ABSTRACT
The GroEL/ES chaperonin cavity surface charge properties, especially the negative charges, play an important role in its capacity to assist intracavity protein folding. Remarkably, the larger fraction of GroEL/ES negative charges are not conserved among different bacterial species, resulting in a large variation in negative-charge density in the GroEL/ES cavity across prokaryotes. Intriguingly, eukaryotic GroEL/ES homologs have the lowest negative-charge density in the chaperonin cavity. This prompted us to investigate if GroEL's chaperoning mechanism changed during evolution. Using a model in vivo GroEL/ES substrate, we show that the ability of GroEL/ES to buffer entropic traps in the folding pathway of its substrate was partially dependent upon the negative-charge density inside its cavity. While this activity of GroEL/ES was found to be essential for Escherichia coli, it has been perfected in some organisms and diminished in others. However, irrespective of their charges, all the tested homologs retained their ability to regulate polypeptide chain collapse and remove enthalpic traps from folding pathways. The ability of these GroEL/ES homologs to buffer mutational variations in a model substrate correlated with their negative-charge density. Thus, Hsp60/10 chaperonins in different organisms may have changed to accommodate a different spectrum of mutations on their substrates.
Subject(s)
Chaperonin 60 , Protein Folding , Chaperonin 60/metabolism , Hydrophobic and Hydrophilic Interactions , Molecular Chaperones/metabolism , Peptides/chemistryABSTRACT
BACKGROUND: Parkinsonism has a toxic cascade of neurodegeneration, with akinesia as a major manifestation. Some antioxidants have shown promise against the disease. Astaxanthin is a powerful antioxidant, demonstrates free radical scavenging, and is also a potential neuroprotective agent. OBJECTIVE: The objective of this study was to formulate astaxanthin-laden nanostructured lipid carriers based thermoreversible gel for better neuronal uptake and better neuronal efficacy. METHODS: The method for fabricating astaxanthin-nanostructured lipid carriers (ATX-NLC) was melt-emulsification, and these were optimized using factorial design and further evaluated for diverse parameters. Neurotoxicity was induced in rats by haloperidol. The treated and non-treated rats were then witnessed for their behaviour. TBARs and GSH levels were also determined. Pharmacokinetics was studied via HPLC. RESULTS: The average particle size (by DLS), entrapment efficiency and zeta potential of optimized ATX-NLC were 225.6 ± 3.04 nm, 65.91 ± 1.22% and -52.64 mV, respectively. Astaxanthin release (after 24 h in simulated nasal fluid) from optimized ATX-NLC was 92.5 ± 5.42%. Its thermoreversible nasal gel (ATX-NLC in-situ gel) was prepared using poloxamer-127. The obtained gel showed in-vivo betterment in the behaviour of animals when studied using the rotarod and akinesia test. Pharmacokinetic studies showed better availability of astaxanthin in the brain on the rats treated with ATX-NLC in-situ gel as compared to those treated with ATX-in-situ gel. CONCLUSION: Astaxanthin-loaded lipidic nanoparticulate gel can be a hopeful adjuvant therapy for Parkinsonism and holds scope for future studies.
Subject(s)
Nanostructures , Parkinsonian Disorders , Animals , Drug Carriers , Haloperidol , Lipids , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/drug therapy , Particle Size , Rats , XanthophyllsABSTRACT
Cyclocondensation of thiosemicarbazone of 2-acetylferrocene with α-haloacids and α-haloketones afford new ferrocenyl hydrazono thiazolidin-4-ones and ferrocenyl hydrazono thiazoles respectively. Ferrocenyl hydrazono thiazolidin-4-one is easily converted into enamino ketone with N,N-dimethylformamide dimethyl acetal (DMF-DMA). The compounds were characterized by spectroscopic means and the structure of the new ferrocenyl hydrazono thiazolidin-4-one (3a) was determined by means of X-ray crystallography. The photophysical properties of these compounds were studied by means of UV/visible absorption spectroscopy and fluorescence spectroscopy. Density functional theory (DFT) calculations have been carried out with Gaussian 09W using B3LYP density functional method and 6-31G (d) basis set. (1)H and (13)C Nuclear Magnetic Resonance (NMR) have been calculated and correlated with experimental results. Antimicrobial activity studies of some new compounds have been reported.
Subject(s)
Ferrous Compounds/chemistry , Hydrazones/chemistry , Thiazolidines/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Crystallography, X-Ray , Ferrous Compounds/chemical synthesis , Ferrous Compounds/pharmacology , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Models, Molecular , Molecular Structure , Quantum Theory , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , Stereoisomerism , Thiazolidines/chemical synthesis , Thiazolidines/pharmacologyABSTRACT
The reaction of semicarbazide or thiosemicarbazide with 2-arylidene-1-tetralones under alkaline condition affords 3,3a,4,5-tetrahydro-2H-benzo[g]indazole-2-carbo(thio)amides as a mixture of cis and trans diastereoisomers of 3-H and 3a-H. The synthesis of new indazolyl-thiazol-4(5H)-ones from the condensation of cis isomer and α-halo acids is reported. A DFT study along with X-ray single crystal data of a representative compound is presented. All the eight newly synthesised indazolyl-thiazol-4(5H)-ones were screened for their antibacterial and antifungal activities and some compounds have shown promising activities.