The effect of yoghurt on the cytotoxic and phagocytic activity of macrophages in tumour‐bearing mice

In a previous paper, it was demonstrated that feeding yoghurt was able to inhibit the growth of an intestinal tumour induced chemically with 1,2‐dimethylhydrazine (DMH). This effect was due to the increase in IgA‐producing cells and a diminution of the inflammatory immune response. In this paper the phagocytic and cytotoxic capacity of macrophages both involved and not involved in the target organ are studied. The study was aimed at determining whether in the intestinal tumour inhibition demonstrated previously the systemic immune response was also increased. The cytotoxic capacity and ß‐glucuronidase enzyme levels of the peritoneal macrophages were analyzed together with the cytolytic effect of the serum on tumour cells and the phagocytic activity of the macrophages infiltrating the intestinal mucosa. Groups of mice were split into three experimental groups. One group was treated with DMH. The others were treated with DMH, and their diets were supplemented with yoghurt for 7 or 10 consecutive days, during 24 weeks. It was demonstrated that feeding yoghurt for 7 or 10 days increased cytotoxic and ß‐glucuronidase levels in peritoneal macrophages, and also the cytolytic capacity of serum, reaching values significantly higher than those in the DMH control. Enhancement of the phagocytic activity of the macrophages associated with the large intestine was also observed. This increase in the macrophage activity involved in the systemic and mucosal immune responses could also be responsible for the tumour inhibition observed in the group of mice fed with yoghurt. The presence in the serum of lytic factors (cytokines) which were released by immune cells activated by feeding yoghurt may also have had a role in tumour inhibition.     

Fenugreek affects the activity of beta-glucuronidase and mucinase in the colon

The effect of fenugreek seeds on the activities of beta-glucuronidase and mucinase during 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats was studied. Rats were given a weekly subcutaneous injection of DMH at a dose of 20 mg/kg body weight, for 15 weeks. Fenugreek seed powder was weighed depending upon the weight of individual rats and incorporated in the powdered pellet diet at a dose of 2 g/kg body weight. After an experimental period of 30 weeks the activity of beta-glucuronidase significantly increased in the colon, intestine, liver and colon contents in DMH administered rats when compared to an untreated control group. Increase in beta-glucuronidase may increase the hydrolysis of carcinogen-glucuronide conjugate, liberating carcinogen and/or co-carcinogen within the colonic lumen. Inclusion of fenugreek seed powder in the diet significantly decreased the activity of beta-glucuronidase in all the tissues studied. This may prevent the free carcinogens from acting on colonocytes. Mucinase helps in hydrolysing the protective mucin. Mucinase activity was increased in the colon content and fecal content of animals given DMH when compared to control, while the activity was significantly reduced in animals given DMH + fenugreek when compared to animals given DMH only. Our study shows that supplementation of fenugreek seeds in the diet inhibits colon carcinogenesis, by modulating the activities of beta-glucuronidase and mucinase. The beneficial effect may be attributed to the presence of fibre, flavonoids and/or saponins.     

螺旋藻对二甲肼诱导SD大鼠肠癌的保护作用

继前螺旋藻可以抑制接触致癌剂动物大肠细胞增生及癌前病变向肠癌转化的研究，本文报道进一步研究螺旋藻对大肠癌发病率的影响及其机理。将１４０只ｓＤ雄性大鼠分为阳性对照组；阴性对照组、螺旋藻低剂量保护组（１５０ｍｇ／ｋｇ）和螺旋藻高剂量保护组（１５００ｍｇ／ｋｇ）。从第１周开始给阳性对照组和保护组腹腔注射二甲肼（ＤＭＨ）（２Ｏｍｇ／ｋｇ×２４次），同时予保护组饲喂螺旋藻干粉，分别于第９、１３、１６、２１和２４ｗｋ每组处死５动物。观察淋巴细胞ＵＤＳ、ＮＫ细胞活性、肠癌发生率和病理组织学表现。结果表明：保护组动物肠癌出现时间比阳性对照组推迟５ｗｋ，总发癌率显著低于阳性对照组（Ｐ＜０．０５）。螺旋藻保护组在第９、１３、１６ｗｋ（ＮＫ细胞活性）较高，晚期活性降低，各级间Ｎｋ细胞活性无显著差异。但在动态观察时见螺旋藻有延缓ＮＫ细胞活性下降趋势。在第９、１３、１６ｗｋ螺旋藻保护组ＵＤＳ显著高于阳性对照组（Ｐ＜０．０１）．而在第２１、２４ｗｋ各组间差异无显著意义。     

Transplantable colonic adenocarcinomas in rats

The induction of colonic adenocarcinoma using two different regimens of dimethylhydrazine (DMH) in Fischer F344 rats is described. Rats receiving 20 mg/kg of DMH per week for 20 weeks developed primary tumors with metastases, whereas rats receiving the same weekly dose for 15 weeks developed primary tumors only. The most common route of metastases was transcelomic which often was associated with ascites. The epithelial origin of malignant ascites cells was confirmed by immunofluorescent staining with antidesmosomal antibodies and demonstration of desmosomes by electron microscopy. When transplanted into syngeneic rats, the cells of the malignant ascites resulted in the development of adenocarcinomatous metastases.     

Epigallocatechin gallate inhibits dimethylhydrazine-induced colorectal cancer in rats

BACKGROUND Epigallocatechin gallate(EGCG) is a polyhydroxy phenolic compound extracted from tea and its antitumor effect has received widespread attention. We explored the inhibitory effect of EGCG on dimethylhydrazine(DMH)-induced colorectal cancer(CRC) using a rat model, predicted the interaction between EGCG and CRC target genes using a database, and explained the EGCG associated target pathways and mechanisms in CRC.AIM To understand the inhibitory mechanisms of EGCG on CRC cell proliferation and identify its pharmacological targets by network pharmacology analysis.METHODS DMH(40 mg/kg, s.c., twice weekly for eight weeks) was used to induce CRC in rats. After model establishment, the rats were administered with EGCG(50, 100,or 200 mg/kg, p.o., once daily for eight weeks) and killed 12 and 20 wk after the start of the experiment. Formation of aberrant crypt foci and tumor was studied by histological analysis. Using network pharmacology analysis, candidate and collective targets of EGCG and CRC were identified, and Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the pathways altered by EGCG.RESULTS At week 12, high-dose EGCG treatment significantly reduced the tumor formation rate, total number of tumors, cancerous and non-cancerous tumors,tumor volume, ascites formation, and aberrant crypt foci count. At week 20, all three doses of EGCG were effective. Seventy-eight collective targets of EGCG and CRC were identified, of which 28 genes were dysregulated in CRC. Kyoto Encyclopedia of Genes and Genomes and GO analyses showed that the dysregulated genes were enriched in hsa05210(CRC), hsa04115(p53 signaling pathway), and hsa04151(PI3K-Akt signaling pathway), GO:0043124(negative regulation of I-kappaB kinase/NF-kappaB signaling pathway), GO:0043409(negative regulation of mitogen-activated protein kinase cascade), and GO:2001244(positive regulation of intrinsic apoptotic signaling pathway)respectively.CONCLUSION EGCG inhibits the formation of DMH-induced CRC by regulating key pathways involved in tumorigenesis.     

Gallic acid prevents 1, 2‐Dimethylhydrazine induced colon inflammation,toxicity, mucin depletion,and goblet cell disintegration

1,2‐Dimethylhydrazine (DMH), an environmental toxicant specifically targets the colon. The present study was aimed to evaluate the efficacy of gallic acid (GA) against colon toxicity induced by DMH in Wistar rats. GA, a phenolic acid has numerous beneficial properties, which include antiviral, antifungal and antioxidant properties which help cells to overcome oxidative stress and balance the redox homeostasis. GA was administered orally at two doses (25 and 50 mg/kg body weight) once daily for 14 days and a single dose (40 mg/kg body weight) of DMH was administered subcutaneously on 14th day. Animals were sacrificed on the 15th day and we could find that GA at both the doses significantly ameliorates DMH‐induced increased toxicity markers and also substantially increases the glutathione content level and activities of detoxifying enzymes. It also ameliorates the expression of proliferation, inflammation, apoptosis, goblet cell disintegration, and mucin depletion in the colon that was elevated upon administration of DMH. Histological alterations provide further confirmation of the protective role of GA against DMH‐induced colon toxicity. The results of this study clearly indicate supplementation of GA is beneficial in ameliorating DMH‐induced oxidative stress, inflammation, proliferation, apoptosis, mucin depletion, and goblet cell disintegration in colon of Wistar rats.     

双组元火箭推进剂引起急性肺损伤的研究进展

在推进剂作业环节中偏二甲肼（UDMH）和四氧化二氮（N2O2）可能通过呼吸道、皮肤或经口吸人造成作业人员急性肺损伤乃至急性呼吸窘迫综合征,从而对健康构成威胁。急性肺损伤的特征为肺泡毛细血管膜损伤和肺间质水肿等,临床上表现为急性发生的呼吸窘迫和非心源性肺水肿。作者对具有清除体内自由基、抗脂质过氧化活性强、有抑制炎症反应等作用的药物如N一乙酸半胱氨酸、丹参、黄岑苷、乌司他丁、盐酸戊乙奎醚与地塞米松联合使用等的药物作用进行了综述,为指导推进剂引起的急性肺损伤的防治提供参考方向,从而有效地保障推进剂作业人员的生命安全。     

二甲基肼诱发大鼠大肠癌模型的观察

目的通过动物模型的构建,为大肠癌研究提供可靠的实验依据。方法以二甲基肼诱发Wistar大鼠大肠癌,分别于给药后12、18、24周处死动物,观察各时期实验组及对照组大鼠大肠粘膜的病理变化。结果诱癌过程中大鼠大肠依次出现轻、中、重度不典型增生。诱癌12周时实验组未见肿瘤形成;18周肿瘤的发生率为60%,50%为大肠癌;24周肿瘤的发生率为100%,大肠癌的发生率为80%。结论二甲基肼诱导大鼠大肠癌成功率高,与人类大肠癌发生、发展相似,可用于模拟人类大肠癌的实验研究。     

Chemopreventive Effects of Nonsteroidal Anti-Inflammatory Drugs in the Membrane Lipid Composition and Fluidity Parameters of the 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in Rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, celecoxib, and etoricoxib are reported to act as chemopreventive agents in experimental colon cancer induced by 1,2-dimethylhydrazine (DMH) as they are known cyclooxygenase (COX) enzyme inhibitors. To determine whether NSAIDs can also effectively modulate the membrane lipid compositions and the fluidity parameters of colonic brush border membrane, rats were injected subcutaneously (s.c.) with DMH 30 mg/kg body weight per week for 6 weeks. The animals were simultaneously treated with NSAIDs orally at the dose of aspirin, 60 mg/kg body weight; celecoxib, 6 mg/kg body weight; and etoricoxib, 0.6 mg/kg body weight. The animals were sacrificed after 6 weeks of treatments. Brush border membrane was isolated from proximal and distal portions of the colon. Membrane lipids were extracted and analyzed while the fluidity parameters were assessed by steady-state fluorescence polarization technique using the membrane extrinsic fluorophore 1,6-diphenyl-1,3,5-hexatriene (DPH). The translational diffusion was measured by using the excimer formation of pyrene incorporated in the membrane. Colonic mucosal changes in DMH alone and DMH + NSAID treated animals were assessed histologically. The results demonstrate that (a) there is a distinct occurrence of premalignant alterations in DMH-induced colon in the form of multiple plaque lesions (MPLs), which were greatly reduced by the NSAIDs used, (b) the membrane lipid changes in DMH-induced colon were completely restored back, (c) the alterations in membrane fluorescence polarization and the fluidity parameters are partially recovered, particularly with etoricoxib, and (d) the pyrene excimer formation process was completely restored. It may be concluded that the NSAIDs, particularly the coxib group of the drugs (COX-2 selective), are effective in chemoprevention in the DMH-induced colon carcinogenesis and membrane alterations.     

Selenium as a chemopreventive agent in experimentally induced colon carcinogenesis

AIM: To elucidate the chemopreventive efficacy of selenium during experimentally induced colon carcinogenesis.METHODS: Thirty-two male wistar rats were divided into four groups: group I (normal control); group II [1,2-dimethylhydrazine (DMH) treated]; group III (selenium treated); and group IV (DMH + selenium treated). Groups II and IV were given subcutaneous injections of DMH (30 mg/kg body weight) every week for 20 wk. Selenium, in the form of sodium selenite, was given to groups III and IV at 1 ppm in drinking water ad libitum for 20 wk. At the end of the study, rats were sacrificed and their colons were analyzed for the development of tumors, antioxidant enzyme levels and histological changes.RESULTS: 100% of the DMH treated rats developed tumors, which was reduced to 60% upon simultaneous selenium supplementation. Similarly, tumor multiplicity decreased to 1.1 following selenium supplementation to DMH treated rats. Levels of lipid peroxidation, glutathione-S-transferase, superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) decreased following DMH treatment, whereas levels of glutathione (GSH) and glutathione reductase (GR) significantly increased in DMH treated rats. Selenium administration to DMH treated rats led to an increase in the levels of lipid peroxidation, SOD, catalase, glutathione-S-transferase and GPx, but decreased the levels of GSH and GR. Histopathological studies on DMH treated rats revealed dysplasia of the colonic histoarchitecture, which showed signs of improvement following selenium treatment.CONCLUSION: The study suggests the antioxidative potential of selenium is a major factor in providing protection from development of experimentally induced colon carcinogenesis.