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1.
Front Pharmacol ; 13: 1033003, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36408214

RESUMO

Purpose: Michael receptor molecules derived from plants are biologically active due to electrophilic groups in their structure. They can target nucleophilic residues on disease-related proteins, with significant therapeutic effects and low toxicity for many diseases. They provide a good option for relevant disease treatment. The aim of this study is to summarize the existing MAMs and their applications, and lay a foundation for the application of Michael receptor molecules in life science in the future. Methods: This review summarizes the published studies on Michael receptor molecules isolated from plants in literature databases such as CNKI, Wanfang Data, PubMed, Web of Science, ScienceDirect, and Wiley. Latin names of plants were verified through https://www.iplant.cn/. All relevant compound structures were verified through PubChem and literature, and illustrated with ChemDraw 20.0. Result: A total of 50 Michael receptor molecules derived from various plants were discussed. It was found that these compounds have similar pharmacological potential, most of them play a role through the Keap1-Nrf2-ARE pathway and the NF-κB pathway, and have biological activities such as antioxidant and anti-inflammatory. They can be used to treat inflammatory diseases and tumors. Conclusion: The Michael receptor molecule has electrophilicity due to its unsaturated aldehyde ketone structure, which can combine with nucleophilic residues on the protein to form complexes and activate or inhibit the protein pathway to play a physiological role. Michael receptor molecules can regulate the Keap1-Nrf2-ARE pathway and the NF-κB pathway. Michael receptor molecules can be used to treat diseases such as inflammation, cancer, oxidative stress, etc.

2.
Nano Lett ; 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36449360

RESUMO

Here we present an innovative, universal, scalable, and straightforward strategy for cultivating a resilient, flexible lithium-ion battery (LIB) based on the bacterial-based self-growing approach. The electrodes and separator layers are integrated intrinsically into one unity of sandwich bacterial cellulose integrated film (SBCIF), with various active material combinations and tailored mechanical properties. The flexible LIB thereof showcases prominent deformation tolerance and multistage foldability due to the unique self-generated wavy-like structure. The LTO|LFP (Li4Ti5O12 and LiFePO4) SBCIF-based flexible LIB demonstrates reliable long-term electrochemical stability with high flexibility, by exhibiting a high capacity retention (>95%) after 500 cycles at 1C/1C after experiencing a 10 000 bending/flattening treatment. The LTO|LFP SBCIF battery subjected to a simultaneous bending/flattening and cycling experiment shows an extraordinary capacity retention rate (>68%) after 200 cycles at 1C/1C. The biobased self-growing approach offers an exciting and promising pathway toward the tailored, integrated high-performance flexible LIBs.

3.
Drug Des Devel Ther ; 16: 2517-2527, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35946039

RESUMO

Purpose: Endothelial-to-mesenchymal transition (EndMT) is an important mechanism underlying cardiac fibrosis. The anti-ischemic drug trimetazidine (TMZ) is reportedly useful in ventricular remodeling and associated with NADPH oxidase (NOX) 2. This study aimed to investigate the possible effect of TMZ on cardiac fibrosis exerted via the inhibition of NOX2-mediated EndMT. Methods: A cardiac fibrosis model was established in Sprague-Dawley rats through a subcutaneous injection of isoproterenol (ISO, 5 mg/kg/d). Echocardiographic parameters, myocardial fibrosis, NOX2 expression and EndMT were assessed. An in vitro model of EndMT was developed using human umbilical vein endothelial cells (HUVECs) via treatment with transforming growth factor-ß (TGF-ß) at 10 ng/mL for 24 h. HUVECs were administrated with TMZ or TMZ and lentivirus, the expression of EndMT and related proteins was observed by wound healing assay, immunoblotting, and immunofluorescence. Results: Rats injected with ISO exhibited severe interstitial cardiac fibrosis and perivascular fibrosis, decreased left ventricular ejection fraction, and increased NOX activity. TMZ treatment mitigated cardiac fibrosis, ameliorated left ventricular dysfunction, and reduced NOX activity. In addition, TMZ effectively inhibited EndMT in ISO-treated rat hearts and TGF-ß-treated HUVECs, as manifested by increased CD31 expression, decreased α-SMA expression, and suppressed cell migration. Compared with the control group, the expression of NOX2, nuclear factor-κB (NF-κB), and Snail was increased in vivo and in vitro but decreased with TMZ treatment. Furthermore, the overexpression of NOX2 by lentivirus abolished the protective effects of TMZ on TGF-ß-induced EndMT. Conclusion: TMZ may ameliorate EndMT and ISO-induced cardiac fibrosis through the NOX2/NF-κB/Snail pathway. The findings of the study may provide new insights into the potential role of TMZ in the pathophysiology of cardiac fibrosis.


Assuntos
Cardiomiopatias , Trimetazidina , Animais , Cardiomiopatias/metabolismo , Transição Epitelial-Mesenquimal , Fibrose , Células Endoteliais da Veia Umbilical Humana , Humanos , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Volume Sistólico , Fator de Crescimento Transformador beta/metabolismo , Trimetazidina/metabolismo , Trimetazidina/farmacologia , Função Ventricular Esquerda
4.
Cell Death Dis ; 13(7): 624, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35853880

RESUMO

Prostate cancer (PCa) is a malignant tumor that seriously threatens men's health worldwide. Recently, stromal cells in the tumor microenvironment (TME) have been reported to contribute to the progression of PCa. However, the role and mechanism of how PCa cells interact with stromal cells to reshape the TME remain largely unknown. Here, using a spontaneous prostate adenocarcinoma (PRAD) model driven by the loss of Pten and Hic1, we found that M2 macrophages markedly infiltrated the stroma of Pten and Hic1 double conditional knockout (dCKO) mice compared with those in control (Ctrl) mice due to higher TGF-ß levels secreted by HIC1-deleted PCa cells. Mechanistically, TGF-ß in TME promoted the polarization of macrophages into "M2" status by activating the STAT3 pathway and modulating c-Myc to upregulate CXCR4 expression. Meanwhile, TGF-ß activated the fibroblasts to form cancer-associated fibroblasts (CAFs) that secrete higher CXCL12 levels, which bound to its cognate receptor CXCR4 on M2 macrophages. Upon interaction with CAFs, M2 macrophages secreted more CXCL5, which promoted the epithelial-mesenchymal transition (EMT) of PCa via CXCR2. Moreover, using the TGF-ß receptor I antagonist, galunisertib, significantly inhibited the tumor growth and progression of the TRAMP-C1 cell line-derived subcutaneous tumor model. Finally, we confirmed that the stromal microenvironment was shaped by TGF-ß in HIC1-deficient PCa and was associated with the progression of PCa.


Assuntos
Fibroblastos Associados a Câncer , Fatores de Transcrição Kruppel-Like , Neoplasias da Próstata , Fator de Crescimento Transformador beta , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral
5.
Biomed Pharmacother ; 149: 112839, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35325852

RESUMO

Type 2 diabetes mellitus (T2DM) is one of the most risk factors threatening human health. Although genetic and environmental factors contribute to the development of T2DM, gut microbiota has also been found to be involved. Gut microbiota-derived metabolites are a key factor in host-microbe crosstalk, and have been revealed to play a central role in the physiology and physiopathology of T2DM. In this review, we provide a timely and comprehensive summary of the microbial metabolites that are protective or causative for T2DM, including some amino acids-derived metabolites, short-chain fatty acids, trimethylamine N-oxide, and bile acids. The mechanisms by which metabolites affect T2DM have been elaborated. Knowing more about these processes will increase our understanding of the causal relationship between gut microbiota and T2DM. Moreover, some frontier therapies that target gut microbes and their metabolites to improve T2DM, including dietary intervention, fecal microbiota transplantation, probiotics, prebiotics or synbiotics intervention, and drugging microbial metabolism, have been critically discussed. This review may provide novel insights for the development of targeted and personalized treatments for T2DM based on gut microbial metabolites. More high-quality clinical trials are needed to accelerate the clinical translation of gut-targeted therapies for T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Probióticos , Diabetes Mellitus Tipo 2/metabolismo , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/fisiologia , Humanos , Prebióticos , Probióticos/uso terapêutico
6.
Xenobiotica ; 52(2): 186-198, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35078381

RESUMO

The objective of this study was to clarify the species differences of metabolic stability of E28 in liver microsomes, and to study metabolic phenotypes of E28 in human liver microsomes by chemical inhibition method.The metabolites in plasma, urine, and faeces samples from mice received caudal vein intravenous were detected and identified by UHPLC-HRMS, and the tissue distribution was studied after oral administration.E28 was metabolised rapidly in liver microsomes of each species with a short half-live T1/2 and a moderate clearance, except for rats. The metabolic properties of E28 were similar in human and mouse liver microsomes. Data from metabolic phenotype studies indicated that CYP2D6, CYP3A4 and CYP2C9 were the main metabolic enzymes participating in the metabolism of E28.The main metabolic pathways implicated include oxidation, methylation, amide hydrolysis, acetylation, glucuronide conjugation.Tissue distribution studies showed that E28 could be detected in all organs and tissues after oral administration, with the highest level in the stomach and the lowest in the brain. In bone marrow cells, the concentration of E28 in all sample points were consistently higher than its half inhibitory concentration against MV4-11 tumour cells.


Assuntos
Microssomos Hepáticos , Inibidores de Proteínas Quinases , Animais , Glucuronídeos/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Ratos , Distribuição Tecidual
7.
Small ; 18(5): e2104986, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34850544

RESUMO

The formation of solid-electrolyte interphase (SEI) in "water-in-salt" electrolyte (WiSE) expands the electrochemical stability window of aqueous electrolytes beyond 3.0 V. However, the parasitic hydrogen evolution reaction that drives anode corrosion, cracking, and the subsequent reformation of SEI still occurs, compromising long-term cycling performance of the batteries. To improve cycling stability, an unsaturated monomer acrylamide (AM) is introduced as an electrolyte additive, whose presence in WiSE reduces its viscosity and improves ionic conductivity. Upon charging, AM electropolymerizes into polyacrylamide, as confirmed both experimentally and computationally. The in situ polymer constitutes effective protection layers at both anode and cathode surfaces, and enables LiMn2 O4 ||L-TiO2 full cells with high specific capacity (157 mAh g-1 at 1 C), long-term cycling stability (80% capacity retention within 200 cycles at 1 C), and high rate capability (79 mAh g-1 at 30 C). The in situ electropolymerization found in this work provides an alternative and highly effective strategy to design protective interphases at the negative and positive electrodes for high-voltage aqueous batteries of lithium-ion or beyond.

8.
Chin J Integr Med ; 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34874520

RESUMO

OBJECTIVE: To investigate the effect of seabuckthorn berries extract (SBE) on pulmonary vascular hyperpermeability in the mice model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). METHODS: Sixty Kunming mice were allocated into 6 groups by a random number table, including control, LPS, dexamethasone (Dex, 1 mg/kg), and 120, 240 and 480 mg/kg SBE groups, 10 mice in each group. Except the control group, mice were pre-treated with Dex and SBE, respectively, for 7 days before LPS was intraperitoneally injected to induce ALI. Pulmonary vascular hyperpermeability was evaluated by histopathologic observation and transvascular leakage determination. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels in serum were measured using enzyme-linked immunosorbent assay. The expression of nuclear factor-kappa B (NF-κB) p65 in lung cells was determined by immunofluorescence analysis. The contents of cytoplasmic inhibitor of nuclear factor-κB kinase (IKK) and nuclear p65, as well as downstream proteins of E-selectin (CD62E) and intercellular adhesion molecule-1 (ICAM-1), were determined using Western blot analysis. RESULTS: Histopathological observation confirmed SBE treatment alleviated morphological lesion induced by LPS. Compared with the LPS group, 480 mg/kg SBE significantly decreased the water content of lung, Evans blue accumulation in lung tissue, and protein concentration and neutrophils count in bronchoalveolar lavage fluid (P<0.01); moreover, 480 mg/kg SBE significantly suppressed release of TNF-α and IL-6, and down-regulated expressions of IKK, nuclear p65, ICAM-1 and CD62E (P<0.01). CONCLUSION: SBE maintained alveolar-capillary barrier integrity under endotoxin challenge in mice by suppressing the key factors in the pathogenesis of ALI.

9.
Angew Chem Int Ed Engl ; 60(42): 22812-22817, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34379346

RESUMO

The introduction of "water-in-salt" electrolyte (WiSE) concept opens a new horizon to aqueous electrochemistry that is benefited from the formation of a solid-electrolyte interphase (SEI). However, such SEI still faces multiple challenges, including dissolution, mechanical damaging, and incessant reforming, which result in poor cycling stability. Here, we report a polymeric additive, polyacrylamide (PAM) that effectively stabilizes the interphase in WiSE. With the addition of 5 molar % PAM to 21 mol kg-1 LiTFSI electrolyte, a LiMn2 O4 ∥L-TiO2 full cell exhibits enhanced cycling stability with 86 % capacity retention after 100 cycles at 1 C. The formation mechanism and evolution of PAM-assisted SEI was investigated using operando small angle neutron scattering and density functional theory (DFT) calculations, which reveal that PAM minimizes the presence of free water molecules at the anode/electrolyte interface, accelerates the TFSI- anion decomposition, and densifies the SEI.

10.
Front Cardiovasc Med ; 8: 706979, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447791

RESUMO

Objectives: To evaluate the effect of thrombus aspiration (TA) strategy on the outcomes and its interaction with D-dimer levels in patients with ST-segment elevation myocardial infarction (STEMI) during primary percutaneous coronary intervention (PCI) in "real-world" settings. Materials and Methods: This study included 1,295 patients with STEMI who had undergone primary PCI with or without TA between January 2013 and June 2017. Patients were first divided into a TA+PCI group and a PCI-only group, and the baseline characteristics and long-term mortality between the two groups were analyzed. Furthermore, we studied the effect of TA on the clinical outcomes of patients grouped according to quartiles of respective D-dimer levels. The primary outcome was all-cause mortality, and the secondary outcomes were new-onset heart failure (HF), rehospitalization, re-PCI, and stroke. Results: In the original cohort, there were no significant differences in all-cause mortality between the TA+PCI and PCI-only groups (hazard ratio, 0.789; 95% confidence interval, 0.556-1.120; p = 0.185). After a mean follow-up of 2.5 years, the all-cause mortality rates of patients in the TA + PCI and PCI-only groups were 8.5 and 16.2%, respectively. Additionally, differences between the two groups in terms of the risk of HF, re-PCI, rehospitalization, and stroke were non-significant. However, after dividing into quartiles, as the D-dimer levels increased, the all-cause mortality rate in the PCI group gradually increased (4.3 vs. 6.0 vs. 7.0 vs. 14.7%, p < 0.001), while the death rate in the TA+PCI group did not significantly differ (4.6 vs. 5.0 vs. 4.0 vs. 3.75%, p = 0.85). Besides, in the quartile 3 (Q3) and quartile 4 (Q4) groups, the PCI-only group was associated with a higher risk of all-cause mortality than that of the TA+PCI group (Q3: 4.0 vs. 7.0%, p = 0.029; Q4: 3.75 vs. 14.7%, p < 0.001). Moreover, the multivariate logistic regression analysis demonstrated that TA is inversely associated with the primary outcome in the Q4 group [odds ratio (OR), 0.395; 95% CI, 0.164-0.949; p = 0.038]. Conclusions: The findings of our real-world study express that routine manual TA during PCI in STEMI did not improve clinical outcomes overall. However, patients with STEMI with a higher concentration of D-dimer might benefit from the use of TA during primary PCI. Large-scale studies are recommended to confirm the efficacy of TA.

11.
Transl Androl Urol ; 10(7): 3056-3068, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34430408

RESUMO

BACKGROUND: Alternative splicing (AS) is believed to play a vital role in tumor development. Therefore, comprehensive investigation of AS and its biological function in prostate cancer (PCa) is crucial. METHODS: The AS profiling of 489 patients with PCa was obtained from The Cancer Genome Atlas (TCGA) SpliceSeq database. Bioinformatics tools were used to describe splicing associations and build prognostic models. Unsupervised clustering of the determined prognostic AS events and the relationship with immune characteristics were also explored. RESULTS: In total, 20,723 AS events were detected and 2,805 were identified in PCa. In the regulatory networks, the data suggested a significant correlation between splicing factor (SF) expression and AS events. To stratify the progression risk of PCa patients, prognostic models were constructed using splicing patterns. Six AS events were screened out as independent prognostic factors for progression-free survival. Based on the gene features, we constructed the combined prognostic predictors model, and the receiver operating characteristic (ROC) curve for this model reached a high area under the ROC curve (AUC) of 0.729793, indicating a favorable ability to predict patient outcomes. Through unsupervised clustering analysis, the correlations between AS-based clusters and prognosis as well as immune characteristics were revealed. The correlation analysis on TIMER revealed the relationship between gene expression and immune cell infiltration. CONCLUSIONS: This in-depth genome-wide analysis of the AS profiling in PCa revealed unique AS events associated with cancer progression and the infiltration of immune cells, with potential for predicting outcomes and therapeutic responses.

12.
Oxid Med Cell Longev ; 2021: 6678662, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34257817

RESUMO

Metabolic diseases have become major public health issues worldwide. Searching for effective drugs for treating metabolic diseases from natural compounds has attracted increasing attention. Quercetin, an important natural flavonoid, is extensively present in fruits, vegetables, and medicinal plants. Due to its potentially beneficial effects on human health, quercetin has become the focus of medicinal attention. In this review, we provide a timely and comprehensive summary of the pharmacological advances and clinical data of quercetin in the treatment of three metabolic diseases, including diabetes, hyperlipidemia, and nonalcoholic fatty liver disease (NAFLD). Accumulating evidences obtained from animal experiments prove that quercetin has beneficial effects on these three diseases. It can promote insulin secretion, improve insulin resistance, lower blood lipid levels, inhibit inflammation and oxidative stress, alleviate hepatic lipid accumulation, and regulate gut microbiota disorders in animal models. However, human clinical studies on the effects of quercetin in diabetes, hyperlipidemia, and NAFLD remain scarce. More clinical trials with larger sample sizes and longer trial durations are needed to verify its true effectiveness in human subjects. Moreover, another important issue that needs to be resolved in future research is to improve the bioavailability of quercetin. This review may provide valuable information for the basic research, drug development, and clinical application of quercetin in the treatment of metabolic diseases.


Assuntos
Antioxidantes/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Quercetina/uso terapêutico , Adulto , Idoso , Antioxidantes/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quercetina/farmacologia , Adulto Jovem
13.
Front Pharmacol ; 12: 632978, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135751

RESUMO

Background: Mineralocorticoid receptor antagonists (MRA) improve outcomes in chronic kidney disease (CKD) and acute myocardial infarction (AMI) patients. However, the lack of evidence regarding long-term clinical outcomes in the use of MRA, including spironolactone, in patients with AMI combined with CKD. Objectives: This study aimed to investigate whether spironolactone could significantly reduce the risk of all-cause mortality and re-admission in patients with AMI and CKD. Methods: In this single center, observational, retrospective, registry based clinical study, a total of 2,465 AMI patients were initially screened; after excluding patients with estimated glomerular filtration rate more than 60 ml/min/1.73 m2, 360 patients in the standard treatment group and 200 patients in the spironolactone group met the criteria. All enrolled patients follow-up for 30 months. The primary outcomes were all-cause mortality and re-admission. The key safety outcome was hyperkalemia rates during the 30 months follow-up period. Results: 160 (44.4%) and 41 (20.5%) patients in the standard treatment and spironolactone groups died, respectively [hazard ratio (HR): 0.389; 95% confidence interval (CI): 0.276-0.548; p < 0.001]. Re-admission occurred in 217 (60.3%) and 95 (47.5%) patients in the standard treatment and spironolactone groups, respectively (HR: 0.664; 95% CI: 0.522-0.846; p = 0.004). The spironolactone group was divided into two based on the daily dose, low dose group (no more than 40 mg) and high dose group (more than 40 mg); the differences in the mortality rate between low dose group (16.7%) and the standard treatment group (44.4%) (HR: 0.309; 95% CI: 0.228-0.418; p < 0.001) and high dose group (34.1%) (HR: 0.429; 95% CI: 0.199-0.925; p = 0.007) were significant. The differences in re-hospitalization rate between low dose group (43.6%) and the standard treatment group (60.3%) (HR: 0.583; 95% CI: 0.457-0.744; p < 0.001) and high dose group (61.4%) (HR: 0.551; 95% CI: 0.326-0.930; p = 0.007) was significant. Hyperkalemia occurred in 18 (9.0%) and 18 (5.0%) patients in the spironolactone group and standard treatment group, respectively (HR: 1.879; 95% CI: 0.954-3.700; p = 0.068). Whereas, Hyperkalemia occurred in high dose group (20.5%) significantly more often than in the standard treatment group (p < 0.001) and low dose group (5.8%) (p = 0.003). Conclusion: Using MRA, such as spironolactone, may substantially reduce the risk of both all-cause mortality and re-admission in patients with AMI and CKD; the use of low-dose spironolactone has the best efficacy and safety. However, this was a relatively small sample size, single center, observational, retrospective, registry based clinical study and further prospective evaluation in adequately powered randomized trials were needed before further use of spironolactone in AMI with CKD population.

14.
Mycopathologia ; 186(3): 341-354, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34089172

RESUMO

Aspergillus fumigatu (A. fumigatus) is one of the most common important fungal pathogens that cause life-threatening infectious disease in immunocompromised individuals. However, the host immune response against this pathogenic mold is not fully understood. MicroRNAs (miRNAs) play essential roles in regulating innate immunity. Thus, we investigated the function of miR-146a in inflammatory responses in macrophages after A. fumigatus stimulation in this study. We found that TNF-α and IL-6 were increased in THP-1 macrophage-like cells treated with A. fumigatus at both the mRNA and protein levels. The interaction between THP-1 macrophage-like cells and A. fumigatus resulted in a long-lasting increase in miR-146a expression dependent on p38 MAPK and NF-κB signaling. In A. fumigatus-challenged THP-1 macrophage-like cells, overexpression of miR-146a by miR-146a mimics decreased TNF-α and IL-6 production, whereas downregulation of miR-146a by anti-miR-146a significantly enhanced the level of TNF-α and IL-6. Our study demonstrates that the crosstalk between miR-146a and the inflammation-regulating p38 MAPK and NF-κB pathways might be a fine-tuning mechanism in the modulation of the inflammatory response in macrophages infected with A. fumigatus. Our findings illuminate the crucial role of miR-146a in the pathogenesis of human diseases associated with A. fumigatus infection.


Assuntos
Aspergillus fumigatus , MicroRNAs , Fator de Necrose Tumoral alfa , Humanos , Interleucina-6 , Macrófagos
15.
Microb Pathog ; 157: 104963, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34022361

RESUMO

Emerging evidence suggests that long noncoding RNAs (lncRNAs) play important roles in disease development. However, the roles of lncRNAs in the pathogenesis of Candida albicans (C. albicans) remain unclear. Our study aimed to investigate and characterize the mRNA and lncRNA transcriptomes of CD14+ monocytes and THP-1 cells stimulated with insoluble ß-glucan by RNA-seq. We identified a total of 10788 differentially expressed (DE) mRNAs and 2021 DE lncRNAs in CD14+ monocytes, while 3349 DE mRNAs and 291 DE lncRNAs were observed in THP-1 cells. A total of 808 DE mRNAs and 51 DE lncRNAs overlapped between the two groups. We examined five collectively DE mRNAs and lncRNAs in both cells using quantitative real-time PCR, validating the reliability of the RNA-seq results. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the 808 DE mRNAs were mostly enriched in the inflammatory response and NF-kappa B signaling pathway, respectively. Next, lncRNA-mRNA coexpression analysis was performed for the 51 DE lncRNAs and the 808 DE mRNAs in the two groups. We chose the common network pairs of the two groups to construct the coexpression network and revealed 97 network pairs comprising 8 dysregulated lncRNAs and 60 dysregulated mRNAs. We found that lncRNA lnc-CCL3L3-1:1 might be involved in the NF-kappa B signaling pathway in C. albicans infection. In conclusion, the aberrantly expressed lncRNAs might play a role in the pathogenesis of C. albicans infection and could be used as therapeutic targets in the future.


Assuntos
Monócitos , RNA Longo não Codificante , beta-Glucanas , Candida albicans/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , RNA Longo não Codificante/genética , Reprodutibilidade dos Testes , Células THP-1 , Transcriptoma
16.
Oncogenesis ; 10(1): 4, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33419984

RESUMO

Exploring novel anticancer drugs to optimize the efficacy may provide a benefit for the treatment of colorectal cancer (CRC). Disulfiram (DSF), as an antialcoholism drug, is metabolized into diethyldithiocarbamate-copper complex (CuET) in vivo, which has been reported to exert the anticancer effects on various tumors in preclinical studies. However, little is known about whether CuET plays an anti-cancer role in CRC. In this study, we found that CuET had a marked effect on suppressing CRC progression both in vitro and in vivo by reducing glucose metabolism. Mechanistically, using RNA-seq analysis, we identified ALDH1A3 as a target gene of CuET, which promoted cell viability and the capacity of clonal formation and inhibited apoptosis in CRC cells. MicroRNA (miR)-16-5p and 15b-5p were shown to synergistically regulate ALDH1A3, which was negatively correlated with both of them and inversely correlated with the survival of CRC patients. Notably, using co-immunoprecipitation followed with mass spectrometry assays, we identified PKM2 as a direct downstream effector of ALDH1A3 that stabilized PKM2 by reducing ubiquitination. Taken together, we disclose that CuET treatment plays an active role in inhibiting CRC progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway.

17.
Aging (Albany NY) ; 12(18): 18501-18521, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32991321

RESUMO

Treatment of glioblastoma using radiotherapy and chemotherapy has various outcomes, key among them being cellular senescence. However, the molecular mechanisms of this process remain unclear. In the present study, we tested the ability of D-galactose (D-gal), a reducing sugar, to induce senescence in glioblastoma cells. Following pretreatment with D-gal, glioblastoma cell lines (C6 and U87MG) showed typical characteristics of senescence. These included the reduced cell proliferation, hypertrophic morphology, increased senescence-associated ß-galactosidase activity, downregulation of Lamin B1, and upregulation of several senescence-associated genes such as p16, p53, and NF-κB. Furthermore, our results showed that D-gal was more suitable than etoposide (a DNA-damage drug) in inducing senescence of glioblastoma cells. Mechanistically, D-gal inactivated the YAP-CDK6 signaling pathway, while overexpression of YAP or CDK6 could restore D-gal-induced senescence of C6 cells. Finally, metformin, an anti-aging agent, activated the YAP-CDK6 pathway and suppressed D-gal-induced senescence of C6 cells. Taken together, these findings established a new model for analyzing senescence in glioblastoma cells, which occurred through the YAP-CDK6 pathway. This is expected to provide a basis for development of novel therapies for the treatment of glioblastoma.

18.
Adv Mater ; 32(42): e2004793, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32930460

RESUMO

Lithium (Li) metal offers the highest projected energy density as a battery anode, however its extremely high reactivity induces dendrite growth and dead Li formation during repeated charge/discharge processes, resulting in both poor reversibility and catastrophic failure. Approaches reported to date often seek to suppress dendrites formation at the expense of energy density. Here, a strategy that resolves the above conflict and achieves a dendrite-free and long-term reversible Li metal anode is reported. A self-organized core-shell composite anode, comprising an outer sheath of lithiated liquid metal (Lix LMy ) and an inner layer of Li metal, is developed, which posesses high electrical and ionic conductivity, and physically separates Li from the electrolyte. The introduction of Lix LMy not only prevents dendrite formation, but also eliminates the use of copper as an inert substrate. Full cells made of such composite anodes and commercially available LiNi0.6 Co0.2 Mn0.2 O2 (NCM622 ) cathodes deliver ultrahigh energy density of 1500 Wh L-1 and 483 Wh kg-1 . The high capacity can be maintained for more than 500 cycles, with fading rate of less than 0.05% per cycle. Pairing with LiNi0.8 Co0.1 Mn0.1 O2 (NCM811 ) further raises the energy density to 1732 Wh L-1 and 514 Wh kg-1 .

19.
ACS Appl Mater Interfaces ; 12(39): 43596-43604, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32840344

RESUMO

Voltage decay during cycling is still a major issue for Li-rich cathodes in lithium ion batteries. Recently, the increase of Ni content has been recognized as an effective way to mitigate this problem, although it leads to lower-capacity materials. To find a balance between voltage decay and high capacity, particles of Li-rich materials with concentration gradients of transition metals have been prepared. Since voltage decay is caused by oxygen loss and phase transition that occur mainly on the particle surface, the Ni content is designed with a negative gradient of concentration from the surface to the bulk of particles. To do so, microsized Li1.20Ni0.13Co0.13Mn0.54O2 particles are mixed with much smaller LiNi0.8Co0.1Mn0.1O2 particles to form deposits of small particles onto larger particles. The concentration gradient of Ni is achieved as the Ni ions in LiNi0.8Co0.1Mn0.1O2 penetrate into Li1.20Ni0.13Co0.13Mn0.54O2 during a calcination post-treatment. Gradient samples show superior cycling performance and voltage retention as well as improved safety. This systematic study explores a material model combining Li-rich and high-Ni layered cathodes that is shown to be effective in creating a balance between mitigated voltage decay and high energy density.

20.
Cell Death Dis ; 11(8): 638, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32801300

RESUMO

The development of prostate cancer (PCa) from androgen-deprivation therapy (ADT) sensitive to castration resistant (CRPC) seriously impacts life quality and survival of PCa patients. Emerging evidence shows that long noncoding RNAs (lncRNAs) play vital roles in cancer initiation and progression. However, the inherited mechanisms of how lncRNAs participate in PCa progression and treatment resistance remain unclear. Here, we found that a long noncoding RNA LINC00675 was upregulated in androgen-insensitive PCa cell lines and CRPC patients, which promoted PCa progression both in vitro and in vivo. Knockdown of LINC00675 markedly suppressed tumor formation and attenuated enzalutamide resistance of PCa cells. Mechanistically, LINC00675 could directly modulate androgen receptor's (AR) interaction with mouse double minute-2 (MDM2) and block AR's ubiquitination by binding to it. Meanwhile, LINC00675 could bind to GATA2 mRNA and stabilize its expression level, in which GATA2 could act as a co-activator in the AR signaling pathway. Notably, we treated subcutaneous xenografts models with enzalutamide and antisense oligonucleotides (ASO) targeting LINC00675 in vivo and found that targeting LINC00675 would benefit androgen-deprivation-insensitive models. Our findings disclose that the LINC00675/MDM2/GATA2/AR signaling axis is a potential therapeutic target for CRPC patients.


Assuntos
Neoplasias de Próstata Resistentes à Castração/genética , RNA Longo não Codificante/genética , Receptores Androgênicos/genética , Antagonistas de Androgênios/farmacologia , Androgênios/metabolismo , Animais , Benzamidas , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética
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