ABSTRACT
INTRODUCTION: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. METHODS: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. RESULTS: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. CONCLUSION: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Dyslipidemias/drug therapy , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/pharmacology , Pregnanes/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Blood Glucose/drug effects , Cell Line , Cricetinae , Diabetes Mellitus, Experimental/metabolism , Dyslipidemias/metabolism , Fenofibrate/pharmacology , Fenofibrate/therapeutic use , Glucose Transporter Type 4/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/therapeutic use , Male , Mice , Muscle, Skeletal/drug effects , Pregnanes/chemistry , Pregnanes/pharmacokinetics , Pregnanes/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/metabolismABSTRACT
Toll-like receptors (TLRs) constitute a multi-gene family, which plays a pivotal role in sensing invading pathogens by virtue of conserved microbial patterns. TLR repertoire of chicken and zebra finch has been well studied. However TLR family of other avian species is yet to be characterized. In the present study, we identified TLR repertoire of turkey, characterized avian specific receptor TLR15 in turkey and profiled the TLRs expressions in a range of tissues of turkey poults. All ten TLR genes orthologous to chicken TLR repertoire were found in turkey. Turkey TLR genes showed 81-93 % similarity at amino acid level to their chicken counter parts. Phylogenetic analysis confirmed the orthologous relationship of turkey TLRs with chicken and zebra finch TLRs. Open reading frame of turkey TLR15 was 2,607 bp long encoding 868 amino acids similar to that of broiler chicken and showed 92.4, 91.1 and 69.5 % identity at amino acid levels with chicken, Japanese quail and zebra finch TLR15 sequences respectively. Overall TLR expression was highest for TLR4 and lowest for TLR21. TLR1A, 2A, 2B and 21 were significantly higher in liver than other tissues investigated (P < 0.01). TLR3 expression was significantly higher in bone marrow (BM) and spleen in comparison to other tissues studied (P < 0.01). Furthermore, no significant differences in the expression levels of TLR1B, 4, 5, 7 and 15 genes were detected among the tissues studied. Our findings contribute to the characterization of innate immune system of birds and show the innate preparedness of young turkey poults to a range of pathogens.
Subject(s)
Gene Expression Regulation , Toll-Like Receptors/genetics , Turkeys/genetics , Amino Acid Sequence , Animals , Gene Expression Profiling , Genome , Molecular Sequence Data , Phylogeny , Sequence Alignment , Toll-Like Receptors/chemistry , Transcription, GeneticABSTRACT
Virosome based vaccines against Newcastle disease (ND) were prepared and evaluated for their immunogenicity and protective efficacy in chickens. Envelop of Newcastle disease virus (NDV) was solubilised with Triton X-100 to yield virosomes which were later on encapsulated in poly-lactide-co-glycolide (PLG) microspheres. The birds were immunized intranasally with virosomes or PLG microspheres encapsulated virosomes, and efficacy of these preparations was compared with commercial LaSota vaccine. The preparations protected the chickens against virulent virus challenge infection, however the microencapsulated virosome vaccine gave slightly lesser degree of protection than non encapsulated counterpart. The humoral and cell mediated immune response generated as well as the protection afforded by virosome preparations were found to be comparable with LaSota vaccine. The results substantiate the potential of virosome based vaccines to provide high level of immunity and protection against Newcastle disease.
