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1.
Perit Dial Int ; : 896860820915022, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32223521

RESUMO

A simple, noninvasive method for removing peritoneal dialysis (PD) catheters, called the "pull technique," has become popular in recent years. Physicians still worry, however, about the range of its application and possible complications such as infection of the retained cuff and breakage. We, therefore, applied this technique in patients and enriched its administration for removing PD catheters. Altogether, 24 PD catheter removals in 24 patients were reviewed during the period from July 2018 to October 2019 in our hospital. Using the pull technique, the PD catheter's superficial cuff was dissected using an electronic knife, and the deep cuff was retained. All patients' catheters were successfully removed with no breakage. No incision or retained cuff was infected during the follow-up period (1.1-15.6 months). The appropriate peak force of pull traction was approximately 12-13 pounds, not very different from the mean maximum tensile force of 21.48 pounds for silicone tube breakage. The use of intermittent (rather than sustained) traction may reduce the breakage risk of the silicone tube. This method is a safe, practical, minimally invasive method for removing PD catheters, and it is suitable for application on special patients with peritonitis or who are on an immunosuppressant.

2.
Int J Impot Res ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32203432

RESUMO

Defining the risks associated with diabetes mellitus in patients undergoing penile prosthesis implantation remains controversial. Our study aims to assess whether preoperative hemoglobin a1c and preoperative blood glucose levels are associated with an increased risk for postoperative infection in diabetic men. We performed a retrospective review of 932 diabetic patients undergoing primary penile prosthesis implantation from 18 high-volume penile prosthesis implantation surgeons throughout the United States, Germany, Belgium, and South Korea. Preoperative hemoglobin a1c and blood glucose levels within 6 h of surgery were collected and assessed in univariate and multivariate models for correlation with postoperative infection, revision, and explantation rates. The primary outcome is postoperative infection and the secondary outcomes are postoperative revision and explantation. In all, 875 patients were included in the final analysis. There were no associations between preoperative blood glucose levels or hemoglobin a1c levels and postoperative infection rates; p = 0.220 and p = 0.598, respectively. On multivariate analysis, a history of diabetes-related complications was a significant predictor of higher revision rates (p = 0.034), but was nonsignificant for infection or explantation rates. We conclude preoperative blood glucose levels and hemoglobin a1c levels are not associated with an increased risk for postoperative infection, revision, or explantation in diabetic men undergoing penile prosthesis implantation.

4.
J Microbiol ; 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103442

RESUMO

Bovine mastitis is a common disease in the dairy industry that causes great economic losses. As the primary pathogen of contagious mastitis, Staphylococcus aureus (S. aureus) can invade bovine mammary epithelial cells, thus evading immune defenses and resulting in persistent infection. Recently, autophagy has been considered an important mechanism for host cells to clear intracellular pathogens. In the current study, autophagy caused by S. aureus was detected, and the correlation between autophagy and intracellular S. aureus survival was assessed. First, a model of intracellular S. aureus infection was established. Then, the autophagy of MAC-T cells was evaluated by confocal microscopy and western blot. Moreover, the activation of the PI3K-Akt-mTOR and ERK1/2 signaling pathways was determined by western blot. Finally, the relationship between intracellular bacteria and autophagy was analyzed by using autophagy regulators (3-methyladenine [3-MA], rapamycin [Rapa] and chloroquine [CQ]). The results showed that S. aureus caused obvious induction of autophagosome formation, transformation of LC3I/II, and degradation of p62/SQSTM1 in MAC-T cells; furthermore, the PI3K-Akt-mTOR and ERK1/2 signaling pathways were activated. The number of intracellular S. aureus increased significantly with autophagy activation by rapamycin, whereas the number decreased when the autophagy flux was inhibited by chloroquine. Therefore, this study indicated that intracellular S. aureus can induce autophagy and utilize it to survive in bovine mammary epithelial cells.

5.
Yi Chuan ; 42(1): 112-125, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31956101

RESUMO

Alcohol abuse causes tissue and organ damage, and may participate neuropsychiatric diseases. Studies have shown that DNA methylation plays an important role in gene expression and behavioral changes induced by alcohol, however the causative neurobiological mechanisms have not been clarified. In this study, 32 healthy adult male SD rats were randomly divided into a drinking water control group (n=16) and a chronic alcohol exposure group (n=16). The alcohol preference and locomotor activity of rats were evaluated by two-bottle choice test (TBCT) and open-field test (OFT). DNA methylation in the medial prefrontal cortex (mPFC) tissue was detected by the reduced representative bisulfite sequencing (RRBS) technology. The methylation differential genes closely related to alcohol abuse were screened. qRT-PCR was used to verify the mRNA expression patterns of differential genes. qRT-PCR and Western blot were used to detect the expression of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MeCP2). Furthermore, the effect of short-term alcohol exposure (7 days) on DNMTs and MeCP2 in the mPFC of rats was tested (n=8/group). The results indicated that the methylation level of promoter region in the mPFC of rats exposed to chronic alcohol was significantly increased. In addition, the increased methylation levels in the promoter of Ntf3 and Ppm1G were accompanied by down-regulated mRNA levels in the chronic alcohol exposure group. The decreased methylation levels in the promoter of Hap1 and DUSP1 were accompanied by up-regulated mRNA levels. Furthermore, chronic alcohol exposure increased the mRNA and protein levels of DNMT3B and MeCP2. However, short term alcohol exposure did not affect their expression. This present study provides evidence that DNA methylation is associated with the development of alcohol abuse, which may be regulated by DNMT3B and MeCP2. The target genes Ntf3, Ppm1G, Hap1, and DUSP1 related to alcohol abuse were discovered as well, providing new insights into the neurobiological mechanism of alcohol abuse and the potential pharmacological targets for the treatment of alcohol abuse.


Assuntos
Alcoolismo/fisiopatologia , Comportamento Animal , Metilação de DNA , Córtex Pré-Frontal/fisiopatologia , Animais , DNA (Citosina-5-)-Metiltransferases/genética , Locomoção , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley
6.
J Cancer Res Clin Oncol ; 146(4): 1021-1031, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31980929

RESUMO

PURPOSE: In this retrospective study, we evaluated the treatment patterns and survival after positron emission tomography-computed tomography (PET/CT)-guided local consolidation therapy (LCT) for oligometastatic non-small cell lung cancer (NSCLC). METHODS: We reviewed the medical records of Chinese patients with oligometastatic stage IV non-small cell lung cancer (≤ 5 metastases) who had undergone PET/CT and were eligible for systemic therapy at two centers between May 2005 and August 2019. Propensity score matching (1:1) was used to reduce selection bias and imbalanced distribution of confounding factors. RESULTS: We identified 84 eligible patients and used propensity scores to create well-matched groups of 35 patients who did or did not undergo LCT. Among all patients, the 1-year overall survival (OS) rate was 47.6% and the 2-year OS rate was 22.6%. Relative to the group that did not receive LCT, the LCT group had a significantly higher OS rate (13 months vs. 7 months, p = 0.002). The two groups had similar incidences and classifications of LCT-related side effects. In multivariable analysis, LCT was found to be strongly associated with a favorable OS (hazard ratio: 0.508, 95% confidence interval: 0.311-0.828, p = 0.001). CONCLUSION: We concluded that LCT was significantly associated with improved clinical outcomes among the Chinese patients with oligometastatic NSCLC who were eligible for systemic treatment and could undergo PET/CT evaluation.

7.
Surg Today ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31925579

RESUMO

PURPOSE: To investigate the efficacy and safety of flurbiprofen axetil in postoperative analgesia in upper abdominal surgery. METHODS: This was a multicenter, randomized, positive drug parallel controlled double-blind clinical study. Patients undergoing upper abdominal surgery were randomly divided to receive flurbiprofen axetil or tramadol. The VAS pain scores at rest and on coughing (pulmonary function training) were assessed immediately before drug usage (T1) to evaluate the efficacy of postoperative analgesia. Repeat assessment of the VAS was performed after T1. The timing of the recovery of the gastrointestinal function and the preoperative and postoperative IL-6, cortisol, and blood glucose levels were recorded as secondary endpoints. Vital signs and the occurrence of adverse reactions were evaluated for the assessment of safety. RESULTS: A total of 240 patients were enrolled in the current study; 119 used flurbiprofen axetil for postoperative analgesia. The VAS scores at rest and on coughing did not differ between the two groups to a statistically significant extent (P > 0.05). However, the reduction of the VAS score at rest in the flurbiprofen axetil group was greater than that in the tramadol group at 4-24 h after T1. The reduction of the VAS score on coughing at 8 h after T1 was greater in the flurbiprofen axetil group. The incidence of adverse reactions was significantly lower in the flurbiprofen axetil group, with only one adverse reaction recorded. In contrast, 18 adverse reactions were reported in the tramadol group. CONCLUSION: Flurbiprofen axetil showed superior efficacy to tramadol in early postoperative analgesia after upper abdominal surgery. Flurbiprofen axetil was associated with a significantly lower incidence of adverse reactions in comparison to tramadol.

8.
Asian J Androl ; 22(1): 2-7, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31793443

RESUMO

With the onset of a metabolic syndrome epidemic and the increasing life expectancy, erectile dysfunction (ED) has become a more common condition. As incidence and prevalence increase, the medical field is focused on providing more appropriate therapies. It is common knowledge that ED is a chronic condition that is also associated with a myriad of other disorders. Conditions such as aging, diabetes mellitus, hypertension, obesity, prostatic hypertrophy, and prostate cancer, among others, have a direct implication on the onset and progression of ED. Characterization and recognition of risk factors may help clinicians recognize and properly treat patients suffering from ED. One of the most reliable treatments for ED is penile prosthetic surgery. Since the introduction of the penile prosthesis (PP) in the early seventies, this surgical procedure has improved the lives of thousands of men, with reliable and satisfactory results. The aim of this review article is to characterize the epidemiology of men undergoing penile prosthetic surgery, with a discussion about the most common conditions involved in the development of ED, and that ultimately drive patients into electing to undergo PP placement.

9.
Neuro Oncol ; 22(1): 46-57, 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31400279

RESUMO

BACKGROUND: Deregulation of the nuclear factor of activated T cell (NFAT) pathway has been reported in several human cancers. Particularly, NFAT2 is involved in the malignant transformation of tumor cells and is identified as an oncogene. However, the role of NFAT2 in glioblastoma (GBM) is largely unknown. METHODS: The expression and prognostic value of NFAT2 were examined in the databases of the Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas (TCGA) and clinical samples. The functional effects of silencing or overexpression of NFAT2 were evaluated in glioma stem cell (GSC) viability, invasion, and self-renewal in vitro and in tumorigenicity in vivo. The downstream target of NFAT2 was investigated. RESULTS: High NFAT2 expression was significantly associated with mesenchymal (MES) subtype and recurrent GBM and predicted poor survival. NFAT2 silencing inhibited the invasion and clonogenicity of MES GSC-enriched spheres in vitro and in vivo. NFAT2 overexpression promoted tumor growth and MES differentiation of GSCs. A TCGA database search showed that histone deacetylase 1 (HDAC1) expression was significantly correlated with that of NFAT2. NFAT2 regulates the transcriptional activity of HDAC1. Rescue of HDAC1 in NFAT2-knockdown GSCs partially restored tumor growth and MES phenotype. Loss of NFAT2 and HDAC1 expression resulted in hyperacetylation of nuclear factor-kappaB (NF-κB), which inhibits NF-κB-dependent transcriptional activity. CONCLUSION: Our findings suggest that the NFAT2-HDAC1 pathway might play an important role in the maintenance of the malignant phenotype and promote MES transition in GSCs, which provide potential molecular targets for the treatment of GBMs.

10.
Talanta ; 206: 120211, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514873

RESUMO

Urinary glucose determination using a glucose test strip is simple and convenient in daily self-monitoring of diabetes. However, diabetic patients exhibit acquired impaired color vision (ICV), which results in the inability to discriminate between hues. Even with the assistance of a color chart, it is still not easy for these patients to read the urinary glucose results with the naked eye. In this study, a smartphone camera using an image-based colorimetric detection method was successfully developed for quantitative analysis of urine glucose. A horseradish peroxidase-hydrogen peroxide-3,3'5,5'-tetramethylbenzidine (HRP-H2O2-TMB) system was optimized for a reliable and gradual color fading process via a glucose oxidase (GOD) catalyzed oxidation reaction. The color changes of the peroxidase-H2O2 enzymatic reactions in the 96-well microplate were captured by a smartphone RGB camera with subsequent detection of red, green, and blue (RGB) intensities decreasing at each image pixel. The highly quantitative relationships between the glucose concentrations and the color characteristic values of the blue channel of the captured images were successfully established. The high accuracy of this method was demonstrated in urine glucose measurements with a linear response over the 0.039 mg mL-1 to 10.000 mg mL-1 glucose concentration range and a 0.009 mg mL-1 detection limit. The method has great potential as a point-of-need platform for diabetic patients with defective color vision and features high accuracy and low cost.


Assuntos
Diabetes Mellitus/urina , Glucose/análise , Glicosúria/diagnóstico , Smartphone , Armoracia/enzimologia , Benzidinas/química , Compostos Cromogênicos/química , Colorimetria/métodos , Glucose/química , Glucose Oxidase/química , Peroxidase do Rábano Silvestre/química , Humanos , Peróxido de Hidrogênio/química , Limite de Detecção , Fotografação/instrumentação , Testes Imediatos
11.
Huan Jing Ke Xue ; 41(1): 98-105, 2020 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854909

RESUMO

Since the introduction of ultra-low emissions, the characteristics of particulate matter (PM) emissions from coal-fired power plants have changed. We quantitatively evaluate the emission characteristics of each component in PM and the impact of purification equipment by analyzing three ultra-low emission units of coal-fired power plants (FP1, FP2, and FP3). A DGI was used to sample particles from the wet flue gas desulfurization (WFGD) unit and wet electrostatic precipitator (WESP) inlet and outlet, which were then analyzed by various methods. The results showed that the mass concentrations of PM1, PM2.5, and PM10 discharged from the outlets of the three units were 0.25-0.38, 0.31-0.42, and 0.42-0.57 mg·m-3, respectively, and that the mass concentration of PM10 discharged under the two kinds of units was equivalent. However, there were differences in the particle size distribution and composition of the particles. In comparison to the FP1 and FP2 units, the PM2.5/PM10 ratio of the FP3 unit was the highest. A possible reason for this is that the unit was equipped with a WESP, which can better remove particle sizes of 2.5 µm or more. The total concentrations of water-soluble ions in PM2.5 discharged from the FP2 and FP3 units were 0.20 and 0.06 mg·m-3, respectively. The water-soluble ions emitted from the FP2 unit were mainly Ca2+ and SO42-, whereas those mainly emitted from the FP3 unit were NH4+ and SO42-. Analysis of the PM from the WFGD import and export of the FP2 unit showed that the WFGD process increased the water-soluble ion discharge by entraining the desulfurization slurry containing limestone and gypsum. Addition of a WESP after WFGD can effectively remove PM2.5 and PM10 particles and reduce the influence of water-soluble ions on the atmospheric environment.

12.
J Biomol Struct Dyn ; : 1-11, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31787068

RESUMO

The overexpression of PTP-LAR could cause the insulin resistance, so PTP-LAR might be a promising target for treating diabetes. In this study, we applied the computer modeling methods with fragment replace approach to screen the fragment database by targeting PTP domain and site B with the aim to discover potent and selective PTP-LAR inhibitors. A series of novel 4-thiazolidone derivatives were gained. The results of their ADMET predictions indicated that these new compounds might become drug candidates. The series of these derivatives were synthesized. Subsequently, their PTP-LAR inhibitory activities were assayed. The compound7d showed highly selectivity for PTP-LAR (10.41 µM) over its close homolog PTP1B (IC50=44.40 µM), SHP2 (IC50>122.81 µM) and CDC25B (IC50>122.81 µM) and docking and molecular dynamics simulation were applied to propose the most likely binding mode of compound7d with PTP-LAR. Thus, our findings reported here may pave a way for discovering potential selective PTP-LAR inhibitors.AbbreviationsPTP-LARHuman leukocyte common antigen-relatedPTPProtein Tyrosine PhosphataseIRinsulin receptorPTP1BProtein tyrosine phosphatase-1BLRPLung resistance proteinADMETabsorption, distribution, metabolism, excretion, toxicityPPBplasma protein bindingBBBblood brain barrier penetrationCYP450cytochrome P450HIAhuman intestinal absorptionTLCthin-layer chromatographyUVUltra VioletNMRnuclear magnetic resonanceTMStetramethylsilaneMSmass spectrometryANManisotropic network modePDBProtein Data BankDMFN,N-DimethylformamidepNPPpara-nitrophenyl phosphateDTTdithiothreitolMDmolecular dynamicRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationSPCsingle-point chargePMEParticle Mesh EwaldMM-PBSAmolecular mechanics Poisson Boltzmann surface areaH bond, hydrogen bondVDWVan der WaalsCommunicated by Ramaswamy H. Sarma.

13.
Med Sci (Basel) ; 7(12)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835522

RESUMO

The majority of sexual health research has focused on erectile dysfunction following prostate cancer treatment. Ejaculatory and orgasmic dysfunction are significant side effects following the treatment of prostate cancer. Orgasmic dysfunction covers a range of issues including premature ejaculation, anorgasmia, dysorgasmia, and climacturia. This review provides an overview of prevalence and management options to deal with orgasmic dysfunction. A Medline Pubmed search was used to identify articles relating to these problems. We found that orgasmic dysfunction has a very large impact on patients' lives following prostate cancer treatment and there are ways for physicians to treat it. Management of patients' sexual health should be focused not only on erectile dysfunction, but on orgasmic dysfunction as well in order to ensure a healthy sexual life for patients and their partners.

14.
Asian J Androl ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31854332

RESUMO

Penile rehabilitation after inflatable penile prosthesis (IPP) implantation for the treatment of erectile dysfunction includes leaving the device partially inflated so as to preserve the penile length and to maintain hemostasis. With a partially inflated device, the penis becomes more sensitive and more susceptible to unintended insults during the immediate postoperative management. The "Wang Collar," a device intended to protect the penis in the early postoperative period, is hereby described. Three hundred and forty-eight patients had the "Wang Collar" included as part of their post-IPP management from August 2014 to February 2019. The protective collar, devised from a polystyrene cup with the bottom removed, is secured with a tape over the previously dressed and partially inflated penis. In order to evaluate the effectiveness of this device, we conducted surveys on the perioperative staff at three different institutions. The "Wang Collar" has been found to be beneficial in the early postoperative care of patients. Based on the answers to our questionnaire, the perioperative personnel found this device to be highly protective, especially when transporting the patient after IPP surgery, easy to work with, and almost never bothersome or irritative to the patient. We present a novel penile device after IPP placement, which we have found to improve patient satisfaction in the postoperative period. In addition, it eases the care of the patient by the perioperative staff. It is now our routine to use this device after IPP surgery. Further research is necessary to evaluate whether this device can decrease postoperative wound complications.

15.
Huan Jing Ke Xue ; 40(10): 4412-4422, 2019 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854808

RESUMO

A comparative analysis was conducted using total ozone products derived from monitoring atmospheric composition and climate (MACC) reanalysis data validated with ozone data from the atmospheric infrared sounder (AIRS) satellite and ground-based ozone measurements. The results indicate that the relative deviation of total ozone from the MACC reanalysis data and the ground-based ozone total data is controlled within 17%, and all of the correlation coefficients were between 0.79 and 0.97. The total ozone values from the MACC reanalysis data showed good consistency with the ground-based ozone measurements. With respect to the spatial distribution of multi-year averages, the relative deviation of total ozone values in the MACC reanalysis data and the AIRS satellite data was between -3% and 5%. The total ozone values in the MACC reanalysis data were higher than those from AIRS measurements for the Qinghai-Tibet Plateau and the coastal areas of South China, and were lower for northeast China. Furthermore, the seasonal variations in total ozone values in the MACC reanalysis data were consistent with AIRS data. At Mt. Waliguan station, the monthly averaged trends for near-surface ozone in the MACC reanalysis data were also consistent with surface ozone concentrations; the MACC reanalysis data reflect the observed trends for surface-based ozone measurements in spring, summer, and autumn, but show a large deviation in winter.

16.
J Biomol Struct Dyn ; : 1-18, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31842717

RESUMO

Owing to their inhibitory role in regulating oligodendrocyte differentiation and apoptosis, protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related phosphatase (LAR) play a crucial potential role in treating spinal cord injury (SCI) disease. In this research, the computer aided drug design (CADD) methods were applied to discover the potential dual-target drug involving virtual screen, molecular docking and molecular dynamic simulation. Initially, the top 20 compounds with higher docking score than the positive controls (ZINC13749892, ZINC14516161) were virtually screened out from NCI and ZINC databases, and then were submitted in ADMET to predict their drug properties. Among these potential compounds, ZINC72417086 showed a higher docking score and satisfied Lipinski's rule of five. In addition, the post-analysis demonstrated that when ZINC72417086 bound to PTPσ and LAR, it could stable proteins conformations and destroy the residues interactions between P-loop and other loop regions in active pocket. Meanwhile, residue ARG1595 and ARG1528 could play a crucial role in in the inhibition of PTPσ and LAR, respectively. This research offered a novel approach for rapid discovery of dual-target leads compounds to treat SCI. Communicated by Ramaswamy H. Sarma.

17.
Asian J Androl ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31736474

RESUMO

This study aimed to explore whether and how anti-lysyl oxidase (anti-LOX) combined with a vacuum device (VD) could promote penile lengthening and to evaluate the effect on erectile function. This study was performed on four groups of adult rats: control, anti-LOX, VD (negative pressure value of -300 mmHg), and anti-LOX + VD. Penile length was measured by a modified VD method and verified on exposed length data. Intracavernous pressure (ICP) and maximum ICP/mean arterial pressure (MAP) ratio were recorded to assess erectile function. For corpus cavernosum, LOX activity and concentrations of pyridinoline, desmosine, hydroxyproline, and elastin were analyzed; transmission electron microscope and Hart's elastin staining were performed to monitor microstructural changes. Anti-LOX and VD significantly lengthened the penis by 10.8% (3.75 mm) and 8.2% (2.48 mm) compared with the control group, respectively, while anti-LOX + VD achieved the longest penile size (40.58 ± 0.40 mm) which was 17.4% longer than the control group (34.58 ± 0.54 mm). After 1-week washout, no penile retraction was observed. Meanwhile, exposed penile length data confirmed that the penis in the anti-LOX + VD group was also significantly longer. Anti-LOX inhibited LOX activity to reduce pyridinoline level, which led the penile tunica albuginea remodeling. However, it had no effect on hydroxyproline, desmosine, and elastin levels. Moreover, anti-LOX had no impact on erectile function, which was determined by ICP and ICP/MAP ratio. These results suggest that anti-LOX elongates the penis by reducing pyridinoline, which induces tunica albuginea remodeling. This lengthening effect was more obvious when combined with a VD. All procedures had no impact on erectile function.

19.
J Biomol Struct Dyn ; : 1-14, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31588870

RESUMO

Owing to its negative regulatory role in insulin signaling, protein tyrosine phosphatase of leukocyte antigen-related protein (PTP-LAR) was widely thought as a potential drug target for diabetes. Now, it was urgent to search for potential LAR inhibitors targeting diabetes. Initially, the pharmacophore models of LAR inhibitors were established with the application of the HypoGen module. The cost analysis, test set validation, as well as Fischer's test was used to verify the efficiency of pharmacophore model. Then, the best pharmacophore model (Hypo-1-LAR) was applied for the virtual screening of the ZINC database. And 30 compounds met the Lipinski's rule of five. Among them, 10 compounds with better binding affinity than the known LAR inhibitor (BDBM50296375) were discovered by docking studies. Finally, molecular dynamics simulations and post-analysis experiments (RMSD, RMSF, PCA, DCCM and RIN) were conducted to explore the effect of ligands (ZINC97018474 and Compound 1) on LAR and preliminary understand why ZINC97018474 had better inhibitory activity than Compound 1 (BDBM50296375). Abbreviation PTP-LAR protein tyrosine phosphatase of leukocyte antigen-related protein DS Discovery Studio RMSF root-mean-square fluctuations HBD hydrogen bond donors QSAR quantitative structure-activity relationship HBA hydrogen bond acceptors NI negative ionizable HYP hydrophobe area MM/GBSA molecular mechanics combined with generalized Born and surface area solvation RMSD root-mean-squared deviation PME particle mesh Ewald SPC single-point charge DCCM dynamic cross-correlation mapping RIN residue interaction network PCA principal component analysis VDW van der Waals Communicated by Ramaswamy H. Sarma.

20.
J Biomol Struct Dyn ; : 1-17, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31625456

RESUMO

Owing to their unique functions in regulating the synapse activity of protein tyrosine phosphatases delta (PTPδ) that has drawn special attention for developing drugs to autism spectrum disorders (ASDs). In this study, the PTPδ pharmacophore was first established by the structure-based pharmacophore method. Subsequently, 10 compounds contented Lipinski's rule of five was acquired by the virtual screening of the PTPδ pharmacophore against ZINC and PubChem databases. Then, the 10 identified molecules were discovered that had better binding affinity than a known PTPδ inhibitors compound SCHEMBL16375396. Two compounds SCHEMBL16375408 and ZINC19796658 with high binding score, low toxicity were gained. They were observed by docking analysis and molecular dynamics simulations that the novel potential inhibitors not only possessed the same function as SCHEMBL16375396 did in inhibiting PTPδ, but also had more favorable conformation to bind with the catalytic active regions. This study provides a new method for identify PTPδ inhibitor for the treatment of ASDs disease.Communicated by Ramaswamy H. Sarma.

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