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1.
N. S. Hari Narayana Moorthy Sergio F. Sousa Maria J. Ramos Pedro A. Fernandes 《Medicinal chemistry research》2016,25(7):1340-1357
Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets. 相似文献
2.
Enrique Luengo Izaskun Buendia Cristina Fernndez‐Mendívil Paula Trigo‐Alonso Pilar Negredo Patrycja Michalska Borja Hernndez‐García Cristina Snchez‐Ramos Juan A. Bernal Tsuneya Ikezu Rafael Len Manuela G. Lpez 《Journal of pineal research》2019,67(1)
Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD. 相似文献
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M. L. Hernández J. J. Fernández-Ruiz R. de Miguel J. A. Ramos 《Journal of neural transmission (Vienna, Austria : 1996)》1991,83(1-2):77-84
Summary In this work, we have studied the time-course of the effects of pharmacological administration of ovarian steroids on tyrosine hydroxylase (TH) activity in the limbic forebrain of ovariectomized rats. Administration of estradiol produced a late decrease in TH activity. This effect was found 24 hours after the last steroid injection, disappearing at 32 hours. It was antagonized by progesterone, since a single injection of this steroid to estradiol-pretreated rats reversed to control values the estradiol-induced decrease. Nevertheless, the administration of progesterone after estradiol treatment caused a short-time decrease in the limbic activity of TH, which was observed 4 hours after the last steroid injection, disappearing subsequently. On the other hand, the administration of progesterone alone produced a biphasic effect, with a reduction at 24 hours, followed by an increase at 32 hours. These effects were only observed in the animals non-treated with estradiol, disappearing with a previous treatment with estrogens. Hence, it can be concluded that both ovarian steroids may affect the limbic TH activity. Thus, estradiol produced a late inhibitory effect on the activity of this enzyme, which was antagonized by progesterone. Administration of the last one to estradiol-treated rats produced a short-time inhibitory effect, whereas its administration to non-treated rats produced a late biphasic effect (inhibition followed by stimulation), which was not observed in estradiol-treated rats. 相似文献
7.
Occupational airborne allergic contact dermatitis from tylosin 总被引:2,自引:1,他引:1
8.
Juli Busquets Jose Castellote Jaume Torras Juan Fabregat Emilio Ramos Laura Llado Antonio Rafecas Esmeralda de la Banda Juan Figueras 《Journal of gastrointestinal surgery》2007,11(4):458-463
Background Cold ischemia time and the presence of postoperative hepatic arterial thrombosis have been associated with biliary complications
(BC) after liver transplantation. An ABO-incompatible blood group has also been suggested as a factor for predisposal towards
BC. However, the influence of Rh nonidentity has not been studied previously.
Materials Three hundred fifty six liver transplants were performed from 1995 to 2000 at our hospital. BC incidence and risk factors
were studied in 345 patients.
Results Seventy patients (20%) presented BC after liver transplantation. Bile leakage (24/45%) and stenotic anastomosis (21/30%) were
the most frequent complications. Presence of BC in Rh-nonidentical graft–host cases (23/76, 30%) was higher than in Rh-identical
grafts (47/269, 17%) (P = 0.01). BC was also more frequent in grafts with arterial thrombosis (9/25, 36% vs 60/319, 19%; P = 0.03) and grafts with cold ischemia time longer than 430 min (26/174, 15% vs 44/171, 26%; P = 0.01). Multivariate logistic regression confirmed that Rh graft–host nonidentical blood groups [RR = 2(1.1–3.6); P = 0.02], arterial thrombosis [RR = 2.6(1.1–6.4); P = 0.02] and cold ischemia time longer than 430 min [RR = 1.8(1–3.2); P = 0.02] were risk factors for presenting BC.
Conclusion Liver transplantation using Rh graft–host nonidentical blood groups leads to a greater incidence of BC. 相似文献
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JA HYEON KU CHEOL KWAK SEUNG-JUNE OH EUNSIK LEE SANG EUN LEE JAE-SEUNG PAICK 《International journal of urology》2004,11(7):489-493
BACKGROUND: Our aims in the present study were to estimate the influences of pain and urinary symptoms on quality of life, and to determine which of these two variables has the most predictive power with respect to quality of life in young men with chronic prostatitis-like symptoms. METHODS: Chronic prostatitis-like symptoms were measured by the National Institutes of Health-Chronic Prostatitis Symptom Index. Of the 28,841 men aged 20 years who lived in the study community, 18,495 men (a response rate 64.1%) agreed to participate in the study. A total of 1057 men who complained of symptoms indicative of chronic prostatitis were included in the study. The influences of pain and urinary symptoms on quality of life were determined using logistic regression analysis. The receiver operating characteristic (ROC) curve was used to estimate the predictive ability of each of these variables with respect to quality of life. RESULTS: Results from multivariate analysis showed that both pain and urinary symptoms were associated with an increased likelihood of impaired quality of life, although pain contributed more to a reduced quality of life than urinary symptoms. Relative to men who experienced mild pain, men who experienced moderate pain had a 3.9-fold risk of poor quality of life (odds ratio [OR], 3.87; 95% confidence interval [CI], 2.86-5.23; P < 0.001) and those who experienced severe pain had a 15.7-fold risk of reduced quality of life (OR, 15.68; 95% CI, 6.59-37.35; P < 0.001). Moderate urinary symptoms were associated with a 1.4-fold risk of bother (OR, 1.41; 95% CI, 1.01-1.99; P < 0.001) and severe urinary symptoms were associated with 2.4-fold risk (OR, 2.39; 95% CI, 1.37-4.12; P < 0.001), relative to mild urinary symptoms. Comparison of the effects of pain and urinary symptoms showed that pain severity had the most predictive power for bother, quality of life, and quality-of-life impact. The areas under the ROC curves for bother, quality of life, and quality-of-life impact were 71.3%, 69.3% and 72.5%, respectively. CONCLUSION: Urinary symptoms and pain might be associated with an increased likelihood of impaired quality of life in young men with chronic prostatitis-like symptoms. In addition, our findings suggest that pain severity is the most influential variable for determining quality of life in this population. 相似文献