SARS-CoV-2 and the interaction of the virus with hosts are fundamentally important in the fight against SARS-CoV-2. In this review, we briefly summarized the current advances in SARS-CoV-2 research, including the epidemic situation and epidemiological characteristics of the caused disease COVID-19. We further discussed the biology of SARS-CoV-2, including the origin, evolution, and receptor recognition mechanism of SARS-CoV-2. And particularly, we introduced the protein structures of SARS-CoV-2 and structure-based therapeutics development including antibodies, antiviral compounds, and vaccines, and indicated the limitations and perspectives of SARS-CoV-2 research. We wish the information provided by this review may be helpful to the global battle against SARS-CoV-2 infection.