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1.
Nat Commun ; 12(1): 1292, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637710

RESUMO

Surface-enhanced Raman spectroscopy (SERS) has emerged as a powerful tool to detect biomolecules in aqueous environments. However, it is challenging to identify protein structures at low concentrations, especially for the proteins existing in an equilibrium mixture of various conformations. Here, we develop an in situ optical tweezers-coupled Raman spectroscopy to visualize and control the hotspot between two Ag nanoparticle-coated silica beads, generating tunable and reproducible SERS enhancements with single-molecule level sensitivity. This dynamic SERS detection window is placed in a microfluidic flow chamber to detect the passing-by proteins, which precisely characterizes the structures of three globular proteins without perturbation to their native states. Moreover, it directly identifies the structural features of the transient species of alpha-synuclein among its predominant monomers at physiological concentration of 1 µM by reducing the ensemble averaging. Hence, this SERS platform holds the promise to resolve the structural details of dynamic, heterogeneous, and complex biological systems.

2.
Geobiology ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33559972

RESUMO

It is generally accepted that there is a vast, well-populated biosphere in the subsurface, but the depth limit of the terrestrial biosphere has yet to be determined, largely because of the lack of access to the subsurface. Here as part of the Chinese Continental Scientific Drilling (CCSD) project in eastern China, we acquired continuous rock cores and endeavored to probe the depth limit of the biosphere and the depth-dependent distribution of microorganisms at a geologically unique site, that is, a convergent plate boundary. Microbiological analyses of ultra-high-pressure metamorphic rock cores taken from the ground surface to 5,158-meter reveal that microbial distribution was continuous up to a depth of ~4,850 m, where temperature was estimated to be ~137°C. The metabolic state of these organisms at such great depth remains to be determined. Microbial abundance, ranging from 103 to 108  cells/g, was also related to porosity, but not to the depth and rock composition. In addition, microbial diversity systematically decreased with depth. Our results support the notion that temperature is a key factor in determining the lower limit of the biosphere in the continental subsurface.

3.
Nucleic Acids Res ; 49(2): 969-985, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33398341

RESUMO

Investigations of CRISPR gene knockout editing profiles have contributed to enhanced precision of editing outcomes. However, for homology-directed repair (HDR) in particular, the editing dynamics and patterns in clinically relevant cells, such as human iPSCs and primary T cells, are poorly understood. Here, we explore the editing dynamics and DNA repair profiles after the delivery of Cas9-guide RNA ribonucleoprotein (RNP) with or without the adeno-associated virus serotype 6 (AAV6) as HDR donors in four cell types. We show that editing profiles have distinct differences among cell lines. We also reveal the kinetics of HDR mediated by the AAV6 donor template. Quantification of T50 (time to reach half of the maximum editing frequency) indicates that short indels (especially +A/T) occur faster than longer (>2 bp) deletions, while the kinetics of HDR falls between NHEJ (non-homologous end-joining) and MMEJ (microhomology-mediated end-joining). As such, AAV6-mediated HDR effectively outcompetes the longer MMEJ-mediated deletions but not NHEJ-mediated indels. Notably, a combination of small molecular compounds M3814 and Trichostatin A (TSA), which potently inhibits predominant NHEJ repairs, leads to a 3-fold increase in HDR efficiency.


Assuntos
Sistemas CRISPR-Cas , Reparo do DNA por Junção de Extremidades , Edição de Genes , Vetores Genéticos/genética , Parvovirinae/genética , Reparo de DNA por Recombinação , Ribonucleoproteínas/metabolismo , Adulto , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Células HEK293 , Humanos , Ácidos Hidroxâmicos/farmacologia , Mutação INDEL , Células-Tronco Pluripotentes Induzidas , Cinética , RNA Guia/genética , Reparo de DNA por Recombinação/efeitos dos fármacos , Linfócitos T , Transdução Genética
4.
Coron Artery Dis ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33471466

RESUMO

BACKGROUND: C-reactive protein (CRP) has been proposed as a contributor to the pathogenesis of coronary artery disease (CAD) and inflammatory reactions, which are associated with a decrease in serum albumin, and it has been reported that the CRP-to-serum albumin ratio (CAR) can predict CAD severity in inpatient ischemic cardiomyopathy (ICM) patients. However, the relationship between the CAR and long-term adverse outcomes in CAD patients after percutaneous coronary intervention (PCI) is still unknown. METHODS: A total of 3561 CAD patients enrolled in the Outcomes and Risk Factors of Patients with Coronary Heart Disease after PCI: an investigation based on case records and follow-up (CORFCHD-ZZ), a retrospective cohort study conducted from January 2013 to December 2017, and 1630 patients meeting the study inclusion criteria were divided into two groups based on the CAR (CAR < 0.186; n = 1301 and CAR ≥ 0.186; n = 329). The primary outcome was long-term mortality, including all-cause mortality (ACM) and cardiac mortality. The average follow-up time was 37.59 months. RESULTS: We found that there were significant differences between the two groups in the incidences of ACM (P < 0.001) and cardiac mortality (P = 0.003). Cox multivariate regression analyses demonstrated that CAR was an independent predictor of ACM [hazard ratio, 2.678; (95% confidence interval (CI), 1.568-4.576); P < 0.001] and cardiac mortality (hazard ratio, 2.055; 95% CI, 1.056-3.998; P = 0.034) in CAD patients after PCI. CONCLUSION: This study revealed that the CAR is an independent and novel predictor of long-term adverse outcomes in CAD patients who have undergone PCI.

5.
Eur Respir Rev ; 30(159)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33472957

RESUMO

While asthma is known to be associated with an increased risk of progressive lung function impairments and fixed airflow obstruction, there is ongoing debate on whether inhaled corticosteroids (ICS) modify these long-term risks. Searches were performed of the PubMed, Embase and CENTRAL databases up to 22 July 2019 for studies with follow-up ≥1 year that investigated the effects of maintenance ICS on changes in lung function in asthma.Inclusion criteria were met by 13 randomised controlled trials (RCTs) (n=11 678) and 11 observational studies (n=3720). Median (interquartile range) follow-up was 1.0 (1-4) and 8.4 (3-28) years, respectively. In the RCTs, predominantly in individuals with mild asthma, ICS use was associated with improved pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) across all age groups (2.22% predicted (95% CI 1.32-3.12), n=8332), with similar estimates of strength in association for children and adults. Improvements in post-BD FEV1 were observed in adults (1.54% (0.87-2.21), n=3970), but not in children (0.20% (-0.49-0.90), n=3924) (subgroup difference, p=0.006). Estimates were similar between smokers and nonsmokers. There were no RCT data on incidence of fixed airflow obstruction. In the observational studies, ICS use was associated with improved pre-BD FEV1 in children and adults. There were limited observational data for post-BD outcomes.In patients with mild asthma, maintenance ICS are associated with modest, age-dependent improvements in long-term lung function, representing an added benefit to the broader clinical actions of ICS in asthma. There is currently insufficient evidence to determine whether treatment reduces incidence of fixed airflow obstruction in later life.

6.
Sci China Life Sci ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33420926

RESUMO

Genome-edited human induced pluripotent stem cells (iPSCs) hold great promise for therapeutic applications. However, low editing efficiency has hampered the applications of CRISPR-Cas9 technology in creating knockout and homology-directed repair (HDR)-edited iPSC lines, particularly for silent genes. This is partially due to chromatin compaction, inevitably limiting Cas9 access to the target DNA. Among the six HDAC inhibitors we examined, vorinostat, or suberoylanilide hydroxamic acid (SAHA), led to the highest HDR efficiency at both open and closed loci, with acceptable toxicity. HDAC inhibitors equally increased non-homologous end joining (NHEJ) editing efficiencies (∼50%) at both open and closed loci, due to the considerable HDAC inhibitor-mediated increase in Cas9 and sgRNA expression. However, we observed more substantial HDR efficiency improvement at closed loci relative to open chromatin (2.8 vs. 1.1-fold change). These studies provide a new strategy for HDR-editing of silent genes in iPSCs.

7.
J Sci Food Agric ; 101(1): 334-340, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32627840

RESUMO

BACKGROUND: Perennial legumes cultivated under irrigation in the Mountain West USA have non-fibrous carbohydrate (NFC) concentrations exceeding 400 g kg-1 , a level commonly found in concentrate-based ruminant diets. Our objective was to determine the influence of NFC concentration and plant secondary compounds on in vitro rumen digestion of grass, legume and forb forages compared with digestion of their isolated neutral detergent fiber (NDF) fraction. Forages were composited from ungrazed paddocks of rotationally stocked, irrigated monoculture pastures between May and August 2016, frozen in the field, freeze-dried, and ground. RESULTS: The maximum rate (RMax ) of gas production was greater for the legumes alfalfa (ALF; Medicago sativa L.) and birdsfoot trefoil (BFT; Lotus corniculatus L.) than for the legume cicer milkvetch (CMV; Astragalus cicer L.) the grass meadow brome (MBG; Bromus riparius Rehm.) and the non-legume forb small burnet (SMB; Sanguisorba minor Scop.), and intermediate for the legume sainfoin (SNF; Onobrychis viciifolia Scop.). The RMax of isolated NDF was greatest for BFT and CMV, intermediate for ALF, SNF and SMB and least for MBG. CONCLUSIONS: More than 900 g of organic matter kg-1 dry matter of legumes was digested after 96 h. Across forages, the extent of whole-plant digestion increased with NFC and crude protein concentrations, decreased with NDF concentrations, and was modulated by secondary compounds. The extent of digestion of isolated NDF decreased with concentration of lignin and residual tannins. © 2020 Society of Chemical Industry.

8.
Adv Healthc Mater ; : e2001430, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33274859

RESUMO

Herein, a new nanodrug of azobenzene-functionalized interfacial cross-linked reverse micelles (AICRM) with 5-fluorouracil loading (5-FU@AICRM) is reported. Upon irradiation with 530 nm light in water, the surface azobenzenes of the nanoparticles change from polar cis-conformation to nonpolar trans-conformation, resulting in the aggregation of 5-FU@AICRM within minutes. Simultaneously, the conformation change unlocks hydrophilic 5-FU with a strong water immigration propensity, allowing them to spray out from the AICRM quickly. This fast release ensures a thorough release of the drug, before the aggregates are internalized by adjacent cells, making it possible to achieve deep tissue penetration. A study of in vivo anticancer activity in A549 tumor-bearing nude mice shows that the tumor inhibition rate (TIR) of 5-FU@AICRM is up to ≈86.2%, 31.6% higher than that of group without green light irradiation and 20.7% higher than that of carmofur (CF, a hydrophobic analog of 5-FU)-loaded AICRM (CF@AICRM), in which CF is released slowly under light irradiation because of its hydrophobicity. Fast drug release upon nanodrug aggregation provides a good solution for balancing the contradiction of "aggregation and penetration" in tumor treatment with nanodrugs.

9.
NPJ Breast Cancer ; 6(1): 58, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33298949

RESUMO

RNA exosome can target the specific RNAs for their processing/degradation by distinct exosome cofactors. As a key component in exosome cofactors, RNA binding motif protein 7 (RBM7) shows the binding specificity for uridine-rich sequences in mRNAs via its RNA recognition motifs. However, the specific function of RBM7 in human breast cancer remains unclear. In vitro, experiments revealed that knockdown of RBM7 dramatically inhibited breast cancer cell proliferation, while inducing G1 cell cycle arrest; the opposite was true when RBM7 was overexpressed. Meanwhile, experiments in vivo confirmed the oncogenic function of RBM7 in breast cancer. RNA sequencing and the following pathway analysis found that cyclin-dependent kinase1 (CDK1) was one of the main gene regulated by RBM7. Overexpression of RBM7 increased CDK1 expression, while RBM7 knockdown decreased it. RIP assays additionally found that RBM7 bound directly to CDK1 mRNA. It was also showed that RBM7 could directly bind to the AU-rich elements (AREs) in 3'-UTR of CDK1 mRNA, which contributed to the stability of CDK1 mRNA by lengthening its half-life. More importantly, the oncogenic activity reduced by knockdown of RBM7 could be rescued by overexpression of CDK1 both in vitro and in vivo, but mutant CDK1 failed. All the evidences implied RBM7 promoted breast cancer cell proliferation by stabilizing CDK1 mRNA via binding to AREs in its 3'-UTR. As we knew, it was the first attempt to connect the RNA exosome to the tumor development, providing new insights into the mechanisms of RNA exosome-linked diseases.

10.
Biomed Res Int ; 2020: 2380124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299862

RESUMO

Background: The prognosis of non-small-cell lung cancer (NSCLC) has not been significantly improved. In the past several years, research on epigenetics is in full swing. There is a focus on the gene EZH2; however, its role as a predictor of the prognosis of NSCLC is in the debate. Objective: To clarify if the expression level of EZH2 can influence the prognosis of NSCLC and explain its prognostic value. Methods: We have systematically searched PubMed, Web of Science, and Cochrane library, screened relevant articles, and conducted a meta-analysis on the expression level of EZH2 in NSCLC. We collected the hazard ratio (HR) and the 95% confidence interval (CI) and used STATA 12.0 to calculate the combined result of EZH2 overall survival. In addition, we conducted subgroup analyses, a sensitivity analysis, and a funnel plot to test the reliability of the results. We further validated these meta-analysis results using the Kaplan-Meier plotter database and The Cancer Genome Atlas (TCGA) database. In addition, we have investigated the correlation between EZH2 expression and EGFR expression, KRAS expression, BRAF expression, and smoking in TCGA database to further explore the mechanism behind the influence of high EZH2 expression on lung cancer prognosis. Results: 13 studies including 2180 participants were included in the meta-analysis. We found that high expression of EZH2 indicates a poor prognosis of NSCLC (HR = 1.65 and 95% CI 1.16-2.35; p ≤ 0.001). Subgroup analyses showed high heterogeneity in stages I-IV (I 2 = 85.1% and p ≤ 0.001) and stages I-III (I 2 = 66.9% and p = 0.029) but not in stage I (I 2 = 0.00% and p = 0.589). In the Kaplan-Meier plotter database, there was a high expression in 963 cases and low expression in 964 cases (HR = 1.31 and 95% CI 1.15-1.48; p < 0.05). Further analysis found that the high expression of EZH2 was statistically significant in lung adenocarcinoma (HR = 1.27and 95% CI 1.01-1.6; p = 0.045), but not in lung squamous cell carcinoma (HR = 1.03 and 95% CI 0.81-1.3; p = 0.820). The results of the TCGA database showed that the expression of EZH2 in normal tissues was lower than that in lung cancer tissues (p < 0.05). Smoking was associated with high expression of EZH2 (p < 0.001). EZH2 was also highly expressed in lung cancers with positive KRAS expression, and the correlation was positive in lung adenocarcinoma (r = 0.3129 and p < 0.001). The correlation was also positive in lung squamous cell carcinoma (r = 0.3567 and p < 0.001). EZH2 expression was positively correlated with BRAF expression (r = 0.2397 and p < 0.001), especially in lung squamous cell carcinoma (r = 0.3662 and p < 0.001). In lung squamous cell carcinoma, a positive yet weak correlation was observed between EZH2 expression and EGFR expression (r = 0.1122 and p < 0.001). Conclusions: The high expression of EZH2 indicates a poor prognosis of NSCLC, which may be related to tumor stage or cancer type. EZH2 may be an independent prognostic factor for NSCLC. EZH2 high expression or its synergistic action with KRAS and BRAF mutations affects the prognosis of non-small-cell lung cancer.

11.
Biosci Rep ; 40(12)2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33140818

RESUMO

Background The present study was to assess the prognostic value of fasting blood glucose to high-density lipoprotein cholesterol ratio (GHR) in non-diabetic patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). Methods and results A total of 6645 non-diabetic patients from two independent cohorts, the CORFCHD-PCI study (n=4282) and the CORFCHD-ZZ (n=2363) study, were enrolled in Clinical Outcomes and Risk Factors of Patients with Coronary Heart Disease after PCI. Patients were divided into two groups according to the GHR value. The primary outcome included all-cause mortality (ACM) and cardiac mortality (CM). The average follow-up time was 36.51 ± 22.50 months. We found that there were significant differences between the two groups in the incidences of ACM (P=0.013) and CM (P=0.038). Multivariate Cox regression analysis revealed GHR as an independent prognostic factor for ACM. The incidence of ACM increased 1.284-times in patients in the higher GHR group (hazard ratio [HR]: 1.284 [95% confidence interval [CI]: 1.010-1.631], P<0.05). Kaplan-Meier survival analysis suggested that patients with high GHR value tended to have an increased accumulated risk of ACM. However, we did not find significant differences in the incidence of major adverse cardiac events, main/major adverse cardiovascular and cerebrovascular events (MACCE), stroke, recurrent myocardial infarction (MI) and bleeding events. Conclusions The present study indicates that GHR index is an independent and novel predictor of ACM in non-diabetic CAD patients who underwent PCI.

12.
NPJ Breast Cancer ; 6: 58, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33145401

RESUMO

RNA exosome can target the specific RNAs for their processing/degradation by distinct exosome cofactors. As a key component in exosome cofactors, RNA binding motif protein 7 (RBM7) shows the binding specificity for uridine-rich sequences in mRNAs via its RNA recognition motifs. However, the specific function of RBM7 in human breast cancer remains unclear. In vitro, experiments revealed that knockdown of RBM7 dramatically inhibited breast cancer cell proliferation, while inducing G1 cell cycle arrest; the opposite was true when RBM7 was overexpressed. Meanwhile, experiments in vivo confirmed the oncogenic function of RBM7 in breast cancer. RNA sequencing and the following pathway analysis found that cyclin-dependent kinase1 (CDK1) was one of the main gene regulated by RBM7. Overexpression of RBM7 increased CDK1 expression, while RBM7 knockdown decreased it. RIP assays additionally found that RBM7 bound directly to CDK1 mRNA. It was also showed that RBM7 could directly bind to the AU-rich elements (AREs) in 3'-UTR of CDK1 mRNA, which contributed to the stability of CDK1 mRNA by lengthening its half-life. More importantly, the oncogenic activity reduced by knockdown of RBM7 could be rescued by overexpression of CDK1 both in vitro and in vivo, but mutant CDK1 failed. All the evidences implied RBM7 promoted breast cancer cell proliferation by stabilizing CDK1 mRNA via binding to AREs in its 3'-UTR. As we knew, it was the first attempt to connect the RNA exosome to the tumor development, providing new insights into the mechanisms of RNA exosome-linked diseases.

13.
J BUON ; 25(4): 1969-1975, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33099940

RESUMO

PURPOSE: To observe the postoperative efficacy of low-temperature plasma radiofrequency ablation in treating elderly patients with laryngeal carcinoma and its influence on the tumor markers, cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) expressions in laryngeal carcinoma tissues. METHODS: A total of 50 elderly laryngeal carcinoma patients undergoing low-temperature plasma radiofrequency ablation in our hospital from January 2015 to January 2018 were enrolled as observation group, and another 50 elderly laryngeal carcinoma patients receiving conventional surgical treatment as control group. At the end of the treatment course, the efficacy and postoperative complications in the patients were observed, the operation time and pain visual analogue scale (VAS) and mucosal recovery scores were recorded. Besides, the levels of the tumor markers carbohydrate antigen 125 (CA125), CA199 and carcinoembryonic antigen (CEA) were determined, and the expressions of COX-2 and VEGF in laryngeal carcinoma tissues in the two groups were detected using immunohistochemistry and quantitative polymerase chain reaction (PCR). RESULTS: The efficacy in the study group was obviously higher than in the control group (p<0.05), and the cases of postoperative complications declined evidently in the study group (p<0.05). Moreover, the study group exhibited distinctly shorter operation time and lower VAS pain and mucosal recovery scores than the control group (p<0.05). The levels of the tumor markers CA125, CEA and CA19.9 and the expression levels of COX-2 and VEGF in laryngeal carcinoma tissues were substantially lowered in the study group (p<0.05). CONCLUSIONS: Low-temperature plasma radiofrequency ablation has better efficacy in treating elderly laryngeal carcinoma patients, with few postoperative complications, and decreased expression levels of postoperative tumor markers as well as COX-2 and VEGF in laryngeal carcinoma tissues, and it offers better overall effect and notable application value, therefore it is worth trying it in clinical practice.

14.
Surg Today ; 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33128594

RESUMO

PURPOSE: To explore the role of indocyanine green (ICG) fluorescence navigation in laparoscopic hepatectomy and investigate if the timing of its administration influences the intraoperative observation. METHODS: The subjects of this retrospective study were 120 patients who underwent laparoscopic hepatectomy; divided into an ICG-FN group (n = 57) and a non-ICG-FN group (n = 63). We analyzed the baseline data and operative data. RESULTS: There were no remarkable differences in baseline data such as demographic characteristics, lesion-related characteristics, and liver function parameters between the groups. Operative time and intraoperative blood loss were significantly lower in the ICG-FN group. The rate of R0 resection of malignant tumors was comparable in the ICG-FN and non-ICG-FN groups, but the wide surgical margin rate was significantly higher in the ICG-FN group. The administration of ICG 0-3 or 4-7 days preoperatively did not affect the intraoperative fluorescence imaging. Operative time, intraoperative blood loss, and a wide surgical margin correlated with ICG fluorescence navigation. ICG fluorescence navigation helped to minimize intraoperative blood loss and achieve a wide surgical margin. CONCLUSION: ICG fluorescence navigation is safe and efficient in laparoscopic hepatectomy. It helps to achieve a wide surgical margin, which could result in a better prognosis. The administration of ICG 0-3 days preoperatively is acceptable.

15.
Thromb Haemost ; 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129207

RESUMO

OBJECTIVE: In the present study, we aimed to establish a novel score to predict long-term mortality of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients who underwent percutaneous coronary intervention (PCI). METHODS: A total of 2,174 NSTE-ACS patients from the CORFCHD-ZZ study were enrolled as the derivation cohort. The validation cohort including 1,808 NSTE-ACS patients were from the CORFCHD-PCI study. Receiver operating characteristic analysis and area under the curve (AUC) evaluation were used to select the candidate variables. The model performance was validated internally and externally. The primary outcome was cardiac mortality (CM). We also explored the model performance for all-cause mortality (ACM). RESULTS: Initially, 28 risk factors were selected and ranked according to their AUC values. Finally, we selected age, N-terminal pro-B-type natriuretic peptide, and creatinine to develop a novel prediction model named "ABC" model. The ABC model had a high discriminatory ability for both CM (C-index: 0.774, p < 0.001) and ACM (C-index: 0.758, p < 0.001) in the derivation cohort. In the validation cohort, the C-index of CM was 0.802 (p < 0.001) and that of ACM was 0.797 (p < 0.001), which suggested good discrimination. In addition, this model had adequate calibration in both the derivation and validation cohorts. Furthermore, the ABC score outperformed the GRACE score to predict mortality in NSTE-ACS patients who underwent PCI. CONCLUSION: In the present study, we developed and validated a novel model to predict mortality in patients with NSTE-ACS who underwent PCI. This model can be used as a credible tool for risk assessment and management of NSTE-ACS after PCI.

16.
Front Microbiol ; 11: 567654, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117316

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease throughout the world. The relationship between gut microbiota and NAFLD has been extensively investigated. The gut microbiota is involved in the regulation of NAFLD by participating in the fermentation of indigestible food, interacting with the intestinal mucosal immune system, and influencing the intestinal barrier function, leading to signaling alteration. Meanwhile, the microbial metabolites not only affect the signal transduction pathway in the gut but also reach the liver far away from gut. In this review, we focus on the effects of certain key microbial metabolites such as short-chain fatty acids, trimethylamine-N-oxide, bile acids, and endogenous ethanol and indole in NAFLD, and also summarize several potential therapies targeting the gut-liver axis and modulation of gut microbiota metabolites including antibiotics, prebiotics, probiotics, bile acid regulation, and fecal microbiota transplantation. Understanding the complex interactions between microbial metabolites and NAFLD may provide crucial insight into the pathogenesis and treatment of NAFLD.

17.
Theranostics ; 10(24): 11110-11126, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042273

RESUMO

Rationale: Many external factors can induce the melanogenesis and inflammation of the skin. Salidroside (SAL) is the main active ingredient of Rhodiola, which is a perennial grass plant of the Family Crassulaceae. This study evaluated the effect and molecular mechanism of SAL on skin inflammation and melanin production. It then explored the molecular mechanism of melanin production under ultraviolet (UV) and inflammatory stimulation. Methods: VISIA skin analysis imaging system and DermaLab instruments were used to detect the melanin reduction and skin brightness improvement rate of the volunteers. UV-treated Kunming mice were used to detect the effect of SAL on skin inflammation and melanin production. Molecular docking and Biacore were used to verify the target of SAL. Immunofluorescence, luciferase reporter assay, CO-IP, pull-down, Western blot, proximity ligation assay (PLA), and qPCR were used to investigate the molecular mechanism by which SAL regulates skin inflammation and melanin production. Results: SAL can inhibit the inflammation and melanin production of the volunteers. SAL also exerted a protective effect on the UV-treated Kunming mice. SAL can inhibit the tyrosinase (TYR) activity and TYR mRNA expression in A375 cells. SAL can also regulate the ubiquitination degradation of interferon regulatory factor 1 (IRF1) by targeting prolyl 4-hydroxylase beta polypeptide (P4HB) to mediate inflammation and melanin production. This study also revealed that IRF1 and upstream stimulatory factor 1 (USF1) can form a transcription complex to regulate TYR mRNA expression. IRF1 also mediated inflammatory reaction and TYR expression under UV- and lipopolysaccharide-induced conditions. Moreover, SAL derivative SAL-plus (1-(3,5-dihydroxyphenyl) ethyl-ß-d-glucoside) showed better effect on inflammation and melanin production than SAL. Conclusion: SAL can inhibit the inflammation and melanogenesis of the skin by targeting P4HB and regulating the formation of the IRF1/USF1 transcription complex. In addition, SAL-plus may be a new melanin production and inflammatory inhibitor.

18.
Cancer Cell Int ; 20: 476, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33024414

RESUMO

Background: Compelling evidences reported the role of microRNAs (miRNAs) in ovarian cancer. However, little was known regarding the molecular mechanism of miR-367 in ovarian cancer. This study intended to investigate the role and regulatory mechanism of miR-367 in ovarian cancer involving lysophosphatidic acid receptor-1 (LPA1). Methods: Potentially regulatory miRNAs in ovarian cancer were obtained from bioinformatics analysis. RT-qPCR was used to detect miR-367 expression in both ovarian cancer tissues and relevant adjacent normal tissues. Relationship between miR-367 and LPA1 was predicted by miRNA database and further verified using dual luciferase reporter gene assay and RIP. EdU and Transwell assay were used to measure the proliferation and invasion ability of cells. Moreover, tube formation and chick chorioallantois membrane (CAM) assay were performed to determine angiogenesis of human umbilical vein endothelial cells (HUVECs). Finally, the roles of LPA1 in tumor growth was also studied using nude mice xenograft assay. Results: High expression of LPA1 and low expression of miR-367 were observed in ovarian cancer tissues and cells. Overexpressed miR-367 downregulated LPA1 expression to inhibit proliferation, invasion, and angiogenesis of cancer cells. Low expression of LPA1 suppressed tumor formation and repressed angiogenesis in ovarian in vivo. Conclusion: All in all, overexpression of miR-367 downregulated LPA1 expression to inhibit ovarian cancer progression, which provided a target for the cancer treatment.

19.
FEBS Open Bio ; 10(12): 2656-2665, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33058414

RESUMO

Platelet lysate (PL) has been shown to induce chondrogenic differentiation of human umbilical cord-derived mesenchymal stem cells (hUCMSCs). However, the underlying mechanism is still not clear. The aim of this study was to investigate whether long noncoding RNA H19 is involved in this process. hUCMSCs were isolated, identified and cultured in 5% PL-supplemented chondrogenic differentiation medium. Chondrogenic differentiation was assessed by Alcian blue staining. The expressions of H19, miR-29b-3p, SRY-related high-mobility-group box 9 (SOX9), collagen II and aggrecan were determined by quantitative real-time PCR and western blot. The interaction between miR-29b-3p and H19 or SOX9 was analyzed by luciferase reporter assay. During PL-induced chondrogenic differentiation of hUCMSCs, expressions of H19 and SOX9 were increased, whereas miR-29b-3p expression was decreased. H19 overexpression promoted, whereas H19 silencing attenuated the PL-induced chondrogenic differentiation of hUCMSCs. SOX9 was identified as a direct target of miR-29b-3p, and H19 was observed to act as a sponge of miR-29b-3p to up-regulate SOX9 expression. The chondrogenic differentiation-promoting effect of H19 overexpression was negated when miR-29b-3p expression was up-regulated by Lenti-miR-29b-3p infection. In conclusion, PL induced chondrogenic differentiation of hUCMSCs by regulating the H19/miR-29b-3p/SOX9 axis.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33045280

RESUMO

BACKGROUND: STAT3 or dedicator of cytokinesis protein 8 (Dock8) loss-of-function (LOF) mutations cause hyper-IgE syndrome. The role of abnormal T-cell function has been extensively investigated; however, the contribution of B-cell-intrinsic dysfunction to elevated IgE levels is unclear. OBJECTIVE: We sought to determine the underlying molecular mechanism of how STAT3 regulates B-cell receptor (BCR) signaling, B-cell differentiation, and IgE production. METHODS: We used samples from patients with STAT3 LOF mutation and samples from the STAT3 B-cell-specific knockout (KO) mice Mb1CreStat3flox/flox mice (B-STAT3 KO) to investigate the mechanism of hyper-IgE syndrome. RESULTS: We found that the peripheral B-cell homeostasis in B-STAT3 KO mice mimicked the phenotype of patients with STAT3 LOF mutation, having decreased levels of follicular and germinal center B cells but increased levels of marginal zone and IgE+ B cells. Furthermore, B-STAT3 KO B cells had reduced BCR signaling following antigenic stimulation owing to reduced BCR clustering and decreased accumulation of Wiskott-Aldrich syndrome protein and F-actin. Excitingly, a central hub protein, 14-3-3σ, which is essential for the increase in IgE production, was enhanced in the B cells of B-STAT3 KO mice and patients with STAT3 LOF mutation. The increase of 14-3-3σ was associated with increased expression of the upstream mediator, microRNA146A. Inhibition of 14-3-3σ with R18 peptide in B-STAT3 KO mice rescued the BCR signaling, follicular, germinal center, and IgE+ B-cell differentiation to the degree seen in wild-type mice. CONCLUSIONS: Altogether, our study has established a novel regulatory pathway of STAT3-miRNA146A-14-3-3σ to regulate BCR signaling, peripheral B-cell differentiation, and IgE production.

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