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The present study was premeditated to examine the radioprotective effects of aqueous Aloe vera gel extract against whole-body X-ray irradiation-induced hematological alterations and splenic tissue injury in mice. Healthy male balb/c mice were divided into four groups: group 1, control; group 2, A. vera (50 mg/kg body weight) administered per oral on alternate days for 30 days (15 times); group 3, X-ray exposure of 2 Gy (0.25 Gy twice a day for four consecutive days in the last week of the experimental protocol); and group 4, A. vera + X-ray. X-ray exposure caused alterations in histoarchitecture of spleen along with enhanced clastogenic damage as assessed by micronucleus formation and apoptotic index. Irradiation caused an elevation in proinflammatory cytokines like tumor necrosis factor and interleukin-6, total leucocyte counts, neutrophil counts and decreased platelet counts along with unaltered red blood cell counts and hemoglobin. Irradiation also caused an elevation in reactive oxygen species (ROS), lipid peroxidation (LPO) levels, lactate dehydrogenase activity and alterations in enzymatic and nonenzymatic antioxidant defense mechanism in plasma and spleen. However, administration of A. vera gel extract ameliorated X-ray irradiation-induced elevation in ROS/LPO levels, histopathological and clastogenic damage. It also modulated biochemical indices, inflammatory markers, and hematological parameters. These results collectively indicated that the A. vera gel extract offers protection against whole-body X-ray exposure by virtue of its antioxidant, anti-inflammatory and anti-apoptotic potential.

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The present investigation was carried out to evaluate the possible radioprotective potential of an Aloe vera extract against whole-body X-ray irradiation-induced testicular alterations in mice. Male balb/c mice were divided into four groups: control, A. vera, X-ray and A. vera pre-treated + X-ray irradiated. Histopathological examination revealed significant structural alterations in testes after X-ray exposure, which was also associated with the presence of apoptotic cells as assessed by TUNEL assay. X-ray irradiation resulted in elevation in the levels of reactive oxygen species, lipid peroxidation, a reduction in glutathione concentration and enhanced activities of antioxidant enzymes such as glutathione reductase, glutathione peroxidase, catalase, superoxide dismutase and glutathione-S-transferase. Sperm count/motility and testosterone levels were significantly decreased in the irradiated group. Irradiated animals pre-treated with A. vera extract revealed an improvement in antioxidant status, inhibition of lipid peroxides, apoptotic cell formation and enhanced testicular parameters when compared to the X-ray-exposed group. These findings suggest that A. vera extract could ameliorate X-ray-induced damage due to its free radical scavenging properties and its potential to boost cellular antioxidant defence machinery.

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The present study was conducted to understand the influence of zinc on bone mineral metabolism in prednisolone-treated rats. Disturbance in bone mineral metabolism was induced in rats by subjecting them to prednisolone treatment for a period of 8 weeks. Female rats aged 6-8 weeks weighing 150 to 200 g were divided into four treatment groups, viz., normal control, prednisolone-treated (40 mg/kg body weight orally, thrice a week), zinc-treated (227 mg/L in drinking water, daily), and combined prednisolone + zinc-treated groups. Parameters such as changes in mineral levels in the bone and serum, bone mineral density (BMD), bone mineral content (BMC), and bone 99m-technetium-labeled methylene diphosphonate ((99m)Tc-MDP) uptake were studied in various treatment groups. Prednisolone treatment caused an appreciable decrease in calcium levels both in the bone and serum and also in bone dry weight, BMC, and BMD in rats. Prednisolone-treated rats when supplemented with zinc showed further reduction in calcium levels, bone dry weight, BMD, and BMC. The study therefore revealed that moderate intake of zinc as a nutritional supplement during steroid therapy could enhance calcium deficiency in the body and accelerate bone loss.

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The role of host defense mechanisms in preventing the development of subclinical tumors into invasive tumors in an autochithonous host was studied in a model of rat colon carcinoma induced by 1,2-dimethylhydrazine dihydrochloride (DMH). Multiple gastrointestinal (GI) tumors were induced in inbred WF female rats exposed to DMH. In vitro and in vivo data suggested that the excision of the "first" GI tumor induced specific antitumor immune responses. After a complete excision of the first GI tumor, only 2 additional GI tumors were observed in 10 rats, whereas 13 and 12 additional GI tumors in 10 and 9 rats, respectively, were observed if the first GI tumor was left in situ or permitted to grow in an isolated segment of the colon. Furthermore, immunosuppression with antithymocyte globulin decreased the effectiveness of antitumor immunity induced by the immunizing first GI tumor. These experiments supported the view that an effective antitumor immunity is induced against successive tumors of an organ after a complete excision of a tumor originating in the same organ. The results of these experiments are discussed in relation to the observations of multiple primary neoplasms in humans.

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The effect of multimodal immunotherapy was studied in rats bearing primary gastrointestinal tumors induced by 1,2-dimethylhydrazine dihydrochloride. Multimodal immune manipulation consisted of combinations of splenectomy, C. parvum, unblocking serum, unblocked lymphoid cells, and levamisole. Such immunologic intervention resulted in significant inhibition of tumor growth, and their metastasis. Ten of 10 untreated rats, 8 of 8 rats treated with splenectomy alone and 10 of 10 rats treated with normal rabbit serum died of progressive tumor growth. None of the rats treated with combinations of splenectomy, unblocking serum, unblocked lymphoid cells, C. parvum and levamisole succumbed to progressive tumor growth during the observation period. The histologic evidence of tumor destruction was obtained in 18 of 22 tumors in rats of groups receiving multimodal immunotherapy.

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The effect of multimodal immunotherapy was studied in WF rats bearing primary gastrointestinal (GI) tumors induced by 1,2-dimethylhydrazine dihydrochloride. The alterations induced in antitumor immune responses of the treated rats were studied in vitro and were correlated with tumor status in vivo. Multimodal immunotherapy consisted of unblocking serum, unblocked lymphoid cells, and levamisole. Such immunologic intervention resulted in significant inhibition of tumor growth, inhibition of metastases, and prolonged survival of the host. Serum blocking activity could be completely counteracted in 6 rats, all of which showed complete tumor regression. Of 20 rats, 8 showed inadequate counteraction of serum blocking activity and transient appearance of cytotoxic antibodies. All 8 rats showed marked tumor inhibition and prolonged survival. Six remaining rats succumbed from either GI or extra-GI tumors, although they survived significantly longer than untreated rats; these 6 rats had only transient counteraction of their serum blocking activity. All 20 tumors in 14 rats of the therapy group showed histologic evidence of tumor rejection. Our studies suggested that a complete counteraction of blocking activity in conjunction with methods capable of improving the specific and nonspecific immune competence of the host may be important to achieve optimal antitumor effects.

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The effects of different types of diets on colon carcinogenesis by 1,2-dimethylhydrazine and on the immune system were studied in W/Fu rats. Six different types of diets were used in two sets of experiments. Rats in each group were fed the respective diets immediately upon weaning. 1,2-Dimethylhydrazine dihydrochloride was administered s.c. at a dosage of 15 mg/kg weekly in two divided doses. The rats were followed by sequential laparotomies for the development of gastrointestinal (GI) tumors until death. Tumors appeared earlier, and the total number of GI tumors, particularly those of the colon, was higher in rats fed diet enriched with fat from animal sources. In these rats the GI tumors metastasized more frequently, and their survival, after appearance of the first GI tumor, was significantly shortened. The diet low in animal fat and enriched with carbohydrate reduced the number of GI tumors and delayed their appearance. Semisynthetic elemental diet accelerated the appearance of colon tumors without increasing the total number of GI tumors over the life span of the animals. Serum cholesterol levels evaluated during carcinogenesis suggest a correlation between serum cholesterol levels and the increased frequency of colonic tumors. The alterations in serum immunoglobulin G levels, lymphocyte counts, and surface immunoglobulin-bearing lymphocytes evaluated at different times during carcinogenesis suggested a biphasic ("M type") immune response. Rats fed low residue diets and/or diets containing fat from animal sources had depressed serum immunoglobulin G levels. However, the pattern of immune response was similar in groups of rats fed different types of diets.

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Plasma of a patient with metastatic colon carcinoma was perfused over Formalin and heat-killed S. aureus, in an extracorporeal filtration apparatus, in order to nonspecifically remove IgG and its complexes. Twenty ex vivo absorption procedures were done, over a five-month period, with a minimum of discomfort to the patient. Extracorporeal perfusion of plasma on S. aureus effectively reduced the levels of IgG and immune complexes in the perfused plasma. The nonspecific removal of IgG resulted in 1) slight biochemical alterations in the serum, 2) a transient reduction in the serum blocking activity and appearance of complement-dependent serum cytotoxicity, 3) an increase in the serum IgM levels, 4) a transient increase in the Ig surface-bearing lymphocytes and a decrease in "E" rosetting lymphocytes in the first 24-48 hours postperfusion, particularly during the early treatments, 5) an improvement in general condition of the patient and decrease in tumor size, and 6) histological changes in the tumor consistent with tumor destruction. The potential problems and clinical applications of procedures involving ex vivo specific or nonspecific immunoabsorbents are discussed.

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Inbred WF rats were inoculated with crude suspensions prepared from liver and gut tissue of 12- to 15-day fetuses of the same strain. Rats previously unsensitized to syngeneic embryonic tissue were inoculated with fetal material sc three times during exposure to 1, 2-dimethylhydrazine dihydrochloride (DMH), a gastrointestinal (GI) carcinogen in rodents. Properly timed immunization inhibited the development, growth, and metastasis of primary GI tumors. This effects was observed in both sexes; however, it was more prounced in male rats. Nine WF rats with DMH-induced carcinoma of the GI tract were inoculated sc with syngeneic fetal tissue. Of 9 rats, 7 rejected the embryonal tissue implants, which thus demonstrated the presence of a concomitant immune response to embryonic antigen(s). Two rats in which fetal tissue grew out to palpable nodules had multiple GI tumors with metastasis and extra-GI tumors, i.e., a massive tumor load. Ten other rats with DMH-induced GI tumors were treated with unblocking serum. The unblocking serum was inoculated to counteract serum-blocking factors in vivo. These rats were inoculated intradermally with syngeneic fetal tissue. In all 10 rats, inflammation and necrosis were noted at the inoculation site after 24-72 hours, which thus demonstrated a delayed hypersensitivity reaction to embryonic antigens. Our experiments suggest that embryonic antigens common to fetal and tumor cells can induce immunity in an autochthonous host and can act as rejection antigens.

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We have described a clinically feasible method capable of rapidly and repeatedly removing mammalian IgG extracorporeally by adsorption onto heat-killed, formalin-stabilized Staphylococcus aureus Cowan-I. In dogs, 2-13 grams of IgG were removed in 60-70 minutes, lowering the serum concentration of IgG by 30-70 percent. Serum IgG levels returned to pre-run values within 48-72 hours and, in some cases, were higher than pre-run levels at 48-72 hours. Serum biochemical alterations were generally transient and relatively modest. Peripheral lymphocyte counts showed minimal changes but the percentage of erythrocyte rosette forming cells appeared to increase with successive runs. This method is safe and efficient, and can be repetitively performed at short intervals in dogs. This method may prove useful in diseases in which rapid removal of circulating IgG is desired.

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A 1,2-dimethylhydrazine dihydrochloride-induced rat gastrointestinal tract tumor model was used to study the phenomenon of immunologic surveillance. In two different sets of experiments, a properly timed administration of antithymocyte globulin resulted in earlier tumor appearance, increased numbers of tumors, and increased multiplicity of gastrointestinal tumors. Results obtained from histologic examination of the gastrointestinal tract at different times after the last dose of 1,2-dimethylhydrazine dihydrochloride suggested that a normally functioning immune system effectively suppressed the growth of some nascent tumors. However, the immunosuppression of the host with antithymocyte globulin allowed the development of foci of microtumors into grossly visible neoplasms. Our experiments supported the concept that immunologic surveillance against neoplasia depends on the thymus cell system, although other possible mechanisms were not excluded.

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Serum factors present in rats rendered operationally tolerant to skin allografts by inoculation of allogeneic bone-marrow cells as newborns inhibit or "block" the cytotoxic effect of immune lymphocytes in vitro. These blocking factors were specifically removed from tolerant serum by absorption with allogeneic cells and later eluted from the absorbing cells in glycine buffer (pH 3.1). Blocking activity of the eluted material was resolved into fractions of low and higher molecular weight, which may be soluble histocompatibility antigen and specific alloantibody, respectively. Both antigen and antigen-antibody complexes may block in vitro, depending upon the assay used.

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W/Fu rats were neonatally inoculated with bone marrow cells from B/N rats and vice versa. Of the inoculated rats, some were capable of accepting a foreign (B/N or W/Fu) skin graft over the period of observation (i.e. for more than 100 days), while other rats rejected their skin grafts as early as control animals (within 8-12 days) or after a prolonged period of acceptance (20-96 days). Using a microcytotoxicity test, it could be shown that both those rats that rapidly rejected skin grafts and those that kept their grafts during the observation period had lymphocytes capable of destroying cultivated allogeneic cells from the respective strains with whose cells the rats had been inoculated as newborns. The degree of lymphocyte reactivity decreased upon time, so that 4 of 13 rats that had carried "tolerated" skin grafts over more than 84 days had lymphocytes which were nonreactive in the highest dose tested, and the degree of reactivity in the other 9 rats was less than seen early after tolerance induction. Rats that were capable of accepting skin grafts over prolonged periods of time had sera that could specifically block lymphocyte-mediated cytotoxicity, while sera from rats that had rejected their grafts did not block. Sera from rats that rejected their skin grafts after 20-96 days lost the blocking activity 3-10 days before rejection.

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