米诺环素对氟尿嘧啶诱导的小鼠肠黏膜炎的保护作用研究
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摘要
目的研究米诺环素对氟尿嘧啶(5-Fu)诱导的肠黏膜炎的保护作用。方法 40只雄性Balb/c小鼠,随机分为5组,正常组、模型组、米诺环素低剂量组及高剂量组,每组10只。模型组由连续腹腔注射5-Fu(80 mg/kg)3 d诱导,治疗组同时灌胃给予30 mg/kg或60 mg/kg的米诺环素。测定小鼠体质量、腹泻指数,同时对小鼠空肠进行HE染色,测定小肠黏膜中的促炎性细胞因子,并对小鼠肠内容物中的短链脂肪酸进行测定,进而评价米诺环素对小鼠肠黏膜炎的保护作用。结果高剂量米诺环素可显著增加肠黏膜炎模型小鼠的体重(P <0.01),降低其腹泻指数(P <0.01),增加模型小鼠的空肠绒毛长度(P <0.01)。此外高剂量米诺环素可显著抑制肠黏膜中的IL-6(P <0.05)和TNF-α(P <0.01)的表达,同时增加小鼠肠内容物中丁酸及乙酸的含量(P <0.01)。结论米诺环素具有确切的肠黏膜保护作用,其作用与其抗炎及促进短链脂肪酸的生成有关。
Objective Forty investigate the protective effect of Minocycline on 5-Fu induced intestinal mucostitis.Methods 40 male Balb/c mice were randomly divided into four groups(n = 10), Control group, 5-Fu induced mucositis model, high dose or low dose of Minocycline treated group. After the mice were intraperitoneal administrated with 80 mg/kg5-Fu for 3 days and simultaneously treated with 30 or 60 mg/kg orally in Balb/c mice, the body weight loss, diarrhea scores, and HE stain of the intestinal, pro-inflammatory cytokines in intestine tissue and short chain fatty acids in colon contents were also determined. Results Data from this study indicated that high dose minocycline could attenuate the 5-Fu induced body weight loss(P < 0.01), and lower the diarrhea scores(P < 0.01). Also minicycline in high dose increased the intestinal vill length(P < 0.01), decreased the IL-6(P < 0.05) and TNF-α(P < 0.01). In the colon contents, Minocycline could significantly increase the SCFAs concentration, especially for aceticacid butyricacid(P <0.01). Conclusion All these results demonstrated that Minocycline exert protective effects on 5-Fu induced intestinal damage in mice, and these protective effects may partially oriented from its anti-inflammatory effects and enhancing short chain fatty acid production.
Objective Forty investigate the protective effect of Minocycline on 5-Fu induced intestinal mucostitis.Methods 40 male Balb/c mice were randomly divided into four groups(n = 10), Control group, 5-Fu induced mucositis model, high dose or low dose of Minocycline treated group. After the mice were intraperitoneal administrated with 80 mg/kg5-Fu for 3 days and simultaneously treated with 30 or 60 mg/kg orally in Balb/c mice, the body weight loss, diarrhea scores, and HE stain of the intestinal, pro-inflammatory cytokines in intestine tissue and short chain fatty acids in colon contents were also determined. Results Data from this study indicated that high dose minocycline could attenuate the 5-Fu induced body weight loss(P < 0.01), and lower the diarrhea scores(P < 0.01). Also minicycline in high dose increased the intestinal vill length(P < 0.01), decreased the IL-6(P < 0.05) and TNF-α(P < 0.01). In the colon contents, Minocycline could significantly increase the SCFAs concentration, especially for aceticacid butyricacid(P <0.01). Conclusion All these results demonstrated that Minocycline exert protective effects on 5-Fu induced intestinal damage in mice, and these protective effects may partially oriented from its anti-inflammatory effects and enhancing short chain fatty acid production.
引文
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[19]Le Bastard Q,Ward T,Sidiropoulos D,et al.Fecal microbiota transplantation reverses antibiotic and chemotherapy-induced gut dysbiosis in mice[J].Sci Rep,2018,8(1):6219.
[20]Hamouda N,Sano T,Oikawa Y,et al.Apoptosis,dysbiosis and expression of inflammatory cytokines are sequential events in the development of 5-fluorouracil-induced intestinal mucositis in mice[J].Basic Clin Pharmacol Toxicol,2017,121(3):159-168.
[2]Garrido-Mesa N,Zarzuelo A,Gálvez J.Minocycline:far beyond an antibiotic[J].Br J Pharmacol,2013,169(2):337-352.
[3]Livermore DM,Mushtaq S,Warner M,et al.In Vitro Activity of Eravacycline against Carbapenem-Resistant Enterobacteriaceae and Acinetobacter baumannii[J].Antimicrob Agents Chemother,2016,60(6):3840-3844.
[4]Bahrami Z,Firouzi M,Hashemi-Monfared A,et al.The effect of minocycline on indolamine 2,3 dioxygenase expression and the levels of kynurenic acid and quinolinic acid in LPS-activated primary rat microglia[J].Cytokine,2018,107:125-129.
[5]Bonjoch L,Gea-SorlíS,Jordan J,et al.Minocycline inhibits peritoneal macrophages but activates alveolar macrophages in acute pancreatitis[J].J Physiol Biochem,2015,71(4):839-846.
[6]Aketa H,Tatsumi T,Kohga K,et al.The combination therapy ofα-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice[J]Int J Cancer,2013,133(5):1126-1134.
[7]Cheng M,Liu Z,Wan T,et al.Preliminary pharmacology of galactosylated chitosan/5-fluorouracil nanoparticles and its inhibition of hepatocellular carcinoma in mice[J].Cancer Biol Ther,2012,13(14):1407-1416.
[8]Tang M,Lu X,Zhang C,et al.Downregulation of SIRT7 by5-fluorouracil induces radiosensitivity in human colorectal cancer[J].Theranostics,2017,7(5):1346-1359.
[9]Spencer NJ.Motility patterns in mouse colon:gastrointestinal dysfunction induced by anticancer chemotherapy[J]Neurogastroenterol Motil,2016,28(12):1759-1764.
[10]Chang CT,Ho TY,Lin H,et al.5-Fluorouracil induced intestinal mucositis via nuclear factor-kappa B activation by transcriptomic analysis and in vivo bioluminescence imaging[J].PLo S One,2012,7(3):e31808.
[11]Zhang S,Liu Y,Xiang D,et al.Assessment of dose-response relationship of 5-fluorouracil to murine intestinal injury[J].Biomed Pharmacother,2018,106:910-916.
[12]Ohkusa T,Yoshida T,Sato N,et al.Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion:a possible pathogenic mechanism of ulcerative colitis[J].J Med Microbiol,2009,58:535-545.
[13]Shimamura Y,Takeuchi I,Terada H,et al.A mouse model for oral mucositis induced by cancer chemotherapy[J].Anticancer Res,2018,38(1):307-312.
[14]Pinto A,Fidalgo P,Cravo M,et al.Short chain fatty acids are effective in short-term treatment of chronic radiation proctitis:randomized,double-blind,controlled trial[J].Dis Colon Rectum,1999,42(6):788-795,795-796.
[15]Ooi C,Good N,Williams D,et al.Efficacy of butyrate analogues in HT-29 cancer cells[J].Clin Exp Pharmacol Physiol,2010,37(4):482-489.
[16]傅红,师英强,莫善兢.短链脂肪酸对人结肠癌Caco-2细胞增殖分化的影响与临床意义[J].中华消化杂志,2003,23(8):473-475.
[17]Saif MW,Diasio RB.Benefit of uridine triacetate(Vistogard)in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase(DPYD)deficiency[J].Cancer Chemother Pharmacol,2016,78(1):151-156.
[18]Yuan L,Zhang S,Li H,et al.The influence of gut microbiota dysbiosis to the efficacy of 5-Fluorouracil treatment on colorectal cancer[J].Biomed Pharmacother,2018,108:184-193.
[19]Le Bastard Q,Ward T,Sidiropoulos D,et al.Fecal microbiota transplantation reverses antibiotic and chemotherapy-induced gut dysbiosis in mice[J].Sci Rep,2018,8(1):6219.
[20]Hamouda N,Sano T,Oikawa Y,et al.Apoptosis,dysbiosis and expression of inflammatory cytokines are sequential events in the development of 5-fluorouracil-induced intestinal mucositis in mice[J].Basic Clin Pharmacol Toxicol,2017,121(3):159-168.