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BMC Complementary Medicine and Therapies

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Open Access 01-12-2018 | Research article

Weipixiao attenuate early angiogenesis in rats with gastric precancerous lesions

Authors: Jinhao Zeng, Ran Yan, Huafeng Pan, Fengming You, Tiantian Cai, Wei Liu, Chuan Zheng, Ziming Zhao, Daoyin Gong, Longhui Chen, Yi Zhang

Published in: BMC Complementary Medicine and Therapies | Issue 1/2018

Abstract

Background

Angiogenesis is a pathobiological hallmark of gastric cancer. However, rare studies focus on angiogenesis in gastric precancerous lesions (GPL). Weipixiao (WPX), a Chinese herbal preparation, is proved clinically effective in treating GPL. Here, we evaluated WPX’s anti-angiogenic potential for GPL, and also investigated the possibility of its anti-angiogenic mechanisms.

Methods

HPLC analysis was applied to screen the major chemical components of WPX. After modeling N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)-induced GPL in male Sprague-Dawley rats, different doses of WPX were administrated orally for 10 weeks. Next, we performed histopathological examination using routine H&E staining and HID-AB-PAS staining. In parallel, we assessed angiogenesis revealed by microvessel density (MVD) using CD34 immunostaining, and subsequently observe microvessel ultrastructure in gastric mucosa under Transmission Electron Microscope. Finally, we detect expression of angiogenesis-associated markers VEGF and HIF-1α using immunohistochemistry. Moreover, mRNA expressions of ERK1, ERK2, Cylin D1 as well as HIF-1α in gastric mucosa were determined by quantitative real-time reverse transcription- polymerase chain reaction.

Results

We observed the appearance of active angiogenesis in GPL rats, and demonstrated that WPX could reduce microvascular abnormalities and attenuate early angiogenesis in most of GPL specimens with a concomitant regression of most intestinal metaplasia (IM) and a portion of gastric epithelial dysplasia (GED). In parallel, WPX could suppress HIF-1α mRNA expression (P < 0.01) as well as protein expression (although without statistical significance), and could markedly inhibit VEGF protein expression in GPL rats. Mechanistically, WPX intervention, especially at low dose, caused a significant decrease in the ERK1 and Cylin D1 mRNA levels. However, WPX might probably have no regulatory effect on ERK2 amplification.

Conclusions

WPX could attenuate early angiogenesis and temper microvascular abnormalities in GPL rats. This might be partly achieved by inhibiting on the angiogenesis-associated markers HIF-1α and VEGF, and on the ERK1/Cylin D1 aberrant activation.

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Joo YE, Park HK, Myung DS, Baik GH, Shin JE, Seo GS, Kim GH, Kim HU, Kim HY, Cho SI, Kim N. Prevalence and risk factors of atrophic gastritis and intestinal metaplasia: a nationwide multicenter prospective study in Korea. Gut Liver. 2013;7(3):303–10.CrossRefPubMedPubMedCentral

de Vries AC, van Grieken NC, Looman CW, Casparie MK, de Vries E, Meijer GA, Kuipers EJ. Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands. Gastroenterology. 2008;134(4):945–52.CrossRefPubMed

Sun SB, Chen ZT, Zheng D, Huang ML, Xu D, Zhang H, Wang P, Wu J. Clinical pathology and recent follow-up study on gastric intraepithelial neoplasia and gastric mucosal lesions. Hepatogastroenterology. 2013;60(127):1597–601.PubMed

Srivastava A, Lauwers GY. Gastric epithelial dysplasia: the Western perspective. Dig Liver Dis. 2008;40(8):641–9.CrossRefPubMed

Zhang RF, Li JT, He SB, Xiao ZD. Effects of vitacoenzyme on atrophic and intestinal metaplastic lesions in chronic atrophic gastritis--pathologic and histochemical studies of 94 cases. Acad J Sun Yat-Sen Univ Med Sci. 1987;8(2):1–5.

Chen XT, Jiang YH, Chen LH, Li XQ, Kuang ZS, Xie YH, Fang YQ. Effects of Weiyankang plus vitacoenzyme on gastric precancerous lesions and its possible mechanism. Acad J Tradit Chin Med. 2004;22(9):1703–4.

Deng X, Liu ZW, Wu FS, Li LH, Liang J. A clinical study of weining granules in the treatment of gastric precancerous lesions. J Tradit Chin Med. 2012;32(2):164–72.CrossRefPubMed

Li HZ, Wang H, Wang GQ, Liu J, Zhao SM, Chen J, Song QW, Gao W, Qi XZ, Gao Q. Treatment of gastric precancerous lesions with Weiansan. World J Gastroenterol. 2006;12(33):5389–92.CrossRefPubMedPubMedCentral

Zhang X, Zheng Z, Shin YK, Kim KY, Rha SY, Noh SH, Chung HC, Jeung HC. Angiogenic factor thymidine phosphorylase associates with angiogenesis and lymphangiogenesis in the intestinal-type gastric cancer. Pathology. 2014;46(4):316–24.CrossRefPubMed

10.

Gao LM, Wang F, Zheng Y, Fu ZZ, Zheng L, Chen LL. Roles of fibroblast activation protein and hepatocyte growth factor expressions in angiogenesis and metastasis of gastric cancer. Pathol Oncol Res. 2017; https://doi.org/10.1007/s12253-017-0359-3.

11.

Maeda K, Chung YS, Takatsuka S, Ogawa Y, Onoda N, Sawada T, Kato Y, Nitta A, Arimoto Y, Kondo Y. Tumour angiogenesis and tumour cell proliferation as prognostic indicators in gastric carcinoma. Br J Cancer. 1995;72(2):319–23.CrossRefPubMedPubMedCentral

12.

Pinto MP, Owen GI, Retamal I, Garrido M. Angiogenesis inhibitors in early development for gastric cancer. Expert Opin Investig Drugs. 2017;26(9):1007–17.CrossRefPubMed

13.

Rey S, Schito L, Wouters BG, Eliasof S, Kerbel RS. Targeting hypoxia-inducible factors for antiangiogenic cancer therapy. Trends Cancer. 2017;3(7):529–41.CrossRefPubMed

14.

Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala SM, Baek KH, Rosenzweig A, Spiegelman BM. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 2008;451(7181):1008–12.CrossRefPubMed

15.

Shin M, Beane TJ, Quillien A, Male I, Zhu LJ, Lawson ND. Vegfa signals through ERK to promote angiogenesis, but not artery differentiation. Development. 2016;143(20):3796–805.CrossRefPubMedPubMedCentral

16.

Yang JJ, Cho LY, Ma SH, Ko KP, Shin A, Choi BY, Han DS, Song KS, Kim YS, Chang SH, Shin HR, Kang D, Yoo KY, Park SK. Oncogenic CagA promotes gastric cancer risk via activating ERK signaling pathways: a nested case-control study. PLoS One. 2011;6(6):e21155.CrossRefPubMedPubMedCentral

17.

Luo ZY, Wang YY, Zhao ZS, Li B, Chen JF. The expression of TMPRSS4 and Erk1 correlates with metastasis and poor prognosis in Chinese patients with gastric cancer. PLoS One. 2013;8(7):e70311.CrossRefPubMedPubMedCentral

18.

Yang D, Fan X, Yin P, Wen Q, Yan F, Yuan S, Liu B, Zhuang G, Liu Z. Significance of decoy receptor 3 (Dcr3) and external-signal regulated kinase 1/2 (Erk1/2) in gastric cancer. BMC Immunol. 2012;13:28.CrossRefPubMedPubMedCentral

19.

Modi PK, Komaravelli N, Singh N, Sharma P. Interplay between MEK-ERK signaling, cyclin D1, and cyclin-dependent kinase 5 regulates cell cycle reentry and apoptosis of neurons. Mol Biol Cell. 2012;23(18):3722–30.CrossRefPubMedPubMedCentral

20.

Weber JD, Raben DM, Phillips PJ, Baldassare JJ. Sustained activation of extracellular-signal- regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem J. 1997;326(Pt 1):61–8.CrossRefPubMedPubMedCentral

21.

Guo YL, Rao J, Pan HF, Fang J. Effect of the treatment of Jianpi Huayu Jiedu for patients with chronic atrophic gastritis and its influence on cyclin E protein expression. Chin J Exp Tradit Med Form. 2013;19(11):292–5.

22.

He JJ, Zhang BP, Zhao XY. Clinical efficay of Weipixiao in treating chonic atrophic gastritis. J Guangzhou Univ Tradit Chin Med. 2017;34(6):823–7.

23.

Zhang SL. Clinical efficay of Weipixiao in treating chonic atrophic gastritis (spleen-stomach weakness, syndrome type of TCM): a randomized clinical trial. J Pr Tradit Chin Intern Med. 2017;31(9):12–4.

24.

Yin G, Tang D, Dai J, Liu M, Wu M, Sun YU, Yang Z, Hoffman RM, Li L, Zhang S, Guo X. Combination efficacy of Astragalus membranaceus and Curcuma wenyujin at different stages of tumor progression in an imageable orthotopic nude mouse model of metastatic human ovarian cancer expressing red fluorescent protein. Anticancer Res. 2015;35(6):3193–207.PubMed

25.

Wu J, Ke X, Ma N, Wang W, Fu W, Zhang H, Zhao M, Gao X, Hao X, Zhang Z. Formononetin, an active compound of Astragalus membranaceus (Fisch) Bunge, inhibits hypoxia-induced retinal neovascularization via the HIF-1alpha/VEGF signaling pathway. Drug Des Devel Ther. 2016;10:3071–81.CrossRefPubMedPubMedCentral

26.

Chen W, Lu Y, Gao M, Wu J, Wang A, Shi R. Anti-angiogenesis effect of essential oil from Curcuma zedoaria in vitro and in vivo. J Ethnopharmacol. 2011;133(1):220–6.CrossRefPubMed

27.

Cao HY, Ding RL, Li M, Yang MN, Yang LL, Wu JB, Yang B, Wang J, Luo CL, Wen QL. Danshensu, a major water-soluble component of Salvia miltiorrhiza, enhances the radioresponse for Lewis lung carcinoma xenografts in mice. Oncol Lett. 2017;13(2):605–12.CrossRefPubMed

28.

Saito T, Inokuchi K, Takayama S, Sugimura T. Sequential morphological changes in N-methyl-N'-nitro-N-nitrosoguanidine carcinogenesis in the glandular stomach of rats. J Natl Cancer Inst. 1970;44(4):769–83.PubMed

29.

Tatematsu M, Aoki T, Inoue T, Mutai M, Furihata C, Ito N. Coefficient induction of pepsinogen 1-decreased pyloric glands and gastric cancers in five different strains of rats treated with N-methyl-N'-nitro-N-nitrosoguanidine. Carcinogenesis. 1988;9(3):495–8.CrossRefPubMed

30.

Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1–8.CrossRefPubMed

31.

Correa P. A human model of gastric carcinogenesis. Cancer Res. 1988;48(13):3554–60.PubMed

32.

Dinis-Ribeiro M, Lopes C, da Costa-Pereira A, Guilherme M, Barbosa J, Lomba-Viana H, Silva R, Moreira-Dias L. A follow up model for patients with atrophic chronic gastritis and intestinal metaplasia. J Clin Pathol. 2004;57(2):177–82.CrossRefPubMedPubMedCentral

33.

Li D, Bautista MC, Jiang SF, Daryani P, Brackett M, Armstrong MA, Hung YY, Postlethwaite D, Ladabaum U. Risks and predictors of gastric adenocarcinoma in patients with gastric intestinal metaplasia and dysplasia: a population-based study. Am J Gastroenterol. 2016;111(8):1104–13.CrossRefPubMed

34.

Di Gregorio C, Morandi P, Fante R, De Gaetani C. Gastric dysplasia. A follow-up study. Am J Gastroenterol. 1993;88(10):1714–9.PubMed

35.

Gonzalez CA, Sanz-Anquela JM, Companioni O, Bonet C, Berdasco M, López C, Mendoza J, Martín-Arranz MD, Rey E, Poves E, Espinosa L, Barrio J, Torres MÁ, Cuatrecasas M, Elizalde I, Bujanda L, Garmendia M, Ferrández Á, Muñoz G, Andreu V, Paules MJ, Lario S, Ramírez MJ, Gisbert JP. Incomplete type of intestinal metaplasia has the highest risk to progress to gastric cancer: results of the Spanish follow-up multicenter study. J Gastroenterol Hepatol. 2016;31(5):953–8.CrossRefPubMed

36.

Tarnawski AS, Ahluwalia A, Jones MK. Angiogenesis in gastric mucosa: an important component of gastric erosion and ulcer healing and its impairment in aging. J Gastroenterol Hepatol. 2014;29(Suppl 4):112–23.CrossRefPubMed

37.

Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417–27.CrossRefPubMed

38.

Spina D, Vindigni C, Presenti L, Schürfeld K, Stumpo M, Tosi P. Cell proliferation, cell death, E-cadherin, metalloproteinase expression and angiogenesis in gastric cancer precursors and early cancer of the intestinal type. Int J Oncol. 2001;18(6):1251–8.PubMed

39.

Walshe TE, D'Amore PA. The role of hypoxia in vascular injury and repair. Annu Rev Pathol. 2008;3:615–43.CrossRefPubMed

40.

Lentsch AB, Ward PA. Regulation of inflammatory vascular damage. J Pathol. 2000;190(3):343–8.CrossRefPubMed

41.

Colgan SP, Campbell EL, Kominsky DJ. Hypoxia and mucosal inflammation. Annu Rev Pathol. 2016;11:77–100.CrossRefPubMedPubMedCentral

42.

Whiteford JR, De Rossi G, Woodfin A. Mutually supportive mechanisms of inflammation and vascular remodeling. Int Rev Cell Mol Biol. 2016;326:201–78.CrossRefPubMed

43.

Li HW, Pan HF, Zhao ZM, Shi YF, Yan Y, Yuan YM, Zeng JH, Lin ZY, Zhao JY. Effect of Weipixiao on plasma tumor necrosis factor alpha and interleukin-4 expression in rats with gastric precancerous lesions. J Guangzhou Univ Tradit Chin Med. 2015;32(2):271–4.

44.

Span PN, Bussink J. Biology of hypoxia. Semin Nucl Med. 2015;45(2):101–9.CrossRefPubMed

45.

Pan HF, Zhao ZM, Ren JL, Shi YF. Effect of Weipixiao on gastric epithelial intestinal metaplasia in chronic atrophic gastritis rats. Tradit Chin Drug Res Clin Pharmacol. 2012;23(1):55–7.

46.

Pan HF, Ren JL, Zhao ZM, Liu J. Effect of Weipixiao on cell generation cycle distribution and apoptosis-related gene expression in gastric mucosal epithelial cells of gastric precancerous lesion rats with spleen-deficiency chronic atrophic gastritis. J Guangzhou Univ Tradit Chin Med. 2010;27(5):488–91.

47.

Gao Y, Deng J, Yu XF, Yang DL, Gong QH, Huang XN. Ginsenoside Rg1 inhibits vascular intimal hyperplasia in balloon-injured rat carotid artery by down-regulation of extracellular signal-regulated kinase 2. J Ethnopharmacol. 2011;138(2):472–8.CrossRefPubMed

48.

Leung KW, Cheung LW, Pon YL, Wong RN, Mak NK, Fan TP, Au SC, Tombran-Tink J, Wong AS. Ginsenoside Rb1 inhibits tube-like structure formation of endothelial cells by regulating pigment epithelium-derived factor through the oestrogen beta receptor. Br J Pharmacol. 2007;152(2):207–15.CrossRefPubMedPubMedCentral

49.

Wang C, Duan H, He L. Inhibitory effect of atractylenolide I on angiogenesis in chronic inflammation in vivo and in vitro. Eur J Pharmacol. 2009;612(1–3):143–52.CrossRefPubMed

50.

Wang SG, Xu Y, Chen JD, Yang CH, Chen XH. Astragaloside IV stimulates angiogenesis and increases nitric oxide accumulation via JAK2/STAT3 and ERK1/2 pathway. Molecules. 2013;18(10):12809–19.CrossRefPubMedPubMedCentral

51.

Wang S, Chen J, Fu Y, Chen X. Promotion of astragaloside IV for EA-hy926 cell proliferation and angiogenic activity via ERK1/2 pathway. J Nanosci Nanotechnol. 2015;15(6):4239–44.CrossRefPubMed

52.

Zhang S, Tang D, Zang W, Yin G, Dai J, Sun YU, Yang Z, Hoffman RM, Guo X. Synergistic inhibitory effect of traditional Chinese medicine astragaloside IV and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma. Anticancer Res. 2017;37(2):465–73.CrossRefPubMed

Title: Weipixiao attenuate early angiogenesis in rats with gastric precancerous lesions
Authors: Jinhao Zeng
Ran Yan
Huafeng Pan
Fengming You
Tiantian Cai
Wei Liu
Chuan Zheng
Ziming Zhao
Daoyin Gong
Longhui Chen
Yi Zhang
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Complementary Medicine and Therapies / Issue 1/2018
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/s12906-018-2309-3

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Weipixiao attenuate early angiogenesis in rats with gastric precancerous lesions

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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