ABSTRACT
The M680I and M694V mutations located in the B30.2 pyrin domain are responsible for the manifestation of the most common forms of Familial Mediterranean fever. It is well known that a malfunction of the pyrin-caspase-1 complex is the main cause of inflammation in FMF. The purpose of this study was to identify possible changes in the tertiary structure of mutated B30.2 domain and to determine their potential consequences in the formation of the pyrin-caspase-1 complex. Using computer modeling, it was found that the above mutations change the tertiary structure of B30.2 domain, causing shifts of binding sites and altering the energy of interaction between B30.2 and caspase-1.
Subject(s)
Caspase 1/chemistry , Cytoskeletal Proteins/chemistry , Molecular Dynamics Simulation , Mutation , Familial Mediterranean Fever/metabolism , Humans , Kinetics , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Pyrin , Thermodynamics , User-Computer InterfaceABSTRACT
The results of experiments on male mongrel mice showed that a three-day treatment with T-activin in a dose of 2.5 micrograms/kg restored the activity of natural killer cells reduced by acute poisoning (1 LD50) with ethylene glycol (EG), methanol (MeOH), and ethanol (EtOH). In a dose of 5 micrograms/kg, T-activin produced the same action in the test animals upon acute poisoning with dimethyldichlorovinyl phosphate (DDVP), carbophos (CP), dichloroethane (DE), acrylonitrile (AN), Acetonitrile (AcN), atropine (AT). The degree of suppression of the native killer cell activity by the above chemicals increases in the following order: EtOH < EG < MeOH < CP < AT < AcN < DE < AN < DDVP.
Subject(s)
Adjuvants, Immunologic/pharmacology , Hazardous Substances/toxicity , Killer Cells, Natural/drug effects , Peptides/pharmacology , Poisoning/immunology , Thymus Extracts/pharmacology , Acute Disease , Animals , Cytotoxicity, Immunologic , Male , MiceABSTRACT
Acute poisoning with alcohols and cholinotropic preparations carboxyphosphamide and atropine (0.8 LD(50)) was modeled on male outbred mice weighing 18-24 g. The decrease in activity of natural killer cells was most pronounced after injection of atropine, but insignificant after treatment with ethanol. The inhibitory effect of ethylene glycol, methanol, and methanol on functional activity of natural killer cells in vitro directly depended on their concentration. The effects of alcohols in equimolar concentrations of 10, 100, and 500 mM were similar. Therefore, immunotoxicity of alcohols was associated with the action of their metabolites. The ability of products formed after biotransformation of ethylene glycol, methanol, and ethanol in equimolar concentrations to cause damage to natural killer cells decreased in the following order: glyoxylic acid>formic acid>acetaldehyde>glycolaldehyde>glycolic acid. T-Activin injected subcutaneously in doses of 2.5 and 5.0 microg/kg for 3 days normalized activity of natural killer cells suppressed after acute poisoning with alcohols and cholinotropic preparations.
Subject(s)
Alcoholic Intoxication/immunology , Killer Cells, Natural/drug effects , Organosilicon Compounds/poisoning , Peptides/pharmacology , Thymus Extracts/pharmacology , Acute Disease , Animals , Killer Cells, Natural/immunology , Male , MiceABSTRACT
In vitro experiments on splenocytes from noninbred mice showed that ethylene glycol, methanol, and ethanol dose-dependently suppressed functional activity of T and B cells. These compounds in equimolar concentrations (10, 100, and 500 mM) produced similar effects, hence their immunotoxicity is determined by their metabolites. The suppressive effects of alcohol biotransformation products to antibody-forming activity of T and B cells decreased in the following order: glyoxylic acid - formic acid - glycolaldehyde - glycolic acid - acetaldehyde. The effects of these substances were dose-dependent. Suppression of T cells was more pronounced.