Ligands with the polysaccharide headgroups have been recently reported by our group to possess enhanced interaction with asialoglycoprotein receptor (ASGPR) in silico as compared to ligands having ...galactose moieties. This enhanced interaction is a result of the polymer's backbone support in anchoring the ligand in a specific orientation within the bilayer. In this paper, we have attempted to provide an in vitro proof of concept by performing a comparative evaluation of polysaccharide and monosaccharide-based ligands. Docking was performed to understand interaction with ASGPR in silico. Agarose and galactose conjugates with behenic acid were synthesized, purified, and characterized to yield biocompatible hepatospecific ligands which were incorporated into nanoliposomes. Cellular internalization of these targeted liposomes was studied using confocal microscopy and flow cytometry. The toxicity potential was assessed in vivo. Results indicated that the polysaccharide-based ligand increased cellular uptake due to better interaction with the receptor as compared to ligand bearing a single galactose group. In addition to developing novel liver targeting ligands, the study also established proof of concept that has been suggested by earlier in silico investigations. The approach can be used to design targeting ligands and develop formulations with improved targeting efficacy.
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•Design and one pot synthesis of biocompatible monosaccharide and polysaccharide based fatty acid esters.•Development, characterization and comparative assessment of cellular uptake of targeted liposomes.•Validation and establishing proof of concept of enhanced targeting efficacy of polysaccharide-based ligands.•Development of biocompatible platform for hepatospecific delivery.
To identify metabolic brain networks that are associated with Tourette syndrome (TS) and comorbid obsessive-compulsive disorder (OCD).
We utilized (18)F-fluorodeoxyglucose and PET imaging to examine ...brain metabolism in 12 unmedicated patients with TS and 12 age-matched controls. We utilized a spatial covariance analysis to identify 2 disease-related metabolic brain networks, one associated with TS in general (distinguishing TS subjects from controls), and another correlating with OCD severity (within the TS group alone).
Analysis of the combined group of patients with TS and healthy subjects revealed an abnormal spatial covariance pattern that completely separated patients from controls (p < 0.0001). This TS-related pattern (TSRP) was characterized by reduced resting metabolic activity of the striatum and orbitofrontal cortex associated with relative increases in premotor cortex and cerebellum. Analysis of the TS cohort alone revealed the presence of a second metabolic pattern that correlated with OCD in these patients. This OCD-related pattern (OCDRP) was characterized by reduced activity of the anterior cingulate and dorsolateral prefrontal cortical regions associated with relative increases in primary motor cortex and precuneus. Subject expression of OCDRP correlated with the severity of this symptom (r = 0.79, p < 0.005).
These findings suggest that the different clinical manifestations of TS are associated with the expression of 2 distinct abnormal metabolic brain networks. These, and potentially other disease-related spatial covariance patterns, may prove useful as biomarkers for assessing responses to new therapies for TS and related comorbidities.
Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker ...development and the evidence to support the use of four radiotracers as biomarkers in PD: 18Ffluorodopa PET, (+)-11Cdihydrotetrabenazine PET, 123Ibeta-CIT SPECT, and 18Ffluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.
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To investigate comparative in vitro and in vivo performance of lipid vesicular and particulate systems in escalating oral bioavailability for superior hepatoprotection.
Systems were ...fabricated using easy to scale up process and novel excipients to deliver Silibinin. In vitro characterization followed by pharmacokinetic and pharmacodynamic evaluation in rats was conducted to establish a correlation.
Nanoformulations resulted in 20 fold increase in solubilisation and significant increase in permeation. 2.5 fold increase in bioavailability was evident in vivo. Vesicles demonstrated greatest hepatoprotective potential in efficacy study.
The findings establish a link between in vitro and in vivo performance to rank order lipid nanoartchitects. Concurrently, a significant potential in therapeutic intervention of hepatotoxicity is envisaged as elucidated.
Multiple system atrophy (MSA), the most common of the atypical parkinsonian disorders, is characterized by the presence of an abnormal spatial covariance pattern in resting state metabolic brain ...images from patients with this disease. Nonetheless, the potential utility of this pattern as a MSA biomarker is contingent upon its specificity for this disorder and its relationship to clinical disability in individual patients.
We used (18)Ffluorodeoxyglucose PET to study 33 patients with MSA, 20 age- and severity-matched patients with idiopathic Parkinson disease (PD), and 15 healthy volunteers. For each subject, we computed the expression of the previously characterized metabolic covariance patterns for MSA and PD (termed MSARP and PDRP, respectively) on a prospective single-case basis. The resulting network values for the individual patients were correlated with clinical motor ratings and disease duration.
In the MSA group, disease-related pattern (MSARP) values were elevated relative to the control and PD groups (p < 0.001 for both comparisons). In this group, MSARP values correlated with clinical ratings of motor disability (r = 0.57, p = 0.0008) and with disease duration (r = -0.376, p = 0.03). By contrast, MSARP expression in the PD group did not differ from control values (p = 1.0). In this group, motor ratings correlated with PDRP (r = 0.60, p = 0.006) but not with MSARP values (p = 0.88).
MSA is associated with elevated expression of a specific disease-related metabolic pattern. Moreover, differences in the expression of this pattern in patients with MSA correlate with clinical disability. The findings suggest that the MSARP may be a useful biomarker in trials of new therapies for this disorder.
To determine whether changes in D(2) receptor availability are present in carriers of genetic mutations for primary dystonia.
Manifesting and nonmanifesting carriers of the DYT1 and DYT6 dystonia ...mutations were scanned with (11)C raclopride (RAC) and PET. Measures of D(2) receptor availability in the caudate nucleus and putamen were determined using an automated region-of-interest approach. Values from mutation carriers and healthy controls were compared using analysis of variance to assess the effects of genotype and phenotype. Additionally, voxel-based whole brain searches were conducted to detect group differences in extrastriatal regions.
Significant reductions in caudate and putamen D(2) receptor availability were evident in both groups of mutation carriers relative to healthy controls (p < 0.001). The changes were greater in DYT6 relative to DYT1 carriers (-38.0 +/- 3.0% vs -15.0 +/- 3.0%, p < 0.001). By contrast, there was no significant difference between manifesting and nonmanifesting carriers of either genotype. Voxel-based analysis confirmed these findings and additionally revealed reduced RAC binding in the ventrolateral thalamus of both groups of mutation carriers. As in the striatum, the thalamic binding reductions were more pronounced in DYT6 carriers and were not influenced by the presence of clinical manifestations.
Reduced D(2) receptor availability in carriers of dystonia genes is compatible with dysfunction or loss of D(2)-bearing neurons, increased synaptic dopamine levels, or both. These changes, which may be present to different degrees in the DYT1 and DYT6 genotypes, are likely to represent susceptibility factors for the development of clinical manifestations in mutation carriers.
Abnormalities in motor sequence learning have been observed in non-manifesting carriers of the DYT1 dystonia mutation. Indeed, motor sequence learning deficits in these subjects have been associated ...with increased cerebellar activation during task performance. In the current study, we determined whether similar changes are also present in clinically manifesting DYT1 carriers as well as in carriers of other primary dystonia mutations such as DYT6. Additionally, we determined whether sequence learning performance and associated brain activation in these subjects correlate with previously described genotype-related abnormalities of cerebellar pathway integrity and striatal D2 dopamine receptor binding. Nineteen DYT1 carriers (10 non-manifesting DYT1: 51.5±15.1 years; nine manifesting DYT1: 46.1±15.1 years) and 12 healthy control subjects (42.8±15.3 years) were scanned with H2(15)O positron emission tomography while performing controlled sequence learning and reference tasks. Eleven DYT6 carriers (four non-manifesting DYT6: 38.0±22.1; seven manifesting DYT6: 35.3±14.2 years) were evaluated during task performance without concurrent imaging. DYT1 and DYT6 carriers also underwent diffusion tensor magnetic resonance imaging for the assessment of tract integrity and 11C-raclopride positron emission tomography to measure caudate/putamen D2 receptor binding. These imaging measures were correlated with sequence learning performance and associated activation responses. Sequence learning deficits of similar magnitude were observed in manifesting and non-manifesting DYT1 carriers. In contrast, learning deficits were not detected in DYT6 carriers, irrespective of clinical penetrance. Affected DYT1 carriers exhibited significant increases in sequence learning-related activation in the left lateral cerebellar cortex and in the right premotor and inferior parietal regions. Increases in premotor cortical activation observed in the mutation carriers correlated with reductions in cerebellar pathway integrity measured using magnetic resonance diffusion tensor imaging and probabilistic tractography. Additionally, the cerebellar tract changes correlated with reductions in dentate nucleus activation recorded during task performance. Sequence learning performance and task-related activation responses did not correlate with striatal D2 receptor binding. In summary, we found that sequence learning deficits and concomitant increases in cerebellar activation are specific features of the DYT1 genotype. The close relationship between reduced cerebellar pathway integrity and increased learning-related activation of the premotor cortex is compatible with the view of DYT1 dystonia as a neurodevelopmental circuit disorder.
Context. The gamma-ray binary LS 5039 and the isolated pulsar PSR J1825−1446 were proposed to have been formed in the supernova remnant (SNR) G016.8−01.1. Aims. We aim to obtain the Galactic ...trajectory of LS 5039 and PSR J1825−1446 to find their origin in the Galaxy, and in particular to check their association with SNR G016.8−01.1 to restrict their age. Methods. By means of radio and optical observations we obtained the proper motion and the space velocity of the sources. Results. The proper motion of PSR J1825−1446 corresponds to a transverse space velocity of 690 km s-1 at a distance of 5 kpc. Its Galactic velocity at different distances is not compatible with the expected Galactic rotation. The velocity and characteristic age of PSR J1825−1446 make it incompatible with SNR G016.8−01.1. There are no clear OB associations or SNRs crossing the past trajectory of PSR J1825−1446. We estimate the age of the pulsar to be 80–245 kyr, which is compatible with its characteristic age. The proper motion of LS 5039 is μαcosδ = 7.09 and μδ = −8.82 mas yr-1. The association of LS 5039 with SNR G016.8−01.1 is unlikely, although we cannot discard it. The system would have had to be formed in the association Ser OB2 (at 2.0 kpc) if the age of the system is 1.0–1.2 Myr, or in the association Sct OB3 (distance 1.5–2 kpc) for an age of 0.1–0.2 Myr. If the system were not formed close to Ser OB2, the pseudo-synchronization of the orbit would be unlikely. Conclusions. PSR J1825−1446 is a high-velocity isolated pulsar ejected from the Galaxy. The distance to LS 5039, which needs to be constrained by future astrometric missions such as Gaia, is a key parameter for restricting its origin and age.
Mixtures of surfactants can result in formation of various structures like micelles, vesicles and inverted micelles. Catanionic vesicular systems are preferred on account of their ease of formation ...and thermodynamic stability. Furthermore, their charge and surfactant properties render them as useful vehicles for DNA delivery and cytotoxic compounds. They suffer from disadvantages of being leaky and yielding low encapsulation efficiencies which are averse to drug delivery purposes. Extensive efforts are being undertaken to overcome these barriers and render these vesicles amenable to spatial placement and temporal delivery of drugs. This manuscript addresses diverse aspects of catanionic vesicles including their formation, fabrication and stability. The manuscript focuses further on applications of catanionic vesicles in nanodrug delivery. Novel trends in the field of catanionics with respect to bio-compatibility and novel technologies developed using these systems have also been reviewed. An attempt has been made to compile catanionic systems reported in literature detailing surfactants and therapeutic agents employed to aid understanding and yield information of various facets that drive fabrication and potential utility of these systems in therapeutics.
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