It was shown that activation of dopaminergic (Daergic) system induced an increase of the immune responsiveness independent of the CBA mice behaviour typeanimals without experience of victories and defeats (control), with aggression and submission. Administration of SKF-38393, a selective agonist of DA D1-receptors, resulted in enhanced immune response as tested by plaque-forming cells and rosette-forming cells number. Similar immunostimulation was observed after injection of p-chlorophenylalanine realizing its influence on the immune response through DA D2-receptors as shown by us elsewhere. It was suggested that activation of Da-ergic system produces a new neurochemical pattern (Daergic neurochemical set) which are responsible for character and intensity changes of the immune response in mice with alternative form of social behaviour.
We measured activity and content of cathepsin B in tumor tissues, liver, and spleen in mice with Lewis adenocarcinoma and LS-lymphosarcoma. Cathepsin B activity in Lewis adenocarcinoma cells was lower than in LS-lymphosarcoma cells, which was probably related to differences in their metastatic properties. Antitumor therapy increased activity and content of cathepsin B in tumor tissues. Changes in the content and activity of cathepsin B in tumor tissues can serve as a prognostic criterion for tumor regression during therapy. Cathepsin B is probably involved in apoptosis of tumor cells during chemotherapy of lymphosarcoma-LS with cyclophosphamide.
The activities of three cytochrome P450 families involved in metabolic transformation of cyclophosphamide (CP) (CYP2B and CYP2C responsible for metabolic activation of CP and CYP3A responsible for inactivation of CP) have been investigated in lymphosarcoma and liver microsomes of tumor-bearing CBA mice. Two strains of mouse lymphosarcoma distinguished by their sensitivity to cytostatic action of CP were used in this study for implantation in mice femur muscle. There was certain relationship between CP resistance of lymphosarcoma and tumor P450s activity. CYP2B, CYP2C and CYP3A activities in the CP sensitive tumor were comparable to those in liver, and CYP2B, CYP2C were induced by phenobarbital and dexamethasone. CYP2B and CYP2C in the CP resistant tumor were inactive and only slightly induced by dexamethasone. CYP3A activity was lower than in LS tumor and unchanged during drug treatment. Implantation of LS and RLS tumor in mice caused different effects on P450 activities. LS insignificantly influenced liver CYP2B, CYP2C and CYP3A activities and their inducibility by phenobarbital and dexamethasone was similar to that obtained in liver of mice without tumor. At the same time, CYP2B and CYP2C activity in liver of RLS-bearing mice were essentially reduced, the activity CYP3A remained unchanged, and inducibility of CYP2B, CYP2C and CYP3A by phenobarbital and dexamethasone was similar to that in liver of mice without tumor. These results prove the role of cytochromes P450 activating CP in formation drug resistant phenotype of mice lymphosarcoma and suggest possibility of overcoming of this resistance using cytochrome P450 inducers.
Lysosomal enzyme activity in the bile and blood serum was compared in mice with experimental intrahepatic cholestasis induced by alpha-naphthyl isothiocyanate and Triton WR 1339. Triton WR 1339 increases the synthesis of cholesterol (fatty acid precursor) in liver cells. The development of intrahepatic cholestasis was confirmed by the increase in activities of alkaline phosphatase and gamma-glutamyltransferase in blood serum. Administration of Triton WR 1339 in a dose of 100 mg/100 g was followed by a 10-fold increase in beta-galactosidase activity (hepatocyte lysosomal enzyme) in the bile, but not in the serum of mice. beta-Galactosidase activity significantly increased in the bile, but decreased in the serum of mice after treatment with a-naphthyl isothiocyanate in a dose of 200 mg/kg. Our results indicate that intrahepatic cholestasis is manifested in increased secretion of lysosomal glycosidases into the bile. Bile components can aggravate damage to liver cells by affecting the processes of hepatocyte apoptosis and necrosis.
Accelerated bone marrow cell death and activation of the sympathoadrenal system were observed during aging of highly leukemic 2-7-month-old AKR/JY mice compared to that in (CBA/CaLacxAKR/JY)F1 strain. Close correlation was revealed between activity of the sympathoadrenal system and necrotic and apoptotic forms of cell death. This can promote tumor process, because maximum changes in hemopoietic cells occur during advanced stage of the disease.
The role of central adrenergic structures in the regulation of the erythroid hematopoietic stem was studied during administration of cyclophosphamide and 5-fluorouracil. The central nervous system contributed to suppression of erythropoiesis during cytostatic treatment. The suppressive effect of brain adrenergic structures on the erythron after treatment with cyclophosphamide and 5-fluorouracil was related to dysfunction of adherent cells in the hemopoiesis-inducing microenvironment (formation of hemopoietic islets and secretion of erythropoietic activity) and production of growth factors by myelokaryocytes, respectively. Brain norepinephrine had an inhibitory effect on proliferative activity and differentiation of erythroid precursors that were associated with the erythropoietin and peripheral alpha-adrenergic structures. However, stimulation of beta-adrenergic structures was followed by an increase in the rate of erythroid cell maturation.
It was investigated both melatonin blood level in the adult and old CBA-mice after immunization by sheep erythrocytes and the link between thymus and adrenal glands function in the old immunizated mice with high melatonin content in the pineal gland. It has been revealed that in the adult mice blood melatonin level was influenced by the phase changes in dynamic of immunization, namely raised significantly in 20 min with following suppression after 3 hrs and rehabilitation up to normal in 4 days. In the old mice fluctuations of melatonin level were impaired and characterized by gradually decrease in dynamics of immunization. The increase of melatonin content in pineal gland by administration of epithalamine improved the dynamics of fluctuations of thymic hormone and corticosterone level in the immunizated old mice.
The thymic serum factor (FTS) titer and corticosterone level in blood of adult and old CBA mice after immunization by T-dependent antigen was investigated. It has been revealed that in adult mice these indices influenced by phase changes in dynamics of immunization whereas in old mice fluctuations of FFS and corticosterone levels were monotonous. In both adult and old mice the correlation exists between thymic hormone and corticosterone. The increasing of thymic function by thymaline administration did not improve the dynamics of FTS titer and corticosterone level in immunized old mice.
Expression of mRNA for interleukin-6, interleukin-6Delta3, and interleukin-6Delta5 was detected in placental tissue (second and third trimesters of pregnancy) and spleen of mice immunized with sheep erythrocytes in high dose. We hypothesize that translation of mRNA yields proteins capable of binding to individual subunits of the interleukin-6 receptor and possessing effector functions.
Immunogenic properties of TVGRGDPHQ nonapeptide which is correspondent to the region 1094-1102 of B. pertussis filamentous hemagglutinin (FHA) were studied. The conjugate of bovine serum albumin with nonapeptide was used for immunization of BALB/c and CBA mice. Antisera of the both lines of mice cross-reacted with a number of antigens, but using affinity chromatography peptide and FHA specific antibodies were extracted. Affinity purified rabbit antibodies to TVGRGPHQ which recognize FHA were also obtained. Therefore the antibodies to the peptide which placed RGD-containing region responsible for macrophage CR3-integrin interaction are capable to distinguish the native antigen. Thus these data are an additional evidence for the nonapeptide use as a component of synthetic vaccine against whooping-cough.