Research progress in establishment of N-methyl-N'-nitro-N-nitroso-guanidine-induced rat model of Precancerous lesion of gastric cancer / 中国中药杂志

Gastric cancer(GC), one of the most common malignancies worldwide, seriously threatens human health due to its high morbidity and mortality. Precancerous lesion of gastric cancer(PLGC) is a critical stage for preventing the occurrence of gastric cancer, and PLGC therapy has frequently been investigated in clinical research. Exploring the proper animal modeling methods is necessary since animal experiment acts as the main avenue of the research on GC treatment. At present, N-methyl-N'-nitro-N-nitroso-guanidine(MNNG) serves as a common chemical inducer for the rat model of GC and PLGC. In this study, MNNG-based methods for modeling PLGC rats in related papers were summarized, and the applications and effects of these methods were demonstrated by examples. Additionally, the advantages, disadvantages, and precautions of various modeling methods were briefly reviewed, and the experience of this research group in exploring modeling methods was shared. This study is expected to provide a reference for the establishment of MNNG-induced PLGC animal model, and a model support for the following studies on PLGC.

Gum arabic and red propolis protecteting colorectal preneoplastic lesions in a rat model of azoxymethane

Abstract Purpose: To evaluate red propolis, gum arabic and L-lysine activity on colorectal preneoplastic lesions induced by azoxymethane (AOM). Methods: The study featured 4 control groups (I-IV) and 4 experimental groups (V-VIII), totaling 48 rats. Once a week for 2 weeks, animals on control groups received saline, while animals in experimental groups received azoxymethane (15 mg/kg i.p.). The follow up along 16 weeks included daily oral gavage to administer water (I and V), L-lysine (150 mg/kg)(II and VI), própolis (100mg/5ml/kg)(III and VII), or gum arabic (5ml/kg)(IV and VIII). Was performed surgery on the animals in the end of this time in order to collect blood for biological assays (TBARS, GSH), followed by their sacrifice to tissue extract. Results: Oxidative stress (TBARS) and the number of aberrant crypt foci (ACF) in distal colon were lower using própolis (p<0.01 for both parameters). Gum arabic reduced preneoplastic lesions (ACF ≤ 4 crypts) on distal colon and on the entire colon (p<0.05). Conclusions: Red propolis reduced AOM-induced oxidative stress (TBARS) and total number of ACF in the distal colon. L-lysine neither protected against nor enhanced AOM-induced ACF. Gum arabic reduced the number of ACF.

Use of defatted flaxseed meal reduces precancerous colon lesions in C57BL/6 mice

PURPOSE: To investigate the hemopreventive effect of defatted flaxseed meal in C57BL/6 mice after induction of precancerous colon lesions with 1.2-dimethylhydrazine (DMH). METHODS: Thirty-six 12-week-old C57BL/6 mice were divided into three treatment groups(n=12 in each group): (1) diet with 10% defatted flaxseed meal; (2) diet with defatted flaxseed meal and precancerous colon lesions induced by DMH; and (3) precancerous colon lesions induced by DMH, without defatted flaxseed meal. The incidence of aberrant crypt foci (ACF), oxidative processes, expression of tumor suppressor proteins and cyclins, as well as the profile of short-chain fatty acids (SCFA) in animal feces were investigated in the presence and absence of DMH. RESULTS: The rats consuming defatted flaxseed meals showed lesions with lower multiplicity and a reduced incidence of lesions. No changes in the expression of tumor suppressor proteins and those involved in cell cycle control were detected. CONCLUSION: Defatted flaxseed meal protected the distal colon of mice from precancerous lesions.

Effect of probiotics on the development of dimethylhydrazine-induced preneoplastic lesions in the mice colon

PURPOSE: To determine the effect of probiotics on the development of chemically induced (1, 2-dimethylhydrazine) colonic preneoplastic lesions, in mice. METHODS: The animals were divided into five groups. The control group was injected with carcinogen alone and the other groups also received probiotics (1- Lactobacillus delbrueckii UFV-H2b20; 2- Bifidobacterium animalis var. lactis Bb12; 3- L. delbrueckii UFV-H2b20 plus B. animalis var. lactis Bb12; and 4- Saccharomyces boulardii) administered orally in drinking water throughout fourteen weeks. RESULTS: Consumption of lactobacilli and bifidobacteria alone resulted in a significant reduction of the total number of aberrant crypt foci (55.7% and 45.1%, respectively). Significant reduction in the number of these small foci (<3 aberrant crypts) was only observed in the group treated with lactobacilli (52.2%) in comparison to control group. The number of larger foci (>3 aberrant crypts) crypts had no significant reduction. CONCLUSION: L. delbrueckii UFV-H2b20 and B. animalis var. lactis Bb12 administered alone protect colonic preneoplastic lesions in mice, while the combined treatment of these bacteria and the administration of S.boulardii were not effective in reducing such colonic lesions.

Effect of green propolis on oral epithelial dysplasia in rats / Efeito da própolis verde sobre displasias epiteliais orais em ratos

Studies have demonstrated that flavonoid compounds of green propolis have antitumoral activity. STUDY DESIGN: Experimental study. AIMS: To evaluate the effect of a hydroalcoholic extract of green propolis (EPV) on chemically induced epithelial dysplasias in rat tongues. METHODS AND MATERIALS: DMBA was brushed on the lingual dorsum of rats 3x/week on alternate days - 100 (PROP1), 200 (PROP2) and 300 mg/kg (PROP3) EPV was administered orally for 20 weeks. EPV or DMBA were replaced by their vehicles and applied as positive (TUM1 and TUM2) and negative controls (CTR1 and CTR2), respectively. The lingual epithelium was histologically analyzed and graded according a binary system and the WHO classification; the data were compared using ANOVA (*p<0.05). RESULTS: The EPV yield was 41 percent and the flavonoid yield was 0.95±0.44 percent. According to the Binary System, TUM1, TUM2 and PROP1 were considered high risk lesions, with significantly higher morphological alteration rates compared to the other groups (p<0.05), which were considered low risk lesions. Based on the WHO classification, moderate dysplasia was TUM1 and TUM2, mild dysplasia was PROP1, PROP2 and PROP3, and non-dysplastic epithelium was CTR1 and CTR2. CONCLUSION: EPV seems to play an important protective role against chemically-induced lingual carcinogenesis in rats.

Estudos têm demonstrado que componentes hidrossolúveis da própolis verde, flavonóides, apresentam atividade antitumoral. FORMA DE ESTUDO: Estudo experimental. OBJETIVO: Avaliar o efeito do extrato hidroalcoólico de própolis verde (EPV) sobre displasias epiteliais linguais quimicamente induzidas em ratos. MATERIAIS E MÉTODOS: Neste estudo, foi pincelado DMBA (9,10-dimetil-1,2- benzatraceno) no dorso lingual de ratos 3x/semana, em dias alternados, administrado 100 (PROP1), 200 (PROP2) e 300 mg/kg (PROP3) de EPV (v.o.), durante 20 semanas. A substituição do EPV ou DMBA pelos seus veículos foi usada nos controles positivos (TUM1 e TUM2), negativos (CTR1 e CTR2), respectivamente. O epitélio lingual foi analisado histologicamente, graduado pelo Sistema Binário e classificação OMS, e os dados comparados por análise de variância (ANOVA) (p<0,05). RESULTADOS: O rendimento do EPV foi 41,43 por cento e o teor de flavonóides 0,95±0,44 por cento. Segundo o Sistema Binário, TUM1, TUM2 e PROP1 foram considerados lesões de alto risco, apresentando índices de alterações morfológicas significativamente mais elevados (p<0,05), e os demais de baixo risco. Segundo a classificação OMS, observou-se displasia moderada em TUM e TUM2, leve em PROP1, PROP2 e PROP3, e ausente em CTR1 e CTR2. Conclusão: Sugere-se que o EPV possa desempenhar um papel protetor importante durante a carcinogênese lingual quimicamente induzida em ratos. CONCLUSÃO: Sugere-se que o EPV possa desempenhar um papel protetor importante durante a carcinogênese lingual quimicamente induzida em ratos.

Sodium butyrate does not decrease the evolution of precancerous lesions in rats / Butirato de sódio não diminui a evolução de lesões pré-neoplásicas em ratos

PURPOSE: To evaluate the preventive effect of sodium butyrate in the appearance of aberrant crypt foci (ACF) in rats after induction with the carcinogen 1,2-dimethylhydrazine (DMH). METHODS: Forty Wistar rats were separated into four groups (n=10) distributed as follows: control 1, control 2, butyrate 1 and butyrate 2. The groups control 1 and butyrate 1 remained under experimentation for 4 weeks, while the groups control 2 and butyrate 2 remained for 8 weeks. In the first four weeks, the animals of the control groups received water ad libitum and the animals of the butyrate groups received a sodium butyrate solution (3.4 percent) ad libitum. Injections of the drug 1,2-dimethylhydrazine were applied during the two first weeks of the experiment in all the animals, concurrently with the application of sodium butyrate. The large intestine of the animals was removed, for the analysis of the ACF and of the content of polyamines. The animal feces were collected for the analysis of the SCFA profile. RESULTS: The spermidine presented a higher concentration in the group butyrate 2 in comparison to the group control 2. There was a significant difference in the concentration value (µmol/mL) of acetate in comparison to the groups control 2 and butyrate 2. CONCLUSION: The use of sodium butyrate together with the induction of colorectal cancer was not effective in the prevention of the disease progression.

OBJETIVO: Avaliar o efeito preventivo do butirato de sódio no surgimento de focos de cripta aberrante (FCA) em ratos após a indução com o carcinógeno 1,2-dimetilhidrazina. MÉTODOS: Quarenta ratos foram divididos em quatro grupos, com dez animais em cada. Os grupos controle 1 e butirato 1 ficaram em experimentação por 4 semanas e os grupos controle 2 e butirato 2 por oito semanas. Nas primeiras quatro semanas, os animais dos grupos controle receberam água ad libitum e os animais dos grupos butirato receberam solução de butirato de sódio (3,4 por cento) ad libitum. Em todos os animais foram aplicadas quatro injeções subcutâneas da droga 1,2-dimetilhidrazina nas duas primeiras semanas, concomitante a administração do butirato de sódio. Foi retirado o intestino grosso dos animais, para análise dos FCA e do teor de poliaminas. As fezes dos animais foram recolhidas para análise do perfil de AGCC. RESULTADOS: A espermidina apresentou maior concentração no grupo butirato 2 em relação ao grupo controle 2. Foi encontrada diferença significativa no valor da concentração de acetato quando comparado os grupos controle 2 e butirato 2. CONCLUSÃO: A utilização do butirato de sódio concomitante à indução do câncer colorretal não se mostrou efetiva na prevenção da progressão da doença.

Water extracts of cabbage and kale inhibit ex vivo H2O2-induced DNA damage but not rat hepatocarcinogenesis

The chemopreventive potential of water extracts of the Brassica vegetables cabbage and kale was evaluated by administering their aqueous extracts in drinking water ad libitum to Wistar rats submitted to Ito’s hepatocarcinogenesis model (CB group and K group, respectively - 14 rats per group). Animals submitted to this same model and treated with water were used as controls (W group - 15 rats). Treatment with the vegetable extracts did not inhibit (P > 0.05) placental glutathione S-transferase-positive preneoplastic lesions (PNL). The number of apoptotic bodies did not differ (P > 0.05) among the experimental groups. Ex vivo hydrogen peroxide treatment of rat livers resulted in lower (P < 0.05) DNA strand breakage in cabbage- (107.6 ± 7.8 µm) and kale- (110.8 ± 10.0 µm) treated animals compared with control (120.9 ± 12.7 µm), as evaluated by the single cell gel (comet) assay. Treatment with cabbage (2 ± 0.3 µg/g) or kale (4 ± 0.2 µg/g) resulted in increased (P < 0.05) hepatic lutein concentration compared with control (0.5 ± 0.07 µg/g). Despite the absence of inhibitory effects of cabbage and kale aqueous extracts on PNL, these Brassica vegetables presented protection against DNA damage, an effect possibly related to increased hepatic lutein concentrations. However, it must be pointed out that the cause-effect relationship between lutein levels and protection is hypothetical and remains to be demonstrated.

Fish oil ingestion reduces the number of aberrant crypt foci and adenoma in 1, 2-dimethylhydrazine-induced colon cancer in rats

We determined the effect of fish oil (FO) ingestion on colonic carcinogenesis in rats. Male Wistar rats received 4 subcutaneous injections (40 mg/kg body weight each) of 1,2-dimethylhydrazine (DMH) at 3-day intervals and were fed a diet containing 18 percent by weight FO (N = 10) or soybean oil (SO, N = 10) for 36 weeks. At sacrifice, the colon was removed, aberrant crypt foci were counted and the fatty acid profile was determined. Intestinal tumors were removed and classified as adenoma or carcinoma. Liver and feces were collected and analyzed for fatty acid profile. FO reduced the mean (± SEM) number of aberrant crypt foci compared to SO (113.55 ± 6.97 vs 214.60 ± 18.61; P < 0.05) and the incidence of adenoma (FO: 20 percent vs SO: 100 percent), but carcinoma occurred equally in FO and SO rats (2 animals per group). The polyunsaturated fatty acid (PUFA) profile of the colon was affected by diet (P < 0.05): total ù-3 (FO: 8.18 ± 0.97 vs SO: 1.71 ± 0.54 percent) and total ù-6 (FO: 3.83 ± 0.59 vs SO: 10.43 ± 1.28 percent). The same occurred in the liver (P < 0.05): total ù-3 (FO: 34.41 ± 2.6 vs SO: 6.46 ± 0.59 percent) and total ù-6 (FO: 8.73 ± 1.37 vs SO: 42.12 ± 2.33 percent). The PUFA profile of the feces and liver polyamine levels did not differ between groups (P > 0.05). In conclusion, our findings indicate that chronic FO ingestion protected against the DMH-induced preneoplastic colon lesions and adenoma development, but not against carcinoma in rats.

Long-term aerobic swimming training by rats reduces the number of aberrant crypt foci in 1, 2-dimethylhydrazine-induced colon cancer

We determined the effect of long-term aerobic swimming training regimens of different intensities on colonic carcinogenesis in rats. Male Wistar rats (11 weeks old) were given 4 subcutaneous injections (40 mg/kg body weight each) of 1,2-dimethyl-hydrazine (DMH, dissolved in 0.9 percent NaCl containing 1.5 percent EDTA, pH 6.5), at 3-day intervals and divided into three exercise groups that swam with 0 percent body weight (EG1, N = 11), 2 percent body weight (EG2, N = 11), and 4 percent body weight of load (EG3, N = 10), 20 min/day, 5 days/week for 35 weeks, and one sedentary control group (CG, N = 10). At sacrifice, the colon was removed and counted for tumors and aberrant crypt foci. Tumor size was measured and intra-abdominal fat was weighed. The mean number of aberrant crypt foci was reduced only for EG2 compared to CG (26.21 ± 2.99 vs 36.40 ± 1.53 crypts; P < 0.05). Tumor incidence was not significantly different among groups (CG: 90 percent; EG1: 72.7 percent; EG2: 90 percent; EG3: 80 percent). Swimming training did not affect either tumor multiplicity (CG: 2.30 ± 0.58; EG1: 2.09 ± 0.44; EG2: 1.27 ± 0.19; EG3: 1.50 ± 0.48 tumors) or size (CG: 1.78 ± 0.24; EG1: 1.81 ± 0.14; EG2: 1.55 ± 0.21; EG3: 2.17 ± 0.22 cm³). Intra-abdominal fat was not significantly different among groups (CG: 10.54 ± 2.73; EG1: 6.12 ± 1.15; EG2: 7.85 ± 1.24; EG3: 5.11 ± 0.74 g). Aerobic swimming training with 2 percent body weight of load protected against the DMH-induced preneoplastic colon lesions, but not against tumor development in the rat.

Proliferation of the superficial epithelium of ovaries in senile female rats following oral administration of conjugated equine estrogens

OBJECTIVE: To evaluate the effect of different concentrations of estrogen on the ovarian superficial epithelium in senile female rats. Design: Fifty female rats at 15 months of age and with irregular estrous cycles were selected and randomly divided into five experimental groups containing equal numbers of animals in each: GPROP, control group receiving vehicle only; GE0.05mg, group receiving conjugated equine estrogens (CEE) at a dose of 50 µg/kg; GE0.5mg, group receiving CEE at 500 µg/kg; GE1mg, group receiving CEE at 1 mg/kg; and GE2mg, receiving CEE at 2 mg/kg. The length of treatment was 21 days. After this period, the animals were anesthetized and the ovaries were fixed in 10 percent formaldehyde and processed for routine histology. Histomorphology was analyzed by light microscopy, and histomorphometrics were evaluated using the Imagelab program. RESULTS: In the GPROP and GE0.05mg groups, the superficial epithelium of the ovary had a simple cuboidal shape, and as the estrogen dose increased, the epithelium thickened, with pseudo-stratified or stratified epithelium appearing in the GE2mg group. The animals in the group given the highest estrogen dose (GE2mg) showed the thickest ovarian epithelium and the largest perimeter and surface area of the surface ovarian epithelium (P < 0.01). However, the difference in epithelium thickness between the GE0.5mg and GE1mg groups was only slight. CONCLUSION: Our data suggest that CEE at a dose of 2 mg/kg may induce marked proliferation of rat ovarian epithelium.

Inhibition of lipid peroxidation and enhancement of GST activity by cardamom and cinnamon during chemically induced colon carcinogenesis in Swiss albino mice.

Globally, colorectal cancer is the third commonest cancer in men since 1975.The present study focuses on the preventive strategies aimed at reducing the incidences and mortality of large bowel cancer. Chemoprevention of colon cancer appears to be a very realistic possibility because various intermediate stages have been identified preceding the development of malignant colonic tumors. Several studies have demonstrated that generous consumption of vegetables reduces the risk of colon cancer. This idea has prompted the present investigation to search for some novel plant products, which may have possible anticarcinogenic activity. It has already been proved from various experiments that chemopreventive agents, by virtue of their anti-oxidant, anti-inflammatory, anti-proliferative, apoptosis-inducing activity, act at various levels including molecular, cellular, tissue and organ levels to interfere with carcinogens. Previous studies from our laboratory have already reported the inhibitory effect of cinnamon and cardamom on azoxymethane induced colon carcinogenesis by virtue of their anti-inflammatory, anti-proliferative and pro-apoptotic activity. This particular experiment was carried out to assess the anti-oxidative potential of these spices. Aqueous suspensions of cinnamon and cardamom have been shown to enhance the level of detoxifying enzyme (GST activity) with simultaneous decrease in lipid peroxidation levels in the treatment groups when compared to that of the carcinogen control group.

Effect of 2-(carboxyphenyl) retinamide and genistein on the formation of early lesions in 1,2-dimethylhydrazine-induced colon carcinogenesis in rats.

Aberrant crypt foci (ACF) are recognized as preneoplastic lesions for colon cancer, and ACF in rodents are widely used as an intermediate biomarker to predict tumorigenicity in the colon. However, a lack of correlations between the formation of ACF and the development of colonic tumors has been reported in several studies. For example, 2-(carboxyphenyl) retinamide (2-CPR) and genistein were reported to inhibit the carcinogen-induced formation of ACF, whereas both of them were later found to enhance colon tumorigenesis in rats treated with azoxymethane (AOM). Recently, we have identified b-catenin-accumulated crypts (BCAC) in the colon of rats shortly after administration of AOM, and provided evidence that these are independent early lesions of classical ACF, and BCAC might be direct precursors for colon cancers. In the present study, we performed a comparative analysis of the modifying effects of 2-CPR and genistein on 1,2-dimethylhydrazine (DMH)-induced BCAC and ACF in male F344 rats. Dietary administration of 2-CPR (315 ppm) significantly reduced the total number, multiplicity and size of ACF in DMH-exposed colonic mucosa, while genistein (250 ppm) had no significant effects on DMH-induced ACF formation. In contrast, both of 2-CPR and genistein significantly enhanced the multiplicity and size of DMH-induced BCAC when compared with DMH alone group. In addition, both 2-CPR and genistein significantly increased the proliferating cell nuclear antigen (PCNA) index preferentially in BCAC. Together with previous findings that 2-CPR and genistein are tumor promoters in the colon, our results support the concept that BCAC are precursors of colon tumors and suggest that these lesions are more reliable short-term biomarkers for colon carcinogenesis in rodents than ACF.

Preventive effects of a flavonoid myricitrin on the formation of azoxymethane-induced premalignant lesions in colons of rats.

The preventive effect of dietary exposure to a flavonoid myricitrin of azoxymethane (AOM)-induced aberrant crypt foci (ACF) and beta-catenin-accumulated crypts (BCAC) formation was investigated in male F344 rats. Thirty-four rats were divided randomly into five experimental groups. Rats in groups 1-3 were given subcutaneous injections of AOM (15 mg/kg body weight) once a week for 3 weeks. Starting 1 week before the first injection of AOM, rats in groups 2 and 3 were fed a diet containing 500 or 1000 ppm myricitrin, respectively, for 11 weeks. Rats in group 4 were fed a diet containing 1000 ppm myricitrin. Rats in groups 1 and 5 were given the basal diet alone during the study. The experiment was terminated 11 weeks after the start. The frequency of ACF per colon in group 3 treated with AOM and 1000 ppm myricitrin was significantly lower than that in group 1 treated with AOM alone (p<0.01). Furthermore, dietary myricitrin at both doses (groups 2 and 3) significantly inhibited the formation of BCAC when compared to group 1 (p<0.05). These results indicate that myricitrin had possible chemopreventive effects in the present short-term colon carcinogenesis bioassays and suggest that longer exposure may cause suppression of tumor development.

Antioxidative and modifying effects of a tropical plant Azadirachta indica (Neem) on azoxymethane-induced preneoplastic lesions in the rat colon.

The purpose of the present study was to examine whether Neem leaf (Azadirachta indica) has short-term chemopreventive effects on endpoint preneoplastic lesions involved in rat colon carcinogenesis and might also exert antioxidative activity. Forty- two male F344 rats were randomly divided into 6 experimental groups. Groups 1 to 4 were given a subcutaneous injection of azoxymethane (AOM, 20 mg/kg body weight) once a week for 2 weeks. Starting one week before the first injection of AOM, rats in groups 2 to 4 received an aqueous extract of Neem leaf (20, 100, and 250 mg/kg, respectively) by gavage 3 times per week, for 5 weeks. Rats in group 5 also were given the Neem extract by gavage feeding 3 times per week for 5 weeks, while group 6 served as untreated controls. The experiment was terminated 5 weeks after the start. Dietary feeding of the Neem extract at all dose levels significantly inhibited the induction of aberrant crypt foci (ACF) (P<0.0002), when compared to the AOM-treated group (group 1). In groups 2 to 4, treatment of rats with the Neem extract also significantly decreased the proliferating cell nuclear antigen (PCNA) labeling indices (P<0.0006) of colon epithelium and ACF. Moreover, the Neem extract also showed antioxidative activity. The finding that dietary Neem has possible chemopreventive effects in the present short-term colon carcinogenesis bioassay suggests that longer-term exposure may cause suppression of tumor development.

Study of superoxide dismutase's expression in the colon produced by azoxymethane and inositol hexaphosfate's paper, in mice

PURPOSE: To investigate the expression of superoxide dismutase (SOD), with use of antioxidant inositol hexaphosfate, in the presence of the carcinogen azoxymethane, in FCA of colon rats. METHODS: Wistar rats (n=48) were distributed in four groups of 12 mice. Divided in control (n=12); with azoxymethane administration AOM (n=12); administration of IP6 (n=12) and with administration of IP6/AOM (n=12). The subcutaneous administration of azoxymethane happened in the week 3 and 4 of the experiment, in dose 20mg/Kg, weekly; and administration of IP6 to 1 percent in water of drinking for 6 weeks in the group 3 and 4. The identification of the expression SOD-1 was accomplished through the quantification imunohistochemistry by the image processing attended by computer in crypts and focus of aberrant crypts in right colon. RESULTS: The group control presented expression of SOD1, on average 16,0 percent; group AOM, 26,7 percent; group IP6, 16,9 percent; group IP6/AOM, 20,9 percent. Variance analysis among the groups, was calculated 0,0078. CONCLUSION: The azoxymethane increase expression SOD1, while inositol hexaphosphate decreases in a significant way the expression of SOD1 promoted by the administration of the carcinogen azoxymethane.

OBJETIVO: Investigar a expressão de superóxido dismutase, com uso de antioxidante inositol hexafosfato, na presença do carcinógeno azoximetano em FCA de cólon de ratos. MÉTODOS: Quarenta e oito ratos Wistar, distribuídos em 4 grupos, divididos em controle (n=12); com administração de azoximetano AOM (n=12); administração de IP6 (n=12) e com administração de IP6/AOM (n=12). A administração subcutânea de azoximetano aconteceu na semana 3 e 4 do experimento, em dose 20mg/Kg, semanal; e administração de IP6 a 1 por cento em água de beber durante 6 semanas no grupo 3 e 4. A identificação da expressão SOD1 foi realizada através da quantificação imunohistoquimíca pelo processamento de imagem assistida por computador em criptas e focos de cripta aberrante em cólon direito. RESULTADOS: O grupo controle apresentou expressão de SOD1, em média 16,0 por cento; grupo AOM, 26,7 por cento; grupo IP6, 16,9 por cento; grupo IP6/AOM, 20,9 por cento. Análise de variância entre os grupos calculou-se 0,0078. CONCLUSÃO: A expressão de SOD-1 mostrou aumento significativo na presença de azoximetano e quando administrou-se IP6 concomitante houve diminuição na expressão de SOD1 promovido pela administração do carcinógeno azoximetano.

A new experimental model to study preneoplastic lesions in achalasia of the esophagus

OBJETIVO: Desenvolver um modelo experimental que permitisse o estudo de lesões preneoplásicas induzidas por diethylnitrosamina em ratos com acalasia. MÉTODOS: Ratos Wistar machos foram distribuídos em quatro grupos: controle - C (n=8); ratos com megaesôfago - B (n=8); ratos tratados com DEN – D (n=15) e ratos com megaesôfago mais DEN - BD (n=15). O megaesôfago pode ser obtido experimentalmente através da aplicação tópica de cloreto de benzalcônio. Foi avaliada a morfologia do epitélio e a proliferação celular do epitélio pelo método do PCNA. RESULTADOS: A análise morfométrica mostrou aumento da espessura epitelial no grupo BD (2166±1012mm2) em relação aos outros grupos (C = 878±278mm2; B = 1746±144mm2 e D = 1691±697mm2), principalmente devido a uma hiperplasia da camada basal e um aumento na queratina da camada superficial. O índice de marcação pelo PCNA na camada basal foi significantemente maior neste mesmo grupo (0,695±0,111) quando comparado com os outros (C-0,490±0,132; B-0,512±0,215 e D-0,477±0,198). CONCLUSÕES: Estes dados confirmam através de um modelo experimental o aumento proliferativo celular durante o processo de carcinogênese na acalasia do esôfago e podem ser úteis durante estudos de endoscopia realizados em pacientes que possuem acalasia.

Dietary cardamom inhibits the formation of azoxymethane-induced aberrant crypt foci in mice and reduces COX-2 and iNOS expression in the colon.

Recently, considerable attention has been focused on identifying naturally occurring chemopreventive compounds capable of inhibiting, retarding, or reversing the multi-step carcinogenesis. The primary aim of the present study was to identify the effects of a commonly consumed spice, viz., cardamom against azoxymethane (AOM) induced colonic aberrant crypt foci (ACF) in Swiss Albino mice. The secondary aim, was to explore the ability of cardamom to modulate the status of proliferation and apoptosis, and to understand its role in altering cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Male Swiss albino mice were injected with AOM (dose: 5mg/Kg body weight) or saline (Group 1) weekly once for two weeks. The AOM-injected mice were randomly assigned to two groups (Groups 2 and 3). While all the groups were on standard lab chow, Group 3 received oral doses of 0.5% cardamom, in aqueous suspension, daily for 8 weeks. Following treatment, significant reduction in the incidences of aberrant crypt foci (p<0.05) was observed. This reduction in ACF was accompanied by suppression of cell proliferation (mean Brdu LI in carcinogen control =13.91+/-3.31, and 0.5% cardamom =2.723+/-0.830) and induction of apoptosis (mean AI in carcinogen control=1.547+/-0.42 and 0.5% cardamom = 6.61+/-0.55). Moreover, reduction of both COX-2 and iNOS expression was also observed. These results suggest that aqueous suspensions of cardamom have protective effects on experimentally induced colon carcinogenesis. Cardamom as a whole and its active components require further attention if the use of this spice is to be recommended for cancer prevention.

Chemopreventive effect of orange oil on the development of hepatic preneoplastic lesions induced by N-nitrosodiethylamine in rats: an ultrastructural study.

Orange peel oil is used extensively as an approved flavour enhancer in fruit drinks, carbonated beverages and as a scenting agent in soaps and cosmetics. Limonene, which is a monocyclic monoterpene is present in orange peel oil from 90 to 95% (w/w). Monoterpenes have been shown to be very effective chemopreventive agents against several rodent tumors and are currently in clinical trials. However, not much information is available regarding the ultrastructural changes associated with the chemopreventive effects of the monoterpenes. The effect of orange oil on the suppression of preneoplastic hepatic lesions during N-nitrosodiethylamine (DEN) induced hepatocarcinogenesis was studied electron microscopically. Rats were administered 200 ppm DEN through drinking water for a period of 1 month. After an interval of 2 weeks, the animals were administered orange oil by gavage for a period of 5 1/2 months. The chemopreventive effect of orange oil was monitored on the basis of liver weight profile, histological pattern by light microscopy and ultrastructural alterations by electronmicroscopy. Orange oil administration following DEN treatment showed decreased liver weights, increased intercellular gap junctional complexes, cell density and polarity when compared with only the DEN treated rats. In the present study chemopreventive effect of orange oil on DEN-induced hepatic preneoplasia in rats which is associated with the restoration of the normal phenotype and upregulation of junctional complexes has been demonstrated.

Effect of metanil yellow and malachite green on DNA synthesis in N-nitrosodiethylamine induced preneoplastic rat livers.

Metanil yellow (MY) and malachite green (MG) are textile dyes, which, despite the ban occurs unsrupulously as food colouring agents. Accordingly they constitute a serious public health hazard and are of sufficient environmental concern. We have earlier reported that both MY and MG have tumor enhancing effects on the development of hepatic preneoplastic lesions induced by N-nitrosodiethylamine in rats. In order to understand the possible mechanisms by which MY and MG enhance tumor development, in this study we have tested the effects of MY and MG on DNA synthesis and PCNA expression in preneoplastic hepatic lesions during N-nitrosodiethylamine (DEN) induced hepatocarcinogenesis in male Wistar (WR) rats. Rats were administered 200 ppm DEN through drinking water for a period of one month. Administration of DEN for a period of one month showed an upregulation of cell cycle regulatory proteins namely cyclin D1, CDK4, cyclin E and CDK2. Accordingly, in other experiments, the animals were further administered MY and MG for a period of one month following one month DEN treatment. The effects of MY and MG were monitored on the basis of cell proliferation markers--DNA synthesis and PCNA expression both by immunohistochemical and immunoblotting. Following DEN administration, MY, MG and PB showed stimulation of DNA synthesis and increased PCNA expression when compared with either the corresponding controls or only DEN treated animals. In the present study, enhancing effect of MY, MG and PB on the cell proliferation markers during DEN-induced hepatic preneoplasia in rats was observed.