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1.
J Infect Dis ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574141

RESUMO

BACKGROUND: To investigate serum Mac-2-binding protein glycosylation isomer (M2BPGi) levels in predicting hepatocellular carcinoma (HCC) and mortality at virological remission (VR, HBV DNA <20 IU/mL) following antiviral therapy in chronic hepatitis B (CHB) patients with cirrhosis. METHODS: This retrospective cohort study included patients with CHB-related Child-Pugh A cirrhosis undergoing long-term antiviral therapy. Serum M2BPGi levels were quantified and multivariable Cox proportional hazards regression models were used to identify risk predictors for HCC and death. RESULTS: A total of 126 and 145 patients were included in the derivation and validation cohorts, respectively. The mean age was 56, and the mean M2BPGi level was 1.86 cut-off index (COI) in the derivation cohort. After adjustment for confounders, a higher M2BPGi level at VR significantly predicted HCC (hazard ratio [HR]: 1.58, 95% confidence interval [CI]: 1.19-2.10, P=0.002) and death (HR: 2.17, 95% CI: 1.02-4.62, P=0.044). The M2BPGi ≥3 COI significantly increased the risk of HCC and death in the derivation and validation cohorts. Serial M2BPGi levels declined significantly (P=0.0001) in non-HCC patients only, and remained significantly lower than those who developed HCC afterwards (P=0.039). CONCLUSIONS: Serum M2BPGi levels at antiviral therapy-induced VR predict HCC development and death in patients with CHB-related Child-Pugh A cirrhosis.

2.
Chin Med J (Engl) ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31592906

RESUMO

BACKGROUND: The predominant method for Manske type IIIB and IV thumb hypoplasia is pollicization. However, for those who are not willing to sacrifice the index finger, a method that could reconstruct a functionally capable and aesthetically acceptable thumb remains desirable. This study aimed to investigate and assess the functional and radiographic outcomes of utilizing a reversed vascularized second metatarsal composite flap for thumb reconstruction as a new alternative. METHODS: From May 2014 to January 2017, 15 patients with Manske type IIIB or IV thumb hypoplasia who were admitted to the Department of Hand Surgery, Beijing Jishuitan Hospital were included in this study. An osteocutaneous flap containing a section of second metatarsal and its distal head was transferred in reversed position to reconstruct carpometacarpal joint. The donor site was reconstructed by a split half of the third metatarsal. Various functional reconstructions were commenced at second stage. The reconstructed thumbs were evaluated using the Kapandji score, pinch force, and the capacities of performing daily activities through a detailed questionnaire. RESULTS: Among these 15 patients (seven type IIIB and eight type IV), there were ten boys and five girls with median age of 4.2 years (range: 2.0-7.0 years). There were seven right, three left, and five bilateral thumbs for whom only the right thumb received surgery. There were 14 metatarsal flaps survived (14/15). With an average follow-up of 19.2 months, the reconstructed thumbs had acceptable functional and aesthetic outcomes and the donor foot presented in decent appearance without signs of impaired function. All 15 children have improved the Kapandji score (from 0 to an average of 6.7), pinch force (from 0 to an average of 1.5 kg), with ability of grip and pen holding. X-ray indicated continuous bone growth. Patients and parents had good acceptance of the new thumb. CONCLUSIONS: Reconstruction of an unstable hypoplastic thumb (Manske type IIIB and IV) with use of a vascularized metatarsal is an effective strategy. It offers an alternative solution for parents insisting on saving the thumb.

3.
J Cell Mol Med ; 2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31565849

RESUMO

Diabetic cardiomyopathy is characterized by diabetes-induced myocardial abnormalities, accompanied by inflammatory response and alterations in inflammation-related signalling pathways. Kirenol, isolated from Herba Siegesbeckiae, has potent anti-inflammatory properties. In this study, we aimed to investigate the cardioprotective effect of kirenol against DCM and underlying the potential mechanisms in a type 2 diabetes mellitus model. Kirenol treatment significantly decreased high glucose-induced cardiofibroblasts proliferation and increased the cardiomyocytes viability, prevented the loss of mitochondrial membrane potential and further attenuated cardiomyocytes apoptosis, accompanied by a reduction in apoptosis-related protein expression. Kirenol gavage could affect the expression of pro-inflammatory cytokines in a dose-dependent manner but not lower lipid profiles, and only decrease fasting plasma glucose, fasting plasma insulin and mean HbA1c levels in high-dose kirenol-treated group at some time-points. Left ventricular dysfunction, hypertrophy, fibrosis and cell apoptosis, as structural and functional abnormalities, were ameliorated by kirenol administration. Moreover, in diabetic hearts, oral kirenol significantly attenuated activation of mitogen-activated protein kinase subfamily and nuclear translocation of NF-κB and Smad2/3 and decreased phosphorylation of IκBα and both fibrosis-related and apoptosis-related proteins. In an Electrophoretic mobility shift assay, the binding activities of NF-κB, Smad3/4, SP1 and AP-1 in the nucleus of diabetic myocardium were significantly down-regulated by kirenol treatment. Additionally, high dose significantly enhanced myocardial Akt phosphorylation without intraperitoneal injection of insulin. Kirenol may have potent cardioprotective effects on treating for the established diabetic cardiomyopathy, which involves the inhibition of inflammation and fibrosis-related signalling pathways and is independent of lowering hyperglycaemia, hyperinsulinemia and lipid profiles.

4.
Chem Commun (Camb) ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31576835

RESUMO

The first palladium-catalyzed ortho-amidation of ketoximes has been developed with readily available, easy to handle and environment-friendly N,N-disubstituted oxamic acids as the amidation sources. When N-monosubstituted oxamic acids are used as the substrates, the formed ortho-amidated ketoximes undergo further intramolecular cyclization to provide 3-methyleneisoindolinones.

5.
Toxicol Lett ; 2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31577921

RESUMO

Toluene-diisocyanate (TDI) is mainly used in the manufacturing process of polyurethane foams, and is a potent inducer of occupational asthma characterized by airway inflammation and airway hyperreactivity. Thymic stromal lymphopoietin (TSLP) plays an important role in the development of asthma, and correlating with the differentiation of Th2 and Th17 cells. However, the role of TSLP in TDI-induced asthma remains unclear. In this study, 96 TDI-exposed workers as well as a mouse model of TDI-induced asthma were investigated. The air exposure assessment result of TDI in the workplace showed that workers were exposed to inhalation of a very high concentration of TDI, approximately 8 times the recommended level, leading to a decrease in pulmonary function and an increase in inflammatory cells, as well as TSLP and IgE levels in the supernatant of sputum obtained from exposed workers. In order to further investigate the role of TSLP in the pathogenesis of TDI-induced asthma, a mouse model of TDI-induced asthma was also employed. Histopathological analysis of mouse lung and bronchus showed an obvious infiltration of inflammatory cells around the bronchus. The levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in bronchoalveolar lavage fluid (BALF), the expression levels of TSLP protein and ROR-γt and IL-17 mRNA in mouse lung tissues were also significantly increased. However, after treatment with TSLP neutralizing antibody (TSLP-Ab), the degree of pulmonary and bronchial inflammation in mice was significantly alleviated, and the levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in BALF, and the expression levels of ROR-γt and IL-17 mRNA in lung tissue were significantly decreased. Our data shows that TSLP plays an important role in the pathogenesis of TDI-induced asthma, and that TSLP-Ab can effectively alleviate TDI-induced airway inflammation of asthma.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31582217

RESUMO

A wealth of studies illustrate the powerful antioxidant activities and health-promoting functions of dietary phenolic compounds, e.g., anthocyanins, flavonoids, and phenolic compounds. Ferulate is methylated from caffeoyl CoA using S-adenosyl-L-methionine (SAM) as methyl donor catalyzed by caffeoyl CoA methyltransferase (CCoAOMT). Here we show that Arabidopsis CCoAOMT7 contributes to ferulate content in the stem cell wall. CCoAOMT7 was further shown to bind S-adenosyl-L-homocysteine hydrolase (SAHH), a critical step in SAM synthesis to release feedback suppression on CCoAOMT. CCoAOMT7 also bound S-adenosyl-L-methionine synthases (SAMSs) in vivo, which were mediated by SAHH1. Interruptions of endogenous SAHH1 by artificial miRNA or SAMSs by T-DNA insertion significantly reduced ferulate contents in the stem cell wall. This data reveals a novel protein complex of SAM synthesis cycle associated with O-methyltransferase and provides new insights into cellular methylation processes.

7.
Nat Prod Res ; : 1-5, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31502480

RESUMO

The serotonin (5-hydroxytryptamine) type 3 receptor is an important target in the control of digestive dysfunction such as anorexia and bulimia, and 5-HT3 receptor antagonists are effective against eating disorder and the early-phase chemotherapy and radiotherapy evoked vomiting. Our previous research of Valeriana jatamansi revealed the presence of iridoids, which showed potent antitumor activities. Here, we explored the effects of 10π aromatic iridoid desacylbaldrinal isolated from V. jatamansi on the 5-HT3 receptor current. We performed whole cell recordings of 5-HT3A receptor currents in the presence of the compound. The result indicated that desacylbaldrinal inhibited the 5-HT-mediated 5-HT3A receptor current.

8.
J Periodontol ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489644

RESUMO

BACKGROUD: The present study was to determine the role of Toll-like receptor 4 (TLR4) signaling in inflammation and alveolar bone resorption using a murine model of Porphyromonas gingivalis (P. gingivalis) associated ligature-induced peri-implantitis. METHODS: Smooth surface titanium implants were placed in the left maxilla alveolar bone 6 weeks after extraction of first and second molars in Wild-type (WT) and TLR4-/- (TLR4 KO) mice. Silk ligatures immersed with P. gingivalis were tied around the implants 4 weeks after the implant placement and confirmation of osteointegration. Two weeks after the ligation, bone resorption, osteoclastogenesis, cellular inflammatory responses and gingival mRNA expression levels of cytokines were assessed by micro-computed tomography, Tartrate-resistant acid phosphatase (TRAP) staining, immunobiological examination and Real-time quantitative PCR respectively. RESULTS: In both WT and TLR4 KO mice, the bone resorption around implants was significantly increased in the P. gingivalis/ligation group compared to control group. In P. gingivalis/ligation group, the levels of bone resorption, TRAP+ cell formation, and gingival CD3+ and CD45+ cell infiltration were significantly decreased in TLR4 KO mice compared to that in WT mice. RANKL/OPG ratio was significantly increased after P. gingivalis/ligation treatment in WT mice not in TLR4 KO mice. When comparing the P. gingivalis/ligation group with the respective control group, gingival mRNA expressions of IL-1ß, IFN-γ and 1L-17 were significantly increased in TLR4 KO mice. CONCLUSIONS: This study suggests that TLR4 mediates alveolar bone resorption in P. gingivalis associated ligature-induced peri-implantitis through regulation of immune B cell infiltration, RANKL/OPG expression ratio, and differential inflammatory cytokine production. This article is protected by copyright. All rights reserved.

9.
Math Biosci Eng ; 16(5): 6015-6033, 2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31499750

RESUMO

With the rapid development of mobile internet and cloud computing, numerous digital me-dia files in mobile social networking and media sharing software have become the important carriers of steganography. However, these digital media files may be resampled by the media server when being pushed to the intelligent mobile terminals. The resampling of digital media files is a transfor-mation which enlarges or shrinks objects by a scale factor that is the same in all dimensions. In order to reduce embedding distortion while ensuring the correct extraction of secret messages under resam-pling mechanism, a steganographic coding scheme based on dither convolutional trellis is proposed in this paper. The resampling mapping is estimated with finite sample pairs. The resampling stego media files with secret messages embedded are generated from the estimated resampling cover media files by syndrome-trellis codes (STCs). According to the estimated resampling mapping, the dither convolutional trellis for one dimensional resampling is constructed to generate the source stego me-dia files from source cover media files and resampling stego media files. The steganographic coding scheme is also extended to the circumstance of two dimensional resampling such as image scaling. The experimental results show that the proposed steganographic scheme can achieve less embedding dis-tortion while ensuring the accuracy of secret messages extraction under multi-dimensional resampling mechanism.

10.
Theranostics ; 9(20): 5769-5783, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534518

RESUMO

Rationale: Heat shock protein 9 (HSP90) are a family of the most highly expressed cellular proteins and attractive drug targets against cancer, neurodegeneration diseases, etc. HSP90 proteins have also been suggested to be linked to lipid metabolism. However, the specific function of HSP90 paralogs, as well as the underlying molecular cascades remains largely unknown. This study aims to unravel the paralog-specific role of HSP90 in lipid metabolism and try to discover paralog-specific HSP90 inhibitors. Methods: In non-alcohol fatty liver disease (NAFLD) patients, as well as in diet induced obese (DIO) mice, expression of HSP90 paralogs were analyzed by immunohistochemistry and western blot. In hepatocytes and in DIO mice, HSP90 proteins were knockdown by siRNAs/shRNAs, metabolic parameters, as well as downstream signaling were then investigated. By virtue screening, corylin was found to bind specifically to HSP90ß. Using photo-affinity labeling and mass spectrum, corylin binding proteins were identified. After oral administration of corylin, its lipid lowering effects in different metabolic disease mice models were evaluated. Results: We showed that hepatic HSP90ß, rather than HSP90α, was overexpressed in NAFLD patients and obese mice. Hepatic HSP90ß was also clinical relevant to serum lipid level. Depletion of HSP90ß promoted mature sterol regulatory element-binding proteins (mSREBPs) degradation through Akt-GSK3ß-FBW7 pathway, thereby dramatically decreased the content of neutral lipids and cholesterol. We discovered an HSP90ß-selective inhibitor (corylin) that only bound to its middle domain. We found that corylin treatment partially suppressed Akt activity only at Thr308 site and specifically promoted mSREBPs ubiquitination and proteasomal degradation. Corylin treatment significantly reduced lipid content in both liver cell lines and human primary hepatocytes. In animal studies, we showed that corylin ameliorated obesity-induced fatty liver disease, type 2 diabetes and atherosclerosis. Principle conclusions: HSP90ß plays a parolog-specific role in regulating lipid homeostasis. Compound that selectively inhibits HSP90ß could be useful in the clinic for the treatment for metabolic diseases.

11.
Eur J Pharm Sci ; : 105058, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31472255

RESUMO

The biofilm formation of Pseudomonas aeruginosa (P. aeruginosa) is regulated by a phenomenon of quorum sensing (QS). With 5-hydroxyl-3,4-halogenated-5H-furan-2-ones as beginning, analogs bearing alkyl chains, vinyl bromide, or aromatic rings were designed and synthesized. The minimum inhibitory concentration (MIC) of the compounds against P. aeruginosa was assayed and the biofilm inhibition ratio was determined at different concentrations lower than the MIC. C-5 aromatic substituted furanones showed remarkable biofilm formation as well as inhibition of virulence factor production in P. aeruginosa. Fluorescence report analysis identified the QS regulatory mechanism of the most active compound 29. This study provides us a novel candidate for combating drug resistant bacteria strains by merely inhibiting biofilm formation. Without suppressing the regular life cycle of the bacteria, bacterial resistance mechanisms may not be activated.

12.
Mar Biotechnol (NY) ; 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31473865

RESUMO

To consolidate the genetic, physical, and cytogenetic maps of scallop (Patinopecten yessoensis), we constructed a molecular cytogenetic map by localizing 84 fosmid clones that contain different SNP markers from 19 linkage groups (LGs) using fluorescence in situ hybridization (FISH). Among these 84 SNP-anchored clones, 56 clones produced specific and stable signals on one pair of chromosomes. Dual-color FISH assigned 19 LGs to their corresponding chromosomes with 38 SNP-anchored clones as probes. Among these 19 LGs, 17 LGs were assigned to their corresponding one pair of chromosomes, while two clones containing SNPs from LG10 and LG19 were located on two different pairs of chromosomes separately. The orientation of 7 LGs was corrected according to the chromosome location of SNPs within the same LG. In addition, a probe panel of SNP-anchored clones was developed to identify each chromosome of P. yessoensis. The molecular cytogenetic map will facilitate molecular breeding in scallop and enable comparative studies on chromosome evolution of bivalve mollusk.

13.
Front Immunol ; 10: 2050, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552021

RESUMO

The transcription factor Bach2 is a susceptible gene for numerous autoimmune diseases including systemic lupus erythematosus (SLE). Bach2 -/- mice can develop a lupus-like autoimmune disease. However, the exact cellular and molecular mechanisms via which Bach2 protects the hosts from developing autoimmunity remains incompletely understood. Here, we report that Bach2 ablation on T cells, but not B cells, resulted in humoral autoimmunity, and this was associated with expansion of T follicular helper (Tfh) cells and abnormal germinal centers. Bach2 was down-regulated in Tfh cells and directly suppressed by the Tfh-defining transcription factor BCL6. Mechanistically, Bach2 directly suppresses the transcription of Cxcr5 and c-Maf, two key regulators of Tfh cell differentiation. Bach2-deficient Tfh cells were skewed toward the IL-4-producing subset, which induced IgG1 and IgE isotype switching of B cells. Heterozygous Bcl6 deficiency reduced the formation of germinal center and autoantibodies, and ameliorated the pathology in Bach2-deficient mice. Our findings identify Bach2 as a crucial negative regulator of Tfh cells at steady state and prove that Bach2 controls autoimmunity in part by restraining accumulation of pathogenic Tfh cells.

14.
J Infect Dis ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31550363

RESUMO

BACKGROUND: Patients on oral antiviral (OAV) therapy remain at HCC risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. Aim: Develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort. METHODS: Routine practice adult Asian CHB patients on OAV were recruited from 25 centers in the US and Asia-Pacific region. Excluded persons were co-infected with hepatitis C, D, or HIV, had HCC prior to or within 1 year of study entry or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the REAL-B score. RESULTS: A total of 8,048 patients were randomized to the derivation (n=5,365) or validation group (n=2,683).The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and AFP) scores were categorized as: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. AUROCs were >0.80 for HCC risk at 3, 5, and 10 years, and were significantly higher than other risk models (p<0·001). CONCLUSION: The REAL-B score provides three distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy.

15.
Chem Commun (Camb) ; 55(76): 11374-11377, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31478534

RESUMO

An efficient organocatalytic cyclization strategy was developed to synthesize pharmacologically interesting bicyclic imidazoline derivatives. Morita-Baylis-Hillman carbonates were applied as C3 electrophiles to react with N,C-dinucleophiles for the first time, yielding the desired products in good to excellent yields with outstanding diastereoselectivities. The optically pure bicyclic imidazolines were expeditiously prepared by utilizing the readily available chiral ketene aminals as building blocks. The products were found to inhibit MDM2-p53 binding and cell proliferation. The most potent compound 5c induced the accumulation of MDM2, p53 and p21 proteins in HCT116 cells and blocked interaction between MDM2 and p53.

16.
Phys Rev Lett ; 123(5): 050502, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31491305

RESUMO

Superconducting circuits have emerged as a powerful platform of quantum simulation, especially for emulating the dynamics of quantum many-body systems, because of their tunable interaction, long coherence time, and high-precision control. Here in experiments, we construct a Bose-Hubbard ladder with a ladder array of 20 qubits on a 24-qubit superconducting processor. We investigate theoretically and demonstrate experimentally the dynamics of single- and double-excitation states with distinct behaviors, indicating the uniqueness of the Bose-Hubbard ladder. We observe the linear propagation of photons in the single-excitation case, satisfying the Lieb-Robinson bounds. The double-excitation state, initially placed at the edge, localizes; while placed in the bulk, it splits into two single-excitation modes spreading linearly toward two boundaries, respectively. Remarkably, these phenomena, studied both theoretically and numerically as unique properties of the Bose-Hubbard ladder, are represented coherently by pairs of controllable qubits in experiments. Our results show that collective excitations, as a single mode, are not free. This work paves the way to simulation of exotic logic particles by subtly encoding physical qubits and exploration of rich physics by superconducting circuits.

17.
BMC Med Imaging ; 19(1): 77, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477041

RESUMO

BACKGROUND: The value of magnetic resonance imaging (MRI), contrast-enhanced ultrasound (CEUS), and the combination of CEUS and MRI (CCWM) for the diagnosis of periampullary space-occupying lesions (PSOL) was investigated. METHODS: A total of 102 patients diagnosed with PSOLs by surgery or biopsy were recruited retrospectively. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MRI, CEUS, and CCWM were analyzed. RESULTS: MRI, CEUS, and CCWM allowed for the accurate detection of 91.17, 92.15, and 99.01% of PSOLs, respectively. The specificity, PPV, and accuracy of CCWM were significantly different from MRI and CEUS (p < 0.05). However, there the sensitivity and NPV were not significantly different among the three diagnostic technologies. In addition, the specificity, PPV, and accuracy were not significantly different between MRI and CEUS (all p > 0.05). CONCLUSIONS: CCWM is valuable for differentiating benign and malignant PSOL, which provides important guiding significances for the clinic.

18.
Pharmacol Res ; : 104463, 2019 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-31553936

RESUMO

Shikonin is the major bioactive component extracted from the roots of Lithospermum erythrorhizon which is also known as "Zicao" in Traditional Chinese Medicine (TCM). Recent studies have shown that shikonin demonstrates various bioactivities related to the treatment of cancer, inflammation, and wound healing. This review aimed to provide an updated summary of recent studies on shikonin. Firstly, many studies have demonstrated that shikonin exerts strong anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis. Shikonin also triggers Reactive Oxygen Species (ROS) generation, suppressing exosome release, and activate anti-tumor immunity in multiple molecular mechanisms. Examples of these effects include modulating the PI3 K/AKT/mTOR and MAPKs signaling; inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK; and regulating the expression of ERP57, MMPs, ATF2, C-MYC, miR-128, and GRP78 (Bip). Next, the anti-inflammatory and wound-healing properties of shikonin were also reviewed. Furthermore, several studies focusing on shikonin derivatives were reviewed, and these showed that, with modification to the naphthazarin ring or side chain, some shikonin derivatives display stronger anticancer activity and lower toxicity than shikonin itself. Our findings suggest that shikonin and its derivatives could serve as potential novel drug for the treatment of cancer and inflammation.

19.
J Cell Physiol ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31556112

RESUMO

Long noncoding RNAs have been documented to be protective against ischemia/reperfusion (I/R) injury. However, few research works have focused on the protective effects of PRR34-AS1 on I/R injury after total knee arthroplasty (TKA). The objective of the present study was to investigate the possible effect of PRR34-AS1 on I/R injury after TKA. A mouse model with I/R injury after TKA was established. The interaction between PRR34-AS1 and Janus kinase 1 (JAK1) was examined and thoroughly investigated. Next, the effects of PRR34-AS1 on the expression of apoptosis-related proteins, JAS-signal transducer and activator of transcription (STAT) signaling pathways, and inflammation-related genes, chondrocyte proliferation, and apoptosis were analyzed after gain- and loss-of-function experiments. Attenuated symptoms were observed in mice pretreated with propofol, which was evidenced by decreased positive expression rate of JAK1 protein and superoxide dismutase content along with increased malondialdehyde content and IL-10 levels. PRR34-AS1 was poorly expressed in mice with I/R injury after TKA. JAK1 was a target of PRR34-AS1. Upregulated PRR34-AS1 diminished expression of JAK1, STAT1, JAK2, and STAT3 as well as cell apoptosis, while enhancing cell proliferation in vitro. Furthermore, JAK1 silencing could reverse the suppressed cell proliferation and enhanced cell apoptosis of chondrocytes imposed by silencing PRR34-AS1. Upregulation of PRR34-AS1 can potentially relieve I/R injury after TKA in mice pretreated with propofol through inhibition of the JAS-STAT signaling pathway by targeting JAK1.

20.
Bioorg Chem ; 92: 103260, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31525523

RESUMO

As restricted CA-4 analogues, a novel series of [1,2,4]triazolo[1,5-a]pyrimidines possessing 3,4,5-trimethoxylphenyl groups has been achieved successfully via an efficient one-pot three-component reaction of 3-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-5-amine, 1,3-dicarbonyl compounds and aldehydes. Initial biological evaluation demonstrated some of target compounds displayed potent antitumor activity in vitro against three cancer cell lines. Among them, the most highly active analogue 26 inhibited the growth of HeLa, and A549 cell lines with IC50 values at 0.75, and 1.02 µM, respectively, indicating excellent selectivity over non-tumoural cell line HEK-293 (IC50 = 29.94 µM) which suggested that the target compounds might possess a high safety index. Moreover, cell cycle analysis illustrated that the analogue 26 significantly induced HeLa cells arrest in G2/M phase, meanwhile the compound could dramatically affect cell morphology and microtubule networks. In addition, compound 28 exhibited potent anti-tubulin activity with IC50 values of 9.90 µM, and molecular docking studies revealed the analogue occupied the colchicine-binding site of tubulin. These observations suggest that [1,2,4]triazolo[1,5-a]pyrimidines represent a new class of tubulin polymerization inhibitors and well worth further investigation aiming to generate potential anticancer agents.

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