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1.
J Anat ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32162697

RESUMO

Receptor-interacting protein 3 (RIP3) plays an important role in the necroptosis signaling pathway. Our previous studies have shown that the RIP3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis occurs in retinal ganglion cell line 5 (RGC-5) following oxygen-glucose deprivation (OGD). However, upstream regulatory pathways of RIP3 are yet to be uncovered. The purpose of the present study was to investigate the role of p90 ribosomal protein S6 kinase 3 (RSK3) in the phosphorylation of RIP3 in RGC-5 cell necroptosis following OGD. Our results showed that expression of RSK3, RIP3, and MLKL was upregulated in necroptosis of RGC-5 after OGD. A computer simulation based on our preliminary results indicated that RSK3 might interact with RIP3, which was subsequently confirmed by co-immunoprecipitation. Further, we found that the application of a specific RSK inhibitor, LJH685, or rsk3 small interfering RNA (siRNA), downregulated the phosphorylation of RIP3. However, the overexpression of rip3 did not affect the expression of RSK3, thereby indicating that RSK3 could be a possible upstream regulator of RIP3 phosphorylation in OGD-induced necroptosis of RGC-5 cells. Moreover, our in vivo results showed that pretreatment with LJH685 before acute high intraocular pressure episodes could reduce the necroptosis of retinal neurons and improve recovery of impaired visual function. Taken together, our findings suggested that RSK3 might work as an upstream regulator of RIP3 phosphorylation during RGC-5 necroptosis.

2.
J ECT ; 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32118689

RESUMO

OBJECTIVE: The aim of the study was to explore the tendency of modified electroconvulsive therapy (MECT)-related working memory and subjective memory deficits in depressed patients. METHODS: Sixty patients with unipolar/bipolar depression were prepared and enrolled for MECT and 56 subjects were enrolled as healthy controls (HCs). Their demographics (sex, age, body mass index, years of schooling, etc) and clinical characteristics (dosage and number of MECT, etc) were compared. Depression severity, working memory, and subjective memory were measured using the Hamilton Depression Rating Scale 17 (HAMD17), a Digit Span Backwards (DSB), and self-reported assessments, respectively. Measurements were taken at baseline, within 24 hours after each MECT session, and in every month for a 6-month follow-up period. RESULTS: (a) The patients had poorer performance than the HCs on DSB and HAMD17 at baseline, and the DSB score and HAMD17 total scores were negatively correlated. However, after the second MECT session, the patients' HAMD17 score was significantly improved compared with that at the baseline (P < 0.05), whereas the DSB score showed no significant difference compared with the HCs (P > 0.05). (b) After the first MECT session, 62% of the patients reported subjective memory deficits, which were exacerbated over the subsequent sessions and relieved with antidepressant treatment during the follow-up period. (c) The risk factors for prolonged subjective memory deficits were overweight and the maximum MECT dosage/age (dosage/age = the percentage of output part of total dosage × 100/age, unit: 1/year) ≥ 1.5/year (odds ratio [OR] = 15.36 and 7.98). CONCLUSIONS: Depressed patients showed poorer working memory than the HCs. Such memory deficit may be aggravated by MECT, although it may improve with the relief of depression. Although subjective memory deficits can occur after the first MECT session and gradually recover after the treatment, they may last for 6 months or longer. Persistent deficits may be related to being overweight and having a high MECT dosage.

3.
IEEE Trans Cybern ; 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32142465

RESUMO

This article investigates a spatial-L∞-norm-based reliable bounded control problem for a class of nonlinear partial differential equation systems in a finite-time interval. The main novelties are reflected in the following aspects: 1) inspired by the sector-nonlinearity approach, the considered nonlinear system is reconstructed by a Takagi-Sugeno fuzzy model, which provides an effective method for control design. Besides, several actuator failures, such as stuck faulty, outage faulty, and bias faulty, are taken into account and modeled by a novel Markov process; 2) partial areas' states are sampled and transmitted based on a new distributed event-triggered communication strategy, which reduces the cost of the system design and saves the limited network resources to some extent; and 3) on the basis of the first two works, a new piecewise fuzzy controller, which requires fewer actuators compared with the distributed control method, is constructed. Then, some sufficient conditions to guarantee the finite-time boundedness (in the sense of spatial L∞ norm) and mixed L2-L∞/H∞ disturbance attenuation performance are established, and a new linear matrix inequality relax technique is introduced to deal with the strict constraint that is caused by the asynchronous phenomenon between plant and controller. Finally, two simulation studies are given to illustrate the effectiveness and advantages of the developed controller.

4.
Anesth Analg ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32175948

RESUMO

BACKGROUND: Two-thirds of the US population is considered obese and about 8% morbidly obese. Obese patients may present a unique challenge to anesthesia clinicians in airway management. Videolaryngoscopes may provide better airway visualization, which theoretically improves intubation success. However, previous work in morbidly obese patients was limited. We therefore tested the primary hypothesis that the use of McGrath video laryngoscope improves visualization of the vocal cords versus Macintosh direct laryngoscopy (Teleflex, Morrisville, NC) in morbidly obese patients. METHODS: We enrolled 130 surgical patients, aged 18-99 years, with a body mass index ≥40 kg/m and American Society of Anaesthesiologists (ASA) physical status I-III. Patients were randomly allocated 1:1-stratified for patient's body mass index ≥50 kg/m-to McGrath video laryngoscope versus direct laryngoscopy with a Macintosh blade. The study groups were compared on glottis visualization, defined as improved Cormack and Lehane classification, with proportional odds logistic regression model. RESULTS: McGrath video laryngoscope provided significantly better glottis visualization than Macintosh direct laryngoscopy with an estimated odds ratio of 4.6 (95% confidence interval [CI], 2.2-9.8; P < .01). We did not observe any evidence that number of intubation attempts and failed intubations increased or decreased. CONCLUSIONS: McGrath video laryngoscope improves glottis visualization versus Macintosh direct laryngoscopy in morbidly obese patients. Large clinical trials are needed to determine whether improved airway visualization with videolaryngoscopy reduces intubation attempts and failures.

5.
Nephrology (Carlton) ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32180286

RESUMO

AIM: To assess the aetiological factors of chronic kidney disease (CKD) and factors associated with disease progression. METHODS: Single-centre retrospective study evaluating thorough electronic medical records of patients diagnosed with CKD at Peking University People's Hospital (April 2010-April 2015). The objectives were to identify the aetiological factors of CKD in Chinese patients and risk factors associated with CKD progression. RESULTS: Of 15 425 CKD patients, 12 380 had aetiology recorded. The leading aetiologies associated with CKD were chronic glomerulonephritis (CGN; 36.8%), hypertensive nephropathy (HTN; 28.5%) and diabetic nephropathy (DN; 27.1%). CGN was most common in patients with early-stage disease (stages 1-2); DN and HTN were common in advanced stages (stages 3-4). In a longitudinal subcohort of 2923 patients with ≥6-month follow-up, 19.6% experienced CKD progression. Patients with CKD progression were significantly older in age and had a greater number of comorbidities and laboratory anomalies, and were more likely to have DN (40.5%) and CGN (40.5%) than HTN (5.5%) at baseline than patients without progression. In a multivariate analysis, factors associated with disease progression included macro- and microalbuminuria, anaemia, hyperkalaemia, hyperphosphataemia, metabolic acidosis, CKD stage 4, and type 2 diabetes mellitus (T2DM). CONCLUSION: This study identified CGN, DN and HTN as the leading aetiological factors for CKD in Chinese patients. DN was a strong predictor of faster disease progression, with albuminuria (a complication of T2DM) associated with highest risk for disease progression.

6.
Parasitol Res ; 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32219548

RESUMO

Ethanamizuril (EZL) is a novel triazine compound with excellent anticoccidial activity. We carried out a preliminary investigation of the effects of EZL on the different life cycle stages of Eimeria tenella. EZL mainly acted on the schizogony stage, with peak activity during the second-generation merozoite stage. We also studied the possible target of EZL by identifying the majorly differentially expressed gene affected by EZL in second-generation merozoites using real-time polymerase chain reaction, and screening for surface antigen proteins (SAGs). The relative expression levels of SAGs were compared by Western blot analysis showing that expression levels of surface antigen family member (SAGfm) and SAG19 were significantly downregulated by EZL. Immunofluorescence analysis indicated that SAGfm and SAG19 were localized on the surface of second-generation merozoites. In addition, fluorescence signals were significantly stronger in second-generation merozoites of infected non-medicated control (INC) group compared with that of the EZL group. Therefore, it was speculated that SAGs might be a potential target of EZL action. The inhibitory effects of anticoccidial drugs on SAG levels in coccidia thus warrant further research.

7.
J Gene Med ; : e3190, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32222109

RESUMO

BACKGROUND: Neuroblastoma is one of the most common malignant tumors in childhood. Polymorphisms in proto-oncogene MYC are implicated in many cancers, but their role in neuroblastoma remains unclear. Here we tried to explore the association between MYC gene polymorphisms and neuroblastoma susceptibility in Chinese children. METHODS: We included two MYC polymorphisms (rs4645943 and rs2070583) and assessed their effects on neuroblastoma risk in 505 cases and 1070 controls by Taqman method. RESULTS: In single and combined locus analysis, no significant association was found between the two selected polymorphisms and neuroblastoma susceptibility. In stratification analysis, the rs4645943 CT/TT genotypes were significantly associated with a decreased neuroblastoma risk in subjects with tumors originating from other sites [adjusted odds ratio (OR)=0.42, 95% confidence interval (CI)=0.21-0.84, P=0.013]. Meanwhile, the presence of 1-2 protective genotypes was significantly associated with decreased neuroblastoma risk in subjects with tumors arising from other sites (adjusted OR=0.50, 95% CI=0.26-0.96, P=0.036). CONCLUSIONS: This study indicates that MYC gene polymorphisms may have a weak effect on the neuroblastoma risk, which should be further verified.

8.
Arch Pharm Res ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32095942

RESUMO

Unfortunately in the original publication of the article, the Fig. 2 was missed in the PDF version of the article which is given in this correction. The original article has been corrected.

9.
Oxid Med Cell Longev ; 2020: 9585047, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104545

RESUMO

Quercetin, a flavonoid found in fruits and vegetables, is widely distributed as a secondary metabolite in the plant kingdom. Oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). The present study investigated the effects of quercetin dietary supplementation on streptozotocin- (STZ-) induced hyperglycemic Arbor Acre (AA) broilers by determining the levels of fasting blood glucose (FBG), fasting insulin (FINS), biochemical indicators, oxidative stress markers, inflammatory cytokines content, antioxidant enzymes activities in tissues, and mRNA expression of genes relating to the insulin signaling pathway. Three hundred one-day-old healthy AA broilers were randomly assigned into 5 treatments; A, control healthy broilers; B, STZ-induced broilers; C, STZ-induced broiler dietary supplemented with 0.02% quercetin; D, STZ-induced broiler dietary supplemented with 0.04% quercetin; and E, STZ-induced broiler dietary supplemented with 0.06% quercetin. The results showed that quercetin supplementation relieved the side effects of STZ-induced oxidative stress by changing activities of antioxidant enzymes, decreasing malondialdehyde (MDA) and nitric oxide (NO) levels, activating expression of genes relating to PI3K/PKB signaling pathway that modulate glucose metabolism and reduce oxidative damage, thereby decreasing FBG and increasing FINS levels. These findings suggest that quercetin exhibits a protective effect in STZ-induced hyperglycemic AA broilers via decreasing oxidative stress.

10.
Regul Toxicol Pharmacol ; 113: 104623, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32088183

RESUMO

In the current study, to support the safety assessment of ethanamizuril as a new potent anticoccidial agent of triazine compounds, a reproductive toxicity and teratogenic potential assay of ethanamizuril was investigated. Groups of 30 males and 30 females were administered 0, 0.02, 0.1 or 0.2 mg/ml ethanamizuril by gastric incubation through a 10-week prebreed period as well as during mating, gestation, parturition and lactation in any generation. Compared to the control group, no test compound-related changes in copulation index, fertility index, gestation length, litter size, pup weight, pup sex ratio, pup viability, epididymal sperm counts or motility or other functional reproductive measures were noted in any generation, except few significant changes in high dose group in the number of sperm motility at III level in F0 males and the body weights of GD14 and GD21 in F1 rats. There were no compound-related necropsy findings or effects on organ weight. Histopathologic examinations revealed no evidence of compound-related changes in any organs including the reproductive organs of both sexes. In conclusion, long-term administrated 0.2, 1.0 and 2.0 mg/kg of ethanamizuril by means of oral gavage did not affect the reproduction of Sprague-Dawley rats and the development ability of their offspring under the experimental conditions.

11.
J Affect Disord ; 266: 655-670, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056942

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) is a debilitating mental illness that is thought to be associated with brain white matter (WM) alterations. Individual diffusion tensor imaging (DTI) studies to date have reported inconsistent alterations in FA across different brain regions in patients with PTSD. Here, we aimed to investigate FA in PTSD using both region-of-interest (ROI)-based and whole-brain-based meta-analytic approaches. OBJECTIVES: Individual ROI-based meta-analysis was carried out in each eligible white matter tract and seed-based D mapping (SDM) meta-analysis was conducted in the whole brain to identify the convergence of FA alterations in PTSD relative to controls. RESULTS: Seventeen studies were included in ROI-based meta-analysis (≥ 3 studies were included for each ROI, NPTSD ≥ 80 and Ncontrol ≥ 103 per ROI). Fourteen studies with a total of 322 PTSD and 335 controls were included in whole-brain based meta-analysis. Both ROI and whole-brain meta-analyses showed that patients with PTSD have significantly higher FA in the inferior fronto-occipital fasciculus and lower FA in the genu of corpus callosum. Whole-brain meta-analyses also identified higher FA in the left inferior temporal gyrus and lower FA in the anterior cingulum and left corticospinal tract. LIMITATIONS: A small number of studies were included in some ROI tracts. Thus the results should be interpreted with caution. CONCLUSIONS: Our results suggest that PTSD patients have increased FA in areas related to visual processing, but decreased FA in anterior brain regions critical to cognition association and fear regulation.

13.
Arch Pharm Res ; 43(2): 257-270, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894502

RESUMO

As the main metabolite of nitazoxanide, tizoxanide (TIZ) has a broad-spectrum anti-infective effect against parasites, bacteria, and virus. In this study, we investigated the effects of TIZ on autophagy by regulating the PI3K/Akt/mTOR signaling pathway. RAW264.7 macrophage cells were treated with various TIZ concentrations. Cell viability assay, transmission electron microscope, and immunofluorescence staining were used to detect the biological function of the macrophage cells, and the expression levels of the autophagy pathway-related proteins were measured by Western blot. Results revealed that TIZ promoted the conversion of LC3-I to LC3-II, the formation of autophagy vacuoles, and the degradation of SQSTM1/p62 in a concentration- and time-dependent manner in RAW264.7 cells. Treatment with TIZ increased the Beclin-1 expression level and inhibited PI3K, Akt, mTOR, and ULK1 activation. These effects were enhanced by pretreatment with rapamycin but attenuated by pretreatment with LY294002. In addition, the conversion of LC3-I to LC3-II was observed in Vero, 293T, and HepG2 cells treated with TIZ. These data suggested that TIZ may induce autophagy by inhibiting the Akt/mTOR/ULK1 signaling pathway in macrophages and other cells.

14.
J Agric Food Chem ; 68(6): 1563-1570, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927998

RESUMO

Ethanamizuril(N-{4-[4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenoxy]-phenyl}-acetamide, EZL) is a new anticoccidiosis compound and belongs to the class of triazines. In this study, the metabolism, distribution, and excretion of EZL were evaluated in chickens after administration of EZL at a single dosage. According to the relevant drug biotransformation rules, the exact molecular mass detection, the fragmentation characteristics, and the retention times, a total of five metabolites were identified in vivo in chickens, including two phase I metabolites and three phase II conjugated metabolites. The major metabolic pathways of EZL in chickens were deacetylation, hydroxylation, and glucuronidation. Regarding 14C-tissue residues after administration, kidney was considered to be the target tissue, as 14C-tissue residues could be detected at 240 h postdose. DeacetylEZL (M3) was the main metabolite, accounting for 68.65% and 25.62% of 14C in kidney at 6 and 24 h, respectively. In heart, muscle, skin+fat, and lung tissues, EZL was the main radioactive substance accounting for 94.88%, 97.32%, 96.23%, and 91.3% of 14C, respectively. In the liver, EZL and M3 were 20.76% and 54.65% of 14C, respectively. In chicken tissues the ratio of M5 was too low to be quantitated and it was mainly detected in chicken fecal and bile samples. In chicken excreta, EZL, M3, and glucuronidation of EZL (M5) accounted for 7.02%, 12.33%, and 10.32% of the dose, respectively and were eliminated primarily. This study presents the first detection of EZL metabolites, which is helpful for further understanding of the metabolic mechanism and in vivo intermediate processes of EZL. The results of this study will be good bases for better understanding EZL's anticoccidiosis mechanism and will serve as a helpful reference for assessing the risks to animals and humans.


Assuntos
Coccidiostáticos/farmacocinética , Triazinas/farmacocinética , Animais , Biotransformação , Galinhas , Coccidiostáticos/administração & dosagem , Coccidiostáticos/metabolismo , Hidroxilação , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Pulmão/química , Pulmão/metabolismo , Músculos/química , Músculos/metabolismo , Triazinas/administração & dosagem , Triazinas/metabolismo
15.
Vet Microbiol ; 240: 108511, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31902508

RESUMO

Since late 2010, highly virulent PEDV G2-genotype strains have emerged globally extracting heavy losses on the pork industries of numerous countries. We investigated the characteristics of a field strain of PEDV (PEDV strain SH) isolated from a piglet with severe diarrhea on a farm in Shanghai China. Whole genome sequencing and analysis revealed that the SH strain belonged to subtype G2b and has a unique 12-aa deletion (aa 399-410) including the antigenic epitope NEP-1C9 (aa 398-406) of the N protein. PEDV SH strain is highly pathogenic to challenged newborn piglets, resulting in 100 % morbidity and mortality. Pathological examination revealed significant villus atrophy in the jejuna of infected piglets. Mice inoculated with inactivated PEDV SH produced antibodies against the N protein, but no antibodies against the deletions. These results illustrated that deletion of the NEP-1C9 epitope had no effect on the immunogenicity or pathogenicity of PEDV, providing evidence of the necessity to monitor the genetic diversity of the virus. Our study also contributes to development of candidate for vaccines and diagnostics that could differentiate pigs seropositive due to vaccination by conventional strains from wild virus infection.

16.
Sci Total Environ ; 708: 135039, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31787314

RESUMO

The pyrolysis performance of oil sludge (OS) was studied using a thermal gravimetric analysis apparatus and a tube furnace reactor. The oil recovery rate of OS pyrolysis showed a rapid growth trend at 450 °C. Moreover, the co-pyrolysis experiments of the OS and catalysts, including walnut shells, Fe2O3, K2CO3, polyvinyl chloride (PVC), and OS pyrolysis char with addition ratios of 5, 7, and 9 wt%, respectively, were conducted in a tube furnace reactor at 450 °C. The experiments demonstrated that all catalysts increased the oil recovery rate, but the optimal addition ratios differed. The pyrolysis chars produced above 450 °C had a well-developed pore structure, and the catalytic pyrolysis of OS at 450 °C could increase the yield of pyrolysis oil and reduce the potential ecological risk of heavy metals in the pyrolysis char. Therefore, catalytic pyrolysis is an inexpensive and highly efficient approach for treating solid waste.

17.
J Affect Disord ; 260: 91-96, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493645

RESUMO

BACKGROUND: Major depressive disorder (MDD) patients with comorbid anxiety symptoms showed obvious cognitive deficits. However, it remains unclear whether comorbid anxiety symptoms will make a specific contribution to cognitive deficits in MDD. METHODS: Executive function, processing speed, attention and memory were assessed in 162 MDD patients, and 142 healthy controls (HCs) by a comprehensive neuropsychological battery. 14-item Hamilton Anxiety Rating Scale (HAM-A) was used for anxiety symptoms and MDD patients with HAM-A total score >14 were classified into MDD with comorbid anxiety (MDDA) group. A multivariate analysis of covariance and regression models was conducted to evaluate the effects of anxiety symptoms on cognitive deficits. RESULTS: There were no significantly differences in all 4 cognitive domains between MDD alone and MDDA patients (all p < 0.05). In MDDA subgroup, HAM-A total score contributed to executive function and memory (both p < 0.05), while HAM-A psychic symptoms contributed to all 4 domains (all p < 0.05). Moreover, after controlling for the severity of depression, either anxiety symptoms shown as HAMA total score or psychic anxiety symptoms only contributed significantly to the executive function performance. LIMITATIONS: The cross-sectional design made it hard to acquire a cognitive performance trajectory accompanied by the fluctuations in anxiety symptoms. CONCLUSION: Our findings suggest that there is no significant difference in cognitive performance between MDD alone and MDDA patients. However, comorbid anxiety, especially psychic anxiety may contribute to extensive cognitive deficits in MDDA patients. Notably, anxiety symptoms only independently triggered executive dysfunction when eliminating effect of the severity of depression.

18.
Regul Toxicol Pharmacol ; 111: 104550, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31843591

RESUMO

In the current study, to support the safety assessment of ethanamizuril as a new potent anticoccidial agent of triazine compounds, a 90-day repeated-dose oral toxicity assay of ethanamizuril was investigated. Treatment related clinical signs of alopecia on back and neck have been observed in some male and female at the 65 and 130 mg/kg dose groups. The body weight and feed conversion efficacy of 65 and 130 mg/kg females and 65 mg/kg males were significantly increase than those of the control in treatment time, but noted decreased in the 130 mg/kg males. Dose related changes of hematologic and biochemical parameters such as MCV, MCH, TG, and the significant increased in the organ weight and the relative organ weight of the liver, kidney, heart, lung and spleen in both genders in the 65 and 130 mg/kg treated groups were observed. Furthermore, histopathological observations revealed that 65 and 130 mg/kg ethanamizuril induced pathological damage such as hepatocyte steatosis and focal necrosis, renal tubular atrophy, tubule protein casts. Fortunately, the observed toxicities were recoverable in convalescence. The results indicated that liver, kidneys and lung were the main target organs. The NOAEL of ethanamizuril for rats was estimated to be 20 mg/kg dietary dose level.

19.
Front Psychiatry ; 10: 836, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798480

RESUMO

Background: Major depressive disorder (MDD) is associated with a wide range of cognitive deficits. However, it remains unclear whether there will be a major cognitive deficit independently caused by depression at acute episodes of MDD. Method: A comprehensive neurocognitive test battery was used to assess the executive function, processing speed, attention, and memory in 162 MDD patients and 142 healthy controls (HCs). A multivariate analysis of variance, hierarchical regression analyses and general linear regression analyses were used to explore the possible major cognitive deficits and their predictor variables. Results: MDD patients showed extensive impairment in all four cognitive domains. Impairment of executive function and processing speed were found to persist even with other cognitive domains and clinical variables being accounted for. Executive function and processing speed were further predicted by total disease duration and depression severity, respectively. Conclusions: Executive function and processing speed may be two distinct major deficits at acute episodes of MDD. Furthermore, the executive function is likely originated from the cumulative effect of disease duration and processing speed is possibly derived from the temporary effect of current depressive episode.

20.
J Med Chem ; 62(24): 11218-11231, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31804827

RESUMO

Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of 11 (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50 values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.

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