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151.
The objective of the present investigation was to develop in situ gelling nasal spray formulation of carvedilol (CRV) nanosuspension to improve the bioavailability and therapeutic efficiency. Solvent precipitation–ultrasonication method was opted for the preparation of CRV nanosuspension which further incorporated into the in situ gelling polymer phase. Optimized formulation was extensively characterized for various physical parameters like in situ gelation, rheological properties and in vitro drug release. Formation of in situ gel upon contact with nasal fluid was conferred via the use of ion-activated gellan gum as carrier. In vivo studies in rabbits were performed comparing the nasal bioavailability of CRV after oral, nasal, and intravenous administration. Optimized CRV nanosuspension prepared by combination of poloxamer 407 and oleic acid showed good particle size [d (0.9); 0.19 μm], zeta potential (+10.2 mV) and polydispersity (span; 0.63). The formulation containing 0.5% w/v gellan gum demonstrated good gelation ability and desired sustained drug release over period of 12 h. In vivo pharmacokinetic study revealed that the absolute bioavailability of in situ nasal spray formulation (69.38%) was significantly increased as compared to orally administered CRV (25.96%) with mean residence time 8.65 h. Hence, such in situ gel system containing drug nanosuspension is a promising approach for the intranasal delivery in order to increase nasal mucosal permeability and in vivo residence time which altogether improves drug bioavailability.KEY WORDS: bioavailability, Carvedilol, in situ gel, intranasal, nanosuspension 相似文献
152.
Chitnis NS Paul ER Lawrence PK Henderson CW Ganapathy S Taylor PV Virdi KS D'Costa SM May AR Bilimoria SL 《Journal of virology》2011,85(24):13144-13152
Apoptosis and inhibition of host gene expression are often associated with virus infections. Many viral polypeptides modulate apoptosis by direct interaction with highly conserved apoptotic pathways. Some viruses induce apoptosis during late stages of the infection cycle, while others inhibit apoptosis to facilitate replication or maintain persistent infection. In previous work, we showed that Chilo iridescent virus (CIV) or CIV virion protein extract induces apoptosis in spruce budworm and cotton boll weevil cell cultures. Here, we characterize the product of a CIV gene (iridovirus serine/threonine kinase; istk) with signature sequences for S/T kinase and ATP binding. ISTK appears to belong to the superfamily, vaccinia-related kinases (VRKs). The istk gene was expressed in Pichia pastoris vectors. Purified ISTK (48 kDa) exhibited S/T kinase activity. Treatment with ISTK induced apoptosis in budworm cells. A 35-kDa cleavage product of ISTK retaining key signature sequences was identified during purification. Pichia-expressed 35-kDa polypeptide, designated iridoptin, induced apoptosis and inhibition of host protein synthesis in budworm and boll weevil cells. A mutation in the ATP-binding site eliminated both kinase and apoptosis activity of iridoptin, suggesting that kinase activity is essential for induction of apoptosis. Analysis with custom antibody confirmed that ISTK is a structural component of CIV particles. This is the first demonstration of a viral kinase inducing apoptosis in any virus-host system and the first identification of a factor inducing apoptosis or host protein shutoff for the family Iridoviridae. 相似文献
153.
To improve our understanding of the contributions of different stabilizing interactions to protein stability, including that of residual structure in the unfolded state, the small sweet protein monellin has been studied in both its two variant forms, the naturally occurring double-chain variant (dcMN) and the artificially created single-chain variant (scMN). Equilibrium guanidine hydrochloride-induced unfolding studies at pH 7 show that the standard free energy of unfolding, ΔG°(U), of dcMN to unfolded chains A and B and its dependence on guanidine hydrochloride (GdnHCl) concentration are both independent of protein concentration, while the midpoint of unfolding has an exponential dependence on protein concentration. Hence, the unfolding of dcMN like that of scMN can be described as two-state unfolding. The free energy of dissociation, ΔG°(d), of the two free chains, A and B, from dcMN, as measured by equilibrium binding studies, is significantly lower than ΔG°(U), apparently because of the presence of residual structure in free chain B. The value of ΔG°(U), at the standard concentration of 1 M, is found to be ~5.5 kcal mol(-1) higher for dcMN than for scMN in the range from pH 4 to 9, over which unfolding appears to be two-state. Hence, dcMN appears to be more stable than scMN. It seems that unfolded scMN is stabilized by residual structure that is absent in unfolded dcMN and/or that native scMN is destabilized by strain that is relieved in native dcMN. The value of ΔG°(U) for both protein variants decreases with an increase in pH from 4 to 9, apparently because of the thermodynamic coupling of unfolding to the protonation of a buried carboxylate side chain whose pK(a) shifts from 4.5 in the unfolded state to 9 in the native state. Finally, it is shown that although the thermodynamic stabilities of dcMN and scMN are very different, their kinetic stabilities with respect to unfolding in GdnHCl are very similar. 相似文献
154.
Mengxi Jiang Jinhan He Heidi Kucera Nilesh W. Gaikwad Bin Zhang Meishu Xu Robert M. O'Doherty Kyle W. Selcer Wen Xie 《The Journal of biological chemistry》2014,289(12):8086-8097
The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this report, we first showed that the liver expression of Sts was induced in both the high fat diet (HFD) and ob/ob models of obesity and type 2 diabetes and during the fed to fasting transition. In defining the functional relevance of STS induction in metabolic disease, we showed that overexpression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity by converting biologically inactive estrogen sulfates to active estrogens and consequently improved the metabolic functions, whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue and skeletal muscle as well as a pattern of skeletal muscle gene expression that favors energy expenditure. The metabolic benefit in male STS transgenic mice was retained after castration. Treatment with the STS substrate estrone sulfate also improved metabolic functions in both the HFD and ob/ob models. Our results have uncovered a novel function of STS in energy metabolism and type 2 diabetes. Liver-specific STS induction or estrogen/estrogen sulfate delivery may represent a novel approach to manage metabolic syndrome. 相似文献
155.
Nilesh Dinkar Gawande Swaminathan Subashini Marimuthu Murugan Mohankumar Subbarayalu 《Bioinformation》2014,10(11):679-683
Glutathione S-transferases (GSTs) are one of the major families of detoxifying enzymes that detoxifies different chemical
compounds including insecticides in different insect species. Among the GST subclasses, sigma GSTs are found to be the most
abundant and conserved among different insect orders. These GSTs are found to play an important role in lipid peroxidation as
well as detoxification. Cotton aphid, Aphis gossypii is the most damaging sucking pest with a wide range of hosts and vector of
more than 50 plant viruses. Resistance to insecticides in A. gossypii is reported in India and in other countries. Glutathione S
transferases (GSTs), an oxidative enzyme is understood to have a role in insecticide resistance and plant resistance breakdown. In
relation to this, we have focused on the sigma 1 (GenBank Accession No: ) and sigma 2 (GenBank Accession No:
JN989964.1) GSTs of A. gossypii and their interaction with plant natural compounds and insecticides. Molecular screening of
different insecticides (Chlorphinamidine, Mevinphos, Nitenpyrum, Piperonyl butoxide, Tetrachlorovinphos, Pyrethrins,
Resmetrin, Pirimicarb and Dinotefuran) and known plant derived natural compounds (Catechin, Gossypol, Myrcene, Kaempferol,
P-coumaric acid, Quercetin, Tannins, α-mangostin, Capsaicin, Cinnamic acid, Citronellal, Curcumin, Dicumarol, Ellagic acid,
Eugenol, Geriniol, Isoeugenol, Juglone, Menadione, Methyl jasmonate, Morin, Myricetin, Myristicin, Piperine, Plumbagin,
Tangitinin C, Thymol, Vanillin, Alpha pipene, α-terpineol Apigenin and β-Caryophyllene) with sigma 1 and sigma 2 GST protein
models was completed using Maestro 9.3 (Schrodinger, USA). This exercise showed the binding of piperonyl butoxide with sigma
1 GST and tannin with sigma 2 GST for further consideration. JN989965.1相似文献
156.
Bernhard M. Kaess Jacek Jó?wiak Christopher P. Nelson Witold Lukas Miros?aw Mastej Adam Windak Tomasz Tomasik W?adys?aw Grzeszczak Andrzej Tykarski Jerzy G?sowski Izabella ?l?zak-Prochazka Andrzej ?l?zak Fadi J. Charchar Naveed Sattar John R. Thompson Nilesh J. Samani Maciej Tomaszewski 《PloS one》2014,9(1)
Objective
The impact of fast changes in obesity indices on other measures of metabolic health is poorly defined in the general population. Using the Polish accession to the European Union as a model of political and social transformation we examined how an expected rapid increase in body mass index (BMI) and waist circumference relates to changes in lipid profile, both at the population and personal level.Methods
Through primary care centres in 444 Polish cities, two cross-sectional nationwide population-based surveys (LIPIDOGRAM 2004 and LIPIDOGRAM 2006) examined 15,404 and 15,453 adult individuals in 2004 and 2006, respectively. A separate prospective sample of 1,840 individuals recruited in 2004 had a follow-up in 2006 (LIPIDOGRAM PLUS).Results
Two years after Polish accession to European Union, mean population BMI and waist circumference increased by 0.6% and 0.9%, respectively. This tracked with a 7.6% drop in HDL-cholesterol and a 2.1% increase in triglycerides (all p<0.001) nationwide. The direction and magnitude of the population changes were replicated at the personal level in LIPIDOGRAM PLUS (0.7%, 0.3%, 8.6% and 1.8%, respectively). However, increases in BMI and waist circumference were both only weakly associated with HDL-cholesterol and triglycerides changes prospectively. The relation of BMI to the magnitude of change in both lipid fractions was comparable to that of waist circumference.Conclusions
Moderate changes in obesity measures tracked with a significant deterioration in measures of pro-atherogenic dyslipidaemia at both personal and population level. These associations were predominantly driven by factors not measureable directly through either BMI or waist circumference. 相似文献157.
Non-Invasive Prenatal Chromosomal Aneuploidy Testing - Clinical Experience: 100,000 Clinical Samples
Ron M. McCullough Eyad A. Almasri Xiaojun Guan Jennifer A. Geis Susan C. Hicks Amin R. Mazloom Cosmin Deciu Paul Oeth Allan T. Bombard Bill Paxton Nilesh Dharajiya Juan-Sebastian Saldivar 《PloS one》2014,9(10)
Objective
As the first laboratory to offer massively parallel sequencing-based noninvasive prenatal testing (NIPT) for fetal aneuploidies, Sequenom Laboratories has been able to collect the largest clinical population experience data to date, including >100,000 clinical samples from all 50 U.S. states and 13 other countries. The objective of this study is to give a robust clinical picture of the current laboratory performance of the MaterniT21 PLUS LDT.Study Design
The study includes plasma samples collected from patients with high-risk pregnancies in our CLIA–licensed, CAP-accredited laboratory between August 2012 to June 2013. Samples were assessed for trisomies 13, 18, 21 and for the presence of chromosome Y-specific DNA. Sample data and ad hoc outcome information provided by the clinician was compiled and reviewed to determine the characteristics of this patient population, as well as estimate the assay performance in a clinical setting.Results
NIPT patients most commonly undergo testing at an average of 15 weeks, 3 days gestation; and average 35.1 years of age. The average turnaround time is 4.54 business days and an overall 1.3% not reportable rate. The positivity rate for Trisomy 21 was 1.51%, followed by 0.45% and 0.21% rate for Trisomies 18 and 13, respectively. NIPT positivity rates are similar to previous large clinical studies of aneuploidy in women of maternal age ≥35 undergoing amniocentesis. In this population 3519 patients had multifetal gestations (3.5%) with 2.61% yielding a positive NIPT result.Conclusion
NIPT has been commercially offered for just over 2 years and the clinical use by patients and clinicians has increased significantly. The risks associated with invasive testing have been substantially reduced by providing another assessment of aneuploidy status in high-risk patients. The accuracy and NIPT assay positivity rate are as predicted by clinical validations and the test demonstrates improvement in the current standard of care. 相似文献158.
159.
Atopic dermatitis (AD) is a strongly heritable, chronic relapsing dermatosis that frequently co-occurs with other atopic phenotypes including asthma and allergic rhinitis (the so-called atopic triad disorders). However, despite high levels of co-morbidity, relatively low levels of genomic co-incidence have been observed between atopic triad disorders. Conversely, current mapping data have revealed a striking pattern of co-localisation between AD disease loci and those mapped using another chronic dermatological disease - psoriasis. In this review, we examine the evidence for co-localisation between AD and a range of atopic, infectious, inflammatory and autoimmune diseases, and consider the implications of these data for the AD disease concept and future research in the field. 相似文献
160.
Scaling up experimental ocean acidification and warming research: from individuals to the ecosystem
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Ana M. Queirós José A. Fernandes Sarah Faulwetter Joana Nunes Samuel P. S. Rastrick Nova Mieszkowska Yuri Artioli Andrew Yool Piero Calosi Christos Arvanitidis Helen S. Findlay Manuel Barange William W. L. Cheung Stephen Widdicombe 《Global Change Biology》2015,21(1):130-143
Understanding long‐term, ecosystem‐level impacts of climate change is challenging because experimental research frequently focuses on short‐term, individual‐level impacts in isolation. We address this shortcoming first through an interdisciplinary ensemble of novel experimental techniques to investigate the impacts of 14‐month exposure to ocean acidification and warming (OAW) on the physiology, activity, predatory behaviour and susceptibility to predation of an important marine gastropod (Nucella lapillus). We simultaneously estimated the potential impacts of these global drivers on N. lapillus population dynamics and dispersal parameters. We then used these data to parameterize a dynamic bioclimatic envelope model, to investigate the consequences of OAW on the distribution of the species in the wider NE Atlantic region by 2100. The model accounts also for changes in the distribution of resources, suitable habitat and environment simulated by finely resolved biogeochemical models, under three IPCC global emissions scenarios. The experiments showed that temperature had the greatest impact on individual‐level responses, while acidification had a similarly important role in the mediation of predatory behaviour and susceptibility to predators. Changes in Nucella predatory behaviour appeared to serve as a strategy to mitigate individual‐level impacts of acidification, but the development of this response may be limited in the presence of predators. The model projected significant large‐scale changes in the distribution of Nucella by the year 2100 that were exacerbated by rising greenhouse gas emissions. These changes were spatially heterogeneous, as the degree of impact of OAW on the combination of responses considered by the model varied depending on local‐environmental conditions and resource availability. Such changes in macro‐scale distributions cannot be predicted by investigating individual‐level impacts in isolation, or by considering climate stressors separately. Scaling up the results of experimental climate change research requires approaches that account for long‐term, multiscale responses to multiple stressors, in an ecosystem context. 相似文献