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1.
Biomed Pharmacother ; 126: 110066, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32172065

RESUMO

BACKGROUND: As one of the most common genitourinary malignancies worldwide, bladder cancer affects about 3.4 million people globally, with 430,000 new cases a year since 2015. Despite the advances in bladder cancer diagnosis and therapy, there has been little progress in the patients' overall survival in nearly 30 years. Therefore, investigating novel molecular therapeutic targets is required to gain insight into the tumorigenesis of bladder cancer, which ultimately may be used to develop more effective therapeutic strategies. METHODS: Herein, we used gene knockdown in vitro and in vivo to unveil the unknown roles of ZSCAN16 in bladder cancer. Afterward, to decipher the unknown regulatory role of ZSCAN16 in tumor progression, we verified that a bunch of genes including NF-κB, AKT, mTOR, and P38 were the key downstream regulators of ZSCAN16 by western blot and rescue experiments. RESULTS: We found high expression of ZSCAN16 transcripts in bladder cancer cells and tumor samples from the TCGA database and tissue microarray bank, demonstrated in correlation with poor prognosis for bladder cancer patients. The in vitro experiments indicated that the silencing of ZSCAN16 by shRNA lentivirus promoted apoptosis and inhibited proliferation, colony formation, as well as migration and invasion in T24 cells. By investigating the signaling pathways, we proved ZSCAN16 play a novel role as oncogenic gene in bladder cancer by regulating NF-κB, AKT, mTOR, P38 and other genes. Furthermore, the in vivo experiments identified that ZSCAN16 knockdown retarded the tumor growth in nude mice. CONCLUSIONS: In summary, these findings revealed that ZSCAN16 is a potential novel oncogene in the development and progression of bladder cancer. This study will shed light on developing novel therapeutic targets in the future treatment of bladder cancer.

2.
Dalton Trans ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32163063

RESUMO

Four D-A type Zn(ii) coordination complexes, [Zn(C29H29N3O2)·(CH3OH)]·(CH3OH) (1), Zn2(C74H90N6O4)·(CH3OH) (2), [Zn(C30H28N4O2)·(CH3OH)]·(CH3OH) (3) and [Zn(C38H44N4O2)·(C2H5OH)]·(C2H5OH) (4), were designed, synthesized, and studied. Their fluorescence properties in the solid state and in THF solution were comprehensively analysed based on their single-crystal structures. The results showed that the red-shift of fluorescence emission from complexes 1 to 4 was successfully achieved via the strategy of enhancing intramolecular charge transfer (ICT) effects by increasing the number of electron-pulling and pushing groups gradually. Meanwhile, because of the fluorescence recognition abilities of these four complexes towards iodide anions in THF, they could be regarded as potential fluorescent sensors for I- in this organic solution in the future.

3.
J Xray Sci Technol ; 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32116287

RESUMO

OBJECTIVE: To demonstrate the value of optimizing non-contrast head imaging tasks by using the multiple virtual monochromatic spectral imaging (VMSI) sets in dual-energy spectral computed tomography (CT) and determine the optimal energy levels for various tasks in imaging head. MATERIALS AND METHODS: This retrospective study includes 55 patients (29 women and 26 men, average age of 54.5±12.3years) who underwent non-contrast head CT in spectral imaging mode. For each patient, 21 VMSI sets from 40 to 140 keV at 5 keV intervals and 120 kVp-like image were reconstructed. Signal-to-noise ratio (SNR) for gray matter (GM) and white matter (WM), contrast-to-noise ratio (CNR) between GM and WM, subcalvarial artifact index (SAI) and posterior fossa artifact index (PFAI) were measured by placing regions-of-interest (ROIs) in nine areas of the brain. Two radiologists subjectively rated the image quality in terms of GM-WM differentiation, beam hardening artifacts in the subcalvarial space, and posterior fossa. The overall image noise was evaluated using a 5-point Likert scale. Measurement data were then statistically analyzed. RESULTS: The optimal energy level for viewing the supratentorial brain and reducing beam hardening artifacts in the subcalvarial space and posterior fossa was 65 keV and 75 keV, respectively. All corresponding measurements at these energy levels were significantly better than those measured at other energy levels (all P < 0.05). CONCLUSIONS: Dual-energy spectral CT imaging provides a set of virtual monochromatic spectral imaging and can be selected on-demand to optimize the imaging tasks in non-contrast head CT. VMSI reconstruction of dual-energy unenhanced head CT scans at 65-75 keV enables to maximize image quality.

4.
Med Sci Monit ; 26: e922556, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32214058

RESUMO

BACKGROUND The aim of this study was to compare changes in the extracellular matrix after implantation of a stent that elutes a matrix metalloproteinase (MMP) inhibitor (GM6001); and to determine the effects of the GM6001-eluting stent upon prevention of in-stent restenosis (ISR). MATERIAL AND METHODS We included 48 Guangxi Bama mini-pigs in this study. A GM6001-eluting stent was placed in one iliac artery and a stent that did not elute GM6001 was placed in the contralateral iliac artery. The iliac arteries were removed at 6 hours as well as 1, 7, 14, 56, 84, and 336 days after stent placement. Arteries were analyzed for morphometry, gelatinase content, different phenotypes of vascular smooth muscle cells (VSMCs), collagen content, apoptotic rate, and cell density. RESULTS The vascular lumen areas of the GM6001 group were significantly increased and the neointimal areas were significantly reduced compared with the control group from the 7 days to the 336 days. In the 2 groups, expression of MMP-2 and MMP-9 peaked simultaneously, but GM6001-eluting stents inhibited expression of MMP-2 and MMP-9 in the vascular media and neointima (especially around the struts) significantly. In the GM6001 group, expression of tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2, myosin heavy chain 10 (MYH-10, marker of the proliferative phenotype of VSMCs), collagen content, percentage of apoptotic cells, and cell density were also decreased significantly compared with those in the control group. CONCLUSIONS Use of GM6001-eluting stents resulted in persistent and potent inhibition of intimal hyperplasia, an increase in luminal area, and no obvious thrombosis in the arteries of the mini-pigs.

5.
Cell Oncol (Dordr) ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32130660

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) are transcribed pervasively in the genome and act to regulate chromatin remodeling and gene expression. Dysregulated lncRNA expression has been reported in many cancers, but the role of lncRNAs in esophageal cancer (EC) has so far remained poorly understood. In this study, we aimed to understand the effect of lncRNA LINC01234 on EC development through competitively binding to microRNA-193a-5p (miR-193a-5p). METHODS: The Gene Expression Omnibus (GEO) database was used for microarray-based EC expression profiling. Gain- and loss-of-function analyses were carried out in human EC-derived Eca-109 and EC9706 cells. Expression analyses of miR-193a-5p, LINC01234, CCNE1, caspase-3, p21, Bax, cyclinD1 and Bcl-2 were performed using RT-qPCR and Western blotting. Cell proliferation, colony formation and apoptosis analyses were carried out using MTT, Hoechst 33258 and flow cytometry assays. A xenograft EC model in nude mice was used to evaluate in vivo tumor growth and CCNE1 expression. RESULTS: Microarray-based analyses revealed that LINC01234 expression was increased in primary EC samples, whereas that of miR-193a-5p was decreased. We found that CCNE1 was a target of miR-193a-5p and that LINC01234, in turn, sponges miR-193a-5p. After treatment with si-LINC01234 or miR-193a-5p mimic, EC cells (Eca-109 and EC9706) exhibited cyclinD1 and Bcl-2 downregulation, and caspase-3, p21, Bax and cleaved caspase-3 upregulation. LINC01234 silencing or miR-193a-5p upregulation resulted in decreased proliferation and colony formation, and increased apoptosis of EC cells. In addition, LINC01234 silencing or miR-193a-5p upregulation resulted in reduced in vivo EC tumor growth and CCNE1 expression in nude mice. CONCLUSIONS: We found that silencing of LINC01234 suppresses EC development by inhibiting CCNE1 through competitively binding to miR-193a-5p, which suggests that LINC01234 may represent a novel target for EC therapy.

6.
J Hum Hypertens ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32157158

RESUMO

Triglyceride-glucose (TyG) index is considered a simple and feasible indicator of insulin resistance (IR). This study aims to delve into the association and interaction of TyG index on the risk of prehypertension in Chinese adults. A community based cross-sectional survey conducted in Chinese population. Eligible participants were recruited, and questionnaire survey, anthropometric tests, and blood samples collection were performed. TyG index was obtained as ln [fasting TG(mg/dl) × FPG(mg/dl)/2]. Logistic regression model and the area under the receiver-operating characteristics (ROC) curves (AUC) were analyzed. Interaction analysis was conducted by calculating relative excess risk for interaction (RERI), attributable proportion for interaction (AP) as well as synergy index (SI). A total of 3115 recruited participants (1307 males and 1808 females) were aged 60.82 years on average. The prevalence of prehypertension reached 36.4% on the whole, 37.6% in male and 35.5% in female, respectively. The results of multivariable logistic regression model suggested that the adjusted OR for prehypertension was upregulated across TyG index quartiles, up to 2.06 (95% CI:1.53-2.77) for quartiles 4 versus quartiles 1. Furthermore, TyG index outperformed FPG (Z = 2.15, p = 0.032) and TG (Z = 6.10, p < 0.001) in discriminating prehypertension risk. Besides, TyG index with abdominal obesity (RERI:1.53, 95% CI:0.39-2.67; AP: 0.37, 95% CI: 0.16-0.59; SI:1.96, 95% CI:1.15-3.34) displayed a noticeable interaction on risk of prehypertension. Our study indicated that a higher TyG index rose the risk of prehypertension independently and synergistically with abdominal obesity in Chinese adults. Furthermore, it exhibited a higher predictability compared with conventional indices.

7.
Int J Clin Oncol ; 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32162011

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are considered as promising cancer biomarkers. The aim of the present study is to investigate the prognostic significance of miR-200c in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Quantitative real-time PCR (qRT-PCR) was used to determine the expression levels of miR-200c in 204 pairs of OSCC and adjacent noncancerous. Correlations between miR-200c expression levels and clinicopathological characteristics were investigated. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Multivariate analysis of the prognostic factors was performed with a Cox proportional hazards regression model. RESULTS: The expression of miR-200c was significantly down-regulated in OSCC tissues compared with adjacent non-tumor tissues (p < 0.0001). Low expression of miR-200c in tumor tissues was significantly correlated with the positive N classification (p = 0.013), advanced TNM stage (p = 0.007) and poor differentiation grade (p = 0.026). Lower miR-200c expression in patients was significantly associated with poor recurrence-free survival (RFS, p = 0.0003) and overall survival (OS, p = 0.0026). Multivariate analysis confirmed that low miR-200c expression was an independent predictor for poor RFS (hazard ratio (HR) 1.705, 95% CI 1.136-2.56, p = 0.01) and OS (HR 1.669, 95% CI 1.03-2.703, p = 0.037) in patients with OSCC. CONCLUSION: Our results suggest that the miR-200c might be a potential prognostic biomarker for OSCC.

8.
Eur J Med Chem ; 192: 112153, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32135407

RESUMO

NEDDylation pathway regulates multiple physiological process, unlike inhibitors, NEDDylation activators are rarely studied. Novel amide derivatives were synthesized and evaluated for antiproliferative activity against MGC803, MCF-7 and PC-3 cells. Among them, Ⅶ-31 displayed the most potent activity with an IC50 value of 94 nmol/L against MGC803 cells. Cellular mechanisms elucidated that Ⅶ-31 inhibited the cell viability, arrested cell cycle at G2/M phase and induced apoptosis via intrinsic and extrinsic pathways against MGC803 cells. In addition, Ⅶ-31 activated NAE1-Ubc12-Cullin1 NEDDylation via interacting with NAE1 directly. Furthermore, the activation of NEDDylation resulted in the degradation of inhibitor of apoptosis proteins (IAPs). Importantly, Ⅶ-31 inhibited tumor growth in xenograft models in vivo without the apparent toxicity. In summary, it is the first time to reveal that Ⅶ-31 deserves consideration for cancer therapy as a NEDDylation activator.

9.
Mol Cancer Ther ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32220969

RESUMO

Renal cell carcinoma (RCC) bone metastases (RCCBM) are typically osteolytic. We previously showed that BIGH3 (beta Ig-h3/TGFbI), secreted by 786-O RCC, plays a role in osteolytic bone lesion in RCCBM through inhibition of osteoblast (OSB) differentiation. To study this interaction, we employed three-dimensional (3D) hydrogels to co-culture bone-derived 786-O RCC cells (Bo-786) with MC3T3-E1 pre-osteoblasts (OSB). Culturing pre-osteoblasts in the 3D hydrogels preserved their ability to differentiate into mature OSB; however, this process was decreased when pre-osteoblasts were co-cultured with Bo-786 cells. Knockdown of BIGH3 in Bo-786 cells recovered OSB differentiation. Further, treatment with bone morphogenetic protein 4 (BMP4), which stimulates osteoblast differentiation, or cabozantinib (CBZ), which inhibits VEGFR1 and MET tyrosine kinase activities, also increased OSB differentiation in the co-culture. CBZ also inhibited pre-osteoclast RAW264.7 cell differentiation. Using RCCBM mouse models, we showed that CBZ inhibited Bo-786 tumor growth in bone. CBZ treatment also increased bone volume and OSB number, and decreased osteoclast number and blood vessel density. When tested in SN12PM6 RCC cells that have been transduced to overexpress BIGH3, CBZ also inhibited SN12PM6 tumor growth in bone. These observations suggest that enhancing OSB differentiation could be one of the therapeutic strategies for treating RCCBM that exhibit OSB inhibition characteristics, and that this 3D co-culture system is an effective tool for screening osteoanabolic agents for further in vivo studies.

10.
Chem Commun (Camb) ; 56(12): 1899, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32016277

RESUMO

Correction for 'A facile strategy to realize a single/double photon excitation-dependent photosensitizer for imaging-guided phototherapy against HeLa cancer cells at separate irradiation channels' by Lin Kong et al., Chem. Commun., 2020, 56, 571-574.

11.
J Neurol Sci ; 411: 116720, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32044686

RESUMO

Prolactinomas are tumors of the pituitary gland, which overproduces prolactin leading to dramatic fluctuations of endogenous hormone levels throughout the body. While it is not fully understood how endogenous hormone disorders affect a patient's brain, it is well known that fluctuating hormone levels can have negative neuropsychological effects. Using resting-state functional magnetic resonance imaging (rs-fMRI), we investigated whole-brain functional connectivity (FC) and its relationship with hormone levels in prolactinomas. By performing seed-based FC analyses, we compared FC metrics between 33 prolactinoma patients and 31 healthy controls matched for age, sex, and hand dominance. We then carried out a partial correlation analysis to examine the relationship between FC metrics and hormone levels. Compared to healthy controls, prolactinoma patients showed significantly increased thalamocortical and cerebellar-cerebral FC. Endogenous hormone levels were also positively correlated with increased FC metrics, and these hormone-FC relationships exhibited sex differences in prolactinoma patients. Our study is the first to reveal altered FC patterns in prolactinomas and to quantify the hormone-FC relationships. These results indicate the importance of endogenous hormones on functional compensation of the brain in patients with prolactinomas.

12.
Ann Hematol ; 99(3): 539-547, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31953585

RESUMO

Macrophages within tissues display a strong plastic ability in respond to environmental cues in both physiologic influences and disease. However, the macrophage phenotype and its distribution in the bone marrow biopsies (BMB) samples of human acute leukemia (AL) remain poorly understood. In this study, 97 BMB samples of patients with acute leukemia and 30 iron-deficiency anemias (IDA) as control group were evaluated with immunohistochemistry. In comparison with controls, the counts of CD68+, CD163+, and CD206+macrophages were remarkably increased in BMB samples of acute leukemia (P < 0.01), as well as their infiltration density was roaring up-regulation (P < 0.01). The expression levels of CD68+, CD163+, and CD206+macrophages were decreased in patients with complete remission, but there still existed statistically significant contrast to the control group (P < 0.01). The ratios of the CD163-positive cells or CD206-positive cells to CD68-positive cells were most prevalent in the BMB samples of human acute leukemia compared with the control group (P < 0.01), which support that macrophages were polarized to M2 macrophages.


Assuntos
Antígenos de Diferenciação/metabolismo , Medula Óssea , Leucemia , Macrófagos , Proteínas de Neoplasias/metabolismo , Doença Aguda , Adolescente , Adulto , Idoso , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Humanos , Leucemia/metabolismo , Leucemia/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade
13.
Bioresour Technol ; 300: 122709, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31901771

RESUMO

Bio-valorization of organic waste streams, such as food waste and waste activated sludge, to lactic acid (LA) has recently drawn much attention. It offers an opportunity for resource recovery, alleviates environmental issues and potentially turns a profit. In this study, both stable and high LA yield (0.72 ± 0.15 g/g total chemical oxygen demand) and productivity rate (0.53 g/L•h) were obtained through repeated batch fermentation. Moreover, stable solubilization and increase in the critical hydrolase activities were achieved. Depletions of ammonia and phosphorus were correlated with the LA production. The relative abundance of the key LA bacteria genera (i.e., Alkaliphilus, Dysgonomonas, Enterococcus and Bifidobacterium) stabilized in the repeated batch reactor at a higher level (44.5 ± 2.53%) in comparison with the batch reactor (26.2 ± 4.74%). This work show a practical way for the sustainable valorization of organic wastes to LA by applying the repeated batch mode during biological treatment.


Assuntos
Eliminação de Resíduos , Esgotos , Reatores Biológicos , Fermentação , Alimentos , Ácido Láctico
14.
Org Lett ; 22(3): 1071-1075, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31939304

RESUMO

Incarnolides A (1) and B (2), two schinortriterpenoids (SNTs) featuring a tricyclo[9.2.1.02,8]tetradecane-bridged system, together with two biosynthetically related known SNTs, lancifonins A (3) and C (4), were isolated from the stems of Schisandra incarnata. Their structures were elucidated by extensive spectroscopic analyses, and the absolute configurations were assigned by single-crystal X-ray diffraction and electronic circular dichroism calculation. The hypothetical biogenetic pathway of 1 and 2 was postulated. Compound 1 exhibited antiviral and neuroprotective activities.

15.
Chemosphere ; 247: 125876, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31978652

RESUMO

Aluminium oxide nanoparticles (Al2O3 NPs) potentially cause health hazards after their release into the environment. The crystalline phase of Al2O3 NPs determines their surface structure and the number of functional groups. The adsorption of natural organic matter (NOM) or biomolecules on the surface Al2O3 NPs also alters their surface properties and subsequent interactions with organisms. In this study, the roles of the Al2O3 crystalline phase and the surface coating of the nanoparticles on the membrane integrity and fluidity were investigated. Giant and small unilamellar vesicles (GUVs and SUVs) were prepared as model cell membranes to detect membrane disruption after exposure to Al2O3 NPs. Due to amorphous structure and high surface activity of γ-Al2O3 NPs, they had a stronger affinity with the membrane and caused more serious membrane rupture than that of α-Al2O3 NPs. The deposition of Al2O3 NPs on the membrane and the induced membrane disruption were monitored by a quartz crystal microbalance with dissipation (QCM-D) method. HA-coated Al2O3 NPs disrupted the SUV layer on the QCM-D sensor, while BSA-coated Al2O3 NPs only adhered to the membrane and induced unremarkable vesicle disruption. In addition, untreated γ-Al2O3 NPs induced remarkable gelation of a negatively charged membrane, but other types of Al2O3 NPs caused negligible membrane phase changes. The outcomes of this study demonstrate that the crystalline phase of the Al2O3 NPs affects the integrity and fluidity of cell membranes. The protein coatings on the NPs weaken the NP-membrane interaction, while HA coatings increase the damage of the NP-induced interaction.

16.
Int J Infect Dis ; 93: 77-83, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31982625

RESUMO

OBJECTIVES: To improve the diagnostic efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for Chinese patients with fever of unknown origin (FUO) and inflammation of unknown origin (IUO), with combined clinical parameters. MATERIALS AND METHODS: FUO/IUO patients who underwent a standard diagnostic work-up and 18F-FDG PET/CT scanning were enrolled and divided into a local uptake lesion subgroup and a non-specific abnormal uptake subgroup. Beneficial clinical parameters for improving the diagnostic efficacy of PET/CT were identified. RESULTS: From January 2014 to January 2019, 253 FUO/IUO patients were studied. In total, 147 patients had local uptake lesions and 106 patients had non-specific abnormal uptake. In the local uptake lesion group, the positioning accuracy of PET/CT was 37.2% in grades 1 and 2, and 66.3% in grades 3 and 4. With the following combination of clinical parameters, the positioning accuracy increased to 75.0% and 90.0%, respectively: time from admission to performing PET/CT scanning <6.5 days and C-reactive protein level >95 mg/l. In the non-specific abnormal uptake group, the combination of sex (male), bicytopenia, and lactic dehydrogenase improved the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignancy from 64.3%, 69%, 60%, and 72.7%, respectively, to 83.3%, 81%, 81.4%, and 82.9%, respectively. With the combination of sex (male), white blood count, serum ferritin level, and hepatosplenomegaly, the infection prediction model had a sensitivity, specificity, PPV, and NPV of 78%, 76.2%, 76.6%, and 77.6%, respectively. CONCLUSIONS: Combined clinical parameters improved the localization diagnostic value of 18F-FDG PET/CT in the local uptake lesion subgroup and the etiological diagnostic value in the non-specific abnormal uptake subgroup.

17.
J Hazard Mater ; 384: 121460, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31690502

RESUMO

Phase-selective organogelators (PSOGs) have drawn wide attention due to their potential applications in recovery of leaked aromatics and spilled oils. However, powder form PSOGs with fast gelling abilities and broad applicabilities are still limited. Herein, we developed three D-gluconic acetal-based gelators with different alkyl chains, all of which show excellent gel properties for hydrocarbon solvents. The spectroscopic and X-ray results revealed that the gel formation was the synergy of hydrogen bonding, π-π stacking and van der Waals forces. Surprisingly, the powder form gelator A with a cis double bond in the alkyl chain could instantly and selectively gel aromatic hydrocarbons, and also rapidly solidify crude oils with widely ranging viscosities from seawater at room temperature within minutes. Further research revealed that A powder exhibited porous amorphous morphology because the cis double bonds broke the crystalline chain-chain interdigitation between the assemblies. Therefore, the fast dispersion and recombination of fibers under the action of oil molecules lead to the fast room temperature gel process. Overall, a non-toxic and low-cost powder form PSOG with rapid room temperature phase selective gelation ability for a wide range of oils makes it promising for the emergency treatment of oil spill and aromatics leakage.

18.
Bioorg Med Chem Lett ; 30(2): 126791, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740251

RESUMO

Neddylation modification is often over-expressed in a variety of human tumor cells. Therefore, targeting neddylation pathway may represent a potential approach to the treatment of human tumors. Herein, we describe the discovery of a hit scaffold from our in-house library and further structure-based optimizations. In this work, compound V11 could block the neddylation and inhibit the activity of NAE (with an EC50 value of 3.56 µM), and a dose-dependent reduction of the Ubc12-NEDD8 conjugations was also observed. Molecular docking results suggest compound V11 could bind tightly to NAE via hydrogen bonds and hydrophobic interactions. Compound V11 showed the best antiproliferative ability with an IC50 value of 8.22 µM against gastric cancer MGC-803 cells. Further anticancer activity studies suggested that compound V11 inhibited MGC-803 cell growth, caused a cell cycle arrestment at G2/M phase and induced apoptosis via extrinsic and intrinsic apoptosis pathways. All the findings suggest that 1,2,4-triazine scaffold might provide a novel scaffold for the further development of neddylation inhibitors and compound V11 might be a potential neddylation inhibitor with anticancer activity.

19.
J Org Chem ; 85(3): 1416-1424, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31609620

RESUMO

Macrocyclic peptides have proven to be highly effective inhibitors of protein-protein interactions but generally lack cell permeability to access intracellular targets. We show herein that macrocyclic peptides may be rendered highly cell-permeable and biologically active by conjugating them with a cyclic cell-penetrating peptide (CPP). A previously reported cyclic peptidyl inhibitor against the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid-2 (Nrf2) interaction (KD = 18 nM) was covalently attached to a cyclic CPP through a flexible linker. The resulting bicyclic peptide retained the Keap1-binding activity, resisted proteolytic degradation, readily entered mammalian cells, and activated the transcriptional activity of Nrf2 at nanomolar to low micromolar concentrations in cell culture. The inhibitor provides a useful tool for investigating the biological function of Keap1-Nrf2 and a potential lead for further development into a novel class of anti-inflammatory and anticancer agents. Our data suggest that other membrane-impermeable cyclic peptides may be similarly rendered cell-permeable by conjugation with a cyclic CPP.

20.
World Neurosurg ; 133: e342-e347, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31562968

RESUMO

OBJECTIVE: This study was carried out to analyze the surgical effect of cervical spine sagittal alignment for patients with Hirayama disease (HD). METHODS: Forty-four subjects were retrospectively analyzed for the parameters of cervical spine sagittal alignment. The case group consisted of 23 patients with HD, whereas the control group consisted of 21 healthy adolescent subjects. Pre- and postoperative cervical spine sagittal parameters of the patients with HD were collected; the cervical sagittal parameters of the healthy adolescent subjects were also collected. Sagittal alignment parameters were compared between the patients with HD and the healthy adolescent subjects, and between the pre- and postoperative parameters for the patients with HD. RESULTS: Forty-four subjects completed the follow-up, with the average follow-up period being 18.0 months. No significant differences were detected between the HD and control groups for clinical parameters (P > 0.05). The preoperative HD group had smaller values compared with the control group in the sagittal parameters of C2-7 cervical lordosis (CL) angle, T1 slope, thoracic inlet angle (TIA), and cervical tilt angle (P < 0.05). For the patients with HD, the preoperative values were smaller compared with the postoperative HD values for the parameters of C2-7 CL angle, T1 slope, and cervical tilt angle (P < 0.05). We found no significant differences between the postoperative patients with HD and the healthy subjects, including C2-7 CL angle, C2-7 sagittal vertical axis, T1 slope, TIA, neck tilt angle, cervical tilt angle, and cranial tilt angle (P > 0.05). CONCLUSIONS: Patients with HD have sagittal imbalance of the cervical spine compared with age-matched healthy adolescent subjects, and surgical treatment could correct the sagittal imbalance.


Assuntos
Vértebras Cervicais/patologia , Discotomia , Fusão Vertebral , Atrofias Musculares Espinais da Infância/cirurgia , Adolescente , Adulto , Antropometria , Placas Ósseas , Parafusos Ósseos , Feminino , Seguimentos , Humanos , Cifose/diagnóstico por imagem , Cifose/etiologia , Cifose/patologia , Lordose/diagnóstico por imagem , Lordose/etiologia , Lordose/patologia , Masculino , Aparelhos Ortopédicos , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Estudos Retrospectivos , Atrofias Musculares Espinais da Infância/complicações , Adulto Jovem
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