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1.
Pharmacol Res ; 175: 106040, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34954029

RESUMO

Inducing homologous recombination (HR) deficiency is a promising strategy to broaden the indication of PARP1/2 inhibitors in pancreatic cancer treatment. In addition to inhibition kinases, repression of the transcriptional function of FOXM1 has been reported to inhibit HR-mediated DNA repair. We found that FOXM1 inhibitor FDI-6 and PARP1/2 inhibitor Olaparib synergistically inhibited the malignant growth of pancreatic cancer cells in vitro and in vivo. The results of bioinformatic analysis and mechanistic study showed that FOXM1 directly interacted with PARP1. Olaparib induced the feedback overexpression of PARP1/2, FOXM1, CDC25A, CCND1, CDK1, CCNA2, CCNB1, CDC25B, BRCA1/2 and Rad51 to promote the acceleration of cell mitosis and recovery of DNA repair, which caused the generation of adaptive resistance. FDI-6 reversed Olaparib-induced adaptive resistance and inhibited cell cycle progression and DNA damage repair by repressing the expression of FOXM1, PARP1/2, BUB1, CDC25A, BRCA1 and other genes-involved in cell cycle control and DNA damage repair. We believe that targeting FOXM1 and PARP1/2 is a promising combination therapy for pancreatic cancer without HR deficiency.

2.
Cell Death Dis ; 12(12): 1138, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34880209

RESUMO

Inducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G2/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34966156

RESUMO

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a lethal complication of biliary-pancreatic surgery (BPS). The role of endoscopic intervention has not been fully defined in such a critical condition. The aim of this study was to assess the efficacy and safety of endoscopic hemostasis in a retrospective cohort. MATERIALS AND METHODS: Consecutive patients with acute UGIB after BPS who received interventional endoscopy between January 2007 and August 2020 were included in this study. The clinical characteristics were collected and analyzed to screen for predictive factors significantly associated with successful hemostasis. RESULTS: Among 37,772 patients who underwent BPS, 26 patients (0.069%) developed acute UGIB. The sites and causes of hemorrhage were as follows: gastroenteric anastomoe (n=17), gastric stump (n=2), jejunal anastomose (n=1), duodenal bulb ulcer (n=2), pancreatojejunal anastomosis hemorrhage (n=1), cholangiojejunal anastomose (n=1), gastroenteric anastomose and gastric stump hemorrhage (n=1), and Dieulafoy lesion (n=1). Successful endoscopic hemostasis was achieved in 19 (73.1%) of the 26 UGIB patients. In the 7 patients who failed endotherapy, 1 patient received a successful radiologic intervention, 6 patients underwent reoperation and achieved hemostasis in 4, and the other 2 patients died after reoperation. Logistic regression analysis showed that presentation-to-endoscopy time (≤12 h) was the only independent predictive factor associated with successful endoscopic hemostasis. CONCLUSIONS: Endoscopic hemostasis is relatively safe and effective in controlling UIGB after BPS. Prompt intervention (≤12 h) could improve the success rate of endoscopic hemostasis.

4.
J Med Chem ; 64(23): 17413-17435, 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34813314

RESUMO

Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic cancer.

5.
Cancer Biomark ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34542063

RESUMO

BACKGROUND: Distinguishing between benign and malignant bile duct strictures has long been a diagnostic challenge in clinical practice. OBJECTIVE: This study aimed to discover novel biomarkers in bile to improve the diagnostic accuracy of malignant biliary strictures. METHODS: Bile samples were collected from 6 patients with malignant or benign biliary stricture, respectively. Protein profiles of the bile were analyzed with a semi-quantitative human antibody array of 440 proteins. Then the differential expressed proteins were screened by Venn diagram analysis. Following this, the accuracy of these potential biomarkers for discriminating between malignant and non-malignant biliary strictures was validated in a larger (n= 40) group of patients using lasso analysis. RESULTS: Twenty proteins were found differentially expressed in malignant versus benign biliary strictures, 6 of which were identified by Venn diagram analysis to be up-regulated regardless of the location of biliary strictures. Among the 6 biomarkers, bile lipocalin-2, P-cadherin, and adipsin showed better diagnostic utility than that of bile CA19-9. Lasso analysis identified that lipocalin-2, P-cadherin and CA19-9 as a group of makers best distinguished malignant from benign strictures. CONCLUSIONS: Lipocalin-2 and P-cadherin measurements in bile could be clinically useful for the detection of malignant biliary strictures.

6.
Biochem Soc Trans ; 49(3): 1041-1054, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34156443

RESUMO

Enhancers are cis-regulatory elements that play essential roles in tissue-specific gene expression during development. Enhancer function in the expression of developmental genes requires precise regulation, while deregulation of enhancer function could be the main cause of tissue-specific cancer development. MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. Importantly, large-scale DNA sequencing studies have revealed that they are amongst the most frequently mutated genes associated with human cancers. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. Recent studies have provided a better understanding of the possible mechanisms underlying the roles of MLL3/MLL4 complexes in enhancer regulation. Moreover, accumulating studies offer new insights into our knowledge of the potential role of MLL3/MLL4 in cancer development. In this review, we summarize recent evidence on the molecular mechanisms of MLL3/MLL4 in the regulation of active enhancer landscape and long-range gene expression, and discuss their clinical implications in human cancers.

7.
Huan Jing Ke Xue ; 42(6): 2896-2907, 2021 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-34032089

RESUMO

A pg-C3N4/BiOBr/Ag composite was successfully prepared by simple high-temperature calcination and co-precipitation methods. The composite was characterized by means of XRD, SEM, TEM, XPS, UV-Vis, BET, and photocurrent analyses alongside other detection methods, and the degradation of 10 mg·L-1 sulfamethoxazole was investigated under simulated visible light irradiation. The results showed that the pg-C3N4/BiOBr/Ag composite had the best degradation effect on sulfamethoxazole when the loading ratio of silver was 5%. Compared with pg-C3N4, BiOBr monomer, and pg-C3N4/BiOBr composite, the photocatalytic degradation effect of the pg-C3N4/BiOBr/Ag (5%) was significantly improved, and the degradation rate was almost 100% within 30 min. The reaction rate constant (0.21016 min-1) was 13.15 times that of pg-C3N4/BiOBr. Through radical quenching experiments, it was shown that the main active substances in the photocatalytic degradation were holes (h+), superoxide radicals (·O2-), and singlet oxygen (1O2), among which superoxide radicals (·O2-) contributed the most. Cyclic tests of pg-C3N4/BiOBr/Ag showed that the synthesized material has good recyclability and application prospects.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33829657

RESUMO

BACKGROUND AND AIMS: Endoscopic radiofrequency ablation (RFA) is an emerging technique for the palliation of inoperable malignant biliary strictures (MBSs). We aimed to systemically investigate the long-term outcome of RFA in a large cohort of patients. METHODS: We recruited 883 patients with various MBSs who underwent endoscopic interventions at two large-volume centers; 124 patients underwent RFA and stenting, whereas 759 underwent stenting alone. To overcome selection bias, we performed 1:4 propensity score matching (PSM). The main outcome was overall survival (OS). RESULTS: Following PSM, patients in the RFA group showed significantly longer OS (9.5 months; 95% CI: 7.7-11.3 months) than those in the stenting alone group (6.1 months; 95% CI: 5.6-6.6 months; P < .001). In stratified analyses, the improved OS was only demonstrated in the subgroup of extrahepatic cholangiocarcinoma (11.3 months 95% CI: 10.2-12.4 vs 6.9 months 95% CI: 6.0-7.8; P < .001), but not in the subgroups of gallbladder cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, pancreatic cancer, and other metastatic cancers (all P > .05). The survival benefits were noted only in the patients with non-metastatic cholangiocarcinoma (11.5 vs 7.4 months, P < .001). CONCLUSIONS: The survival benefits of endoscopic RFA appear to be limited to patients with extrahepatic cholangiocarcinoma without distant metastasis.

9.
Front Plant Sci ; 12: 620544, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692816

RESUMO

Plant C2 domain proteins play essential biological functions in numerous plants. In this study, 180 soybean C2 domain genes were identified by screening. Phylogenetic relationship analysis revealed that C2 domain genes fell into three distinct groups with diverged gene structure and conserved functional domain. Chromosomal location analysis indicated that C2 domain genes mapped to 20 chromosomes. The transcript profiles based on RNA-seq data showed that GmC2-58, GmC2-88, and GmC2-148 had higher levels of expression under salt, drought, and abscisic acid (ABA) treatments. GmC2-148, encoding a cell membrane-localized protein, had the highest level of response to various treatments according to real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Under salt and drought stresses, the soybean plants with GmC2-148 transgenic hairy roots showed delayed leaf rolling, a higher content of proline (Pro), and lower contents of H2O2, O2- and malondialdehyde (MDA) compared to those of the empty vector (EV) plants. The results of transgenic Arabidopsis in salt and drought treatments were consistent with those in soybean treatments. In addition, the soybean plants with GmC2-148 transgenic hairy roots increased transcript levels of several abiotic stress-related marker genes, including COR47, NCDE3, NAC11, WRKY13, DREB2A, MYB84, bZIP44, and KIN1 which resulted in enhanced abiotic stress tolerance in soybean. These results indicate that C2 domain genes are involved in response to salt and drought stresses, and this study provides a genome-wide analysis of the C2 domain family in soybean.

10.
Nat Prod Res ; 35(10): 1620-1626, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-31232106

RESUMO

Three new sesquiterpene quinones/hydroquinones, 20-demethoxy-20-isopentylaminodactyloquinone D (1), 20-demethoxy-20-isobutylaminodactyloquinone D (2), and 19-methoxy-dictyoceratin-A (3), and five known related compounds (4-8) were isolated from the marine sponge Dactylospongia elegans. Their structures were elucidated by spectroscopic analysis, ECD calculation, single-crystal X-ray diffraction, and comparison with the literature. Compounds 3 and 5-8 exhibited activities against the human cancer cell lines DU145, SW1990, Huh7, and PANC-1 with IC50 values ranging from 2.33 to 37.85 µM.


Assuntos
Organismos Aquáticos/química , Poríferos/química , Terpenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Terpenos/química
11.
J Immunother Cancer ; 8(2)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33243934

RESUMO

BACKGROUND: The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear. METHODS: Pemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo. RESULTS: Pemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS-ROS-NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth. CONCLUSIONS: Our findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Pemetrexede/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos , Camundongos Nus , Pemetrexede/farmacologia , Transdução de Sinais , Microambiente Tumoral
12.
Surg Laparosc Endosc Percutan Tech ; 30(6): e52-e58, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33075006

RESUMO

BACKGROUND: A reliable large animal model of benign biliary stricture (BBS) is essential to study endoscopic management of BBS. The aim of this study was to establish a swine BBS model of endobiliary electrothermal injury with a diathermic sheath and screen out the optimal energy dose. MATERIALS AND METHODS: Twelve swine were equally randomized into a low (20 W), a medium (30 W), and a high (40 W)-dose group. Endobiliary electrothermal injury was applied to the common bile duct using a diathermic sheath at different energy doses for 20 seconds via endoscopic retrograde cholangiopancreatography. Cholangiographic findings and liver function were evaluated weekly after thermal injury. Two animals from each group were sacrificed at 2 weeks and the other 2 sacrificed 4 weeks after thermal injury for histopathologic evaluation. RESULTS: BBS was established successfully in 10 of the 12 animals. Two of the 4 animals in low-dose group did not produce biliary stricture at 4 weeks; in medium-dose group, BBS was induced in both animals at 2 weeks without causing severe complications; and in high-dose group, BBS was produced in 4 animals at 2 weeks, causing perforation and abdominal abscess formation in 1 animal. CONCLUSIONS: A safe and reproducible swine model of BBS could be established successfully by applying endobiliary electrothermal injury with a diathermic sheath at 30 W for 20 seconds.


Assuntos
Colestase , Animais , Colangiografia , Colangiopancreatografia Retrógrada Endoscópica , Colestase/etiologia , Constrição Patológica , Modelos Animais de Doenças , Suínos
13.
Mar Drugs ; 18(10)2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32993037

RESUMO

Chemical investigation on a marine sponge, Dactylospongia elegans, yielded five new γ-oxygenated butenolide sesterterpene derivatives, dactylospenes A-E (1-5), as well as two known biosynthetically related compounds, luffariellolide (6) and furospinosulin B (7). The structures of these compounds were elucidated on the basis of their spectroscopic data, experimental and calculated electronic circular dichroism (ECD) analysis, as well as comparison of the NMR data with those of known analogs. These metabolites are the first γ-oxygenated butenolide sesterterpenes to be reported from this genus. These compounds were evaluated in antimicrobial, anti-inflammatory, and cytotoxic assays. Only compounds 1, 3, and 6 exhibited moderate cytotoxicity against DU145, SW1990, Huh7, and PANC-1 cancer cell lines with IC50 values in the range of 2.11-13.35 µM. Furthermore, compound 2, without cytotoxicity, exhibited significant inhibitory effects (inhibitory rate 77.5%) on nitric oxide production induced by lipopolysaccharide at 10 µM.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Antineoplásicos/isolamento & purificação , Poríferos/metabolismo , Sesterterpenos/isolamento & purificação , Animais , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Lipopolissacarídeos , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7 , Sesterterpenos/química , Sesterterpenos/farmacologia , Terpenos/isolamento & purificação
14.
Mol Ther Oncolytics ; 18: 189-201, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32695876

RESUMO

Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small cell lung cancer (NSCLC) cells, mainly lung adenocarcinoma, based on their metabolic phenotypes and demonstrated that the aerobic glycolysis-preference NSCLC cell subtype was resistant to the OXPHOS-targeting inhibitors. We identified that monocarboxylate transporter 4 (MCT4), a lactate transporter, was highly expressed in the aerobic glycolysis-preference subtype with function supporting the proliferation of these cells. Glucose could induce the expression of MCT4 in these cells through a ΔNp63α and Sp1-dependent pathway. Next, we showed that knockdown of MCT4 increased intracellular lactate concentration and induced a reactive oxygen species (ROS)-dependent cellular apoptosis in the aerobic glycolysis-preference NSCLC cell subtype. By scanning a panel of monoclonal antibodies with MCT4 neutralizing activity, we further identified a MCT4 immunoglobulin M (IgM) monoclonal antibody showing capable anti-proliferation efficacy on the aerobic glycolysis-preference NSCLC cell subtype. Our findings indicate that the metabolic heterogeneity is a critical factor for NSCLC therapy and manipulating the expression or function of MCT4 can be an effective strategy in targeting the aerobic glycolysis-preference NSCLC cell subtype.

15.
Org Lett ; 22(17): 6703-6708, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32701300

RESUMO

A neutral-loss scanning mass method was used to explore new kynurenine-containing cycloheptapeptides, phakefustatins A-C (1-3), from the marine sponge Phakellia fusca. Their structures were elucidated by spectroscopic analysis and the advanced Marfey's method. 1 was total synthesized via a final-stage ozonolysis strategy by the combination of solid/solution-phase synthesis. Phakefustatin A (1) was identified as a RXRα modulator to inhibit cancer cell growth, and its pharmacophores could be Kyn and guanidine groups.


Assuntos
Cinurenina/química , Peptídeos Cíclicos/química , Poríferos/química , Animais , Estrutura Molecular , Análise Espectral
16.
J Biol Chem ; 295(16): 5509-5518, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32165500

RESUMO

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B-E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B-E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS-PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.


Assuntos
Antibióticos Antineoplásicos/biossíntese , Proteínas de Bactérias/metabolismo , Depsipeptídeos/biossíntese , Hidroxibenzoatos/química , Policetídeo Sintases/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular , Depsipeptídeos/química , Depsipeptídeos/toxicidade , Humanos , Compostos Orgânicos/química , Compostos Orgânicos/metabolismo , Compostos Orgânicos/toxicidade , Streptomyces/enzimologia , Streptomyces/metabolismo
17.
Chem Biodivers ; 17(4): e2000074, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32110847

RESUMO

Two new quinoline alkaloids, aaptolines A and B, were isolated from the marine sponge Aaptos aaptos. Their structures were determined by HR-ESI-MS data, NMR analysis, and X-ray crystallography. Structurally, aaptoline A is characterized as having a quinoline skeleton fused with a 1,4-dioxane motif at the C(7)-C(8) position, whereas aaptoline B possessed an intriguing 1H-pyrrolo[2,3-g]quinoline moiety. The cytotoxic assay of these compounds showed no cytotoxicity towards HepG2, A549, and PC9 cancer cell lines and had IC50 values greater than 20 µm.


Assuntos
Alcaloides/química , Antineoplásicos/química , Poríferos/química , Quinolinas/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Conformação Molecular , Poríferos/metabolismo , Espectrometria de Massas por Ionização por Electrospray
18.
Mater Sci Eng C Mater Biol Appl ; 108: 110189, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924023

RESUMO

Particulate pollution in the air has strong links with increased morbidity of cardiopulmonary diseases. Iron is one of the major carcinogens in air pollution and can produce hydroxyl radical which induce oxidative stress, lead to cell damage and even to cancer. In this work, a novel nitronyl nitroxide radical NITPh(OMe)2 (2-(2,4-dimethoxyphenyl) -4,4,5,5- tetramethylimidazoline- 1- oxyl-3- oxide) was prepared and characterized by electron spin-resonance spectroscopy (ESR), X-ray crystal diffraction, Fourier transform infrared (IR), X-ray powder diffraction (XRD), elemental analysis, ultraviolet and visible spectra (UV-Vis), and the electronic transition processes was also calculated by time-dependent density functional theory (TDDFT) to analysis UV-Vis spectrum. In vitro cell model of oxidative damage was established by ferric ammonium citrate (FAC) overload, and NITPh(OMe)2 was studied as a free radical scavenger to protect peroxidation of A549 cells. Results showed that NITPh(OMe)2 could significantly alleviate the damage of A549 cells by iron overload in cell morphology, cell viability, cell proliferation and cell apoptosis. The apoptotic signaling pathway of A549 cells induced by FAC and the protection mechanism of NITPh(OMe)2 were all discussed through the expression of three relating proteins, Bcl-2, Bax and DDIT3. This work confirms that nitroxide radicals are effective antioxidants, and have potential application in clinical practice as therapeutic agents.


Assuntos
Antioxidantes , Apoptose/efeitos dos fármacos , Óxidos N-Cíclicos , Sobrecarga de Ferro/metabolismo , Óxidos de Nitrogênio , Células A549 , Antioxidantes/química , Antioxidantes/farmacologia , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacologia , Humanos , Sobrecarga de Ferro/patologia , Óxidos de Nitrogênio/química , Óxidos de Nitrogênio/farmacologia , Oxirredução/efeitos dos fármacos
19.
J Gastroenterol Hepatol ; 35(7): 1150-1157, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31802535

RESUMO

BACKGROUND AND AIM: Endoscopic stenting for unresectable malignant hilar biliary strictures (MHBS) remains challenging. Post-endoscopic retrograde cholangiopancreatography cholangitis (PEC) can be the most common and fatal adverse event. In the present study, we aimed to systematically evaluate the incidence, severity, risk factors, and consequences of PEC after endoscopic procedures for advanced MHBS. METHODS: Of 924 patients, we identified 502 patients with MHBS (Bismuth types II to IV) who underwent endoscopic stenting as the primary therapy at two centers over 16 years. PEC and its severity were verified according to the current Tokyo guidelines. RESULTS: A total of 108 patients (21.5%) experienced acute PEC. Mild, moderate, and severe cholangitis were encountered in 51 (10.1%), 42 (8.4%), and 15 (3.0%) patients, respectively. Multivariate analyses showed that metal stenting (verse plastic stenting) (OR 0.328, 95% CI 0.200-0.535, P < 0.001) and Bismuth classification (IV vs III/II) (OR 2.499, 95% CI 1.150-5.430) were independent predictors for PEC and the moderate/severe type. Patients with PEC had significantly lower clinical success rates (86.3% vs 41.7%, P < 0.001), a higher rate of early death (6.5% vs 0.5%, P < 0.001), a shorter median stent patency (4.9 vs 6.4 months, P < 0.001), and shorter overall survival (2.6 vs 5.2 months, P < 0.001) compared with the noncholangitis group. CONCLUSIONS: After endoscopic stenting for advanced MHBS, cholangitis may occur in as many as 21.5% of patients, which may be associated with a poor prognosis. The risk is high in patients with Bismuth type IV and may be reduced by using metal stents.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Colangite/etiologia , Colestase/cirurgia , Icterícia Obstrutiva/cirurgia , Complicações Pós-Operatórias/etiologia , Stents/efeitos adversos , Doença Aguda , Idoso , Colangite/enzimologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Prognóstico , Estudos Retrospectivos , Risco , Índice de Gravidade de Doença
20.
Nature ; 577(7788): 121-126, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31853060

RESUMO

Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by 'reader' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.


Assuntos
Linhagem da Célula , Cromatina/genética , Proteínas de Ligação a DNA/metabolismo , Mutação com Ganho de Função , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Camundongos , Néfrons/metabolismo , Néfrons/patologia , Fatores de Transcrição/química , Fatores de Transcrição/genética
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