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1.
J Pharm Pharmacol ; 73(3): 388-397, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33793880

RESUMO

OBJECTIVES: To determine the kinetics of the formation of 10,11-dihydro-10-hydroxy-carbazepine (MHD)-O-glucuronide in human liver microsomes (HLMs), human intestine microsomes (HIMs), human kidney microsomes (HKMs) and recombinant human UDP-glucuronosyltransferase (UGTs), and identify the primary UGT isoforms catalyzing the glucuronidation of MHD. METHODS: The kinetics of the glucuronidation of MHD was determined in HLMs, HIMs as well as HKMs. Screening assays with 13 recombinant human UGTs, inhibition studies and correlation analysis were performed to identify the main UGTs involved in the glucuronidation of MHD. KEY FINDINGS: MHD-O-glucuronide was formed in HLMs, HIMs as well as HKMs, HLMs showed the highest intrinsic clearance of MHD. Among 13 recombinant human UGTs, UGT2B7 and UGT1A9 were identified to be the principal UGT isoforms mediating the glucuronidation of MHD, while UGT1A4 played a partial role. In addition, inhibition studies and correlation analysis further confirmed that UGT2B7 and UGT1A9 participated in the formation of MHD-O-glucuronide. CONCLUSIONS: MHD could be metabolized by UGTs in the liver, intestine and kidney, and the hepatic glucuronidation was the critical metabolic pathway. UGT2B7 and UGT1A9 were the primary UGT isoforms mediating the formation of MHD-O-glucuronide in the liver.

2.
J Alzheimers Dis ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33814429

RESUMO

BACKGROUND: Cerebral microbleed (CMB) is an increasingly important risk factor for cognitive impairment due to population aging. Controversies, however, remain regarding the exact association between CMB and cognitive dysfunction. OBJECTIVE: We aimed to determine the relationship between CMB burden and cognitive impairment, and also explore the characteristics of cognitive decline in CMB patients for middle-aged and elderly people. METHODS: The present cross-sectional study included 174 participants (87 CMB patients and 87 controls) who underwent brain magnetic resonance imaging and a battery of neuropsychological test. Global cognitive function was measured using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Compound z-scores were calculated for three cognitive subdomains: memory, executive function and processing speed. RESULTS: CMB patients had lower scores of MMSE (p <  0.001) and MoCA (p <  0.001). Patients at each category of CMB count had worse performance in global cognitive function and all three cognitive subdomains (p <  0.001). In multiple linear regression models, CMB patients had significantly greater declines in executive function (p <  0.001), processing speed (p <  0.001), and MoCA (p = 0.003) with increasing number of CMB. We found no relationship between CMB location and cognition (p <  0.05). CONCLUSION: CMB is associated with impairment in global cognition as well as for all tested subdomains. Strongest effect sizes were seen for tests which rely on executive functioning, where performance deficits increased in proportion to degree of CMB burden. Prospective studies are needed to evaluate whether the association between CMB and executive dysfunction is causal.

3.
Hum Mol Genet ; 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33835157

RESUMO

To identify novel risk genes and better understand the molecular pathway underlying Alzheimer's disease (ad), whole-exome sequencing (WES) was performed in 215 early-onset ad (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOad. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation, and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of ad patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.

4.
Nat Cell Biol ; 23(4): 341-354, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33795875

RESUMO

Dysregulated translation is a common feature of cancer. Uncovering its governing factors and underlying mechanism are important for cancer therapy. Here, we report that enhancer of zeste homologue 2 (EZH2), previously known as a transcription repressor and lysine methyltransferase, can directly interact with fibrillarin (FBL) to exert its role in translational regulation. We demonstrate that EZH2 enhances rRNA 2'-O methylation via its direct interaction with FBL. Mechanistically, EZH2 strengthens the FBL-NOP56 interaction and facilitates the assembly of box C/D small nucleolar ribonucleoprotein. Strikingly, EZH2 deficiency impairs the translation process globally and reduces internal ribosome entry site (IRES)-dependent translation initiation in cancer cells. Our findings reveal a previously unrecognized role of EZH2 in cancer-related translational regulation.

5.
Clin Exp Med ; 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33837881

RESUMO

Mesangial IgM deposition is found in patients with immunoglobulin A nephropathy (IgAN). This study aims to investigate the relationships between mesangial IgM deposition and disease progression in IgAN patients. A total of 1239 patients with biopsy-proven primary IgAN were enrolled in this multicenter, observational study between January 2013 and August 2017. According to the degree of IgM deposition, 1239 patients were divided into three groups: Grade 0 (no or trace; n = 713, 57.55%), Grade 1 (mild; n = 414, 33.41%), Grades 2 + 3 (moderate and marked; n = 112, 9.04%). Using a 1:1 propensity score matching (PSM) method identifying age, gender and treatment modality to minimize confounding factors, 1042 matched patients (out of 1239) with different degrees of IgM deposition were enrolled to evaluate the severity of baseline clinicopathological features and renal outcome: Grade 0 (n = 521, 50.00%), Grade 1 (n = 409, 39.25%), Grades 2 + 3 (n = 112, 10.75%). Kaplan-Meier and Cox proportional hazards analyses were performed to determine whether different degrees of mesangial IgM deposition are associated with varying renal outcomes in IgAN. During a mean follow-up of 48.90 ± 23.86 and 49.01 ± 23.73 months, before and after adjusting for propensity scores, respectively, the rate of complete remission (CR) was progressively lower with increased IgM deposition in both unmatched (63.39%, 46.14%, 45.54%) and matched cohort (61.80%, 46.45%, 45.54%), whereas the proportion of patients progressing to end-stage renal disease (ESRD) showed reverse correlation (P < 0.001). Kaplan-Meier analysis indicated negative correlation between the intensity of mesangial IgM deposits and cumulative renal survival (all P < 0.05). Moreover, Cox regression analysis revealed that the degree of mesangial IgM deposition predicted renal outcome independent of MESTC score and clinical variables in the unmatched (Grade 1, HR, 1.59; 95% CI, 1.11-2.29; P = 0.01; Grades 2 + 3, HR, 1.69; 95% CI, 1.02-2.08; P = 0.04) and matched cohort (Grade 1, HR, 1.84; 95% CI, 1.19-2.85; P = 0.01; Grades 2 + 3, HR, 1.91; 95% CI, 1.01-3.24; P = 0.04). Mesangial IgM deposition is associated with histological activity, clinical severity and renal outcome and is an independent risk factor for poor renal prognosis in IgAN. TRIAL REGISTRATION: TCTR, TCTR20140515001. Registered May 15, 2014, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=1074 .

7.
Int J Biol Macromol ; 180: 252-261, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33741369

RESUMO

Strong inhibition of the human UDP-glucuronosyltransferase enzymes (UGTs) may lead to undesirable effects, including hyperbilirubinaemia and drug/herb-drug interactions. Currently, there is no good way to examine the inhibitory effects and specificities of compounds toward all the important human UGTs, side-by-side and under identical conditions. Herein, we report a new, broad-spectrum substrate for human UGTs and its uses in screening and characterizing of UGT inhibitors. Following screening a variety of phenolic compound(s), we have found that methylophiopogonanone A (MOA) can be readily O-glucuronidated by all tested human UGTs, including the typical N-glucuronidating enzymes UGT1A4 and UGT2B10. MOA-O-glucuronidation yielded a single mono-O-glucuronide that was biosynthesized and purified for structural characterization and for constructing an LC-UV based MOA-O-glucuronidation activity assay, which was then used for investigating MOA-O-glucuronidation kinetics in recombinant human UGTs. The derived Km values were crucial for selecting the most suitable assay conditions for assessing inhibitory potentials and specificity of test compound(s). Furthermore, the inhibitory effects and specificities of four known UGT inhibitors were reinvestigated by using MOA as the substrate for all tested UGTs. Collectively, MOA is a broad-spectrum substrate for the human UGTs, which offers a new and practical tool for assessing inhibitory effects and specificities of UGT inhibitors.

8.
Sci Rep ; 11(1): 5467, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750830

RESUMO

It was reported that histopathologic lesions are risk factors for the progression of IgA Nephropathy (IgAN). The aim of this study was to investigate the relationships between mesangial deposition of C1q and renal outcomes in IgAN. 1071 patients with primary IgAN diagnosed by renal biopsy were enrolled in multiple study centers form January 2013 to January 2017. Patients were divided into two groups: C1q-positive and C1q-negative. Using a 1: 4 propensity score matching (PSM) method identifying age, gender, and treatment modality to minimize confounding factors, 580 matched (out of 926) C1q-negative patients were compared with 145 C1q-positive patients to evaluate severity of baseline clinicopathological features and renal outcome. Kaplan-Meier and Cox proportional hazards analyses were performed to determine whether mesangial C1q deposition is associated with renal outcomes in IgAN. During the follow-up period (41.89 ± 22.85 months), 54 (9.31%) patients in the C1q negative group and 23 (15.86%) patients in C1q positive group reached the endpoint (50% decline of eGFR and/or ESRD or death) respectively (p = 0.01) in the matched cohort. Significantly more patients in C1q negative group achieved complete or partial remission during the follow up period (P = 0.003) both before and after PSM. Three, 5 and 7-year renal survival rates in C1q-positive patients were significantly lower than C1q-negative patients in either unmatched cohort or matched cohort (all p < 0.05). Furthermore, multivariate Cox regression analysis showed that independent risk factors influencing renal survival included Scr, urinary protein, T1-T2 lesion and C1q deposition. Mesangial C1q deposition is a predictor of poor renal survival in IgA nephropathy.Trial registration TCTR, TCTR20140515001. Registered May 15, 2014, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=1074 .

9.
J Immunol Res ; 2021: 6694392, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33728352

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is known for its high resistance and low response to treatment. Tumor immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Karyopherin alpha 2 (KPNA2), a member of the nuclear transporter family, is elevated in multiple human cancers and accelerates carcinogenesis. However, the specific role of KPNA2 in PDAC remains unclear. In this study, we found that expression of KPNA2 was significantly upregulated in PDAC compared to adjacent nontumor tissue and its high expression was correlated with poor survival outcome by analyzing the GEO datasets. Similar KPNA2 expression pattern was also found in both human patient samples and KPC mouse models through IHC staining. Although KPNA2 knockdown failed to impair the vitality and migration ability of PDAC cells in vitro, the in vivo tumor growth was significantly impeded and the expression of immune checkpoint ligand PD-L1 was reduced by silencing KPNA2. Furthermore, we uncovered that KPNA2 modulated the expression of PD-L1 by mediating nuclear translocation of STAT3. Collectively, our data suggested that KPNA2 has the potential to serve as a promising biomarker for diagnosis in PDAC.

10.
Zhongguo Zhong Yao Za Zhi ; 46(1): 139-145, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33645063

RESUMO

Polygonum multiflorum is a traditional Chinese herbal medicine and has many biological activities such as hair-blacking, anti-atherosclerosis, anti-inflammatory and anti-aging. However, the liver injury induced by P. multiflorum has aroused wide attention in recent years. 2,3,5,4'-tetrahydroxystibane-2-O-ß-D-glucoside(TSG) is a main component of P. multiflorum, but the role of TSG in inducing liver injury is unclear. The aim of present study was to evaluate TSG's potential liver injury and effects on bile acid homeostasis and phospholipids efflux. C57 BL/6 J mice received intraperitoneal administration of 400 mg·kg~(-1) of TSG daily for 15 days, and then biochemical indexes of liver injury and changes of phospholipid content were detected. The changes of bile acid compositions were detected by LC-MS/MS. The results showed TSG 400 mg·kg~(-1) significantly increased the content of serum total bile acid(TBA) and alkaline phosphatase(ALP). Elevated free bile acid levels were observed in TSG-treated groups, including ß-muricholic acid(ß-MCA), ursodeoxycholic acid(UDCA), hyodeoxycholic acid(HDCA), chenodeoxycholic acid(CDCA), deoxcholic acid(DCA) in serum and ß-MCA, CDCA in liver. TSG inhibited the protein expression of farnesoid X receptor(FXR) and down stream bile salt export pump(BSEP), which may result in the accumulation of bile acid. TSG also inhibited the expression of 25-hydroxycholesterol-7 alpha-hydroxylase(CYP7 B1), which may disturb the alternative pathway for bile acid synthesis. In addition, intraperitoneal injection of TSG 400 mg·kg~(-1) significantly decreased the content of phospholipids in bile. The research showed that TSG significantly inhibited the expression of multidrug resistance protein 2(MDR2) and destroyed the regular distribution of MDR2 on the bile duct membrane of liver. In vitro results showed that the IC_(50) of TSG on HepG2 cells was about 1 500 µmol·L~(-1) and TSG at 500 µmol·L~(-1)(for 24 h) could destroy the distribution of MDR2 on the bile duct membrane of liver. In conclusion, TSG induced liver injury by disrupting bile acid homeostasis and phospholipids efflux.


Assuntos
Ácidos e Sais Biliares , Glucosídeos , Animais , Cromatografia Líquida , Homeostase , Fígado , Camundongos , Fosfolipídeos , Espectrometria de Massas em Tandem
13.
Eur Respir J ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574077

RESUMO

OBJECTIVE: To evaluate pulmonary function and clinical symptoms in coronavirus disease 2019 (COVID-19) survivors within 3 months after hospital discharge, and to identify risk factors associated with impaired lung function. METHODS AND MATERIAL: COVID-19 patients were prospectively followed up with pulmonary function tests and clinical characteristics for 3 months following discharge from a hospital in Wuhan, China between January and February 2020. RESULTS: 647 patients were included. 87 (13%) patients presented with weakness, 63 (10%) with palpitation and 56 (9%) with dyspnea. Prevalences of the three symptoms were markedly higher in severe patients than non-severe patients (19% versus 10% for weakness, p=0.003; 14% versus 7% for palpitation, p=0.007; 12% versus 7% for dyspnea, p=0.014). Results of multivariable regression showed an increased odd in the ongoing symptoms among severe patients (OR: 1.7, 95%CI: 1.1-2.6, p=0.026) or patients with longer hospital stay (OR: 1.03, 95%CI: 1.00-1.05, p=0.041). Pulmonary function test results were available for 81 patients, including 41 non-severe and 40 severe patients. In this subgroup, 44 (54%) patients manifested abnormal diffusion capacity for carbon monoxide (DLCO) (68% severe versus 42% non-severe patients, p=0.019). Chest CT total severity score (TSS)>10.5 (OR: 10.4; 95%CI: 2.5-44.1; p=0.001) on admission and ARDS (OR: 4.6; 95%CI: 1.4-15.5; p=0.014) were significantly associated with impaired DLCO. Pulmonary interstitial damage may be associated with abnormal DLCO. CONCLUSION: Pulmonary function, particularly DLCO, declined in COVID-19 survivors. This decrease was associated with TSS of chest CT >10.5 and ARDS occurrence. Pulmonary interstitial damage might contribute to the imparied DLCO.

14.
Hum Vaccin Immunother ; : 1-6, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33545016

RESUMO

Background: Currently, children aged 6-9 years have the highest incidence rate of mumps in China. Although China has introduced a two-dose schedule of measles-mumps-rubella vaccine into routine immunization (at 8 months and 18 months), the incidence rate of mumps in high-risk populations might not decrease due to waning immunity. Here we report a mumps outbreak supporting this hypothesis. Methods: The descriptive epidemiological method was used to summarize the overall characteristics of the course of the outbreak. We conducted a retrospective cohort study to evaluate the vaccine effectiveness (VE) of mumps-containing vaccine (MuCV). Results: A total of 78 cases were identified during the outbreak and the estimated vaccination coverage was 84.7%. Of 454 vaccinated students, 335 (73.8%) had received one-dose MuCV, 93 (20.5%) two-dose, and 26 (5.7%) three-dose. The VEs for both the one-dose (-17.0%, 95%CI: -120.3-38.2%) and two-dose groups (-10.0%, 95%CI: -138.0-48.8%) were not performed well, whereas the VE for the three-dose group was 100%. However, we found that the overall VE was 74.2% (95% CI: 9.7-92.6%) for students vaccinated within 5 years. We also observed that there was a broadly linear increase in mumps infection risk in both one-dose and two-dose group when the time since last dose vaccination was more than 5 years. Conclusions: The overall VE for both one-dose and two-dose MuCV was discouraging, but it appeared to be moderately effective within 5 years after vaccination. Further surveillance and seroepidemiological data are needed to understand the impact of the new vaccination strategy on mumps in China.

15.
Environ Sci Technol ; 55(4): 2662-2673, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33539079

RESUMO

Although several molecular-based studies have demonstrated the involvement of ammonia-oxidizing archaea (AOA) in ammonia oxidation in wastewater treatment plants (WWTPs), factors affecting the persistence and growth of AOA in these engineered systems have not been resolved. Here, we show a seasonal prevalence of AOA in a full-scale WWTP (Shatin, Hong Kong SAR) over a 6-year period of observation, even outnumbering ammonia-oxidizing bacteria in the seasonal peaks in 3 years, which may be due to the high bioavailable copper concentrations. Comparative analysis of three metagenome-assembled genomes of group I.1a AOA obtained from the activated sludge and 16S rRNA gene sequences recovered from marine sediments suggested that the seawater used for toilet flushing was the primary source of the WWTP AOA. A rare AOA population in the estuarine source water became transiently abundant in the WWTP with a metagenome-based relative abundance of up to 1.3% over three seasons of observation. Correlation-based network analysis revealed a robust co-occurrence relationship between these AOA and organisms potentially active in nitrite oxidation. Moreover, a strong correlation between the dominant AOA and an abundant proteobacterial organism suggested that capacity for extracellular polymeric substance production by the proteobacterium could provide a niche for AOA within bioaggregates. Together, the study highlights the importance of long-term observation in identifying biotic and abiotic factors governing population dynamics in open systems such as full-scale WWTPs.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33611582

RESUMO

OBJECTIVES: Left ventricular systolic dysfunction (LVSD) is common and associated with adverse events in patients receiving coronary artery bypass grafting (CABG). However, the prognosis of mild LVSD has not been clearly described. We aimed to evaluate the mid-term outcomes of patients with mild LVSD following CABG. METHODS: This multicentre cohort study using propensity score matching took place from December 2012 to October 2019 in Jiangsu Province, China, with a mean and maximum follow-up of 3.2 and 7.2 years, respectively. Patients were classified to normal left ventricular systolic function (left ventricular ejection fraction ≥53%) and mild LVSD (left ventricular ejection fraction >40%/<53%). The primary outcomes were death from all causes and death from cardiovascular causes. The secondary outcomes were heart failure, myocardial infarction, repeat revascularization and a composite of all mentioned outcomes, including death from all causes (major adverse events). RESULTS: A total of 581 pairs were formed after matching. In-hospital death (1.5% vs 2.1%, P = 0.51) did not differ between 2 cohorts. Throughout 7 years, mild LVSD was associated with higher rates of death from all causes [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.39-0.89; P = 0.012], death from cardiovascular causes (HR 0.55, 95% CI 0.36-0.90; P = 0.017), heart failure (HR 0.60, 95% CI 0.37-0.93; P = 0.023) and major adverse events (HR 0.66, 95% CI 0.49-0.91; P = 0.009). There was no difference in the rates of myocardial infarction and repeat revascularization. CONCLUSIONS: Mild LVSD was associated with a worse mid-term prognosis in patients following CABG.

17.
BMC Med Imaging ; 21(1): 32, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607959

RESUMO

BACKGROUND: The background parenchymal enhancement at breast magnetic resonance imaging use to predict breast cancer attracts many searchers to draw a possible relationship. However, the results of their relationships were conflicting. This meta-analysis was performed to assess breast cancer frequency associations with background parenchymal enhancement. METHODS: A systematic literature search up to January 2020 was performed to detect studies recording associations between breast cancer frequency and background parenchymal enhancement. We found thirteen studies including 13,788 women at the start with 4046 breast cancer. We calculated the odds ratio (OR) and the 95% confidence intervals (CIs) between breast cancer frequency and background parenchymal enhancement by the dichotomous technique with a random or fixed-effect model. RESULTS: Women with minimal or mild background parenchymal enhancement at breast magnetic resonance imaging did not have any risk of breast cancer compared to control women (OR, 1.20; 95% CI 0.54-2.67). However, high background parenchymal enhancement at breast magnetic resonance imaging (OR, 2.66; 95% CI 1.36-5.19) and moderate (OR, 2.51; 95% CI 1.49-4.21) was associated with a significantly higher rate of breast cancer frequency compared to control women. CONCLUSIONS: Our meta-analysis showed that the women with high and moderate background parenchymal enhancement at breast magnetic resonance imaging have higher risks, up to 2.66 fold, of breast cancer. We suggest that women with high or moderate background parenchymal enhancement at breast magnetic resonance imaging to be scheduled for more frequent follow-up and screening for breast cancer to avoid any complications.

18.
Cell Chem Biol ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33626323

RESUMO

Emerging evidence indicates the involvement of O-GlcNAc modification in placental development and pregnant health through mechanisms that are not well understood. Herein, by applying the quantitative O-GlcNAc proteomics, we established a database of O-GlcNAcylated proteins in human placental trophoblasts. Hundreds of proteins that were dynamically O-GlcNAcylated during trophoblast differentiation were identified, among which cystathionine γ-lyase (CSE) exhibited the most significant change. Site-specific analysis by mass spectrometry revealed Ser138 as the core O-GlcNAc site in CSE, and its O-GlcNAcylation promoted the enzymatic activity to produce H2S, which in turn repressed trophoblast differentiation via inhibiting androgen receptor dimerization. Consistently, in preeclamptic placentas, remarkably enhanced CSE O-GlcNAcylation and H2S production were associated with restricted trophoblast differentiation. The findings establish a resource of O-GlcNAc dynamics in human placenta, and provide a deeper insight into the biological significance of O-GlcNAcylation in placental development as well as potential therapeutic targets for the relevant pregnant complications.

19.
J Struct Biol ; 213(2): 107710, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33610655

RESUMO

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90 N (Hsp90N). Absence of complex crystal structure of Hsp90N-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90N-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 Å; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, Kd, 7.30 ± 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90N. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC50, 8.16 µM for A549; 14.29 µM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90N-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90N evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.

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