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1.
Gene ; 809: 146022, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34673209

RESUMO

BACKGROUND: Genome-wide association studies have demonstrated that genetic variants are closely related to tumorigenesis and progression of cancer. However, the correlation between genetic variants in splicing factor genes and bladder cancer susceptibility remains unclear. METHOD: A case-control study with 580 cases of bladder cancer and 1,101 controls was conducted to explore the association of single-nucleotide polymorphisms (SNPs) in splicing factors with bladder cancer susceptibility by logistic regression models, and multiple testing errors were justified by the false discovery rate (FDR) method. Next, we used the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) datasets to further analyze the differential expression of candidate genes. RESULTS: We found that rs978416 G>A in RBFOX3 contributed to a reduced risk of bladder cancer [adjusted odds ratio (OR) = 0.72, 95% confidence internal (CI) = 0.62-0.84, P = 3.54 × 10-5], especially in individuals who never smoked (P = 7.83 × 10-5). Stratified analysis showed that the protective effect of rs978416 was more significant in the subgroup of low grade and non-muscle invasive bladder cancer. Furthermore, the RBFOX3 mRNA expression was decreased in bladder tumor tissues. However, the relatively high expression of RBFOX3 was related to a higher bladder cancer stage. CONCLUSIONS: Our findings indicated that SNP rs978416 G>A in RBFOX3 may be related to bladder cancer predisposition in Chinese population and might serve as a novel biomarker for bladder cancer risk.


Assuntos
Antígenos Nucleares/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Fatores de Processamento de RNA/genética , Neoplasias da Bexiga Urinária/genética , /genética , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Neoplasias da Bexiga Urinária/patologia
2.
J Am Chem Soc ; 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34854674

RESUMO

Selective hydrogenation of alkynes to alkenes requires a catalytic site with suitable electronic properties for modulating the adsorption and conversion of alkyne, alkene as well as dihydrogen. Here, we report a complex palladium hydride, CaPdH2, featured by electron-rich [PdH2]δ- sites that are surrounded by Ca cations that interacts with C2H2 and C2H4 via σ-bonding to Pd and unusual cation-π interaction with Ca, resulting in a much weaker chemisorption than those of Pd metal catalysts. Concomitantly, the dissociation of H2 and hydrogenation of C2Hx (x = 2-4) species experience significant energy barriers over CaPdH2, which is fundamentally different from those reported Pd-based catalysts. Such a unique catalytic environment enables CaPdH2, the very first complex transition-metal hydride catalyst, to afford a high alkene selectivity for the semihydrogenation of alkynes.

3.
Transl Lung Cancer Res ; 10(10): 3912-3928, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34858781

RESUMO

Background: Female menstrual and reproductive factors, as remarkable indicators of hormone effect, were hypothesized to be associated with lung cancer risk, whereas the existed epidemiological evidence was inconsistent. Our study aims to investigate the association between menstrual and reproductive factors and lung cancer risk based on the Chinese Lung Cancer Screening Program. Methods: This study was based on a large-scale multi-center population cohort across China recruiting individuals aged 40-74 years old between 2013-2018. Cox regression model was applied to estimate the HRs and 95% CIs. Restricted cubic spline (RCS) analysis was used to estimate dose-response relationships and test for nonlinear associations. Results: Among 553,434 female participants, 1,529 incident lung cancer cases were identified with a median follow-up of 3.61 years. With adjustment for multiple covariates and all significant hormonal factors, elevated lung cancer risk was associated with later age (15, or ≥16 years) at menarche (HR =1.27, 95% CI: 1.04-1.56; HR =1.45, 95% CI: 1.19-1.76), later age (25-29, or ≥30 years) at first live birth (HR =1.27, 95% CI: 1.13-1.43; HR =1.23, 95% CI: 1.00-1.51), and benign breast disease history (HR =1.25, 95% CI: 1.10-1.41). For postmenopausal females specifically, surgical menopause (HR =1.62; 95% CI: 1.29-2.05) and other surgeries on the reproductive system (HR =1.19; 95% CI: 1.01-1.40) both appeared to be predictive of elevated lung cancer risk. Concerning age at menopause, a nonlinear association was observed (P-nonlinear =0.0126). Increased lung cancer risk was observed among females with age at menopause especially above 50. Although we observed no significant associations between longer time (≥13 months) of breastfeeding and lung cancer risk among all participants (HR =0.86; 95% CI: 0.71-1.04), significant decreased adenocarcinoma risk (HR =0.65; 95% CI: 0.53-0.81) was noted among nonsmoking females. Conclusions: Our findings add some support for the role of menstrual and reproductive factors in lung carcinogenesis. However, these relationships were complex, and required further investigations addressing the biological mechanisms.

4.
Genes (Basel) ; 12(12)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34946935

RESUMO

Kapok is the main host of Glenea cantor (Fabricius), which causes serious damage and is difficult to control. In severe cases, it often causes the kapok trees to die continuously, which seriously affects the results of urban landscaping. To provide reference for the functional research on related genes in G. cantor, we screened the stable expression of candidate reference genes at different developmental stages (i.e., eggs, larvae, pupae, and adults), in various adult tissues (i.e., head, thorax, abdomen, feet, antennae, and wings), and sexes (i.e., male pupae, female pupae, male adults, and female adults). In this study, 12 candidate reference genes (i.e., ACTINLIKE, ACTININ, TUB, RPL36, RPL32, RPS20, TBP, GAPDH, 18S rRNA, EF1A1, EF1A2, and UBQ) were evaluated using different adult tissues, developmental stages, and sexes. RefFinder, geNorm, NormFinder, and BestKeeper were used to evaluate and comprehensively analyze the stability of the expression of the candidate reference genes. The results show that RPL32 and EF1A1 were the most suitable reference genes in the different adult tissues, and RPL36 and EF1A1 were best at the different developmental stages. RPL36 and EF1A2 were the best fit for the qRT-PCR reference genes in the different sexes, while RPL36 and EF1A1 were the most appropriate qRT-PCR reference genes in all samples. Results from geNorm showed that the optimal number of reference genes was two. We also surveyed the expression of cellulase at the different developmental stages and in the different adult tissues. Results further verified the reliability of the reference genes, and confirmed the best reference genes under the different experimental conditions. This study provides a useful tool for molecular biological studies on G. cantor.

5.
Pharmaceutics ; 13(12)2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34959271

RESUMO

The co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor. The released PTX@TF entered cancer cells via transferrin-receptor-mediated endocytosis and inhibited the survival of tumor cells. MMST was intelligently employed as an immunomodulator to improve immunotherapy by inhibiting matrix metalloproteinases to reduce chemokine degradation and recruit T cells. The TMNPs promoted the tumor infiltration of CD3+ T cells by 2-fold, including memory/effector CD8+ T cells (4.2-fold) and CD4+ (1.7-fold), but not regulatory T cells. Our in vivo anti-tumor experiment suggested that TMNPs possessed the highest tumor growth inhibitory rate (80.86%) compared with the control group. We demonstrated that the nanoplatform could effectively inhibit the growth of tumors and enhance T cell recruitment through the co-delivery of paclitaxel and marimastat, which could be a promising strategy for the combination of chemotherapy and immunotherapy for cancer treatment.

6.
Mater Horiz ; 8(2): 471-500, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34821265

RESUMO

Organic electrode materials have been considered as promising candidates for the next generation rechargeable battery systems due to their high theoretical capacity, versatility, and environmentally friendly nature. Among them, organosulfur compounds have been receiving more attention in conjunction with the development of lithium-sulfur batteries. Usually, organosulfide electrodes can deliver a relatively high theoretical capacity based on reversible breakage and formation of disulfide (S-S) bonds. In this review, we provide an overview of organosulfur materials for rechargeable lithium batteries, including their molecular structural design, structure related electrochemical performance study and electrochemical performance optimization. In addition, recent progress of advanced characterization techniques for investigation of the structure and lithium storage mechanism of organosulfur electrodes are elaborated. To further understand the perspective application, the additive effect of organosulfur compounds for lithium metal anodes, sulfur cathodes and high voltage inorganic cathode materials are reviewed with typical examples. Finally, some remaining challenges and perspectives of the organosulfur compounds as lithium battery components are also discussed. This review is intended to serve as general guidance for researchers to facilitate the development of organosulfur compounds.

7.
Front Immunol ; 12: 686809, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777331

RESUMO

Immune microenvironment of prostate cancer (PCa) is implicated in disease progression. However, previous studies have not fully explored PCa immune microenvironment. This study used ssGSEA algorithm to explore expression levels of 53 immune terms in a combined PCa cohort (eight cohorts; 1,597 samples). The top 10 immune terms were selected based on the random forest analysis and used for immune-related risk score (IRS) calculation. Furthermore, we explored differences in clinical and genomic features between high and low IRS groups. An IRS signature based on the 10 immune terms showed high prediction potential for PCa prognosis. Patients in the high IRS group showed significantly higher percentage of immunotherapy response factors, implying that IRS is effective in predicting immunotherapy response rate. Furthermore, consensus clustering was performed to separate the population into three IRSclusters with different clinical outcomes. Patients in IRScluster3 showed the worst prognosis and highest immunotherapy response rate. On the other hand, patients in IRScluster2 showed better prognosis and low immunotherapy response rate. In addition, VGLL3, ANPEP, CD38, CCK, DPYS, CST2, COMP, CRISP3, NKAIN1, and F5 genes were differentially expressed in the three IRSclusters. Furthermore, CMap analysis showed that five compounds targeted IRS signature, thioridazine, trifluoperazine, 0175029-0000, trichostatin A, and fluphenazine. In summary, immune characteristics of PCa tumor microenvironment was explored and an IRS signature was constructed based on 10 immune terms. Analysis showed that this signature is a useful tool for prognosis and prediction of immunotherapy response rate of PCa.

8.
J Food Sci ; 86(11): 4828-4839, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34642954

RESUMO

A phenylhexyl isothiocyanate (PITC) precolumn derivatization quantitative analysis of multicomponents by a single marker (QAMS) strategy for the simultaneous analysis of 20 free amino acids (FAA) in Dendrobium huoshanense is proposed. The method was validated by the linearity, limit of detection (LDO), and limit of quantitation (LOQ), recovery, precision, and stability. The results showed that when applying the established method, the LOQ of the FFAs was lower than 1 ng/ml except threonine (1.32 ng) and cysteine (1.16 ng). The QAMS investigation revealed that, using any one of the 20 FAAs as the reference internal standard, no significant differences were observed between the external standard method and the QAMS method for the quantification of FAAs in D. huoshanense by PITC precolumn derivatization [The relative standard deviation (RSD, %) by QAMS and ESM were all below 5%]. HPLC fingerprint investigation combined with similar analysis (the similarity values for S1-S25 were >0.875) and quality fluctuation analysis showed that the cultivation environment might have a great effect on the accumulation of FAAs in D. huoshanense. Overall, our study showed that we might increase the accuracy and scope of the simultaneous quantification of multicomponents using the QAMS technique by being derivatized with a strong UV absorbing group, and QAMS combined with chromatographic fingerprinting can be considered good quality criteria for the quality control of D. huoshanense and may provide analytical technical support for research on Maillard Reaction during the further processing of D. huoshanense.


Assuntos
Dendrobium , Medicamentos de Ervas Chinesas , Aminoácidos , Cromatografia Líquida de Alta Pressão , Controle de Qualidade
9.
Arch Toxicol ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34668023

RESUMO

Autophagy plays a critical role in cancer, since it can either suppress tumorigenesis by inhibiting cancer cell survival, or facilitate tumorigenesis by promoting cancer cell proliferation and tumor growth. However, the role of genetic variants of autophagy-regulated key genes for bladder cancer risk remained unclear. Here, we aimed to explore the association of bladder cancer with genetic variants on genes involved in autophagy pathway. Gene-based analysis was performed with multi-marker analysis of genomic annotation (MAGMA) in 580 bladder cancer cases and 1101 controls. The logistic regression model was used to calculate the SNP effects on bladder cancer susceptibility. Expression quantitative trait loci (eQTL) analysis was conducted by the genotype-tissue expression (GTEx) project. Gene expression was evaluated based on the Cancer Genome Atlas (TCGA) database. Three potentially functional SNPs RPS6KB1 rs1292038, PIK3R1 rs34303, and rs56352616 were demonstrated to be associated with risk of bladder cancer (OR = 0.71, 95% CI = 0.61-0.82, P = 7.88 × 10-6 for rs1292038; OR = 1.25, 95% CI = 1.09-1.45, P = 2.11 × 10-3 for rs34303; OR = 0.74, 95% CI = 0.62-0.90, P = 2.47 × 10-3 for rs56352616). An increasing number of risk genotypes of these three SNPs were associated with a higher risk of developing bladder cancer. Besides, rs1292038 exhibited an eQTL effect for RPS6KB1 in whole blood (P = 3.90 × 10-7). Furthermore, the higher expression of RPS6KB1 and lower expression of PIK3R1 were both significantly associated with bladder cancer risk. Our findings indicated that genetic variants in autophagy pathway genes RPS6KB1 and PIK3R1 confer bladder cancer susceptibility.

10.
Eng Life Sci ; 21(10): 643-652, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34690635

RESUMO

Clavulanic acid (CA) is usually used together with other ß-lactam antibiotics as combination drugs to inhibit bacterial ß-lactamases, which is mainly produced from the fermentation of microorganism such as Streptomyces clavuligerus. Recently, it is still a challenge for downstream processing of low concentration and unstable CA from fermentation broth with high solid content, high viscosity, and small cell size. In this study, an integrated process was developed for simultaneous solid-liquid separation and primary purification of CA from real fermentation broth of S. clavuligerus using salting-out extraction system (SOES). First, different SOESs were investigated, and a suitable SOES composed of ethanol/phosphate was chosen and further optimized using the pretreated fermentation broth. Then, the optimal system composed of 20% ethanol/15% K2HPO4 and 10% KH2PO4 w/w was used to direct separation of CA from untreated fermentation broth. The result showed that the partition coefficient (K) and recovery yield (Y) of CA from untreated fermentation broth were 29.13 and 96.8%, respectively. Simultaneously, the removal rates of the cells and proteins were 99.8% and 63.3%, respectively. Compared with the traditional method of membrane filtration or liquid-liquid extraction system, this developed SOES showed the advantages of simple operation, shorter operation time, lower process cost and higher recovery yield of CA. These results demonstrated that the developed SOES could be used as an attractive alternative for the downstream processing of CA from real fermentation broth.

11.
EMBO Rep ; : e52702, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34693625

RESUMO

TNF stimulation generates pro-survival signals through activation of NF-κB that restrict the build-in death signaling triggered by TNF. The competition between TNF-induced survival and death signals ultimately determines the fate of a cell. Here, we report the identification of Bclaf1 as a novel component of the anti-apoptotic program of TNF. Bclaf1 depletion in multiple cells sensitizes cells to TNF-induced apoptosis but not to necroptosis. Bclaf1 exerts its anti-apoptotic function by promoting the transcription of CFLAR, a caspase 8 antagonist, downstream of NF-κB activation. Bclaf1 binds to the p50 subunit of NF-κB, which is required for Bclaf1 to stimulate CFLAR transcription. Finally, in Bclaf1 siRNA administered mice, TNF-induced small intestine injury is much more severe than in control mice with aggravated signs of apoptosis and pyroptosis. These results suggest Bclaf1 is a key regulator in TNF-induced apoptosis, both in vitro and in vivo.

12.
Asian J Pharm Sci ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34703490

RESUMO

Strong infectivity enables coronavirus disease 2019 (COVID-19) to rage throughout the world. Moreover, the lack of drugs with definite therapeutic effects further aggravates the spread of the pandemic. Remdesivir is one of the most promising anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs. However, the limited clinical effects make its therapeutic effect controversial, which may result from the poor accumulation and activation of remdesivir in the lung. Therefore, we developed lyophilized remdesivir liposomes (Rdv-lips) which can be reconstituted as liposomal aerosol for pulmonary delivery to improve the in vivo behavior of existing remdesivir cyclodextrin conclusion compound (Rdv-cyc) injections. Liposome encapsulation endowed remdesivir with much higher solubility and better biocompatibility. The in vitro liposomal aerosol characterization demonstrated that Rdv-lips possessed a mass median aerodynamic diameter of 4.118 µm and fine particle fraction (<5 µm) higher than 50%, indicating good pulmonary delivery properties. Compared to the Rdv-cyc intravenous injection group, the Rdv-lips inhalation group displayed a nearly 100-fold increase in the remdesivir-active metabolite nucleotide triphosphate (NTP) concentration and better NTP accumulation in the lung than the Rdv-cyc inhalation group. A faster transition from remdesivir to NTP of Rdv-lips (inhalation) could also be observed due to better cell uptake. Compared to other preparations, the superiority of Rdv-lips was further evidenced by the results of an in vivo safety study, with little possibility of inducing inflammation. In conclusion, Rdv-lips for pulmonary delivery will be a potent formulation to improve the in vivo behavior of remdesivir and exert better therapeutic effects in COVID-19 treatment.

13.
J Biomed Nanotechnol ; 17(10): 2043-2052, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34706804

RESUMO

A persimmon tannin-Aloe vera composite powder (PT-A) was investigated for its capacity to protect against ionizing radiation. Human hepatic cells (L02 cells) and human hepatoma cells (HepG2 cells) were pretreated with different concentrations of PT-A or the single compounds (PT or Aloe vera) and radiated with X-rays. After radiation and post-incubation for 12 h or 24 h, the cell viability, apoptosis, and reactive oxygen species (ROS) production were analyzed by Cell Counting Kit 8 (CCK-8), 2',7'-dichlorfluorescein diacetate (DCFH-DA) staining, and Hoechst 33258 staining/flow cytometry, respectively. CCK-8 results illustrated that the optimal radiation dose L02 cells was 8 Gy for L02 cells, and the cell activity was 71.72% (IC50 = 412.1 µg/mL) after post-radiation incubation of 12 h. For HepG2 cells, the optimal radiation dose was 8 Gy, and the cell activity was 62.37% (IC50 = 213.0 µg/mL). The cell apoptotic rate was the lowest at a PT-A concentration of 200 µg/mL in L02 cells (4.32%, P < 0.05), and at 100 µg/mL in HepG2 cells (9.80%, P < 0.05). ROS production induced by radiation could be effectively inhibited by 200 µg/mL of PT-A in L02 cells, and by 100 µg/mL of PT-A in HepG2 cells. The PT-A composite has good radioprotective effects on cell vitality and apoptosis of X-rays radiation exposure towards L02 cells and HepG2 cells compared to the persimmon tannin or Aloe vera. Therefore, PT-A composite might be useful as a natural, harmless anti-ionizing radiation agent, and has various clinical application prospects in future.


Assuntos
Aloe , Carcinoma Hepatocelular , Diospyros , Carcinoma Hepatocelular/tratamento farmacológico , Hepatócitos , Humanos , Taninos/farmacologia , Raios X
14.
Front Genet ; 12: 706661, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712264

RESUMO

Background: Long non-coding RNAs (lncRNAs) are now under discussion as novel promising biomarkers for clear cell renal cell carcinoma (ccRCC). However, the role of genomic instability-associated lncRNA signatures in tumors has not been thoroughly uncovered. The purpose of our study is to probe the role of genomic instability-derived lncRNA signature (GILncSig) and to further investigate the mechanism of genomic instability-mediated ccRCC progression. Methods: The transcriptome data and somatic mutation profiles of ccRCC as well as clinical characteristics used in this study were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database. Lasso regression analysis was performed to construct the GILncSig. Gene set enrichment analysis (GSEA) was performed to elucidate the biological functions and relative pathways. CIBERSORT and EPIC algorithm were applied to calculate the proportion of immune cells in ccRCC. ESTIMATE algorithm was utilized to compute the immune microenvironment scores. Results: In total, 148 novel genomic instability-derived lncRNAs in ccRCC were identified. Immediately, on the basis of univariate cox analysis and lasso analysis, a GILncSig was appraised, through which the patients were allocated into High-Risk and Low-Risk groups with significantly different characteristics and prognoses. In addition, we confirmed that the somatic mutation count, tumor mutation burden, and the expression of UBQLN4, which were ascertainably associated with genomic instability, were significantly correlated with the GILncSig, indicating its reliability as a measurement of the genomic instability. Furthermore, the efficiency of GILncSig in prognostic aspects was better than the single mutation gene in ccRCC. In addition, MNX1-AS1 was defined to be a potential biomarker characterized by strong correlation with clinical features. Moreover, GSEA results indicated that the IL6/JAK/STAT3/SIGNALING pathway could be considered as a potential mechanism of genomic instability to influence tumor progression. Besides, the immune microenvironment showed significant differences between the GS-like group and the GU-like group, which was specifically manifested as high expression of CTLA4, GITR, TNFSF14, and regulatory T cells (Tregs) as well as low expression of endothelial cells (ECs) in the GU-like group. Finally, the prognostic value and clinical relevance of GILncSig were verified in GEO datasets and other urinary tumors in TCGA dataset. Conclusion: In conclusion, our study provided a new perspective for the role of lncRNAs in genomic instability and revealed that genomic instability may mediate tumor progression by affecting immunity. Besides, MNX1-AS1 played critical roles in promoting the progression of ccRCC, which may be a potential therapeutic target. What is more, the immune atlas of genomic instability was characterized by high expression of CTLA4, GITR, TNFSF14, and Tregs, and low expression of ECs.

15.
Cancer Cell Int ; 21(1): 509, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556138

RESUMO

BACKGROUND: Our previous bioinformatics-based study found that midkine (MDK) was associated with poor prognosis of glioblastoma (GBM). However, the mechanism of MDK in GBM remains elusive. METHODS: A public GBM-related dataset and GBM tissues from our center were used validate the aberrant expression of MDK in GBM at the RNA and protein levels. The relationship between MDK expression and survival of GBM patients was also explored through survival analysis. Subsequently, we identified MDK-related GBM-specific genes using differential expression analysis. Functional enrichment analyses were performed to reveal their potential biological functions. CCK-8, 5-ethynyl-2'-deoxyuridine, and Matrigel-transwell assays were performed in GBM cell lines in which MDK was knocked out or overexpressed in order assess the effects of MDK on proliferation, migration, and invasion of GBM cells. Western blotting was performed to detect candidate proteins. RESULTS: Our study showed MDK is a promising diagnostic and prognostic biomarker for GBM because it is highly expressed in the disease and it is associated with poor prognosis. MDK is involved in various cancer-related pathways, such as PI3K-Akt signaling, the cell cycle, and VEGF signaling. A comprehensive transcriptional regulatory network was constructed to show the potential pathways through which MDK may be involved in GBM. In vitro, Overexpression of MDK augmented proliferation, migration, and invasion of GBM cell lines, whereas suppression of MDK led to the opposite effects. Furthermore, our study confirmed that MDK promotes the progression of GBM by activating the PI3K-Akt signaling pathway. CONCLUSIONS: Our present study proposes that MDK promotes GBM by activating the PI3K-Akt signaling pathway, and it describes a potential regulatory network involved.

16.
Med Sci Monit ; 27: e932422, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34564688

RESUMO

BACKGROUND Perioperative neuro-cognitive disorders (PND) are preoperative and postoperative complications of multiple nervous systems, typically manifested as decreased memory and learning ability after surgery. It was used to replace the original definition of postoperative cognitive dysfunctions (POCD) from 2018. Our previous studies have shown that sevoflurane inhalation can lead to cognitive dysfunction in Sprague-Dawley rats, but the specific mechanism is still unclear. MATERIAL AND METHODS Thirty-six male Sprague-Dawley rats were randomly divided into 6 groups (n=6): the SD group was given 24-h acute sleep deprivation; Sevoflurane was inhaled for 2 h in the Sevo group. Two mL propofol was injected into the tail vein of rats in the Prop group. The rats in the SD+Sevo group and SD+Prop group were deprived of sleep before intervention in the same way as before. RESULTS We noted significant behavioral changes in rats treated with SIK3 inhibitors or tau phosphorylation agonists before propofol injection or sevoflurane inhalation, with associated protein levels and dendritic spine density documented. Sevoflurane anesthesia-induced cognitive impairment following acute sleep deprivation was more pronounced than sleep deprivation-induced cognitive impairment alone and resulted in increased brain SIK3 levels, increased phosphorylation of total tau and tau, and decreased acetylation modifications. After using propofol, the cognitive function returned to baseline levels with a series of reversals of cognitive dysfunction. CONCLUSIONS These results suggest that sevoflurane inhalation via the SIK3 pathway aggravates cognitive impairment after acute sleep deprivation and that propofol anesthesia reverses the effects of sleep deprivation by affecting modifications of tau protein.


Assuntos
Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Disfunção Cognitiva/fisiopatologia , Plasticidade Neuronal/efeitos dos fármacos , Propofol/farmacologia , Sevoflurano/farmacologia , Privação do Sono/fisiopatologia , Animais , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Privação do Sono/complicações
17.
Int J Gen Med ; 14: 5397-5404, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34526808

RESUMO

Purpose: Venous thromboembolism (VTE) is a common complication of intracerebral hemorrhage (ICH) patients in intensive care unit (ICU), but anticoagulation therapy of ICH patients with VTE remains controversial. We aim to explore the risk factors and prognosis of anticoagulation therapy in ICH patients with VTE. Patients and Methods: Medical records of ICH patients were collected from the Medical Information Mart for Intensive Care III (MIMIC-III version 1.4) database. The risk factors and prognosis of anticoagulation therapy in ICH patients with VTE were assessed by multivariable logistic regression analysis and Kaplan-Meier survival analysis, respectively. Results: A total of 848 ICH patients were included in our study, of whom 69 ICH patients with VTE were screened, including 58 patients with deep vein thrombosis (DVT), 12 patients with pulmonary embolism (PE), and 1 patient with DVT and PE. In the multivariable logistic regression analysis, malignancy (odds ratio (OR): 4.262, 95% confidence interval (CI): 2.263-8.027, P=0.000), pulmonary circulation disease (OR: 28.717, 95% CI: 9.566-86.208, P=0.000), coagulopathy (OR: 2.453, 95% CI: 1.098-5.483, P=0.029), age > 60 years old (OR: 2.138, 95% CI: 1.087-4.207, P=0.028) and hospitalization time > 16 days (OR: 2.548, 95% CI: 1.381-4.701, P=0.003) were independent risk factors for VTE in ICH patients. Kaplan-Meier survival analysis and log-rank test found that, compared to non-anticoagulation group, anticoagulation group had higher cumulative survival rates during hospitalization, 28-day, 3-month, 1-year, and 4-year after admission, respectively. Conclusion: Malignancy, pulmonary circulation disease, coagulopathy, age >60 years old and hospitalization time >16 days were independent risk factors for VTE in ICH patients, and anticoagulation therapy for VTE in ICH patients may be safe and effective. These findings need to be verified by more high-quality and well-designed randomized controlled trials.

18.
mBio ; 12(5): e0233521, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34544279

RESUMO

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients. IMPORTANCE The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteases 3C de Coronavírus/metabolismo , Proteína DEAD-box 58/metabolismo , Receptores Imunológicos/metabolismo , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Células CACO-2 , Proteases 3C de Coronavírus/genética , Proteína DEAD-box 58/genética , Ensaio de Imunoadsorção Enzimática , Células HCT116 , Células HEK293 , Humanos , Imunidade Inata/genética , Imunidade Inata/fisiologia , Immunoblotting , Interferon Tipo I/metabolismo , Camundongos , Receptores Imunológicos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Ubiquitinação , Replicação Viral/genética , Replicação Viral/fisiologia
19.
Hum Reprod ; 36(10): 2649-2660, 2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34477868

RESUMO

STUDY QUESTION: Do testis-derived circular RNAs (circRNAs) in seminal plasma have potential as biomarkers to predict the outcome of microdissection testicular sperm extraction (micro-TESE) in patients with idiopathic non-obstructive azoospermia (NOA)? SUMMARY ANSWER: Testis-derived circRNAs in the seminal plasma can indeed be used for predicting the outcome of micro-TESE in patients with idiopathic NOA. WHAT IS KNOWN ALREADY: Micro-TESE is an effective method to obtain sperm samples from patients with idiopathic NOA. However, its success rate is only 40-50% in such patients. STUDY DESIGN, SIZE, DURATION: Six idiopathic NOA patients with different micro-TESE results were included as the discovery cohort. Their testicular tissues were used for extracting and sequencing circRNAs. Five circRNAs with the most significantly different expression levels were selected for further verification. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fifty-two patients with idiopathic NOA were included as the validation cohort. Preoperative seminal plasma samples of 52 patients with idiopathic NOA and 25 intraoperative testicular tissues were collected and divided into 'success' and 'failure' groups according to the results of micro-TESE. Quantitative real-time polymerase chain reaction was performed to verify differences in the expression levels of the selected circRNAs between the two groups in the testicular tissues and seminal plasma. MAIN RESULTS AND THE ROLE OF CHANCE: Whether at the seminal plasma or testicular tissue level, the differences in the expression levels of the three circRNAs (hsa_circ_0000277, hsa_circ_0060394 and hsa_circ_0007773) between the success and failure groups were consistent with the sequencing results. A diagnostic receiver operating curve (ROC) analysis of the AUC indicated excellent diagnostic performance of these circRNAs in seminal plasma in predicting the outcome of micro-TESE (AUC values: 0.920, 0.928 and 0.891, respectively). On the basis of least absolute shrinkage and selection operator (LASSO) logistic regression, the three circRNAs were combined to construct a new prediction model. The diagnostic ROC curve analysis of the model showed an AUC value of 0.958. The expression levels of these circRNAs in seminal plasma using three normospermic volunteer samples remained stable after 48 h at room temperature. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: This was a single-center retrospective study with relatively few cases. The functions of these circRNAs, as well as their relationship with spermatogenesis, have not yet been established. WIDER IMPLICATIONS OF THE FINDINGS: Testis-derived circRNAs in seminal plasma can reflect the microenvironment of the testis and can be used as reliable biomarkers to screen patients with idiopathic NOA who might be suitable for micro-TESE. STUDY FUNDING/COMPETING INTEREST(S): This article was funded by the National Natural Science Foundation of China (Grant no. 81871151). There were no competing interests.


Assuntos
Azoospermia , RNA Circular , Azoospermia/genética , Humanos , Masculino , Microdissecção , Estudos Retrospectivos , Sêmen , Recuperação Espermática , Espermatozoides , Testículo
20.
Entropy (Basel) ; 23(7)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34356415

RESUMO

Over previous decades, many nature-inspired optimization algorithms (NIOAs) have been proposed and applied due to their importance and significance. Some survey studies have also been made to investigate NIOAs and their variants and applications. However, these comparative studies mainly focus on one single NIOA, and there lacks a comprehensive comparative and contrastive study of the existing NIOAs. To fill this gap, we spent a great effort to conduct this comprehensive survey. In this survey, more than 120 meta-heuristic algorithms have been collected and, among them, the most popular and common 11 NIOAs are selected. Their accuracy, stability, efficiency and parameter sensitivity are evaluated based on the 30 black-box optimization benchmarking (BBOB) functions. Furthermore, we apply the Friedman test and Nemenyi test to analyze the performance of the compared NIOAs. In this survey, we provide a unified formal description of the 11 NIOAs in order to compare their similarities and differences in depth and a systematic summarization of the challenging problems and research directions for the whole NIOAs field. This comparative study attempts to provide a broader perspective and meaningful enlightenment to understand NIOAs.

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