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1.
Stem Cell Res Ther ; 11(1): 93, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32122385

RESUMO

BACKGROUND: Chondrogenic progenitor cells (CPCs) have high self-renewal capacity and chondrogenic potential. Intra-articular delivery of purified mesenchymal stem cells (MSCs) from MRL/MpJ "superhealer" mice increased bone volume during repair and prevents post-traumatic arthritis. Recently, although extracellular vesicles released from MSCs have been used widely for treating OA, the application of extracellular vesicles secreted by CPCs from MRL/MpJ mice in OA therapy has never been reported. In this study, we evaluated the effects of extracellular vesicles secreted by CPCs from control CBA (CBA-EVs) and MRL/MpJ mice (MRL-EVs) on proliferation and migration of murine chondrocytes. We also determined here if weekly intra-articular injections of CBA-EVs and MRL-EVs would repair and regenerate surgically induced model in mice. METHODS: CPC surface markers were detected by flow cytometry. CBA-EVs and MRL-EVs were isolated using an ultrafiltration method. Nanoparticle tracking analysis, transmission electron microscopy, and western blots were used to identify extracellular vesicles. CBA-EVs and MRL-EVs were injected intra-articularly in a mouse model of surgical destabilization of the medial meniscus (DMM)-induced OA, and histological and immunohistochemistry analyses were used to assess the efficacy of exosome injections. We used miRNA-seq analysis to analyze the expression profiles of exosomal miRNAs derived from CBA-EVs as well as MRL-EVs. Cell-counting and scratch assays were used to evaluate the effects of CBA-EVs and MRL-EVs on proliferation and migration of murine chondrocytes, respectively. Meanwhile, a specific RNA inhibitor assesses the roles of the candidate miRNAs in CPC-EV-induced regulation of function of chondrocytes. RESULTS: Both CBA-EVs and MRL-EVs stimulated chondrocyte proliferation and migration, but MRL-EVs exerted a stronger effect than CBA-EVs. The similar result was also observed in in vivo study, which indicated that injecting either CBA-EVs or MRL-EVs attenuated OA, but MRL-EVs showed a superior therapeutic effect in comparison with CBA-EVs. The results of bioinformatics analyses revealed that the differentially expressed exosomal miRNAs participated in multiple biological processes. We identified 80 significantly upregulated and 100 downregulated miRNAs. Moreover, we found that the top 20 differentially expressed exosomal miRNAs connected OA repair to processes such as AMPK signaling, regulation of autophagy, and insulin signaling. Notably, miRNA 221-3p were highly enriched in MRL-Exos and treatment with miR 221-3p inhibitor markedly decreased chondrocyte proliferation and migration induced by CBA-EVs or MRL-EVs in vitro. CONCLUSIONS: This is the first study to demonstrate MRL-EVs had a greater therapeutic effect on the treatment of OA than CBA-EVs. This study will hopefully provide new insight into the pathogenesis, prevention, and treatment of OA.

2.
Acta Crystallogr F Struct Biol Commun ; 76(Pt 2): 81-85, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32039889

RESUMO

Calpain is a Ca2+-activated, heterodimeric cysteine protease consisting of a large catalytic subunit and a small regulatory subunit. Dysregulation of this enzyme is involved in a range of pathological conditions such as cancer, Alzheimer's disease and rheumatoid arthritis, and thus calpain I is a drug target with potential therapeutic applications. Difficulty in the production of this enzyme has hindered structural and functional investigations in the past, although heterodimeric calpain I can be generated by Escherichia coli expression in low yield. Here, an unexpected structure discovered during crystallization trials of heterodimeric calpain I (CAPN1C115S + CAPNS1ΔGR) is reported. A novel co-crystal structure of the PEF(S) domain from the dissociated regulatory small subunit of calpain I and the RNA-binding chaperone Hfq, which was likely to be overproduced as a stress response to the recombinant expression conditions, was obtained, providing unexpected insight in the chaperone function of Hfq.

3.
Eur Heart J ; 41(10): 1100-1108, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32006423

RESUMO

AIMS: To evaluate the fracture risk among patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. METHODS AND RESULTS: We conducted a real-world nationwide retrospective cohort study using Taiwan's National Health Insurance Research Database. All adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who received NOACs or warfarin were enrolled and followed up until 2017. Patients treated with NOACs were sub-grouped according to the NOAC used (dabigatran, rivaroxaban, and apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (aHRs) for hip, vertebral, and humerus/forearm/wrist fractures. After matching, 19 414 patients were included (9707 in each NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk [aHR = 0.84, 95% confidence interval (CI) = 0.77-0.93; P < 0.001]. Sub-analyses revealed that each NOAC, namely dabigatran (aHR = 0.88, 95% CI = 0.78-0.99; P = 0.027), rivaroxaban (aHR = 0.81, 95% CI = 0.72-0.90; P < 0.001), and apixaban (aHR = 0.67, 95% CI = 0.52-0.87; P = 0.003), had a reduced fracture risk. Analyses including all eligible patients, without propensity score matching, generated similar results. CONCLUSION: Compared with warfarin, NOAC was associated with a reduced fracture risk among AF patients. Therefore, if oral anticoagulants are indicated, NOACs rather than warfarin should be considered to lower the risk of fractures. However, further studies are needed to investigate the underlying mechanisms and elucidate causality.

4.
Molecules ; 25(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033326

RESUMO

The objective of this study was to synthesize the 9-/13-position substituted berberine derivatives and evaluate their cytotoxic and photocytotoxic effects against three human cancer cell lines. Among all the synthesized compounds, 9-O-dodecyl- (5e), 13-dodecyl- (6e), and 13-O-dodecyl-berberine (7e) exhibited stronger growth inhibition against three human cancer cell lines, (HepG2, HT-29 and BFTC905), in comparison with structurally related berberine (1). These three compounds also showed the photocytotoxicity in human cancer cells in a concentration-dependent and light dose-dependent manner. Through flow cytometry analysis, we found out a lipophilic group at the 9-/13-position of berberine may have facilitated its penetration into test cells and hence enhanced its photocytotoxicity on the human liver cancer cell HepG2. Further, in cell cycle analysis, 5e, 6e, and 7e induced HepG2 cells to arrest at the S phase and caused apoptosis upon irradiation. In addition, photodynamic treatment of berberine derivatives 5e, 6e, and 7e again showed a significant photocytotoxic effects on HepG2 cells, induced remarkable cell apoptosis, greatly increased intracellular ROS level, and the loss of mitochondrial membrane potential. These results over and again confirmed that berberine derivatives 5e, 6e, and 7e greatly enhanced photocytotoxicity. Taken together, the test data led us to conclude that berberine derivatives with a dodecyl group at the 9-/13-position could be great candidates for the anti-liver cancer medicines developments.

5.
AAPS PharmSciTech ; 21(3): 90, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32060654

RESUMO

Puerarin is widely used as a therapeutic agent to cardiovascular diseases in clinics in China through intravenous administration, which could elicit adverse drug reactions caused by cosolvents, hindering its application in clinics. Therefore, the development of oral dosage is urgently needed. In our previous studies, we proved that the bioavailability of puerarin increased as particle sizes of nanocrystals decreased; however, we have not optimized the best process parameters for nanocrystals. In this study, we aim to fabricate fine nanocrystals (with smallest particle size) by Box-Behnken design and study the intestinal permeability of puerarin and its nanocrystals via employing everted gut sac model and in situ perfusion model. The results showed that the Box-Behnken design could be used to optimize the producing parameters of puerarin nanocrystals, and the particle sizes of fine nanocrystals were about 20 nm. Results of everted gut sacs showed that the polyvinylpyrrolidone (PVP) and verapamil had no influence on the absorption of puerarin and nanocrystals, and the nanocrystals could increase the Papp of puerarin for 2.2-, 2.9-, and 2.9-folds, respectively, in duodenum, jejunum, and ileum. Enhanced Ka and Peff were observed on the nanocrystal group, compared with puerarin, and PVP and verapamil had no influence on the absorption of nanocrystals, while the absorption of puerarin was influenced by P-gp efflux. Combining the results mentioned above, we can conclude that the Box-Behnken design benefits the optimization for preparation of nanocrystals, and the nanocrystals could enhance the intestinal absorption of puerarin by enhanced permeability and inhibited P-gp efflux.

6.
Development ; 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32108024

RESUMO

Endothelial cell adhesion is implicated in blood vessel sprout formation, yet how adhesion controls angiogenesis, and whether it occurs via rapid remodeling of adherens junctions, focal adhesion assembly, or both, remains poorly understood. Furthermore, how endothelial cell adhesion is controlled in particular tissues and under different conditions remains unexplored. Here, we identified an unexpected role for spatiotemporal c-Src activity in sprouting angiogenesis in the retina, which is in contrast to the dominant focus on c-Src's role in maintenance of vascular integrity. Thus, mice specifically deficient in endothelial c-Src displayed significantly reduced blood vessel sprouting and loss in actin-rich filopodial protrusions at the vascular front of the developing retina. In contrast to what has been observed during vascular leakage, endothelial cell-cell adhesion was unaffected by loss of c-Src. Instead, decreased angiogenic sprouting was due to loss of focal adhesion assembly and cell-matrix adhesion, resulting in loss of sprout stability. These results demonstrate c-Src signaling at specified endothelial cell membrane compartments (adherens junctions or focal adhesions) control vascular processes in a tissue and context dependent manner.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32088667

RESUMO

Context: Traumatic brain injury (TBI) is an injury to the brain that occurs as a result of a direct impact, and affected persons are usually in a long-term coma. The evidence of the safety and effectiveness of acupuncture to treat coma is still not convincing. Objective: The study intended to assess the effectiveness and safety of acupuncture for arousing a patient in a coma following TBI. Design: Medline, Embase, CENTRAL, and 4 Chinese medical databases were searched from their inception to March 1, 2018, without language restrictions. The dataset included randomized controlled trials (RCTs) that examined acupuncture as a therapy for arousing patients in a coma after TBI. The literature was screened ;the data were extracted ;and the methodological quality of the included studies was assessed. Meta-analyses were performed on the included data. Setting: This study was conducted at Tianjin University of Traditional Chinese Medicine (Tianjin City, China). Participants: Participants in the selected RCTs were people of any age and either gender who were in a coma caused by TBI. Interventions: The intervention group in the selected RCTs had received acupuncture for TBI, either as a sole therapy or combined with other treatments, and the control group had received placebo acupuncture, sham acupuncture, conventional treatments, or other treatments. The interventions included traditional acupuncture, electroacupuncture, ear acupuncture, and scalp acupuncture. Outcome Measures: The research team measured the Glasgow Outcome Score (GOS), wake-promoting rates, as well as the Glasgow Coma Score (GCS). Results: Of 884 potentially relevant trials, 24 RCTs met the inclusion criteria. The results of the meta-analysis suggested that the acupuncture group's coma state was significantly lessened after treatment compared with the control on GOS (RR, 1.95, 95% CI [1.64 to 2.31], P < .01; I² = 0%), wake-promoting rates (RR, 1.48, 95% CI [1.19 to 1.83], P < .01; I² = 52%), and GCS (MD, 1.78, 95% CI [1.10 to 2.45], P < .01; I² = 52%) . Conclusion: The systematic review and meta-analysis has suggested that acupuncture can be an effective treatment for patients unconscious following TBI. However, the evidence was too weak for medical practitioners to routinely recommend acupuncture for clinical treatment; further large, rigorously designed studies are needed.

8.
J Med Chem ; 63(6): 3227-3237, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32091206

RESUMO

Inhibition of the bromodomain containing protein 9 (BRD9) by small molecules is an attractive strategy to target mutated SWI/SNF chromatin-remodeling complexes in cancer. However, reported BRD9 inhibitors also inhibit the closely related bromodomain-containing protein 7 (BRD7), which has different biological functions. The structural basis for differential potency and selectivity of BRD9 inhibitors is largely unknown because of the lack of structural information on BRD7. Here, we biochemically and structurally characterized diverse inhibitors with varying degrees of potency and selectivity for BRD9 over BRD7. Novel cocrystal structures of BRD7 liganded with new and previously reported inhibitors of five different chemical scaffolds were determined alongside BRD9 and BRD4. We also report the discovery of first-in-class dual bromodomain-kinase inhibitors outside the bromodomain and extraterminal family targeting BRD7 and BRD9. Combined, the data provide a new framework for the development of BRD7/9 inhibitors with improved selectivity or additional polypharmacologic properties.

9.
Acta Pharmacol Sin ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953509

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

10.
Endocr Relat Cancer ; 27(2): X1-X2, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31995343

RESUMO

The authors and journal apologize for errors in the above paper, which appeared in volume 26 part 3, pages 303­319. The errors relate to the legend of Fig. 1A on page 307 and the artwork of Fig. 8D on page 316:

12.
Chin Med J (Engl) ; 133(4): 424-434, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31977553

RESUMO

BACKGROUND: Traditional tissue engineering methods to fabricate urinary tract patch have some drawbacks such as compromised cell viability and uneven cell distribution within scaffold. In this study, we combined three-dimensional (3D) bioprinting and tissue engineering method to form a tissue-engineered urinary tract patch, which could be employed for the application on Beagles urinary tract defect mode to verify its effectiveness on urinary tract reconstruction. METHODS: Human adipose-derived stem cells (hADSCs) were dropped into smooth muscle differentiation medium to generate induced microtissues (ID-MTs), flow cytometry was utilized to detect the positive percentage for CD44, CD105, CD45, and CD34 of hADSCs. Expression of vascular endothelial growth factor A (VEGFA) and tumor necrosis factor-stimulated gene-6 (TSG-6) in hADSCs and MTs were identified by Western blotting. Then the ID-MTs were employed for 3D bioprinting. The bioprinted structure was encapsulated by transplantation into the subcutaneous tissue of nude mice for 1 week. After retrieval of the encapsulated structure, hematoxylin and eosin and Masson's trichrome staining were performed to demonstrate the morphology and reveal collagen and smooth muscle fibers, integral optical density (IOD) and area of interest were calculated for further semi-quantitative analysis. Immunofluorescent double staining of CD31 and α-smooth muscle actin (α-SMA) were used to reveal vascularization of the encapsulated structure. Immunohistochemistry was performed to evaluate the expression of interleukin-2 (IL-2), α-SMA, and smoothelin of the MTs in the implanted structure. Afterward, the encapsulated structure was seeded with human urothelial cells. Immunofluorescent staining of cytokeratins AE1/AE3 was applied to inspect the morphology of seeded encapsulated structure. RESULTS: The semi-quantitative assay showed that the relative protein expression of VEGFA was 0.355 ±â€Š0.038 in the hADSCs vs. 0.649 ±â€Š0.150 in the MTs (t = 3.291, P = 0.030), while TSG-6 expression was 0.492 ±â€Š0.092 in the hADSCs vs. 1.256 ±â€Š0.401 in the MTs (t = 3.216, P = 0.032). The semi-quantitative analysis showed that the mean IOD of IL-2 in the MT group was 7.67 ±â€Š1.26, while 12.6 ±â€Š4.79 in the hADSCs group, but semi-quantitative analysis showed that there was no statistical significance in the difference between the two groups (t = 1.724, P = 0.16). The semi-quantitative analysis showed that IOD was 71.7 ±â€Š14.2 in non-induced MTs (NI-MTs) vs. 35.7 ±â€Š11.4 in ID-MTs for collagen fibers (t = 3.428, P = 0.027) and 12.8 ±â€Š1.9 in NI-MTs vs. 30.6 ±â€Š8.9 in ID-MTs for smooth muscle fibers (t = 3.369, P = 0.028); furthermore, the mean IOD was 0.0613 ±â€Š0.0172 in ID-MTs vs. 0.0017 ±â€Š0.0009 in NI-MTs for α-SMA (t = 5.994, P = 0.027), while 0.0355 ±â€Š0.0128 in ID-MTs vs. 0.0035 ±â€Š0.0022 in NI-MTs for smoothelin (t = 4.268, P = 0.013), which indicate that 3D bioprinted structure containing ID-MTs could mimic the smooth muscle layer of native urinary tract. After encapsulation of the urinary tract patch for additional cell adhesion, urothelial cells were seeded onto the encapsulated structures, and a monolayer urothelial cell was observed. CONCLUSION: Through 3D bioprinting and tissue engineering methods, we provided a promising way to fabricate tissue-engineered urinary tract patch for further investigation.

13.
Microb Pathog ; 141: 103959, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31958475

RESUMO

Cryptococcosis is a disease predominantly caused by Cryptococcus neoformans in China and C. neoformans is the main form that causes cryptococcal meningitis. In this study, we examined the influence of MiR-30c-5p during Cryptococcus neoformans infection. microRNAs were extracted from Cerebrospinal fluid and sera of patients. To identify pathogenic microRNAs, RNASeq were performed. The results were confirmed with quantitative real-time PCR (qRT-PCR), transient transfection of siRNAs or microRNA mimics into cultured BV2 cell, flow cytometry, immunoblotting, luciferase assay and immunohistochemistry. In this study we found that miR-30c expression was downregulated and that inflammation, apoptosis, and autophagy were activated. The overexpression of miR-30c-5p significantly inhibited inflammation and autophagic activity and decreased apoptosis, and treatment with sieIF2α resulted in a significant decrease in inflammation, apoptosis. In addition, clinical samples of cerebrospinal fluid and serum of patients with cryptococcal meningitis who have undergone standard antifungal treatment showed that the expression of miR-30c-5p was increased while that of eIF2α was decreased, which was in accordance with the in vitro experiments. These studies demonstrated that miRNA-30c-5p can inhibit inflammatory, apoptotic, and autophagic activity through the eIF2α/ATF4 pathway, and it is thus a potential target for the diagnosis, treatment, and detection of cryptococcal meningitis.

14.
J Am Heart Assoc ; 9(2): e013845, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31918601

RESUMO

Background Warfarin, a vitamin K antagonist, has been shown to affect bone mineral density and cause osteoporosis. However, studies investigating the relationship between non-vitamin K antagonist oral anticoagulants (NOACs) and osteoporosis are limited. We thus compared the risk of osteoporosis in patients with atrial fibrillation treated with either NOACs or warfarin. Methods and Results This nationwide, retrospective cohort study used Taiwan's National Health Insurance Research Database. All adult patients in Taiwan who were newly diagnosed with atrial fibrillation and treated with NOACs or warfarin between January 2012 and December 2015 were included and classified into their respective cohorts. Patients who received NOACs were subcategorized into the rivaroxaban, dabigatran, and apixaban subgroups. Propensity score matching was performed for each head-to-head comparison. Adjusted hazard ratios (aHRs) for the risk of osteoporosis were calculated using Cox proportional hazards regression models, with adjustment for confounders. Overall, 17 008 patients were included, with 8504 in each cohort. NOACs were associated with a lower osteoporosis risk than warfarin (aHR=0.82; 95% CI=0.68-0.97). A subgroup effect of treatment duration was identified (namely, the lower osteoporosis risk with NOAC compared with warfarin became stronger in those with longer treatment duration [P for interaction <0.001]). Furthermore, significantly lower risks of osteoporosis were observed in the rivaroxaban (aHR=0.68; 95% CI=0.55-0.83) and apixaban (aHR=0.38; 95% CI=0.22-0.66) subgroups, but not in the dabigatran subgroup (aHR=1.04; 95% CI=0.85-1.27). Conclusions Compared with warfarin, rivaroxaban and apixaban were associated with a significantly lower risk of osteoporosis in patients with atrial fibrillation.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31944653

RESUMO

Structural pulverization of metal chalcogenides such as Sn-based compounds is a serious issue for development of high-performance anode materials and results in serious capacity fading during continuous charge and discharge cycles. In this work, we synthesize ultrasmall SnS quantum dots (QDs) anchored onto nitrogen-enriched carbon (NC) nanospheres through facile hydrothermal and carbonization processes to prepare a progressive anode material for sodium-ion batteries. The optimized SnS QDs@NC electrode delivered an initial discharge capacity of 281 mAh g-1 at 100 mA g-1 and exhibited excellent cycling stability with a capacity retention of 75% after 500 cycles at a high current density of 1000 mA g-1. Ex situ XRD, XPS, FE-SEM, TEM measurements, and kinetics study were performed to unveil the sodium storage mechanism of the SnS QDs@NC electrode. A sodium-ion full cell assembled with an SnS QDs@NC anode and a Na3V2(PO4)3 cathode exhibited high capacity and good cycling stability. Such a superior electrochemical performance of SnS QDs@NC can be attributed to the synergistic effects of NC and SnS QDs where NC serves as a conducting matrix to support SnS QDs and helps avoid structural degradation. This work provides a promising strategy to resolve the pulverization issue of alloying and conversion-type anode materials.

16.
Medicine (Baltimore) ; 99(4): e18607, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977852

RESUMO

Systemic inflammatory response markers are associated with poor survival in many types of malignances. This study aimed to evaluate the prognostic value of preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP) in patients with non-small cell lung cancer (NSCLC).We retrospectively evaluated 254 NSCLC patients who underwent radical surgery between January 2012 and April 2014 in the Sichuan Provincial Cancer Hospital. The cut-off values of NLR, PLR, LMR, and CRP were determined according to the receiver operating characteristic curve, and the correlation of NLR, PLR, LMR, and CRP with prognosis was analyzed based on the cut-off value.The cut-off value for NLR, PLR, LMR, and CRP were 3.18, 122, 4.04, and 8.8, respectively. Univariate analysis showed that age (P = .022), tumor-node-metastasis (TNM) stage (P < .001), T stage (P = .001), and N stage (P < .001) were significantly correlated with disease-free survival (DFS), while age (P = .011), TNM stage (P < .001), T stage (P = .008), N stage (P < .001), and PLR (P = .001) were significantly correlated with overall survival (OS). In multivariate analysis, age (hazard ratio [HR]: 1.564, 95% confidence interval [CI]: 1.087-2.252, P = .016) and TNM stage (HR: 1.704, 95% CI: 1.061-2.735, P = .027) remained independent risk factors affecting DFS, while age (HR: 1.721, 95% CI: 1.153-2.567, P = .008), TNM stage (HR: 2.198, 95% CI: 1.263-3.824, P = .005), and PLR (HR: 1.850, 95% CI: 1.246-2.746, P = .002) were independent risk factors affecting OS.The preoperative PLR is superior to NLR, LMR, and CRP as a biomarker for evaluating the prognosis of patients undergoing curative surgery for NSCLC.


Assuntos
Plaquetas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Inflamação/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Proteína C-Reativa/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neutrófilos/metabolismo , Análise de Sobrevida
17.
J Cell Biochem ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31904144

RESUMO

DNA damage checkpoints act as a supervisor by preventing the course of cell cycle upon DNA damage and keeping the steadiness of genome. Checkpoint kinase 1 (CHK1) cannot be ignore in the etiology of numerous human cancers including nasopharyngeal cancer (NPC). To discuss genetic polymorphisms of CHK1 rs492510 in the occurrence of NPC was our objective. Rs492510 polymorphism of CHK1 was genotyped in 684 patients with NPC and 823 cancer-free controls. We utilize logistic regression models to appraise the correlation of rs492510 and susceptibility of NPC. Comparative expression level about CHK1 in nasopharyngeal carcinoma tissues were determined by real-time polymerase chain reaction. And we made use of Dual-Luciferase Reporter Assay to assess the transcriptional ability of CHK1 with different rs492510 allele. Adjusting multivariate logistic regression based on age, sex, body mass index, smoking, and drinking status showed that CHK1 rs492510 GA + GG genotype carriers presented prominent higher risk in NPC (odds ratio = 1.376, 95% confidence interval: 1.087-1.742; P = .008). As a consequence, we revealed that CHK1 relative expression levels in NPC tissues was higher than rhinitis tissues. Besides, the expressions of CHK1 in rs492510 GA genotype carriers were higher compared with people in AA genotype. The G allele of rs492510 generated remarkable higher transcription activity of CHK1 vs A allele by luciferase reporter assay. Our study considered that single nucleotide polymorphism rs492510 could increase transcription activity of CHK1 with the functionality, contributing to the susceptibility of NPC.

18.
Trials ; 21(1): 49, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915058

RESUMO

BACKGROUND: Cerebrovascular reactivity (CVR) is the change in cerebral blood flow in response to a vaso-active stimulus, and may assist the treatment strategy of ischemic stroke. However, previous studies reported that a therapeutic strategy for stroke mainly depends on the degree of vascular stenosis with steady-state vascular parameters (e.g., cerebral blood flow and CVR). Hence, measurement of CVR by multimodal imaging techniques may improve the treatment of ischemic stroke. METHODS/DESIGN: This is a prospective, randomized, controlled clinical trial that aimed to examine the capability of multimodal imaging techniques for the evaluation of CVR to improve treatment of patients with ischemic stroke. A total of 66 eligible patients will be recruited from Renji Hospital, Shanghai Jiaotong University School of Medicine. The patients will be categorized based on CVR into two subgroups as follows: CVR > 10% group and CVR < 10% group. The patients will be randomly assigned to medical management, percutaneous transluminal angioplasty and stenting, and intracranial and extra-cranial bypass groups in a 1:1:1 ratio. The primary endpoint is all adverse events and ipsilateral stroke recurrence at 6, 12, and 24 months after management. The secondary outcomes include the CVR, the National Institute of Health stroke scale and the Modified Rankin Scale at 6, 12, and 24 months. DISCUSSION: Measurement of cerebrovascular reserve by multimodal image is recommended by most recent studies to guide the treatment of ischemic stroke, and thus its efficacy and evaluation accuracy need to be established in randomized controlled settings. This prospective, parallel, randomized, controlled registry study, together with other ongoing studies, should present more evidence for optimal individualized accurate treatment of ischemic stroke. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-IOR-16009635; Registered on 16 October 2016. All items are from the World Health Organization Trial Registration Data Set and registration in the Chinese Clinical Trial Registry: ChiCTR-IOR-16009635.

19.
Int J Pharm ; 573: 118730, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31705972

RESUMO

Poor water solubility and low bioavailability hinder the clinical application of about 70% of newly synthesized compounds. Nanocrystal technology has become a preferred way to improve bioavailability by improving solubility. However, it remains challenging to produce nanocrystals with ultra-small particle sizes to further enhance the extent of bioavailability. Herein, we constructed ultra-small puerarin nanocrystals (Pue-NCs) (20-40 nm) via formation of hydrogen bond during HPH. We confirmed the formation of hydrogen bonds by 1H NMR and FTIR, and observed the distribution of polymer chains by SEM and TEM. The absorption mechanisms were studied in Caco-2 cell monolayers, and the results showed that the major transport mechanism for puerarin was passive diffusion, meanwhile, for Pue-NCs, the passive transport and micropinocytosis-mediated endocytosis coexisted. The absolute bioavailability of Pue-NCs was 35.28%, which was 11.54 folds compared to that of puerarin. Therapeutic equivalence was demonstrated between Pue-NCs and puerarin injection at 50 mg/kg and 15 mg/kg, respectively, in isoproterenol-induced myocardial ischemia model. This study provides a novel strategy for preparing ultra-small nanocrystals by HPH to increase bioavailability of poorly soluble drugs.

20.
Bioorg Chem ; 94: 103390, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31662212

RESUMO

Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC50 = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 µM. Furthermore, the blood glucose AUC0-2h of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30 mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators.

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