Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

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.     

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

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‐hTau^P301L 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‐hTau^P301L 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.     

Safety profile of the adjuvanted recombinant zoster vaccine: Pooled analysis of two large randomised phase 3 trials

Background

The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was ≥90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies.

Pinealectomy interferes with the circadian clock genes expression in white adipose tissue

Melatonin, the main hormone produced by the pineal gland, is secreted in a circadian manner (24‐hr period), and its oscillation influences several circadian biological rhythms, such as the regulation of clock genes expression (chronobiotic effect) and the modulation of several endocrine functions in peripheral tissues. Assuming that the circadian synchronization of clock genes can play a role in the regulation of energy metabolism and it is influenced by melatonin, our study was designed to assess possible alterations as a consequence of melatonin absence on the circadian expression of clock genes in the epididymal adipose tissue of male Wistar rats and the possible metabolic repercussions to this tissue. Our data show that pinealectomy indeed has impacts on molecular events: it abolishes the daily pattern of the expression of Clock, Per2, and Cry1 clock genes and Pparγ expression, significantly increases the amplitude of daily expression of Rev‐erbα, and affects the pattern of and impairs adipokine production, leading to a decrease in leptin levels. However, regarding some metabolic aspects of adipocyte functions, such as its ability to synthesize triacylglycerols from glucose along 24 hr, was not compromised by pinealectomy, although the daily profile of the lipogenic enzymes expression (ATP‐citrate lyase, malic enzyme, fatty acid synthase, and glucose‐6‐phosphate dehydrogenase) was abolished in pinealectomized animals.     

No Influence of the Fat Mass and Obesity-Associated Gene rs9939609 Single Nucleotide Polymorphism on Blood Lipids in Young Males

The fat mass and obesity-associated gene (FTO) rs9939609 A-allele is linked to obesity and dyslipidemia, yet the independent influence of this polymorphism on blood lipids remains equivocal. We examined the influence of the FTO rs9939609 polymorphism on fasting and postprandial blood lipids in individuals homozygous for the risk A-allele or T-allele with similar anthropometric and demographic characteristics. 12 AA and 12 TT males consumed a standardized meal after fasting overnight. Blood samples were collected at baseline (−1.5 h), before the meal (0 h), and for five hours postprandially to measure lipid, glucose, and insulin concentrations. Time-averaged total area under the curve (TAUC) values (0–5 h) were calculated and compared between genotypes. Fasting triacylglycerol (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, non-esterified fatty acid (NEFA), glucose, and insulin concentrations were similar between groups (p ≥ 0.293). TAUC for TG was similar in AAs and TTs (95% confidence interval (CI) −0.52 to 0.31 mmol/L/h; p = 0.606). Likewise, TAUC values were similar for NEFA (95% CI −0.04 to 0.03 mmol/L/h; p = 0.734), glucose (95% CI −0.41 to 0.44 mmol/L/h; p = 0.951), and insulin (95% CI −6.87 to 2.83 pmol/L/h; p = 0.395). Blood lipids are not influenced by the FTO rs9939609 polymorphism, suggesting the FTO-dyslipidemia link is mediated by adiposity and weight management is important in preventing FTO-related lipid variations.     

The marks of gunshot wounds to the face

IntroductionThis article deals with the occurrence of health problems due to gunshot wounds to the face among military police officers, in the metropolitan region of Rio de Janeiro, who were submitted to surgery at the Oral and Maxillofacial Surgery and Traumatology Clinic of Hospital Central da Polícia Militar.ObjectiveTo identify the profile of patients submitted to surgery as a result of gunshot wounds, the anatomical distribution of maxillofacial fractures, the identified sequelae and complications, the health specialties involved in the rehabilitation of these patients, and to discuss the social, emotional and work performance-related effects of work among these subjects.MethodsA retrospective epidemiological study was carried out based on secondary data from military police officers who were submitted to surgery at Hospital Central da Polícia Militar due to gunshot wounds from June 2003 to December 2017.ResultsDuring the study period, 778 surgeries were performed in the operating room by the Oral and Maxillofacial Surgery and Traumatology service at Hospital Central da Polícia Militar, 186 of which were due to gunshot wounds (23.9%). All patients were males and the mean age 34.7 years. Bone segment loss was the most common sequela. Facial esthetic impairment and reports of insomnia were the most often identified late consequences of impact on health and social life. Regarding the occupational impacts of the sustained injury, the mean time away from work due to medical leave for the treatment of maxillofacial injuries was 11.7 months.ConclusionThe treatment of gunshot wounds patients with facial injuries requires multiple surgical interventions and their rehabilitation requires the involvement of different health specialties. Further studies are needed to qualitatively analyze the impact of this type of facial trauma on the patients' lives and their social consequences.     

VIROLOGICAL AND SEROLOGICAL DIAGNOSIS OF RABIES IN BATS FROM AN URBAN AREA IN THE BRAZILIAN AMAZON

The outbreaks of rabies in humans transmitted by Desmodus rotundus in 2004 and 2005, in the northeast of the Brazilian State of Para, eastern Amazon basin, made this a priority area for studies on this zoonosis. Given this, the present study provides data on this phenomenon in an urban context, in order to assess the possible circulation of the classic rabies virus (RABV) among bat species in Capanema, a town in the Amazon basin. Bats were collected, in 2011, with mist nets during the wet and dry seasons. Samples of brain tissue and blood were collected for virological and serological survey, respectively. None of the 153 brain tissue samples analyzed tested positive for RABV infection, but 50.34% (95% CI: 45.67-55.01%) of the serum samples analyzed were seropositive. Artibeus planirostris was the most common species, with a high percentage of seropositive individuals (52.46%, 95% CI: 52.31 52.60%). Statistically, equal proportions of seropositive results were obtained in the rainy and dry seasons (c² = 0.057, d.f. = 1, p = 0.88). Significantly higher proportions of males (55.96%, 95% CI: 48.96-62.96%) and adults (52.37%, 95% CI: 47.35-57.39%) were seropositive. While none of the brain tissue samples tested positive for infection, the high proportion of seropositive specimens indicates that RABV may be widespread in this urban area.