Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Author(s): Yi Zeng, Li Zhou, Ying Wan, Ting Fu, Paidi Xu, Hongxing Zhang* and Ying Guan*

DOI: 10.2174/0113862073262404231004053116

DownloadDownload PDF Flyer Cite As
Effects of Saikosaponin D on Apoptosis, Autophagy, and Morphological Structure of Intestinal Cells of Cajal with Functional Dyspepsia

Page: [1513 - 1522] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Objective: Functional dyspepsia (FD) is one of the most common gastrointestinal diseases, with a global prevalence of 10%-30%. However, the specific pathogenesis of FD has not yet been determined. As such, the aim of this study was to investigate the effects of saikosaponin D (SSD) administration on the apoptosis, autophagy, and morphological structure of the intestinal cells of Cajal (ICCs) in FD.

MethodsA rat model of FD was constructed by stimulating the rat tail with a sponge clamp at one-third of the distal tail length. An autophagy model was constructed for ICCs using glutamate. The apoptosis rate in each group of cells was determined using flow cytometry. The expressions of ghrelin and substance P (SP) were detected using ELISA.

Results: The body weight and food intake of male and female rats in the SSD group were consistently higher than those in the model group. The SSD group showed substantial improvement compared with the model group, with no inflammatory cell infiltration and normal gastric mucosal structures. After intervention with SSD, the ultrastructure of the ICCs considerably improved and was clear. Compared with the model group, the expressions of LC3 I/II, ghrelin, and SP proteins in the SSD group were significantly upregulated, and the apoptosis rate was significantly reduced.

Conclusion: The administration of SSD improved ICC morphology and structure, inhibited excessive autophagy, and improved FD, a gastrointestinal motility disorder, by regulating ghrelin and SP levels.

Graphical Abstract

[1]
Ford, A.C.; Mahadeva, S.; Carbone, M.F.; Lacy, B.E.; Talley, N.J. Functional dyspepsia. Lancet, 2020, 396(10263), 1689-1702.
[http://dx.doi.org/10.1016/S0140-6736(20)30469-4] [PMID: 33049222]
[2]
Sayuk, G.S.; Gyawali, C.P. Functional dyspepsia: Diagnostic and therapeutic approaches. Drugs, 2020, 80(13), 1319-1336.
[http://dx.doi.org/10.1007/s40265-020-01362-4] [PMID: 32691294]
[3]
Voiosu, T.A.; Giurcan, R.; Voiosu, A.M.; Voiosu, M.R. Functional dyspepsia today. Maedica, 2013, 8(1), 68-74.
[PMID: 24023602]
[4]
Wauters, L.; Talley, N.J.; Walker, M.M.; Tack, J.; Vanuytsel, T. Novel concepts in the pathophysiology and treatment of functional dyspepsia. Gut, 2020, 69(3), 591-600.
[http://dx.doi.org/10.1136/gutjnl-2019-318536] [PMID: 31784469]
[5]
Ohno, T.; Mochiki, E.; Kuwano, H. The roles of motilin and ghrelin in gastrointestinal motility. Int. J. Pept., 2010, 2010, 820794.
[http://dx.doi.org/10.1155/2010/820794]
[6]
Yagi, T.; Asakawa, A.; Ueda, H.; Miyawaki, S.; Inui, A. The role of ghrelin in patients with functional dyspepsia and its potential clinical relevance (Review). Int. J. Mol. Med., 2013, 32(3), 523-531.
[http://dx.doi.org/10.3892/ijmm.2013.1418] [PMID: 23778458]
[7]
Zagari, R.M.; Law, G.R.; Fuccio, L.; Cennamo, V.; Gilthorpe, M.S.; Forman, D.; Bazzoli, F. Epidemiology of functional dyspepsia and subgroups in the Italian general population: an endoscopic study. Gastroenterology, 2010, 138(4), 1302-1311.
[http://dx.doi.org/10.1053/j.gastro.2009.12.057] [PMID: 20074574]
[8]
Futagami, S.; Itoh, T.; Sakamoto, C. Systematic review with meta-analysis: Post-infectious functional dyspepsia. Aliment. Pharmacol. Ther., 2015, 41(2), 177-188.
[http://dx.doi.org/10.1111/apt.13006] [PMID: 25348873]
[9]
Okumura, T.; Tanno, S.; Ohhira, M.; Tanno, S. Prevalence of functional dyspepsia in an outpatient clinic with primary care physicians in Japan. J. Gastroenterol., 2010, 45(2), 187-194.
[http://dx.doi.org/10.1007/s00535-009-0168-x] [PMID: 19997854]
[10]
Du, L.; Chen, B.; Kim, J.J.; Chen, X.; Dai, N. Micro-inflammation in functional dyspepsia: A systematic review and meta-analysis. Neurogastroenterol. Motil., 2018, 30(4), e13304.
[http://dx.doi.org/10.1111/nmo.13304] [PMID: 29392796]
[11]
Otaka, M.; Jin, M.; Odashima, M.; Matsuhashi, T.; Wada, I.; Horikawa, Y.; Komatsu, K.; Ohba, R.; Oyake, J.; Hatakeyama, N.; Watanabe, S. New strategy of therapy for functional dyspepsia using famotidine, mosapride and amitriptyline. Aliment. Pharmacol. Ther., 2005, 21(S2), 42-46.
[http://dx.doi.org/10.1111/j.1365-2036.2005.02473.x] [PMID: 15943846]
[12]
Kelber, O.; Bauer, R.; Kubelka, W. Phytotherapy in functional gastrointestinal disorders. Dig. Dis., 2017, 35(S1), 36-42.
[http://dx.doi.org/10.1159/000485489] [PMID: 29421793]
[13]
Huizinga, J.D.; Lammers, W.J.E.P. Gut peristalsis is governed by a multitude of cooperating mechanisms. Am. J. Physiol. Gastrointest. Liver Physiol., 2009, 296(1), G1-G8.
[http://dx.doi.org/10.1152/ajpgi.90380.2008] [PMID: 18988693]
[14]
Ueshima, S.; Nishida, T.; Koike, M.; Matsuda, H.; Sawa, Y.; Uchiyama, Y. Nitric oxide-mediated injury of interstitial cells of Cajal and intestinal dysmotility under endotoxemia of mice. Biomed. Res., 2014, 35(4), 251-262.
[http://dx.doi.org/10.2220/biomedres.35.251] [PMID: 25152034]
[15]
Thein, W.; Po, W.W.; Choi, W.S.; Sohn, U.D. Autophagy and digestive disorders: Advances in understanding and therapeutic approaches. Biomol. Ther., 2021, 29(4), 353-364.
[http://dx.doi.org/10.4062/biomolther.2021.086] [PMID: 34127572]
[16]
Li, X.; Li, X.; Huang, N.; Liu, R.; Sun, R. A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins. Phytomedicine, 2018, 50, 73-87.
[http://dx.doi.org/10.1016/j.phymed.2018.09.174] [PMID: 30466994]
[17]
Lu, C.N.; Yuan, Z.G.; Zhang, X.L.; Yan, R.; Zhao, Y.Q.; Liao, M.; Chen, J.X. Saikosaponin a and its epimer saikosaponin d exhibit anti-inflammatory activity by suppressing activation of NF-κB signaling pathway. Int. Immunopharmacol., 2012, 14(1), 121-126.
[http://dx.doi.org/10.1016/j.intimp.2012.06.010] [PMID: 22728095]
[18]
Wong, V.K.W.; Zhou, H.; Cheung, S.S.F.; Li, T.; Liu, L. Mechanistic study of saikosaponin-d (Ssd) on suppression of murine T lymphocyte activation. J. Cell. Biochem., 2009, 107(2), 303-315.
[http://dx.doi.org/10.1002/jcb.22126] [PMID: 19301261]
[19]
Zhang, G.; Xie, S.; Hu, W.; Liu, Y.; Liu, M.; Liu, M.; Chang, X. Effects of electroacupuncture on interstitial cells of cajal (ICC) ultrastructure and connexin 43 protein expression in the gastrointestinal tract of functional dyspepsia (FD) rats. Med. Sci. Monit., 2016, 22, 2021-2027.
[http://dx.doi.org/10.12659/MSM.899023] [PMID: 27297942]
[20]
Liu, A.; Tanaka, N.; Sun, L.; Guo, B.; Kim, J.H.; Krausz, K.W.; Fang, Z.; Jiang, C.; Yang, J.; Gonzalez, F.J. Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling. Chem. Biol. Interact., 2014, 223, 80-86.
[http://dx.doi.org/10.1016/j.cbi.2014.09.012] [PMID: 25265579]
[21]
Tan, R.Q.; Zhang, Z.; Ju, J.; Ling, J.H. Effect of chaihu shugan powder-contained serum on glutamate-induced autophagy of interstitial cells of cajal in the rat gastric antrum. Evid. Based Complement. Alternat. Med., 2019, 2019, 7318616.
[http://dx.doi.org/10.1155/2019/7318616]
[22]
Tan, R.Q.; Zhang, Z.; Ning, H.E.; Zhang, L.M.; Wang, Y.; Ling, J.H. Establishment of autophagy model of rat gastric interstitial cells of Cajal induced by glutamic acid. Chin. J. Physiol., 2018, 34, 1532-1536.
[23]
Adad, S.J.; Silva, G.B.; Jammal, A.A. The significantly reduced number of interstitial cells of Cajal in chagasic megacolon (CM) patients might contribute to the pathophysiology of CM. Virchows Archiv: Int. J. Pathology., 2012, 461(4), 385-392.
[24]
Mönkemüller, K.; Malfertheiner, P. Drug treatment of functional dyspepsia. World J. Gastroenterol., 2006, 12(17), 2694-2700.
[http://dx.doi.org/10.3748/wjg.v12.i17.2694] [PMID: 16718755]
[25]
Park, I.K.; Kim, J.H.; Park, C.G.; Kim, M.Y.; Parajuli, S.P.; Hong, C.S.; Choi, S.; Jun, J.Y. Effects of ATP on pacemaker activity of interstitial cells of cajal from the mouse small intestine. Chonnam Med. J., 2018, 54(1), 63-71.
[http://dx.doi.org/10.4068/cmj.2018.54.1.63] [PMID: 29399568]
[26]
Foong, D.; Zhou, J.; Zarrouk, A.; Ho, V.; O’Connor, M.D. Understanding the biology of human interstitial cells of cajal in gastrointestinal motility. Int. J. Mol. Sci., 2020, 21(12), 4540.
[http://dx.doi.org/10.3390/ijms21124540] [PMID: 32630607]
[27]
Corsello, A.; Pugliese, D.; Gasbarrini, A.; Armuzzi, A. Diet and nutrients in gastrointestinal chronic Diseases. Nutrients, 2020, 12(9), 2693.
[http://dx.doi.org/10.3390/nu12092693] [PMID: 32899273]
[28]
Duncanson, K.; Burns, G.; Pryor, J.; Keely, S.; Talley, N.J. Mechanisms of food-induced symptom induction and dietary management in functional dyspepsia. Nutrients, 2021, 13(4), 1109.
[http://dx.doi.org/10.3390/nu13041109] [PMID: 33800668]
[29]
Hajishafiee, M.; Bitarafan, V.; Feinle-Bisset, C. Gastrointestinal sensing of meal-related signals in humans, and dysregulations in eating-related disorders. Nutrients, 2019, 11(6), 1298.
[http://dx.doi.org/10.3390/nu11061298] [PMID: 31181734]
[30]
Bento, C.F.; Renna, M.; Ghislat, G.; Puri, C.; Ashkenazi, A.; Vicinanza, M.; Menzies, F.M.; Rubinsztein, D.C. Mammalian autophagy: How does it work? Annu. Rev. Biochem., 2016, 85(1), 685-713.
[http://dx.doi.org/10.1146/annurev-biochem-060815-014556] [PMID: 26865532]
[31]
Rubinsztein, D.C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature, 2006, 443(7113), 780-786.
[http://dx.doi.org/10.1038/nature05291] [PMID: 17051204]
[32]
Runwal, G.; Stamatakou, E.; Siddiqi, F.H.; Puri, C.; Zhu, Y.; Rubinsztein, D.C. LC3-positive structures are prominent in autophagy-deficient cells. Sci. Rep., 2019, 9(1), 10147.
[http://dx.doi.org/10.1038/s41598-019-46657-z] [PMID: 31300716]
[33]
Zhang, L.; Zeng, L.; Deng, J.; Zhang, Y.; Wang, Y.; Xie, T.; Ling, J. Investigation of autophagy and differentiation of myenteric interstitial cells of Cajal in the pathogenesis of gastric motility disorders in rats with functional dyspepsia. Biotechnol. Appl. Biochem., 2018, 65(4), 533-539.
[http://dx.doi.org/10.1002/bab.1635] [PMID: 29274173]
[34]
Battaglia, E.; Bassotti, G.; Bellone, G.; Dughera, L.; Serra, A.M.; Chiusa, L.; Repici, A.; Mioli, P.; Emanuelli, G. Loss of interstitial cells of Cajal network in severe idiopathic gastroparesis. World J. Gastroenterol., 2006, 12(38), 6172-6177.
[http://dx.doi.org/10.3748/wjg.v12.i38.6172] [PMID: 17036390]
[35]
Farrugia, G. Interstitial cells of Cajal in health and disease. Neurogastroenterol. Motil., 2008, 20(S1), 54-63.
[http://dx.doi.org/10.1111/j.1365-2982.2008.01109.x] [PMID: 18402642]
[36]
Ohlsson, B.; Veress, B.; Lindgren, S.; Sundkvist, G. Enteric ganglioneuritis and abnormal interstitial cells of Cajal. Inflamm. Bowel Dis., 2007, 13(6), 721-726.
[http://dx.doi.org/10.1002/ibd.20095] [PMID: 17230538]
[37]
Huizinga, J.D. Neural injury, repair, and adaptation in the GI tract. IV. Pathophysiology of GI motility related to interstitial cells of Cajal. Am. J. Physiol., 1998, 275(3), G381-G386.
[PMID: 9724247]
[38]
Kazemi, M.H.; Eshraghian, A.; Hamidpour, L.; Taghavi, S.A. Changes in serum ghrelin level in relation to meal‐time in patients with functional dyspepsia. United European Gastroenterol. J., 2015, 3(1), 11-16.
[http://dx.doi.org/10.1177/2050640614563373] [PMID: 25653854]
[39]
Ariyasu, H.; Takaya, K.; Tagami, T.; Ogawa, Y.; Hosoda, K.; Akamizu, T.; Suda, M.; Koh, T.; Natsui, K.; Toyooka, S.; Shirakami, G.; Usui, T.; Shimatsu, A.; Doi, K.; Hosoda, H.; Kojima, M.; Kangawa, K.; Nakao, K. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocrinol. Metab., 2001, 86(10), 4753-4758.
[http://dx.doi.org/10.1210/jcem.86.10.7885] [PMID: 11600536]
[40]
Kršek, M.; Rosická, M.; Haluzík, M.; Svobodová, J.; Kotrlíková, E.; Justová, V.; Lacinová, Z.; Jarkovská, Z. Plasma ghrelin levels in patients with short bowel syndrome. Endocr. Res., 2002, 28(1-2), 27-33.
[http://dx.doi.org/10.1081/ERC-120004535] [PMID: 12108787]
[41]
Kim, S.K.; Joung, J.Y.; Ahn, Y.C.; Jung, I.C.; Son, C.G. Beneficial potential of Banha-Sasim-Tang for stress-sensitive functional dyspepsia via modulation of ghrelin: A randomized controlled trial. Front. Pharmacol., 2021, 12, 636752.
[http://dx.doi.org/10.3389/fphar.2021.636752] [PMID: 33959008]
[42]
Hwang, S.J.; Wang, J.H.; Lee, J.S.; Lee, H.D.; Choi, T.J.; Choi, S.H.; Son, C.G. Yeokwisan, a standardized herbal formula, enhances gastric emptying via modulation of the ghrelin pathway in a loperamide-induced functional dyspepsia mouse model. Front. Pharmacol., 2021, 12, 753153.
[http://dx.doi.org/10.3389/fphar.2021.753153] [PMID: 34630123]
[43]
Mönnikes, H.; van der Voort, I.R.; Wollenberg, B.; Heymann-Mönnikes, I.; Tebbe, J.J.; Alt, W.; Arnold, R.; Klapp, B.F.; Wiedenmann, B.; McGregor, G.P. Gastric perception thresholds are low and sensory neuropeptide levels high in helicobacter pylori-positive functional dyspepsia. Digestion, 2005, 71(2), 111-123.
[http://dx.doi.org/10.1159/000084625] [PMID: 15785037]