ABSTRACT
The comparative study of activity of cysteine protease cathepsin K and matrix metalloproteases (MMPs) in bone tissue of accelerated senescent OXYS rats with early ageing comparatively to Wistar rats of the same age was performed. Early development osteoporosis is a typical feature of OXYS rats. In bone tissue of 3 month old OXYS rats, before appearance of osteoporosis manifestation cathepsin K activity was higher, whereas MMPs activity was lower than in Wistar rats. In Wistar rats (3 and 14 months old) cathepsin K activity of spine was shown to increase, and MMPs activity to decrease. In OXYS rats age-related change of cathepsin K and MMPs activity in bone tissue had the opposite direction. As a result of this there were no differences between Wistar and OXYS rats 14 months old despite the marked osteoporosis in OXYS rats as revealed our early researches. Serum Q2-macroglobulin activity was higher in 14 months old OXYS rats. The role of activation of cathepsin K in bone resorption in the development of osteoporosis in early ageing OXYS rats is discussed.
Subject(s)
Aging/metabolism , Bone and Bones/enzymology , Cathepsin K/metabolism , Matrix Metalloproteinases/metabolism , Osteoporosis/enzymology , Animals , Male , Rats , Rats, Wistar , alpha-Macroglobulins/metabolismABSTRACT
Proteoglycans play a crucial role in bone tissue formation promoting consolidation of collagen fibers and bonds between them and mineral crystals. The composition of extracellular matrix proteoglycans was analyzed in early aging OXYS rats with signs of early osteoporosis versus Wistar rats at the age of 2, 4, 6, and 8 months. It was found that bone mineral density in two month OXYS rats was lower than in age-matched Wistar rats. It increased only till 6 month of age in OXYS rats, and during the whole observation period in Wistar rats. Formation of peak bone mass in Wistar rats was accompanied by change in composition of proteoglycan pools in bone tissue matrix: accumulation of macromolecular keratan sulfate-containing proteoglycans, and decrease of uronic acid and sulfated glycosaminoglycan content. OXYS rats were noted for accumulation of micro- and macromolecular proteoglycans: uronic acids and sulfated glycosaminoglycans. Chondroitin sulfate AC and dermatan sulfate were accumulated in OXYS rat bone tissue with the increase in mineral density difference. Keratin sulfate was completely absent here, in contrast to Wistar rats.
Subject(s)
Aging, Premature/metabolism , Aging/metabolism , Bone Matrix/metabolism , Glycosaminoglycans/metabolism , Osteoporosis/metabolism , Absorptiometry, Photon , Animals , Bone Density , Disease Models, Animal , Electrophoresis, Agar Gel , Male , Osteoporosis/etiology , Proteoglycans/metabolism , Rats , Rats, Inbred StrainsABSTRACT
Development of murine HA-1 hepatoma was accompanied by increased activity of cathepsin B (in ascitic cells), cathepsin D (in ascitic fluid) and increased activity of procathepsin B. There were some changes of cysteine proteinases in liver and spleen, not involved directly into tumor growth. The most prominent changes included the decreased level of cysteine proteinase inhibitors cystatin C and stefin A in ascitic cells (and to a lesser degree in liver tissue). During tumor development serum cystatin C concentration decreased by 3-times compared to intact mice. Treatment by antitumor drug Ukraine increased life span of mice with HA-1 hepatoma (transplanted intravenously), decreased the increment of tumor weight. In ascite such treatment caused a decrease of number of tumor cells and an increase of number of macrophages. Ukraie (administered once or 5-times in a dose of 0.5 mg per mice) increased cystatin C level, revealing protective mechanism of action.
Subject(s)
Alkaloids/therapeutic use , Antineoplastic Agents/therapeutic use , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Liver Neoplasms, Experimental/drug therapy , Animals , Ascites/enzymology , Ascites/metabolism , Ascites/pathology , Berberine Alkaloids , Cathepsin B/metabolism , Cathepsin D/metabolism , Cathepsin L , Cathepsins/metabolism , Cystatin A , Cystatin C , Cystatins/metabolism , Liver Neoplasms, Experimental/enzymology , Liver Neoplasms, Experimental/metabolism , Male , Mice , Neoplasm Transplantation , PhenanthridinesABSTRACT
The concentration of stefin A (cystatin A in mice) was measured in animals with experimental tumors (LS lymphosarcoma, HA-1-hepatoma, and Lewis lung carcinoma) during effective antitumor therapy. In mice with these tumors serum concentrations of stefin A increased, while the concentration of cystatin C (extracellular cystein proteinase inhibitor) decreased. The concentration of stefin A in tumor tissue in Lewis lung carcinoma was higher than in LS lymphosarcoma and HA-1-hepatoma ascitic cells, which can be explained by the degree of their malignancy. The content of stefin A in tumor tissue was similar to that in the liver and spleen of tumor-bearing animals, while its concentration in the liver and spleen of tumor-bearing animals was lower than in intact mice. The level of stefin A is an important marker of malignancy and an indicator of the efficiency of antitumor therapy.
Subject(s)
Cystatins/biosynthesis , Cysteine Proteinase Inhibitors/pharmacology , Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Carcinoma/drug therapy , Carcinoma, Hepatocellular/metabolism , Carcinoma, Lewis Lung/drug therapy , Cystatin A , Cystatin C , Cystatins/blood , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Neoplasm Transplantation , Spleen/metabolism , Time FactorsABSTRACT
Serpin alpha-1-proteinase inhibitor have been studied in human subjects and in mice of different lines as acute phase reactant and during tumor development. In humans, there was no difference of serpin activity between men and women. Increased activity was noted in men with acute trauma (acute phase reaction). Comparatively to male, in female mice of different lines decreased activity of serum alpha-1-proteinase inhibitor, was shown. There was no increase of alpha-1-proteinase inhibitor activity during inflammation induced by zymosan administration in mice. alpha-1-proteinase inhibitor belongs to acute phase reactants in humans but not in mice; for mice alpha-2-macroglobulin is a more typical acute phase reactant as compared to alpha-1-proteinase inhibitor. Murine tumor development (hepatoma HA-1, lymphosarcoma LS, Lewis lung adenocarcinoma) was followed by a decreased activity of serum alpha-1-proteinase inhibitor both in successfully treated and untreated groups. According to data of literature, similar dated were obtained in humans with tumors. It was suggested that changes of expressiln of alpha-1-proteinase inhibitor by tumors and its secretion were involved in decreased activity of alpha-1-proteinase inhibitor.
Subject(s)
Fractures, Bone/blood , Leg Injuries/blood , Neoplasms, Experimental/blood , alpha 1-Antitrypsin/metabolism , Adolescent , Adult , Age Factors , Animals , Female , Humans , Male , Mice , Mice, Inbred Strains , Sex Factors , Species Specificity , alpha 1-Antitrypsin/physiologyABSTRACT
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.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Lewis Lung/enzymology , Cathepsin B/metabolism , Lymphoma, Non-Hodgkin/enzymology , Animals , Carcinoma, Lewis Lung/pathology , Liver/enzymology , Lymphoma, Non-Hodgkin/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Prognosis , Spleen/enzymologyABSTRACT
The growth of LS-lymphosarcoma in CBA mice was accompanied by a decrease in the content of the major extracellular inhibitor cystatin C in the tumor, plasma and, to a lesser extent, in tissues not involved in tumor process (liver and spleen). Cyclophosphamide in a dose of 50 mg/kg prolonged the life-span of animals and decreased tumor size by 80%. Cathepsin B and L activities in the tumor tissue increased by 3 and 7 times, respectively. Cystatin C content in the tumor tissue, spleen, and plasma also increased. Cystatin C assay in tumor tissue and plasma helps to predict the rate of tumor growth and to evaluate the efficiency of antitumor therapy.
Subject(s)
Cathepsin B/metabolism , Cathepsins/metabolism , Cystatins/metabolism , Lymphoma, Non-Hodgkin/metabolism , Animals , Antineoplastic Agents, Alkylating/therapeutic use , Cathepsin B/antagonists & inhibitors , Cathepsin L , Cathepsins/antagonists & inhibitors , Cyclophosphamide/therapeutic use , Cystatin C , Cysteine Endopeptidases , Humans , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/enzymology , Lymphoma, Non-Hodgkin/physiopathology , Male , Mice , Mice, Inbred CBAABSTRACT
We studied the effect of macrophage stimulator water-soluble beta-(1-->3)-D-carboxymethylglucan on the efficiency of cyclophosphamide chemotherapy in Lewis lung carcinoma. Cyclophosphamide inhibited the growth of primary tumor nodes by 57%. The preparation possessed pronounced antimetastatic activity: metastases were found in 40.9% animals. Combination therapy with cyclophosphamide and (1-->3)-beta;-D-glucan inhibited the growth of intramuscular tumors by 75-89% and reduced the incidence of metastases into the lungs by 92-94%. The therapeutic effect was most pronounced after simultaneous administration of these preparations: tumor growth was suppressed by 89.3% and metastases were found in only 7.5% animals (vs. 100% in the control). The potentiating effect of beta-(1-->3)-D-carboxymethylglucan is related to accumulation of cysteine proteinase inhibitors in the tumor tissue and plasma, but not to changes in blood cell composition.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Lewis Lung/drug therapy , Glucans/administration & dosage , beta-Glucans , Animals , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/therapeutic use , Body Weight/drug effects , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Cathepsin B/analysis , Cathepsin L , Cathepsins/analysis , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Cystatin A , Cystatin C , Cystatins/blood , Cysteine Endopeptidases , Drug Synergism , Injections, Intraperitoneal , Lung Neoplasms/secondary , Macrophages/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Neoplasm TransplantationABSTRACT
Serum chitotriosidase activity was determined in different conditions accompanied by macrophage stimulation. Stimulation of macrophages with zymosan, yeast polysaccharide carboxymethylglucan (fraction II), and lysosomotropic preparation Triton WR-1339 1.5-2.0-fold increased enzyme activity. Chitotriosidase activity in intact Wistar rats was similar to that in humans, while in CBA and A/Sn mice this parameter was 5-fold higher. Sharp increase in chitotriosidase activity in the serum from patients with type I Gaucher's disease was probably related to intense secretion of the enzyme by macrophages. Under experimental conditions, stimulation of rat and mouse macrophages (mainly liver cells) caused no increase in chitotriosidase activity typical of patients with Gaucher's disease.
