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1.
J Cell Commun Signal ; 18(1): e12020, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38545254

RESUMO

The objective of this study was to elucidate the involvement of the long noncoding RNA (lncRNA) HOTTIP in acute lung injury and understand the underlying mechanisms. Relevant expression of mRNAs and proteins were assessed by qRT-PCR and western blot assays. Cell viability was determined by employing the CCK-8 assay, and apoptosis was quantified through TUNEL staining. The concentration of inflammatory factors was measured by ELISA. The degree of DNA methylation was quantified through MSP assay. The interaction between HOTTIP and DNA methyltransferase 1 (DNMT1) was examined by RIP assay. LPS upregulated HOTTIP, whereas downregulated SP-C level in AEC II cells. HOTTIP knockdown inhibited LPS-induced apoptosis and the secretion of inflammatory cytokines (TNF-α, IL-1ß and IL-6) in AEC II cells. Mechanistically, HOTTIP recruited DNMT1 to the SP-C promoter, thereby facilitating DNA methylation of SP-C and suppressing its expression. Additionally, inhibitory of SP-C reversed the effects of HOTTIP or DNMT1 knockdown on apoptosis and inflammation in AEC II cells induced by LPS. HOTTIP recruited DNMT1 to epigenetically inhibit SP-C expression, leading to the promotion of lung epithelial cell injury caused by LPS, suggesting that targeting HOTTIP may be an effective strategy for the therapy of lung epithelial cell injury.

3.
Front Pharmacol ; 13: 1034794, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36561336

RESUMO

Background: Glioblastoma (GBM) is highly malignant and has a worse prognosis with age, and next-generation sequencing (NGS) provides us with a huge amount of information about GBM. Materials and Methods: Through the enrichment scores of cell senescence-related pathways, we constructed a consensus matrix and mined molecular subtypes and explored the differences in pathological, immune/pathway and prognostic. Also we identified key genes related to cell senescence characteristics using least absolute shrinkage and selection operator (Lasso) regression and univariate COX regression analysis models. The use of risk factor formats to construct clinical prognostic models also explored the differences in immunotherapy/chemotherapy within the senescence-related signatures score (SRS.score) subgroups. Decision trees built with machine learning to identify the main factors affecting prognosis have further improved the prognosis model and survival prediction. Results: We obtained seven prognostic-related pathways related to cell senescence. We constructed four different molecular subtypes and found patients with subtype C1 had the worst prognosis. C4 had the highest proportion of patients with IDH mutations. 1005 differentially expressed genes (DEGs) were analyzed, and finally 194 Risk genes and 38 Protective genes were obtained. Eight key genes responsible for cell senescence were finally identified. The clinical prognosis model was established based on SRS.score, and the prognosis of patients with high SRS.score was worse. SRS.score and age were the vital risk factors for GBM patients through decision tree model mining. Conclusion: We constructed a clinical prognosis model that could provide high prediction accuracy and survival prediction ability for adjuvant treatment of patients with GBM.

4.
Biochem Biophys Res Commun ; 590: 177-183, 2022 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-34990892

RESUMO

Gram-negative bacteria usually use acyl-homoserine lactones (AHLs)-mediated LuxI/LuxR-type quorum sensing (QS) systems for cell-cell cooperation and/or bacteria-environment communication. LuxI and LuxR are AHLs synthase and receptor, respectively. These two parts could form a positive regulatory feedback loop, controlling various types of group behaviors. However, the autoregulation mechanisms between them are fragmented and could be highly differentiated in different bacteria. Here, we clarified the autoregulation mechanism between LuxI and LuxR in Pseudoalteromonas sp. R3. YasI (LuxI in strain R3) synthesizes two types of AHLs, C8-HSL and 3-OH-C8-HSL. It is worth noting that YasR (LuxR in strain R3) only responds to C8-HSL rather than 3-OH-C8-HSL. YasR-C8HSL can activate the yasI transcription by recognizing "lux box" at yasI upstream. Interestingly, YasR can directly promote the yasR expression with AHL-independent manner, but AHL absence caused by the yasI-deficiency led to the significant decrease in the yasR expression. Further study demonstrated that the yasI-deficiency can result in the decrease in the yasR mRNA stability. Notably, both yasI-deficiency and yasR-deficiency led to the significant decrease in the expression of hfq encoding RNA chaperone. Therefore, it was speculated that not only YasR itself can directly regulate the yasR transcription, but YasR-C8HSL complex indirectly affects the yasR mRNA stability by regulating Hfq.


Assuntos
Proteínas de Bactérias/metabolismo , Homeostase , Pseudoalteromonas/fisiologia , Percepção de Quorum , Acil-Butirolactonas/metabolismo , Sequência de Bases , Regulação Bacteriana da Expressão Gênica , Pseudoalteromonas/genética , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica
5.
Biochem Biophys Res Commun ; 571: 1-7, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34298336

RESUMO

Pseudoalteromonas spp. are Gram-negative bacteria which are ubiquitous in marine environments. Our previous work found that there is a classic LuxI/LuxR-type quorum sensing (QS) system which was named YasI/YasR in Pseudoalteromonas sp. R3, but the factors that control QS in strain R3 are unclear yet. Here, we found that the deficiency of hfq encoding RNA chaperon Hfq down-regulated the transcription levels of yasI encoding acyl-homoserine lactones (AHLs) synthase and yasR encoding AHLs receptor in strain R3. The assay based on fusion reporter of yasI-lacZ showed that Hfq regulates the expression of yasR at both transcriptional and translational levels. In addition, Hfq affects the expression of yasI via yasR. Further analysis indicated that the 5'UTR region of yasR is necessary for Hfq to control QS. In addition, the deletion of hfq increases the unstability of the target yasR mRNA. Based on transcriptome sequencing and bioinformatic analysis together with molecular experiments, Hfq-dependent sRNA00002 was identified to be involved in positively regulating QS in Pseudoalternas sp. R3. It was found that sRNA00002 deficiency causes the decrease in expression of yasI and yasR, and thus abolishes the production of AHLs in strain R3. It was concluded that Hfq-dependent sRNA00002 regulates yasR expression by base-pairing with target yasR mRNA at 5'UTR region and altering the stability of yasR mRNA. Our work paves the way for understanding the regulation mechanism of Hfq-dependent sRNAs on QS in Pseudoalteromonas.


Assuntos
Proteínas de Bactérias/metabolismo , Fator Proteico 1 do Hospedeiro/metabolismo , Pseudoalteromonas/metabolismo , Proteínas Repressoras/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/genética , Fator Proteico 1 do Hospedeiro/genética , Percepção de Quorum , Proteínas Repressoras/genética , Transativadores/genética , Fatores de Transcrição/genética
6.
Cardiovasc Toxicol ; 21(8): 655-668, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34021461

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme for tryptophan metabolism, involved in immune cell differentiation/maturation and cancer biology. IDO1 is also expressed in cardiomyocytes, but its roles in the cardiovascular system are not fully understood. Here, we reported the functions of IDO1 during cardiac hypertrophy. Quantitative real-time PCR and Western blot experiments demonstrated the upregulation of IDO1 mRNA and protein levels in human and hypertrophic mouse hearts, as well as in angiotensin II (Ang II)-induced hypertrophic rat cardiomyocytes. IDO1 activity and metabolite product kynurenine were upregulated in rodent hypertrophic hearts and cardiomyocytes. Inhibition of IDO1 activity with PF-06840003 reduced Ang II-induced cardiac hypertrophy and rescued cardiac function in mice. siRNA-mediated knockdown of Ido1 repressed Ang II-induced growth in cardiomyocyte size and overexpression of hypertrophy-associated genes atrial natriuretic peptide (Anp or Nppa), brain natriuretic peptide (Bnp or Nppb), ß-myosin heavy chain (ß-Mhc or Myh7). By contrast, adenovirus-mediated rat Ido1 overexpression in cardiomyocytes promoted hypertrophic growth induced by Ang II. Mechanism analysis showed that IDO1 overexpression was associated with PI3K-AKT-mTOR signaling to activate the ribosomal protein S6 kinase 1 (S6K1), which promoted protein synthesis in Ang II-induced hypertrophy of rat cardiomyocytes. Finally, we provided evidence that inhibition of PI3K with pictilisib, AKT with perifosine, or mTOR with rapamycin, blocked the effects of IDO1 on protein synthesis and cardiomyocyte hypertrophy in Ang II-treated cells. Collectively, our findings identify that IDO1 promotes cardiomyocyte hypertrophy partially via PI3K-AKT-mTOR-S6K1 signaling.


Assuntos
Cardiomegalia/enzimologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Miócitos Cardíacos/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adulto , Idoso , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Cinurenina/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores
7.
Biochem Biophys Res Commun ; 534: 885-890, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33143873

RESUMO

Bacteria commonly exhibit social activities through acyl-homoserine lactones (AHLs)-based quorum sensing (QS) systems to form their unique social network. The sigma factor RpoS is an important regulator that controls QS system in different bacteria. However, the upstream of RpoS involving regulation on QS system remains unclear. In Escherichia coli RpoS is regulated by stringent starvation protein A (SspA), which is dependent of histone-like nucleoid structuring protein (H-NS). To date, the connection between SspA and QS system is essentially unknown. Here, we characterized a typical LuxI/LuxR-type QS system in marine bacterium Pseudoalteromonas sp. T1lg65 which can produce four types of AHLs. The luxI encoding AHLs synthase and luxR encoding AHLs-responsive receptor are co-transcribed, providing advantages in rapidly amplifying QS signaling. Notably, SspA positively regulated luxI/luxR transcription by activating RpoS expression, which is mediated by H-NS. Interestingly, LuxR in turn positively regulated SspA expression. Therefore, SspA and QS system constitute a mutual positive regulation loop in T1lg65. In view of the crucial roles of SspA and QS system in environmental adaption, we believe that the improvement of bacterial tolerance to marine environments could be related to rapidly tuning SspA-involved QS programming.


Assuntos
Proteínas de Bactérias/metabolismo , Pseudoalteromonas/fisiologia , Percepção de Quorum , Proteínas Repressoras/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Acil-Butirolactonas/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo
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