Geniposide attenuates cadmium‑induced oxidative stress injury via Nrf2 signaling in osteoblasts

He,Tengfeng; Shen,Huasong; Zhu,Jinke; Zhu,Yan; He,Yan; Li,Zhiwen; Lu,Huanxing

doi:10.3892/mmr.2019.10396

Geniposide attenuates cadmium‑induced oxidative stress injury via Nrf2 signaling in osteoblasts

Authors:
- Tengfeng He
- Huasong Shen
- Jinke Zhu
- Yan Zhu
- Yan He
- Zhiwen Li
- Huanxing Lu
View Affiliations

Affiliations: Spine Department, Zhuji People's Hospital, Zhuji, Zhejiang 311800, P.R. China
Published online on: June 19, 2019 https://doi.org/10.3892/mmr.2019.10396
Pages: 1499-1508
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Geniposide, as a type of iridoid glycoside, has antioxidative capacity. However, the mechanism underlying the effect of geniposide in cadmium (Cd)‑induced osteoblast injury remains only partly elucidated. In the present study, Cell Counting Kit‑8 (CCK‑8) was used to determine MC‑3T3‑E1 cell viability. Flow cytometry was used to determine the rate of apoptosis and levels of reactive oxygen species (ROS). Oxidative stress‑related factors were assessed using enzyme‑linked immunosorbent method (ELISA). Quantitative real‑time polymerase chain reaction (qPCR) and western blotting were used to evaluate apoptosis‑ and bone formation‑related genes and nuclear factor erythroid 2‑related factor (Nrf2) signaling. It was demonstrated that geniposide increased the viability of the Cd‑treated MC‑3T3‑E1 cells. Geniposide decreased apoptosis and ROS accumulation compared to these parameters in the Cd group. Geniposide attenuated oxidative stress‑related factors, malondialdehyde and lactate dehydrogenase and increased antioxidant key enzyme superoxidase dismutase (SOD). The expression levels of Bax, Bcl‑2 and survivin were modulated by geniposide. Additionally, the mRNA and protein expression of the receptor activator of NF‑κB ligand (RANKL) and osterix were significantly increased, while osteoprotegerin was decreased by geniposide treatment compared to the Cd groups. Geniposide also enhanced Nrf2, heme oxygenase‑1 (HO‑1) and NAD(P)H quinone dehydrogenase 1 (NQO1) expression. The present study identified a potential agent for the treatment of Cd‑induced osteoblast injury.

View Figures

View References

1	Sato K, Iwamasa T, Tsuru T and Takeuchi T: An ultrastructural study of chronic cadmium chloride-induced neuropathy. Acta Neuropathol. 41:185–190. 1978. View Article : Google Scholar : PubMed/NCBI
2	Sakata S, Iwami K, Enoki Y, Kohzuki H, Shimizu S, Matsuda M and Moriyama T: Effects of cadmium on in vitro and in vivo erythropoiesis: Erythroid progenitor cells (CFU-E), iron and erythropoietin in cadmium-induced iron deficiency anemia. Exp Hematol. 16:581–587. 1988.PubMed/NCBI
3	Blakley BR: Humoral immunity in aged mice exposed to cadmium. Can J Vet Res. 52:291–292. 1988.PubMed/NCBI
4	Saygi S, Deniz G, Kutsal O and Vural N: Chronic effects of cadmium on kidney, liver, testis and fertility of male rats. Biol Trace Elem Res. 31:209–214. 1991. View Article : Google Scholar : PubMed/NCBI
5	Sakamoto M, Itai T and Murata K: Effects of prenatal methylmercury exposure: From minamata disease to environmental health studies. Nihon Eiseigaku Zasshi. 72:140–148. 2017.(In Japanese). View Article : Google Scholar : PubMed/NCBI
6	Morikawa Y, Nakagawa H, Tabata M, Nishijo M, Senma M, Kitagawa Y, Kawano S, Teranishi H and Kido T: Study of an outbreak of itai-itai disease. Nihon Eiseigaku Zasshi. 46:1057–1062. 1992.(In Japanese). View Article : Google Scholar : PubMed/NCBI
7	Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, et al: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 397:315–323. 1999. View Article : Google Scholar : PubMed/NCBI
8	Bhattacharyya MH, Whelton BD, Stern PH and Peterson DP: Cadmium accelerates bone loss in ovariectomized mice and fetal rat limb bones in culture. Proc Natl Acad Sci USA. 85:8761–8765. 1988. View Article : Google Scholar : PubMed/NCBI
9	WHO, . Environmental Health Criteria. Cadmium-Environmental Aspects. 135:134–136. 1992.
10	Martineau C, Abed E, Medina G, Jomphe LA, Mantha M, Jumarie C and Moreau R: Involvement of transient receptor potential melastatin-related 7 (TRPM7) channels in cadmium uptake and cytotoxicity in MC3T3-E1 osteoblasts. Toxicol Lett. 199:357–363. 2010. View Article : Google Scholar : PubMed/NCBI
11	Kawamura J, Yoshida O, Nishino K and Itokawa Y: Disturbances in kidney functions and calcium and phosphate metabolism in cadmium-poisoned rats. Nephron. 20:101–110. 1978. View Article : Google Scholar : PubMed/NCBI
12	Shinichi S and Kiyoshi N: Effects of vitamin D on calcium and bone metabolism. Clin Calcium. 13:863–868. 2003.(In Japanese). PubMed/NCBI
13	Wang C and Bhattacharyya MH: Effect of cadmium on bone calcium and 45Ca in nonpregnant mice on a calcium-deficient diet: Evidence of direct effect of cadmium on bone. Toxicol Appl Pharmacol. 120:228–239. 1993. View Article : Google Scholar : PubMed/NCBI
14	Brama M, Politi L, Santini P, Migliaccio S and Scandurra R: Cadmium-induced apoptosis and necrosis in human osteoblasts: Role of caspases and mitogen-activated protein kinases pathways. J Endocrinol Invest. 35:198–208. 2012.PubMed/NCBI
15	Wallin M, Barregard L, Sallsten G, Lundh T, Karlsson MK, Lorentzon M, Ohlsson C and Mellström D: Low-level cadmium exposure is associated with decreased bone mineral density and increased risk of incident fractures in elderly men: The MrOS Sweden study. J Bone Miner Res. 31:732–741. 2016. View Article : Google Scholar : PubMed/NCBI
16	Wilson AK, Cerny EA, Smith BD, Wagh A and Bhattacharyya MH: Effects of cadmium on osteoclast formation and activity in vitro. Toxicol Appl Pharmacol. 140:451–460. 1996. View Article : Google Scholar : PubMed/NCBI
17	Chen X, Zhu G, Gu S, Jin T and Shao C: Effects of cadmium on osteoblasts and osteoclasts in vitro. Environ Toxicol Pharmacol. 28:232–236. 2009. View Article : Google Scholar : PubMed/NCBI
18	Coonse KG, Coonts AJ, Morrison EV and Heggland SJ: Cadmium induces apoptosis in the human osteoblast-like cell line Saos-2. J Toxicol Environ Health A. 70:575–581. 2007. View Article : Google Scholar : PubMed/NCBI
19	Yang CF, Shen HM, Shen Y, Zhuang ZX and Ong CN: Cadmium-induced oxidative cellular damage in human fetal lung fibroblasts (MRC-5 cells). Environ Health Perspect. 105:712–716. 1997. View Article : Google Scholar : PubMed/NCBI
20	Thompson J and Bannigan J: Cadmium: Toxic effects on the reproductive system and the embryo. Reprod Toxicol. 25:304–315. 2008. View Article : Google Scholar : PubMed/NCBI
21	Joseph P: Mechanisms of cadmium carcinogenesis. Toxicol Appl Pharmacol. 238:272–279. 2009. View Article : Google Scholar : PubMed/NCBI
22	Bertin G and Averbeck D: Cadmium: Cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review). Biochimie. 88:1549–1559. 2006. View Article : Google Scholar : PubMed/NCBI
23	López E, Arce C, Oset-Gasque MJ, Cañadas S and Gonzalez MP: Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture. Free Radic Biol Med. 40:940–951. 2006. View Article : Google Scholar : PubMed/NCBI
24	Koo HJ, Lim KH, Jung HJ and Park EH: Anti-inflammatory evaluation of gardenia extract, geniposide and genipin. J Ethnopharmacol. 103:496–500. 2006. View Article : Google Scholar : PubMed/NCBI
25	Liu E, Han L, Wang J, He W, Shang H, Gao X and Wang T: Eucommia ulmoides bark protects against renal injury in cadmium-challenged rats. J Med Food. 15:307–314. 2012. View Article : Google Scholar : PubMed/NCBI
26	Yin F, Liu J, Zheng X, Guo L and Xiao H: Geniposide induces the expression of heme oxygenase-1 via PI3K/Nrf2-signaling to enhance the antioxidant capacity in primary hippocampal neurons. Biol Pharm Bull. 33:1841–1846. 2010. View Article : Google Scholar : PubMed/NCBI
27	Wang SW, Lai CY and Wang CJ: Inhibitory effect of geniposide on aflatoxin B1-induced DNA repair synthesis in primary cultured rat hepatocytes. Cancer Lett. 65:133–137. 1992. View Article : Google Scholar : PubMed/NCBI
28	Koo HJ, Lee S, Shin KH, Kim BC, Lim CJ and Park EH: Geniposide, an anti-angiogenic compound from the fruits of Gardenia jasminoides. Planta Med. 70:467–469. 2004. View Article : Google Scholar : PubMed/NCBI
29	Wang J, Hou J, Zhang P, Li D, Zhang C and Liu J: Geniposide reduces inflammatory responses of oxygen-glucose deprived rat microglial cells via inhibition of the TLR4 signaling pathway. Neurochem Res. 37:2235–2248. 2012. View Article : Google Scholar : PubMed/NCBI
30	Wang J, Li D, Hou J and Lei H: Protective effects of geniposide and ginsenoside Rg1 combination treatment on rats following cerebral ischemia are mediated via microglial microRNA-155-5p inhibition. Mol Med Rep. 17:3186–3193. 2018.PubMed/NCBI
31	Chang CH, Wu JB, Yang JS, Lai YJ, Su CH, Lu CC and Hsu YM: The suppressive effects of geniposide and genipin on helicobacter pylori infections in vitro and in vivo. J Food Sci. 82:3021–3028. 2017. View Article : Google Scholar : PubMed/NCBI
32	Ha H, Ho J, Shin S, Kim H, Koo S, Kim IH and Kim C: Effects of eucommiae cortex on osteoblast-like cell proliferation and osteoclast inhibition. Arch Pharm Res. 26:929–936. 2003. View Article : Google Scholar : PubMed/NCBI
33	Lin J, Fan YJ, Mehl C, Zhu JJ, Chen H, Jin LY, Xu JH and Wang HM: Eucommia ulmoides Oliv. antagonizes H₂O₂-induced rat osteoblastic MC3T3-E1 apoptosis by inhibiting expressions of caspases 3, 6, 7 and 9. J Zhejiang Univ Sci B. 12:47–54. 2011. View Article : Google Scholar : PubMed/NCBI
34	Liu J, Yin F, Zheng X, Jing J and Hu Y: Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway. Neurochem Int. 51:361–369. 2007. View Article : Google Scholar : PubMed/NCBI
35	Chen Y, Zhang H, Li YX, Cai L, Huang J, Zhao C, Jia L, Buchanan R, Yang T and Jiang LJ: Crocin and geniposide profiles and radical scavenging activity of gardenia fruits (Gardenia jasminoides Ellis) from different cultivars and at the various stages of maturation. Fitoterapia. 81:269–273. 2010. View Article : Google Scholar : PubMed/NCBI
36	Lee P, Lee J, Choi SY, Lee SE, Lee S and Son D: Geniposide from Gardenia jasminoides attenuates neuronal cell death in oxygen and glucose deprivation-exposed rat hippocampal slice culture. Biol Pharm Bull. 29:174–176. 2006. View Article : Google Scholar : PubMed/NCBI
37	Cheng F, Ma C, Sun L, Zhang X, Zhai C, Li C, Zhang S, Ren B, Liu S, Liu S, et al: Synergistic neuroprotective effects of Geniposide and ursodeoxycholic acid in hypoxia-reoxygenation injury in SH-SY5Y cells. Exp Ther Med. 15:320–326. 2018.PubMed/NCBI
38	Hu KH, Li WX, Sun MY, Zhang SB, Fan CX, Wu Q, Zhu W and Xu X: Cadmium induced apoptosis in MG63 cells by increasing ROS, activation of p38 MAPK and inhibition of ERK 1/2 Pathways. Cell Physiol Biochem. 36:642–654. 2015. View Article : Google Scholar : PubMed/NCBI
39	Pathak N and Khandelwal S: Influence of cadmium on murine thymocytes: Potentiation of apoptosis and oxidative stress. Toxicol Lett. 165:121–132. 2006. View Article : Google Scholar : PubMed/NCBI
40	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
41	Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F and Heymann D: The molecular triad OPG/RANK/RANKL: Involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 15:457–475. 2004. View Article : Google Scholar : PubMed/NCBI
42	Roodman GD: Treatment strategies for bone disease. Bone Marrow Transplant. 40:1139–1146. 2007. View Article : Google Scholar : PubMed/NCBI
43	Levesque M, Martineau C, Jumarie C and Moreau R: Characterization of cadmium uptake and cytotoxicity in human osteoblast-like MG-63 cells. Toxicol Appl Pharmacol. 231:308–317. 2008. View Article : Google Scholar : PubMed/NCBI
44	Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR and de Crombrugghe B: The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 108:17–29. 2002. View Article : Google Scholar : PubMed/NCBI
45	Valois AA and Webster WS: The choroid plexus as a target site for cadmium toxicity following chronic exposure in the adult mouse: An ultrastructural study. Toxicology. 55:193–205. 1989. View Article : Google Scholar : PubMed/NCBI
46	Jamall IS, Naik M, Sprowls JJ and Trombetta LD: A comparison of the effects of dietary cadmium on heart and kidney antioxidant enzymes: evidence for the greater vulnerability of the heart to cadmium toxicity. J Appl Toxicol. 9:339–345. 1989. View Article : Google Scholar : PubMed/NCBI
47	Liu E, Han L, Wang J, He W Shang H, Gao X and Wang T: Eucommia ulmoides bark protects against renal injury in cadmium-challenged rats. J Med Food. 15:307–314. 2012. View Article : Google Scholar : PubMed/NCBI
48	Pan YX, Luo Z, Zhuo MQ, Wei CC, Chen GH and Song YF: Oxidative stress and mitochondrial dysfunction mediated Cd-induced hepatic lipid accumulation in zebrafish Danio rerio. Aquat Toxicol. 199:12–20. 2018. View Article : Google Scholar : PubMed/NCBI
49	Mao T, Han C, Wei B, Zhao L, Zhang Q, Deng R, Liu J, Luo Y and Zhang Y: Protective effects of quercetin against cadmium chloride-induced oxidative injury in goat sperm and zygotes. Biol Trace Elem Res. 185:344–355. 2018. View Article : Google Scholar : PubMed/NCBI
50	Wongmekiat O, Peerapanyasut W and Kobroob A: Catechin supplementation prevents kidney damage in rats repeatedly exposed to cadmium through mitochondrial protection. Naunyn Schmiedebergs Arch Pharmacol. 391:385–394. 2018. View Article : Google Scholar : PubMed/NCBI
51	Qu Y, Liu Y, Chen L and Zhu Y, Xiao X, Wang D and Zhu Y: Nobiletin prevents cadmium-induced neuronal apoptosis by inhibiting reactive oxygen species and modulating JNK/ERK1/2 and Akt/mTOR networks in rats. Neurol Res. 40:211–220. 2018. View Article : Google Scholar : PubMed/NCBI
52	Kováčik J, Dresler S, Peterková V and Babula P: Metal-induced oxidative stress in terrestrial macrolichens. Chemosphere. 203:402–409. 2018. View Article : Google Scholar : PubMed/NCBI
53	Varricchi G, Ameri P, Cadeddu C, Ghigo A, Madonna R, Marone G, Mercurio V, Monte I, Novo G, Parrella P, et al: Antineoplastic drug-induced cardiotoxicity: A redox perspective. Front Physiol. 9:1672018. View Article : Google Scholar : PubMed/NCBI
54	Kim J, Kwon WS, Rahman MS, Lee JS, Yoon SJ, Park YJ, You YA and Pang MG: Effect of sodium fluoride on male mouse fertility. Andrology. 3:544–551. 2015. View Article : Google Scholar : PubMed/NCBI
55	Chatterjee S, Kundu S, Sengupta S and Bhattacharyya A: Divergence to apoptosis from ROS induced cell cycle arrest: Effect of cadmium. Mutat Res. 663:22–31. 2009. View Article : Google Scholar : PubMed/NCBI
56	Wang SH, Shih YL, Kuo TC, Ko WC and Shih CM: Cadmium toxicity toward autophagy through ROS-activated GSK-3beta in mesangial cells. Toxicol Sci. 108:124–131. 2009. View Article : Google Scholar : PubMed/NCBI
57	Sporn MB and Liby KT: NRF2 and cancer: The good, the bad and the importance of context. Nat Rev Cancer. 12:564–571. 2012. View Article : Google Scholar : PubMed/NCBI
58	Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S and Yamamoto M: Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem. 275:16023–16029. 2000. View Article : Google Scholar : PubMed/NCBI
59	Lee IT, Wang SW, Lee CW, Chang CC, Lin CC, Luo SF and Yang CM: Lipoteichoic acid induces HO-1 expression via the TLR2/MyD88/c-Src/NADPH oxidase pathway and Nrf2 in human tracheal smooth muscle cells. J Immunol. 181:5098–5110. 2008. View Article : Google Scholar : PubMed/NCBI
60	Nguyen T, Sherratt PJ and Pickett CB: Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 43:233–260. 2003. View Article : Google Scholar : PubMed/NCBI
61	Khor TO, Huang MT, Prawan A, Liu Y, Hao X, Yu S, Cheung WK, Chan JY, Reddy BS, Yang CS and Kong AN: Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res (Phila). 1:187–191. 2008. View Article : Google Scholar : PubMed/NCBI