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Published in: BMC Complementary Medicine and Therapies 1/2019

Open Access 01-12-2019 | Infertility | Research article

The ameliorative effect of monotropein, astragalin, and spiraeoside on oxidative stress, endoplasmic reticulum stress, and mitochondrial signaling pathway in varicocelized rats

Authors: Keshab Kumar Karna, Bo Ram Choi, Jae Hyung You, Yu Seob Shin, Wan Shou Cui, Sung Won Lee, Ji Hoon Kim, Chul Young Kim, Hye Kyung Kim, Jong Kwan Park

Published in: BMC Complementary Medicine and Therapies | Issue 1/2019

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Abstract

Background

Monotropein, astragalin, and spiraeoside (MAS) are active compounds extracted from medicinal herbs; monotropein from Morinda officinalis How (Rubiaceae), astragalin (kaempferol 3-O-glucoside) from Cuscuta chinensis Lamark (Convolvulaceae) and spiraeoside from the outer scales of Allium cepa L. (Liliceae) in a ratio of 6.69:0.41:3.61. Monotropein, astragalin, and spiraeoside are well-known antioxidants, anti-inflammatory, and antinociceptive agents. The current investigation aims to study the molecular mechanism of varicocele-induced male infertility and the underlying pharmacological mechanisms of MAS.

Methods

Four groups were included: control (CTR), MAS 200 group (MAS 200 mg/kg), varicocele group (VC), and VC + MAS 200 group (MAS 200 mg/kg). Sprague-Dawley (SD) rats were treated with 200 mg/kg MAS or vehicle once daily for 28 days. The possible signaling mechanism and effects of MAS were measured via histological staining, immunohistochemistry, western blot, and biochemical assays.

Results

Parameters such as sperm motility and count, Johnsen’s scores, spermatogenic cell density, serum testosterone, testicular superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and expression of the steroidogenic acute regulatory protein (StAR) improved significantly in the VC + MAS 200 group compared with the VC group. MAS treatment of varicocele-induced group significantly decreased the levels of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as testicular interleukin-6 (IL6), tumor necrosis factor-α (TNF-α), ROS/RNS, and malondialdehyde (MDA). It also decreased the apoptotic index and reduced the expression of endoplasmic reticulum (ER) protein levels (Grp78, p-IRE1α, and p-JNK) and apoptotic markers such as cleaved caspase-3 and Bax/Bcl2 ratio.

Conclusion

This study suggests that the crosstalk between oxidative stress, ER stress, and mitochondrial pathway mediates varicocele-induced testicular germ cell apoptosis. MAS promotes spermatogenesis in varicocele-induced SD rat, probably by decreasing cytokines (IL-6, TNF-α) levels, regulating abnormal sex hormones, and decreasing oxidative stress, ER stress, and apoptosis.
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Literature
1.
go back to reference Yoon CJ, Park HJ, Park NC. Reactive oxygen species in the internal spermatic and brachial veins of patients with varicocele-induced infertility. Korean J Urol. 2010;51(5):348–53.PubMedPubMedCentralCrossRef Yoon CJ, Park HJ, Park NC. Reactive oxygen species in the internal spermatic and brachial veins of patients with varicocele-induced infertility. Korean J Urol. 2010;51(5):348–53.PubMedPubMedCentralCrossRef
2.
go back to reference Will MA, Swain J, Fode M, Sonksen J, Christman GM, Ohl D. The great debate: varicocele treatment and impact on fertility. Fertil Steril. 2011;95(3):841–52.PubMedPubMedCentralCrossRef Will MA, Swain J, Fode M, Sonksen J, Christman GM, Ohl D. The great debate: varicocele treatment and impact on fertility. Fertil Steril. 2011;95(3):841–52.PubMedPubMedCentralCrossRef
3.
4.
go back to reference Ko KW, Chae JY, Kim SW, Moon du G, Kim JJ, Yoon DK, Park JY. The effect of the partial obstruction site of the renal vein on testis and kidney in rats: is the traditional animal model suitable for varicocele research? Korean J Urol 2010, 51(8):565–571.PubMedPubMedCentralCrossRef Ko KW, Chae JY, Kim SW, Moon du G, Kim JJ, Yoon DK, Park JY. The effect of the partial obstruction site of the renal vein on testis and kidney in rats: is the traditional animal model suitable for varicocele research? Korean J Urol 2010, 51(8):565–571.PubMedPubMedCentralCrossRef
5.
go back to reference Park YS, Lee SH, Choi HW, Lee HS, Lee JS, Seo JT. Abnormal human sperm parameters contribute to sperm DNA fragmentation in men with Varicocele. World J Mens Health. 2018;36(3):239–47.PubMedPubMedCentralCrossRef Park YS, Lee SH, Choi HW, Lee HS, Lee JS, Seo JT. Abnormal human sperm parameters contribute to sperm DNA fragmentation in men with Varicocele. World J Mens Health. 2018;36(3):239–47.PubMedPubMedCentralCrossRef
6.
go back to reference Paick S, Choi WS. Varicocele and testicular pain: a review. World J Mens Health. 2019;37(1):4–11.PubMedCrossRef Paick S, Choi WS. Varicocele and testicular pain: a review. World J Mens Health. 2019;37(1):4–11.PubMedCrossRef
7.
go back to reference Shiraishi K, Matsuyama H, Takihara H. Pathophysiology of varicocele in male infertility in the era of assisted reproductive technology. Int J Urol. 2012;19(6):538–50.PubMedCrossRef Shiraishi K, Matsuyama H, Takihara H. Pathophysiology of varicocele in male infertility in the era of assisted reproductive technology. Int J Urol. 2012;19(6):538–50.PubMedCrossRef
8.
go back to reference Soni KK, Zhang LT, Choi BR, Karna KK, You JH, Shin YS, Lee SW, Kim CY, Zhao C, Chae HJ, et al. Protective effect of MOTILIPERM in varicocele-induced oxidative injury in rat testis by activating phosphorylated inositol requiring kinase 1alpha (p-IRE1alpha) and phosphorylated c-Jun N-terminal kinase (p-JNK) pathways. Pharm Biol. 2018;56(1):94–103.PubMedPubMedCentralCrossRef Soni KK, Zhang LT, Choi BR, Karna KK, You JH, Shin YS, Lee SW, Kim CY, Zhao C, Chae HJ, et al. Protective effect of MOTILIPERM in varicocele-induced oxidative injury in rat testis by activating phosphorylated inositol requiring kinase 1alpha (p-IRE1alpha) and phosphorylated c-Jun N-terminal kinase (p-JNK) pathways. Pharm Biol. 2018;56(1):94–103.PubMedPubMedCentralCrossRef
10.
go back to reference Chang FW, Sun GH, Cheng YY, Chen IC, Chien HH, Wu GJ. Effects of varicocele upon the expression of apoptosis-related proteins. Andrologia. 2010;42(4):225–30.PubMedCrossRef Chang FW, Sun GH, Cheng YY, Chen IC, Chien HH, Wu GJ. Effects of varicocele upon the expression of apoptosis-related proteins. Andrologia. 2010;42(4):225–30.PubMedCrossRef
11.
go back to reference Soni KK, Kim HK, Choi BR, Karna KK, You JH, Cha JS, Shin YS, Lee SW, Kim CY, Park JK. Dose-dependent effects of cisplatin on the severity of testicular injury in Sprague Dawley rats: reactive oxygen species and endoplasmic reticulum stress. Drug Des Devel Ther. 2016;10:3959–68.PubMedPubMedCentralCrossRef Soni KK, Kim HK, Choi BR, Karna KK, You JH, Cha JS, Shin YS, Lee SW, Kim CY, Park JK. Dose-dependent effects of cisplatin on the severity of testicular injury in Sprague Dawley rats: reactive oxygen species and endoplasmic reticulum stress. Drug Des Devel Ther. 2016;10:3959–68.PubMedPubMedCentralCrossRef
12.
go back to reference Soni KK, Zhang LT, You JH, Lee SW, Kim CY, Cui WS, Chae HJ, Kim HK, Park JK. The effects of MOTILIPERM on cisplatin induced testicular toxicity in Sprague-Dawley rats. Cancer Cell Int. 2015;15:121.PubMedPubMedCentralCrossRef Soni KK, Zhang LT, You JH, Lee SW, Kim CY, Cui WS, Chae HJ, Kim HK, Park JK. The effects of MOTILIPERM on cisplatin induced testicular toxicity in Sprague-Dawley rats. Cancer Cell Int. 2015;15:121.PubMedPubMedCentralCrossRef
13.
go back to reference Hamada A, Esteves SC, Agarwal A. Insight into oxidative stress in varicocele-associated male infertility: part 2. Nat Rev Urol. 2013;10(1):26–37.PubMedCrossRef Hamada A, Esteves SC, Agarwal A. Insight into oxidative stress in varicocele-associated male infertility: part 2. Nat Rev Urol. 2013;10(1):26–37.PubMedCrossRef
14.
go back to reference Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal. 2007;9(12):2277–93.PubMedCrossRef Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal. 2007;9(12):2277–93.PubMedCrossRef
15.
go back to reference Kim JH, Park SJ, Kim TS, Park HJ, Park J, Kim BK, Kim GR, Kim JM, Huang SM, Chae JI, et al. Testicular hyperthermia induces unfolded protein response signaling activation in spermatocyte. Biochem Biophys Res Commun. 2013;434(4):861–6.PubMedCrossRef Kim JH, Park SJ, Kim TS, Park HJ, Park J, Kim BK, Kim GR, Kim JM, Huang SM, Chae JI, et al. Testicular hyperthermia induces unfolded protein response signaling activation in spermatocyte. Biochem Biophys Res Commun. 2013;434(4):861–6.PubMedCrossRef
16.
go back to reference Lee JD, Lee TH, Cheng WH, Jeng SY. Involved intrinsic apoptotic pathway of testicular tissues in varicocele-induced rats. World J Urol. 2009;27(4):527–32.PubMedCrossRef Lee JD, Lee TH, Cheng WH, Jeng SY. Involved intrinsic apoptotic pathway of testicular tissues in varicocele-induced rats. World J Urol. 2009;27(4):527–32.PubMedCrossRef
17.
go back to reference Onur R, Semercioz A, Orhan I, Yekeler H. The effects of melatonin and the antioxidant defence system on apoptosis regulator proteins (Bax and Bcl-2) in experimentally induced varicocele. Urol Res. 2004;32(3):204–8.PubMedCrossRef Onur R, Semercioz A, Orhan I, Yekeler H. The effects of melatonin and the antioxidant defence system on apoptosis regulator proteins (Bax and Bcl-2) in experimentally induced varicocele. Urol Res. 2004;32(3):204–8.PubMedCrossRef
18.
19.
go back to reference Soni KK, Shin YS, Choi BR, Karna KK, Kim HK, Lee SW, Kim CY, Park JK. Protective effect of DA-9401 in finasteride-induced apoptosis in rat testis: inositol requiring kinase 1 and c-Jun N-terminal kinase pathway. Drug Des Devel Ther. 2017;11:2969–79.PubMedPubMedCentralCrossRef Soni KK, Shin YS, Choi BR, Karna KK, Kim HK, Lee SW, Kim CY, Park JK. Protective effect of DA-9401 in finasteride-induced apoptosis in rat testis: inositol requiring kinase 1 and c-Jun N-terminal kinase pathway. Drug Des Devel Ther. 2017;11:2969–79.PubMedPubMedCentralCrossRef
20.
go back to reference Zhang JH, Xin HL, Xu YM, Shen Y, He YQ, Hsien Y, Lin B, Song HT, Juan L, Yang HY, et al. Morinda officinalis how. - a comprehensive review of traditional uses, phytochemistry and pharmacology. J Ethnopharmacol. 2018;213:230–55.PubMedCrossRef Zhang JH, Xin HL, Xu YM, Shen Y, He YQ, Hsien Y, Lin B, Song HT, Juan L, Yang HY, et al. Morinda officinalis how. - a comprehensive review of traditional uses, phytochemistry and pharmacology. J Ethnopharmacol. 2018;213:230–55.PubMedCrossRef
21.
go back to reference Zhu Z, Huang F, Wang F, Zhang Y, Zhao X, Wang W. Morinda Officinalis polysaccharides stimulate hypothalamic GnRH secretion in varicocele progression. Evid Based Complement Alternat Med. 2017;2017:9057959.PubMedPubMedCentral Zhu Z, Huang F, Wang F, Zhang Y, Zhao X, Wang W. Morinda Officinalis polysaccharides stimulate hypothalamic GnRH secretion in varicocele progression. Evid Based Complement Alternat Med. 2017;2017:9057959.PubMedPubMedCentral
22.
go back to reference Zhang L, Zhao X, Wang F, Lin Q, Wang W. Effects of Morinda officinalis polysaccharide on experimental varicocele rats. Evid Based Complement Alternat Med. 2016;2016:5365291.PubMedPubMedCentral Zhang L, Zhao X, Wang F, Lin Q, Wang W. Effects of Morinda officinalis polysaccharide on experimental varicocele rats. Evid Based Complement Alternat Med. 2016;2016:5365291.PubMedPubMedCentral
23.
go back to reference Zhu Z, Zhao X, Huang F, Wang F, Wang W. Morinda Officinalis polysaccharides attenuate varicocele-induced Spermatogenic impairment through the modulation of angiogenesis and relative factors. Evid Based Complement Alternat Med. 2019;2019:8453635.PubMedPubMedCentral Zhu Z, Zhao X, Huang F, Wang F, Wang W. Morinda Officinalis polysaccharides attenuate varicocele-induced Spermatogenic impairment through the modulation of angiogenesis and relative factors. Evid Based Complement Alternat Med. 2019;2019:8453635.PubMedPubMedCentral
24.
go back to reference Liao JC, Chang WT, Lee MS, Chiu YJ, Chao WK, Lin YC, Lin MK, Peng WH. Antinociceptive and anti-inflammatory activities of Cuscuta chinensis seeds in mice. Am J Chin Med. 2014;42(1):223–42.PubMedCrossRef Liao JC, Chang WT, Lee MS, Chiu YJ, Chao WK, Lin YC, Lin MK, Peng WH. Antinociceptive and anti-inflammatory activities of Cuscuta chinensis seeds in mice. Am J Chin Med. 2014;42(1):223–42.PubMedCrossRef
25.
go back to reference Yang L, Chen Q, Wang F, Zhang G. Antiosteoporotic compounds from seeds of Cuscuta chinensis. J Ethnopharmacol. 2011;135(2):553–60.PubMedCrossRef Yang L, Chen Q, Wang F, Zhang G. Antiosteoporotic compounds from seeds of Cuscuta chinensis. J Ethnopharmacol. 2011;135(2):553–60.PubMedCrossRef
26.
go back to reference Bu T, Mi Y, Zeng W, Zhang C. Protective effect of quercetin on cadmium-induced oxidative toxicity on germ cells in male mice. Anat Rec (Hoboken). 2011;294(3):520–6.CrossRef Bu T, Mi Y, Zeng W, Zhang C. Protective effect of quercetin on cadmium-induced oxidative toxicity on germ cells in male mice. Anat Rec (Hoboken). 2011;294(3):520–6.CrossRef
27.
go back to reference Li G, Ma A, Shi W, Zhong X. Quercetin protects hamster spermatogenic cells from oxidative damage induced by diethylstilboestrol. Andrologia. 2010;42(5):285–90.PubMedCrossRef Li G, Ma A, Shi W, Zhong X. Quercetin protects hamster spermatogenic cells from oxidative damage induced by diethylstilboestrol. Andrologia. 2010;42(5):285–90.PubMedCrossRef
28.
go back to reference Karna KK, Choi BR, You JH, Shin YS, Soni KK, Cui WS, Lee SW, Kim CY, Kim HK, Park JK. Cross-talk between ER stress and mitochondrial pathway mediated adriamycin-induced testicular toxicity and DA-9401 modulate adriamycin-induced apoptosis in Sprague–Dawley rats. Cancer Cell Int. 2019;19(1):85.PubMedPubMedCentralCrossRef Karna KK, Choi BR, You JH, Shin YS, Soni KK, Cui WS, Lee SW, Kim CY, Kim HK, Park JK. Cross-talk between ER stress and mitochondrial pathway mediated adriamycin-induced testicular toxicity and DA-9401 modulate adriamycin-induced apoptosis in Sprague–Dawley rats. Cancer Cell Int. 2019;19(1):85.PubMedPubMedCentralCrossRef
29.
go back to reference Celik O, Kutlu O, Tekcan M, Celik-Ozenci C, Koksal IT. Role of TNF-related apoptosis-inducing ligand (TRAIL) in the pathogenesis of varicocele-induced testicular dysfunction. Asian J Androl. 2013;15(2):269–74.PubMedCrossRef Celik O, Kutlu O, Tekcan M, Celik-Ozenci C, Koksal IT. Role of TNF-related apoptosis-inducing ligand (TRAIL) in the pathogenesis of varicocele-induced testicular dysfunction. Asian J Androl. 2013;15(2):269–74.PubMedCrossRef
30.
go back to reference Mendes TB, Paccola CC, de Oliveira Neves FM, Simas JN, da Costa VA, Cabral RE, Vendramini V, Miraglia SM. Resveratrol improves reproductive parameters of adult rats varicocelized in peripuberty. Reproduction. 2016;152(1):23–35.PubMedCrossRef Mendes TB, Paccola CC, de Oliveira Neves FM, Simas JN, da Costa VA, Cabral RE, Vendramini V, Miraglia SM. Resveratrol improves reproductive parameters of adult rats varicocelized in peripuberty. Reproduction. 2016;152(1):23–35.PubMedCrossRef
31.
go back to reference Duarte F, Blaya R, Teloken PE, Becker D, Fernandes M, Rhoden EL. The effects of N-acetylcysteine on spermatogenesis and degree of testicular germ cell apoptosis in an experimental model of varicocele in rats. Int Urol Nephrol. 2010;42(3):603–8.PubMedCrossRef Duarte F, Blaya R, Teloken PE, Becker D, Fernandes M, Rhoden EL. The effects of N-acetylcysteine on spermatogenesis and degree of testicular germ cell apoptosis in an experimental model of varicocele in rats. Int Urol Nephrol. 2010;42(3):603–8.PubMedCrossRef
32.
go back to reference Liu J, Ding D. Varicocele-caused progressive damage in bilateral testis and sertoli cell-only syndrome in homolateral testis in rats. Med Sci Monit. 2014;20:1931–6.PubMedPubMedCentralCrossRef Liu J, Ding D. Varicocele-caused progressive damage in bilateral testis and sertoli cell-only syndrome in homolateral testis in rats. Med Sci Monit. 2014;20:1931–6.PubMedPubMedCentralCrossRef
33.
go back to reference Luo DY, Yang G, Liu JJ, Yang YR, Dong Q. Effects of varicocele on testosterone, apoptosis and expression of StAR mRNA in rat Leydig cells. Asian J Androl. 2011;13(2):287–91.PubMedCrossRef Luo DY, Yang G, Liu JJ, Yang YR, Dong Q. Effects of varicocele on testosterone, apoptosis and expression of StAR mRNA in rat Leydig cells. Asian J Androl. 2011;13(2):287–91.PubMedCrossRef
34.
go back to reference Koskenniemi JJ, Virtanen HE, Toppari J. Testicular growth and development in puberty. Curr Opin Endocrinol Diabetes Obes. 2017;24(3):215–24.PubMedCrossRef Koskenniemi JJ, Virtanen HE, Toppari J. Testicular growth and development in puberty. Curr Opin Endocrinol Diabetes Obes. 2017;24(3):215–24.PubMedCrossRef
35.
go back to reference Jensen CFS, Ostergren P, Dupree JM, Ohl DA, Sonksen J, Fode M. Varicocele and male infertility. Nat Rev Urol. 2017;14(9):523–33.PubMedCrossRef Jensen CFS, Ostergren P, Dupree JM, Ohl DA, Sonksen J, Fode M. Varicocele and male infertility. Nat Rev Urol. 2017;14(9):523–33.PubMedCrossRef
36.
go back to reference de Oliveira FA, Costa WS, B Sampaio FJ, Gregorio BM. Resveratrol attenuates metabolic, sperm, and testicular changes in adult Wistar rats fed a diet rich in lipids and simplecarbohydrates. Asian J Androl. 2019;21(2):201–7.PubMedCrossRef de Oliveira FA, Costa WS, B Sampaio FJ, Gregorio BM. Resveratrol attenuates metabolic, sperm, and testicular changes in adult Wistar rats fed a diet rich in lipids and simplecarbohydrates. Asian J Androl. 2019;21(2):201–7.PubMedCrossRef
37.
go back to reference Alkan I, Yuksel M, Canat HL, Atalay HA, Can O, Ozveri H, Basar MM. Superoxide anion production by the spermatozoa of men with varicocele: relationship with Varicocele grade and semen parameters. World J Mens Health. 2018;36(3):255–62.PubMedPubMedCentralCrossRef Alkan I, Yuksel M, Canat HL, Atalay HA, Can O, Ozveri H, Basar MM. Superoxide anion production by the spermatozoa of men with varicocele: relationship with Varicocele grade and semen parameters. World J Mens Health. 2018;36(3):255–62.PubMedPubMedCentralCrossRef
39.
go back to reference Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–6.PubMedCrossRef Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–6.PubMedCrossRef
40.
go back to reference Huo R, Zhu YF, Ma X, Lin M, Zhou ZM, Sha JH. Differential expression of glucose-regulated protein 78 during spermatogenesis. Cell Tissue Res. 2004;316(3):359–67.PubMedCrossRef Huo R, Zhu YF, Ma X, Lin M, Zhou ZM, Sha JH. Differential expression of glucose-regulated protein 78 during spermatogenesis. Cell Tissue Res. 2004;316(3):359–67.PubMedCrossRef
45.
go back to reference Habibi B, Seifi B, Mougahi SM, Ojaghi M, Sadeghipour HR. Increases in interleukin-6 and interferon-gamma levels is progressive in immature rats with varicocele. Ir J Med Sci. 2015;184(2):531–7.PubMedCrossRef Habibi B, Seifi B, Mougahi SM, Ojaghi M, Sadeghipour HR. Increases in interleukin-6 and interferon-gamma levels is progressive in immature rats with varicocele. Ir J Med Sci. 2015;184(2):531–7.PubMedCrossRef
Metadata
Title
The ameliorative effect of monotropein, astragalin, and spiraeoside on oxidative stress, endoplasmic reticulum stress, and mitochondrial signaling pathway in varicocelized rats
Authors
Keshab Kumar Karna
Bo Ram Choi
Jae Hyung You
Yu Seob Shin
Wan Shou Cui
Sung Won Lee
Ji Hoon Kim
Chul Young Kim
Hye Kyung Kim
Jong Kwan Park
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2019
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-019-2736-9

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