Promotion of chemically induced rat esophageal tumorigenesis with post-initiation ethanol modification.

Post-initiation ethanol modification on N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal carcinogenesis model was investigated in male, 6-week-old, F344 rats that received s.c. injections, 3 times per week, of 0.5 mg/kg NMBA for the first 5 weeks and then were treated with 0% (Group 1), 3.3% (Group 2), and 10% (Group 3) ethanol in the drinking water for up to 20 weeks. Group 4 received 10% ethanol without NMBA administration and Group 5 was maintained without any chemical treatment. There were no statistical differences in the incidence and multiplicity of esophageal tumors among Groups 1 to 3. However, the multiplicity of hyperplasias was statistically greater in Group 3 than in Groups 1 or 2. Esophageal epithelia of all rats in Groups 4 and 5 demonstrated a normal histology. BrdU labelling indices of tumors and hyperplasias in NMBA-treated groups were essentially similar, although cycline D1 was overexpressed to a greater extent in tumors and also hyperplasias of Group 3 than in Groups 1 or 2. The results indicated ethanol to exert weak promotion effects through cycline D1 overexpression on rat esophageal tumorigenesis initiated with NMBA.     

System issues: Organ variation in the mutagenicity of dimethylnitrosamine in Big Blue® mice

Organ specificity in the lacl mutant frequency (MF) induced by dimethylnitrosamine (DMN) was analyzed in lung, liver, kidney, bone marrow, urinary bladder, and testis of Big Blue® mice. Cell proliferative activity was also analyzed in some of these tissues by immunohistochemical staining of proliferating cell nuclear antigen (PCNA). Clastogenicity of DMN was concomitantly analyzed by the peripheral blood micronucleus assay with the same animals used for the lacl mutation assay. Five daily intraperitoneal (ip) treatments with DMN (1 mg/kg) increased MF in liver (6.2 × control), kidney (2.4 × control), and lung (2.1 × control). These are known target organs for DMN carcinogenesis. No MF increase was observed in nontarget organs studied, i.e., bone marrow, bladder, and testis. Single ip treatment with DMN also increased lacl MF in liver but the increases were smaller than in a 5-daily-treatment regimen. This result suggests that multiple dosing is more effective in the transgenic mutation assay. The enhancement of cell proliferation observed was in bronchial epithelia 7 days after treatment. No micronucleus induction in peripheral blood was observed 24 hours after 2 and 3 daily ip treatments with 1 mg/kg DMN. An increase in the incidence of micronucleated reticulocytes in peripheral blood was observed 48 hours after single ip treatment with 5 or 10 mg/kg DMN. The present study demonstrated organ-specific induction of gene mutations by DMN, which suggests a relevance of this assay for the prediction of organ-specific carcinogenesis. © 1996 Wiley-Liss, Inc.     

Lack of synergism among DMAB, BOP, and MNU in induction of carcinomas of the rat ventral prostate.

The present experiment was undertaken to investigate possible synergism in induction of rat prostate tumor. F344 rats were repeatedly administered the prostate carcinogens 3,2'-dimethyl-4-aminobiphenyl (DMAB),N-nitrosobis(2-oxopropyl)amine(BOP), and N-methylnitrosourea (MNU) sequentially or together at times of hormonal castration induced regenerative cell proliferation of prostate epithelial cells. Group 1 animals received two 100 mg/kg doses of DMAB, two 20 mg/kg applications of BOP, and two times 15 mg/kg of MNU. Groups 2, 3, and 4, respectively, received each of the carcinogen treatment alone. Group 5 was given 6 applications of all three in combination, each at one-third the dose administered to the other groups. The results showed a clear synergism in enhanced tumor development in the colon but not in the prostate, in which the incidence of lesions induced by the three carcinogens was similar to that with DMAB alone.     

Modification of pancreatic carcinogenesis in the hamster model. 6. The effect of ductal ligation and excision

The effect of ligation and excision of the pancreatic duct in pancreatic carcinogenesis was examined in the hamster model. Animals were treated with a single dose (20 mg/kg body weight) of N-nitrosobis(2-oxopropyl)amine (BOP) either immediately (Group 1) or on Days 1 (Group 2), 3 (Group 3) or 7 (Group 4) after ligation and excision of the duct of the splenic lobe. Group 5 received BOP shortly after laparoscopy, and Group 6 consisted of BOP-treated controls. All hamsters were killed 46 weeks after BOP treatment. The results showed that despite advanced atrophy of the splenic lobe distal to the excised duct in Groups 1-4, some hamsters in Groups 2, 3, and 4 showed hyperplasia, dysplasia, and increased mitotic activities of ductal and ductular cells. However, carcinomas in the duct-excised atrophic lobe were found only in Groups 1-3. These data indicate that BOP carcinogenesis is mediated through blood circulation, and that cancer development is not inhibited in the duct-excised lobe for up to 3 days after surgery. However, in the entire pancreas, a significant reduction in tumor incidence was seen when the carcinogen was given immediately, or to a lesser extent, 1 day after surgery, regardless of whether or not excision was made. On the contrary, BOP, when given 3 and 7 days after duct excision, enhanced tumor development in the nonexcised (intact) pancreas, compared with other test groups and with BOP controls. Both inhibition and enhancement seemed due to a proportional decrease and increase, respectively, of BOP-responsive cells throughout the intact pancreas.     

Inhibitory effects of biochanin A on mouse lung tumor induced by benzo(a)pyrene.

Biochanin A, an isoflavone compound, is reported to have an inhibitory effect on benzo(a)pyrene [B(a)P] metabolism. We examined the modifying effect of biochanin A on in vivo carcinogenesis using a mouse lung tumor model. As carcinogens, a single subcutaneous injection of 0.5mg of B(a)P was given within 24 hours after birth. The test groups were injected with 0.125mg of biochanin A in 0.1ml DMSO by i.p. 3 times a week for 6 weeks after weaning. All mice were sacrificed at week 9 and the incidence and multiplicity of lung tumors were examined. Concomitant administration of biochanin A showed a significant inhibitory effect on the incidence of tumor-bearing mice (12.5%, P < 0.01), as well as the mean number of tumors (0.13, P < 0.001), compared with the group treated with B(a)P alone in which the incidence was 57.1% and the mean number was 1.0. These results suggest that biochanin A has inhibitory potential on the development of mouse lung tumor induced by B(a)P.     

Effects of fasting and intermittent fasting on rat hepatocarcinogenesis induced by diethylnitrosamine

The influences of fasting on DEN-initiation and of intermittent fasting (IF) on the rat liver chemical carcinogenesis process were evaluated in a 52-week long assay. Three groups of adult male Wistar rats were used: Groups 1 to 3 were treated with a single i.p. injection of 200 mg/kg of diethylnitrosamine (DEN). Group 2 was submitted to 48 h fasting prior to DEN treatment. After the 4th week, Group 3 was submitted to IF, established as 48 h weekly fasting during 48 weeks, while Groups 1 and 2 were fed ad libitum until the 52nd week. All animals were submitted to 70% partial hepatectomy and sacrificed at the 3rd and 52nd weeks, respectively. Fasting prior to DEN-initiation did not influence the development of altered foci of hepatocytes (AFHs) and of hepatic nodules (Group 2 vs. Group G1). IF inhibited the development of preneoplastic lesions, since this dietary regimen decreased the number and the size of glutathione S-transferase (GST-P) positive foci and the number and size of liver nodules (Group G3 vs. Group G1). The inhibitory effect of IF was also reflected in the development of clear and basophilic cell foci. These results indicate that long-term IF regimen exerts an anti-promoting effect on rat hepatocarcinogenesis induced by DEN.     

Possible model of liver carcinogenesis using inhibitors of NAD+ ADP ribosyl transferase in rats

The response of cellular NAD+ metabolism to DEN and/or ABA and the carcinogenesis of the liver initiated by DEN and ABA were studied in rats. The liver NAD+ level was depleted by an ip injection of 20 mg or 200 mg/kg body weight of DEN. ABA, administered ip at a dose of 600 mg/kg simultaneously with or 4 hours after DEN, prevented the depletion of NAD+ by DEN. These biochemical findings correlated with the changes of conspicuous intranuclear immunofluorescence of poly(ADP-ribose), which were studied by immunohistochemistry. When initiated by 20 mg/kg body weight DEN and 600 mg/kg ABA and then processed to selection pressure, the liver was found to be capable of developing hepatocellular carcinomas with or without PB promotion. These results suggest that the inhibition of poly(ADP-ribosylation) might lead to irreversible initiation of liver carcinogenesis by DEN in rats.     

Inhibitory effect of 1α-hydroxyvitamin D3 on N-nitrosobis(2-oxopropyl)amine-induced cholangiocarcinogenesis in Syrian hamsters

Sixty-three male 5-week-old Syrian hamsters received the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in 5 weekly injections (the first, 70 mg/kg body, and the remaining, 20mg/kg each). The hamsters that received BOP were given intragastric administration of 0.2 ml of medium chain triglyceride (MCT) with or without 0.04 μg of 1α-hydroxyvitamin D3 [1α(OH)D3] through a feeding tube for 12 weeks. Thus, 3 groups were assigned:Group 1;BOP alone (n＝20), Group 2;BOP＋MCT (n＝18) and Group 3;BOP＋1α(OH)D3 (n＝25). The mean body weight of Group 3 was lower than those of Groups 1 and 2 at the end of the experiment (p＜0.001,Tukey-Kramer HSD test). At the end of week 12, all surviving hamsters were put to sleep. The incidences of liver tumors were 80%, 72% and 32% in Groups 1, 2 and 3, respectively. The incidence of tumors in Group 3 was significantly lower than in Group 1 and Group 2 (p＜0.05, χ2-test). All tumors were cholangiocarcinoma. These results indicated that BOP-induced cholangiocarcinogenesis was suppressed by the supplemental administration of 1α(OH)D3.     

Evaluation of carcinogenic responses in the Eker rat following short-term exposure to selected nephrotoxins and carcinogens

This study examined the response of the Eker rat to nephrotoxic compounds and to genotoxic nonrenal carcinogens. Groups of male Eker rats received either no treatment; a vehicle treatment; treatment with a noncarcinogenic nephrotoxin (aluminum nitrilotriacetate, 2 mg/kg/day of aluminum, intraperitoneally, 3 days per week or cyclosporine A, 30 mg/kg/day, orally by gavage, 7 days/week); or treatment with a genotoxic nonrenal carcinogen (furan, 8 mg/kg/day, orally by gavage, 5 days/week or 2,4-diaminotoluene, 6.5 mg/kg/day, orally by gavage, 7 days/week or 2-nitropropane, 89 mg/kg/day, orally by gavage, 3 days/week). Duration of treatment was 4 and/or 6 months. Tissues from the Eker rats were evaluated microscopically and numbers of proliferative renal lesions were counted. Administration of nephrotoxic compounds (Al-NTA and cyclosporine) significantly increased the number of preneoplastic and neoplastic renal lesions in the Eker rat compared to concurrent vehicle controls. The genotoxic nonrenal carcinogens had no consistent effect on numbers of preneoplastic or neoplastic renal lesions and did not produce neoplasms in the expected target organ (liver).     

Modification of pancreatic carcinogenesis in the hamster model. 2. The effect of partial pancreatectomy.

The effect of partial pancreatectomy (PP) on the pancreatic carcinogenicity of N-nitrosobis (2-oxopropyl)amine (BOP) was investigated in Syrian golden hamsters by subcutaneous injection of a single dose of BOP (20 mg/kg, body weight) given 30 minutes after (Group 1), 1 week after (Group 2), or 1 week before 70% PP (Group 3). Additional groups consisted of animals with PP alone (Group 4), sham operation (laparotomy) followed 30 minutes later by BOP treatment (Group 5), and BOP treatment only (Group 6). The experiment was terminated 46 weeks after BOP administration in each group. The pancreas and extrahepatic bile ducts, including the common duct and gallbladder, were examined histologically. Tumor patterns were compared in hamsters with PP and in the corresponding segments of the pancreas in BOP-treated control groups. The pancreatic cancer incidence was highest (31%) in Group 2 and lowest in Group 1 (3%), a difference that was statistically significant (P less than 0.01). Also, a statistically highly significant larger number of tumors occurred in Group 2, compared with group 1, 3, or 5 (P less than 0.0005). In a comparison of the number of carcinomas per tumor-bearing hamster, there were greater numbers of carcinomas in Group 2 (2.6 carcinomas) than in Groups 1, 3, 5, and 6 (1.0, 1.0, 1.3, and 2.6 tumors, respectively). Moreover, pancreatic tumors in Group 2 hamsters were larger (average diameter, 10 mm) than in Group 1 (4 mm), Group 3 (3.5 mm), Group 5 (4 mm), and Group 6 (average, 9mm). The incidence of extrapancreatic tumors did not vary among the PP groups but was equally lower than those in BOP-treated control groups. The data indicated BOP carcinogenesis was inhibited by surgery (regardless of whether PP was per formed) when the carcinogen was given 30 minutes after the surgery but was significantly enhanced when BOP was administered 1 week after PP. The possible reasons for these conflicting results are discussed. Morphologically all tumors were of ductular, ductal, and mixed ductular-insular patterns and most developed at the resected margins, where proliferation of islets, ducts, and ductules, but not of acinar cells, occurred. The results confirm our view that the ductal and ductular cells are the progenitor cells for BOP-induced pancreatic tumors in hamsters.     

Thresholds for the effects of 2-acetylaminofluorene in rat liver

To explore for practical thresholds for DNA-reactive carcinogens in rat liver carcinogenicity, we have conducted a series of exposure-response studies using 2 well-studied hepatocarcinogens, 2-acetylaminofluorene (AAF) and diethylnitrosamine (DEN). Findings with AAF, including as yet unpublished experiments, are reviewed here and related to DEN observations. In these studies, we have administered exact intragastric doses during an initiation segment (IS) of 12-16 weeks followed in some experiments by phenobarbital (PB) as a liver tumor promoter for 24 weeks to enhance manifestation of initiation. The cumulative doses (CD) of AAF at the end of ISs ranged from 0.094 to 282.2 mg/kg. Our findings for AAF in the IS can be summarized as follows: (1) the earliest parameter to be affected with administration of low doses was the appearance of DNA adducts (around 4 weeks), followed at higher doses by cell proliferation; (2) formation of DNA adducts was nonlinear, with a no-observed effect level (NOEL) at a CD of 0.094 mg/kg and a plateau at higher doses (94.1 mg/kg); (3) cytotoxicity (necrosis) showed a NOEL at a CD of 28.2 mg/kg; (4) compensatory hepatocellular proliferation showed a NOEL at a CD of 28.2 mg/kg and was supralinear at a high CD (282.2 mg/kg); (5) formation of preneoplastic hepatocellular altered foci (HAF) showed a NOEL at a CD of 28.2 mg/kg, and was supralinear at a high CD (282.2 mg/kg); (6) a NOEL (CD 28.2 mg/kg) was found for tumor development and the exposure-response was supralinear. We interpret these findings to reflect practical thresholds for hepatocellular initiating effects of AAF and exaggerated responses at high-exposures doses, as also found for DEN. Thus, mechanisms of carcinogenesis can differ between low and high doses.     

Evaluation of carcinogenic potential of diuron in a rat mammary two-stage carcinogenesis model

This study aimed to evaluate the carcinogenic potential of the herbicide Diuron in a two-stage rat medium-term mammary carcinogenesis model initiated by 7,12-dimethylbenz(a)anthracene (DMBA). Female seven-week-old Sprague-Dawley (SD) rats were allocated to six groups: groups G1 to G4 received intragastrically (i.g.) a single 50 mg/kg dose of DMBA; groups G5 and G6 received single administration of canola oil (vehicle of DMBA). Groups G1 and G5 received a basal diet, and groups G2, G3, G4, and G6 were fed the basal diet with the addition of Diuron at 250, 1250, 2500, and 2500 ppm, respectively. After twenty-five weeks, the animals were euthanized and mammary tumors were histologically confirmed and quantified. Tumor samples were also processed for immunohistochemical evaluation of the expressions of proliferating cell nuclear antigen (PCNA), cleaved caspase-3, estrogen receptor-α (ER-α), p63, bcl-2, and bak. Diuron treatment did not increase the incidence or multiplicity of mammary tumors (groups G2 to G4 versus Group G1). Also, exposure to Diuron did not alter tumor growth (cell proliferation and apoptosis indexes) or immunoreactivity to ER-α, p63 (myoephitelial marker), or bcl-2 and bak (apoptosis regulatory proteins). These findings indicate that Diuron does not have a promoting potential on mammary carcinogenesis in female SD rats initiated with DMBA.     

Assessment of chronic toxicity and carcinogenicity in an accelerated cancer bioassay in rats of moxifloxacin, a quinolone antibiotic

The chronic toxicity and carcinogenicity of Moxifloxacin (MOX), a bacterial gyrase-inhibiting fluoroquinolone antibiotic, were studied in male and female Wistar rats in an accelerated cancer bioassay (ACB). The ACB is a mechanistic initiation/promotion chronic toxicity and carcinogenicity study designed to assess potential carcinogenic activity of a test substance in critical organs in which human carcinogens are active. The organs studied were liver, lungs, urinary bladder, mammary gland, bone marrow, thymus, spleen and stomach. MOX was given daily by intragastric instillation at 500 mg/kg bw/day for the first 13 weeks to produce potential initiation, followed by promoters (PROs) for 24 weeks, or for the last 24 weeks after 13 weeks of exposure to initiators (INs). The INs, administered during the first 13 weeks, were diethylnitrosamine for the liver, N-n-butyl-N-(4-hydroxybutyl)nitrosamine for the urinary bladder, ethylnitrosourea for the hematolymphoreticular system, N-nitrosodimethylamine for lungs, methylnitrosourea for the stomach and 7,12-dimethylbenz(a)-anthracene for the mammary gland. The PROs, administered during the last 24 weeks after MOX, were phenobarbital for the liver, nitrilotriacetic acid for the urinary bladder, azathioprine for the bone marrow, butylated hydroxytoluene for the lung, butylated hydroxyanisole for the forestomach, and diethylstilbestrol for the mammary gland. The INs produced preneoplastic and neoplastic lesions which were not enhanced by MOX, and MOX plus PROs elicited no neoplastic effects, documenting that MOX did not produce either initiation or promotion of neoplasia in any of the target sites, or in any of the other twenty tissues examined.     

The oxidant and antioxidant effects of 25-hydroxyvitamin D3 in liver, kidney and heart tissues of diabetic rats

Previous studies have implicated protective effects of vitamin D on insulin secretion and pancreas beta cell function. The goal of the present study is to determine if a combination therapy of 25-hydroxyvitamin D3 and insulin had any advantage over insulin therapy alone on lipid peroxidation and antioxidant activity in the streptozotocin (STZ)-induced diabetic rat. The lipid peroxidation product, thiobarbituric acid-reacting substances (TBARS), was measured to assess free radical activity in the heart, kidney and liver tissues. The enzymatic activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) were measured as indicators of antioxidation in these tissues. Sprague-Dawley rats were made diabetic with a single injection of STZ (75 mg/kg i.p.). Rats were separated into three groups, each containing 10 animals: Group 1, non-diabetic and no drug treatment was given; Group 2, diabetic rats were treated with 3 IU/day subcutaneous (s.c.) insulin; and Group 3, diabetic rats were treated with 3 IU/day (s.c.) insulin plus 1 mg/kg/day per oral (p.o.) 25-hydroxyvitamin D3 for a period of 4 weeks. At the end of the study, TBARS contents of the liver, kidney and heart tissues in Groups 2 and 3 were found to be significantly increased as compared to Group 1 (P<0.05) and kidney MDA levels in Group 3 were also significantly increased as compared to Group 2 (P<0.05). The SOD and CAT contents of the heart in Group 2 were significantly increased as compared to Groups 1 and 3 (P<0.05). GSH-Px activity was unaltered in all groups (P>0.05). We suggest that a combination of insulin with 25-hydroxyvitamin D3 treatment would not be more beneficial than the use of insulin alone in antioxidant defence of diabetic liver and kidney tissues.     

Effects of ginger (Zingiber officinale Roscoe) on DNA damage and development of urothelial tumors in a mouse bladder carcinogenesis model

Extracts of the spice ginger (Zingiber officinale Roscoe) are rich in gingerols and shogaols, which exhibit antioxidant, anti-inflammatory, antifungal, antimycobacterial, and anticarcinogenic proprieties. The present study evaluated the chemoprotective effects of a ginger extract on the DNA damage and the development of bladder cancer induced by N-butyl-N-(4-hydroxibutyl) nitrosamine (BBN)/N-methyl-N-nitrosourea (MNU) in male Swiss mice. Groups G1-G3 were given 0.05% BBN in drinking water for 18 weeks and four i.p. injections of 30 mg/kg body weight MNU at 1, 3, 10, and 18 weeks. Group G4 and G5 received only the BBN or MNU treatments, respectively, and groups G6 and G7 were not treated with BBN or MNU. Additionally, Groups G2, G3, and G6 were fed diets containing 1, 2, and 2% ginger extract, respectively, while Groups G1, G4, G5, and G7 were fed basal diet. Samples of peripheral blood were collected during the experiment for genotoxicity analysis; blood collected 4 hr after each MNU dose was used for the analysis of DNA damage with the Comet assay (assay performed on leukocytes from all groups), while reticulocytes collected 24 hr after the last MNU treatment of Groups G5-G7 were used for the micronucleus assay. At the end of the experiment, the urinary bladder was removed, fixed, and prepared for histopathological, cell proliferation, and apoptosis evaluations. Ginger by itself was not genotoxic, and it did not alter the DNA damage levels induced by the BBN/MNU treatment during the course of the exposure. The incidence and multiplicity of simple and nodular hyperplasia and transitional cell carcinoma (TCC) were increased by the BBN/MNU treatment, but dietary ginger had no significant effect on these responses. However, in Group G2 (BBN/MNU/2% ginger-treated group), there was an increased incidence of Grade 2 TCC. The results suggest that ginger extract does not inhibit the development of BBN-induced mouse bladder tumors.     

Protective action of propolis on the rat colon carcinogenesis

Propolis is a honeybee product with several biological and therapeutical properties. Its effect on the process of colon carcinogenesis and DNA damage were evaluated in the male Wistar rats using the aberrant crypt foci (ACF) assay and the comet assay, respectively. For both tests, animals were treated with the colon carcinogen 1,2 dimethylhydrazine (DMH, 40 mg/kg, s.c.) for 2 weeks (two injections/week) in order to induce both DNA damage and ACF. The animals were divided into groups that received propolis (ethanolic extract) at three different doses (10, 30, and 90 mg/kg b.w., by gavage), either simultaneously or after DMH treatment. For the comet assay, peripheral blood samples were collected 4 h after the last DMH treatment. All animals were sacrificed at the 5th week for evaluation of ACF. The results show that only the intermediate dose (30 mg/kg) of propolis, administered after DMH initiation, is significantly associated to a smaller number of aberrant crypts in the distal colon. No effect on DNA damage in peripheral blood cells, however, was verified by the comet assay. These data suggest that propolis has a protective influence on the process of colon carcinogenesis, suppressing the development of preneoplastic lesions, and probably exerts no protection against the initiation of carcinogenesis.     

Identification, by cDNA microarray, of A-raf and proliferating cell nuclear antigen as genes induced in rat lung by exposure to diesel exhaust

Diesel exhaust particles (DEP) contain various carcinogens and mutagens, and chronic exposure to diesel exhaust (DE) induces pulmonary cancer in experimental animals. However, the oncogenes involved in pulmonary carcinogenesis have not been identified. After F344 rats were exposed to DE containing 6 mg/m3 DEP for 4 weeks, oncogenes and related genes expressed in their lungs were surveyed using a new technique, cDNA microarray, and the results were confirmed by northern blot analysis. Expression of A-raf and proliferating cell nuclear antigen (PCNA) mRNAs was induced in rat lung by exposure to DE. These results suggest that A-raf and PCNA might contribute to pulmonary carcinogenesis in rats.     

单唾液酸神经节苷脂(GM_1)对经MPTP破坏的小鼠黑质纹状体多巴胺神经元的保护作用

将1一甲基一4苯基一1.2.3.6四氢吡啶(MPTP)经腹腔注入小鼠,连续注射6天,一组动物注射后次日处死;另一组动物存活二周后处死;第三组动物在给予1—甲基一4苯基一1.2.3.6四氢吡啶的同时,经腹膜腔注射神经节苷脂持续三周;第四组为对照组.各组动物脑用酪氨酸羟化酶抗体进行免疫组化观察.结果发现1一甲基一4苯基一1.2.3.6四氢吡啶连续注射后次日处死的动物黑质致密部酪氨酸羟化酶阳性神经元数量明显减少,纹状体中酪氨酸羟化酶阳性终末亦明显稀疏.损害后存活二周组,不论黑质或纹状体的损害均略轻.单唾液酸神经节苷脂组黑质致密部酪氨酸羟化酶阳性神经元及纹状体中酪氨酸羟化酶阳性终末均较上两组明显增多.实验表明,单唾液酸神经节苷脂对经1一甲基一4苯基一1.2.3.6四氢吡啶破坏后的小鼠黑质纹状体系多巴胺神经元有保护作用,防止多巴胺神经元因损害引起的继发性退变.     

Pathological reactions in lung, liver, thymus, and spleen of rats after subacute parenteral administration of nickel sulfate

Male Fischer-344 rats (10 to 12 rats per group) were given 14 i.m. injection of nickel sulfate (NiSO4) over a period of 26 days in order to delineate the two-year survival, body weight curves, hematocrit responses, and histopathological reactions, including carcinogenesis. Group A (vehicle controls) received the NaCl vehicle; Groups B, C, and D received NiSO4 solution at dosages of 63, 83, or 125 mumol per kg, respectively. Rats in Group D all died during the period from 4 to 32 days after the first injection; survival of rats in Groups B and C did not differ significantly from the controls (Group A). No differences were found at any time between the mean body weights or blood hematocrits of the NiSO4-treated groups vs. the controls. In Group D, histopathological lesions of the lung, liver, thymus, and spleen were consistently observed; these lesions were most severe in rats that died during the period from 22 to 32 days after the first injection. The lungs showed proliferation of alveolar lining cells, thickening of the alveolar wall, and proteinaceous alveolar exudate. The livers showed microvesicular steatosis, and necrotic hepatocytes were scattered throughout the lobules. Degeneration of lymphocytes, with pyknosis and karyorrhexis, was observed in the thymic cortex and the white pulp of the spleen. At necropsy, no significant differences were found between the NiSO4-treated rats of Groups B and C and the controls (Group A). No sarcomas or other neoplasms occurred near the injection sites in NiSO4-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Emblica officinalis Gaertn and serum cholesterol level in experimental rabbits.

Twelve albino rabbits of either sex weighing 1.0-1.25 kg were fed a standard laboratory diet of green grass and sattu (roasted Bengal gram). After a 2-week run-in period their serum cholesterol levels were estimated. All animals were now fed 0.5 g cholesterol and 1.0 g clarified butter daily and were not divided into 3 groups of 4 animals each. While all received the standard cholesterol-rich diet, Group A animals received no additional substances, animals in Group B were each fed 10 mg vitamin C daily, while those in Group C were each given 1.0 g fresh Amla (Emblica officinalis Gaertn). Mean serum cholesterol levels in all three groups rose to significantly higher levels by the end of the second week. There was a further rise by the end of the third and fourth weeks in Groups A and B. However, animals in Group C (i.e. those given Amla) showed significantly lower mean serum cholesterol levels at the end of the second week than their counterparts in Groups A and B. At the end of the third and fourth weeks the differences were even more pronounced.