Skip to main content
SpringerLink
Log in

Apigetrin ameliorates streptozotocin-induced pancreatic β-cell damages via attenuating endoplasmic reticulum stress

  • Published:
In Vitro Cellular & Developmental Biology - Animal Aims and scope Submit manuscript

Abstract

The pathogenesis of diabetes is associated with dysfunction of pancreatic β-cells. To ameliorate the β-cell dysfunction, it has propelled great interest to search pharmacological agents from natural plants. This study explored the protective effect of apigetrin, a flavonoid present in natural plants, against streptozotocin (STZ)-induced cell damages in RINm5F cells and the potential mechanisms. Apigetrin was found to inhibit the elevation of intracellular reactive oxygen species levels, restore the impairment of antioxidant enzymes, and recover the disruption of redox homeostasis in the STZ-treated pancreatic β-cells. Moreover, treatment of apigetrin significantly suppressed the STZ-induced apoptosis in the analysis of apoptotic sub-G1 population and the protein expressions of cleaved poly(ADP-ribose) polymerase and caspase-3. Furthermore, apigetrin attenuated STZ-induced endoplasmic reticulum (ER) stress, indicated by the reduction of ER stress biomarkers, including overloading of mitochondrial calcium, increase in glucose-regulated protein 78, phosphorylation of protein kinase RNA-like ER kinase and its downstream eukaryotic initiation factor 2α, cleavage of activating transcription factor 6 and caspase-12, up-regulation of CCAAT/enhancer binding protein homologous protein, and induction of spliced X-box binding protein 1. Additionally, pretreatment with 4-phenylbutyric acid, a classic ER stress inhibitor, augmented these beneficial effects of apigetrin. In conclusion, these results demonstrated that apigetrin could improve the STZ-induced pancreatic β-cell damages via mitigation of oxidative stress and ER stress and supported the application of apigetrin to developing the novel therapeutics of diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
Figure 7.
Figure 8.
Figure 9.
Figure 10.

Similar content being viewed by others

References

  • Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47:936–942

    CAS  PubMed  Google Scholar 

  • Chen Z, Guo H, Lu Z, Sun K, Jin Q (2019) Hyperglycemia aggravates spinal cord injury through endoplasmic reticulum stress mediated neuronal apoptosis, gliosis and activation. Biomed Pharmacother 112:108672

    Article  CAS  Google Scholar 

  • Choi S, Quan X, Bang S, Yoo H, Kim J, Park J, Park KS, Chung J (2017) Mitochondrial calcium uniporter in drosophila transfers calcium between the endoplasmic reticulum and mitochondria in oxidative stress-induced cell death. J Biol Chem 292:14473–14485

  • Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P (2017) Endoplasmic reticulum stress and eIF2α phosphorylation: the achilles heel of pancreatic β cells. Mol Metab 6:1024–1039

    Article  CAS  Google Scholar 

  • Dong Y, Xing Y, Sun J, Sun W, Xu Y, Quan C (2020) Baicalein alleviates liver oxidative stress and apoptosis induced by high-level glucose through the activation of the PERK/Nrf2 signaling pathway. Molecules 25:599

    Article  CAS  Google Scholar 

  • Đorđević M, Mihailović M, Arambašić Jovanović J, Grdović N, Uskoković A, Tolić A, Sinadinović M, Rajić J, Mišić D, Šiler B, Poznanović G, Vidaković M, Dinić S (2017) Centaurium erythraea methanol extract protects red blood cells from oxidative damage in streptozotocin-induced diabetic rats. J Ethnopharmacol 202:172–183

    Article  Google Scholar 

  • Drews G, Krippeit-Drews P, Düfer M (2010) Oxidative stress and beta cell dysfunction. Pflugers Arch 460:703–718

    Article  CAS  Google Scholar 

  • Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29:42–61

    Article  CAS  Google Scholar 

  • Gerber PA, Rutter GA (2017) The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Signal 26:501–518

    Article  CAS  Google Scholar 

  • Ghosh S, Chowdhury S, Das AK, Sil PC (2018) Taurine ameliorates oxidative stress induced inflammation and ER stress mediated testicular damage in STZ-induced diabetic Wistar rats. Food Chem Toxicol 124:64–80

    Article  Google Scholar 

  • Guo H, Li M, Xu LJ (2018) Apigetrin treatment attenuates LPS-induced acute otitis media though suppressing inflammation and oxidative stress. Biomed Pharmacother 109:1978–1987

    Article  Google Scholar 

  • Guzelmeric E, Vovk I, Yesilada E (2015) Development and validation of an HPTLC method for apigenin 7-o-glucoside in chamomile flowers and its application for fingerprint discrimination of chamomile-like materials. J Pharm Biomed Anal 107:108–118

    Article  CAS  Google Scholar 

  • Hadrich F, Sayadi S (2018) Apigetrin inhibits adipogenesis in 3T3-L1 cells by downregulating PPARγ and CEBP-α. Lipids Health Dis 17:95

    Article  Google Scholar 

  • Hasnain SZ, Prins JB, Mcguckin MA (2016) Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes. J Mol Endocrinol 56:R33–R54

    Article  CAS  Google Scholar 

  • Hu H, Tian M, Ding C, Yu S (2019) The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol 9:3083

    Article  Google Scholar 

  • Hu Y, Liu J, Yuan Y, Chen J, Cheng S, Wang H, Xu Y (2016) Sodium butyrate mitigates type 2 diabetes by inhibiting PERK-CHOP pathway of endoplasmic reticulum stress. Environ Toxicol Pharmacol 64:112–121

    Article  Google Scholar 

  • Jia Y, Ma Y, Cheng G, Zhang Y, Cai S (2019) Comparative study of dietary flavonoids with different structures as α-glucosidase inhibitors and insulin sensitizers. J Agric Food Chem 67:10521–10533

  • Jiang D, Wan F (2018) Exendin-4 protects INS-1 cells against palmitate-induced apoptosis through the IRE1α-XBP1 signaling pathway. Exp Ther Med 16:1029–1035

    PubMed  PubMed Central  Google Scholar 

  • Kamarehei M, Kabudanian Ardestani S, Firouzi M, Zahednasab H, Keyvani H, Harirchian MH (2019) Increased expression of endoplasmic reticulum stress-related caspase-12 and CHOP in the hippocampus of EAE mice. Brain Res Bull 147:174–182

    Article  CAS  Google Scholar 

  • Kaneto H, Matsuoka TA (2012) Involvement of oxidative stress in suppression of insulin biosynthesis under diabetic conditions. Int J Mol Sci 13:13680–13690

  • Katsube H, Hinami Y, Yamazoe T, Inoue YH (2019) Endoplasmic reticulum stress-induced cellular dysfunction and cell death in insulin-producing cells results in diabetes-like phenotypes in Drosophila. Biol Open 8:bio046524

    Article  Google Scholar 

  • Kozuka C, Sunagawa S, Ueda R, Higa M, Tanaka H, Shimizu-Okabe C, Ishiuchi S, Takayama C, Matsushita M, Tsutsui M, Miyazaki J, Oyadomari S, Shimabukuro M, Masuzaki H (2015) γ-Oryzanol protects pancreatic β-cells against endoplasmic reticulum stress in male mice. Endocrinology 156:1242–1250

    Article  CAS  Google Scholar 

  • Kumar D, Bhat ZA (2014) Apigenin 7-glucoside from Stachys tibetica Vatke and its anxiolytic effect in rats. Phytomedicine 21:1010–1114

    Article  CAS  Google Scholar 

  • Lee H, Im SW, Jung CH, Jang YJ, Ha TY, Ahn J (2016) Tyrosol, an olive oil polyphenol, inhibits ER stress-induced apoptosis in pancreatic β-cell through JNK signaling. Biochem Biophys Res Commun 469:748–752

    Article  CAS  Google Scholar 

  • Li G, Scull C, Ozcan L, Tabas I (2010) NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol 191:1113–1125

    Article  CAS  Google Scholar 

  • Lim HS, Kim OS, Kim BY, Jeong SJ (2016) Apigetrin from Scutellaria baicalensis Georgi inhibits neuroinflammation in BV-2 microglia and exerts neuroprotective effect in HT22 hippocampal cells. J Med Food 19:1032–1040

    Article  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−delta delta C(T)) method. Methods 25:402–408

    Article  CAS  Google Scholar 

  • Ly LD, Xu S, Choi SK, Ha CM, Thoudam T, Cha SK, Wiederkehr A, Wollheim CB, Lee IK, Park KS (2017) Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes. Exp Mol Med 49:e291

    Article  CAS  Google Scholar 

  • Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139:271–279

    Article  CAS  Google Scholar 

  • Niu X, Zhang J, Ling C, Bai M, Peng Y, Sun S, Li Y, Zhang Z (2018) Polysaccharide from angelica sinensis protects H9c2 cells against oxidative injury and endoplasmic reticulum stress by activating the ATF6 pathway. J Int Med Res 46:1717–1733

    Article  CAS  Google Scholar 

  • Rashid K, Chowdhury S, Ghosh S, Sil PC (2017) Curcumin attenuates oxidative stress induced NFκB mediated inflammation and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes. Biochem Pharmacol 143:140–155

    Article  CAS  Google Scholar 

  • Song J, Zhang Q, Wang S, Yang F, Chen Z, Dong Q, Ji Q, Yuan X, Ren D (2018) Cleavage of caspase-12 at ASP94, mediated by endoplasmic reticulum stress (ERS), contributes to stretch-induced apoptosis of myoblasts. J Cell Physiol 233:9473–9487

  • Suganya N, Dornadula S, Chatterjee S, Mohanram RK (2018) Quercetin improves endothelial function in diabetic rats through inhibition of endoplasmic reticulum stress-mediated oxidative stress. Eur J Pharmacol 819:80–88

    Article  CAS  Google Scholar 

  • Sun J, Cui J, He Q, Chen Z, Arvan P, Liu M (2015) Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes. Mol Asp Med 42:105–118

    Article  CAS  Google Scholar 

  • Sun Q, Lu NN, Feng L (2018) Apigetrin inhibits gastric cancer progression through inducing apoptosis and regulating ROS-modulated STAT3/JAK2 pathway. Biochem Biophys Res Commun 498:164–170

    Article  CAS  Google Scholar 

  • Takatani T, Shirakawa J, Roe MW, Leech CA, Maier BF, Mirmira RG, Kulkarni RN (2016) IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation. Sci Rep 6:28177

    Article  CAS  Google Scholar 

  • Thivolet C, Vial G, Cassel R, Rieusset J, Madec AM (2017) Reduction of endoplasmic reticulum-mitochondria interactions in beta cells from patients with type 2 diabetes. PLoS One 12:e0182027

    Article  Google Scholar 

  • Ullah O, Li Z, Ali I, Xu L, Liu H, Jin HZ, Fang YY, Jin QG, Fang N (2019) Pterostilbene exerts a protective effect via regulating tunicamycin-induced endoplasmic reticulum stress in mouse preimplantation embryos. In Vitro Cell Dev Biol Anim 55:82–93

    Article  CAS  Google Scholar 

  • Wang N, Yi WJ, Tan L, Zhang JH, Xu J, Chen Y, Qin M, Yu S, Guan J, Zhang R (2017b) Apigenin attenuates streptozotocin-induced pancreatic β cell damage by its protective effects on cellular antioxidant defense. In Vitro Cell Dev Biol Anim 53:554–563

    Article  CAS  Google Scholar 

  • Wang Y, Gu YH, Liu M, Bai Y, Liang LY, Wang HL (2017a) TBHQ alleviated endoplasmic reticulum stress-apoptosis and oxidative stress by PERK-Nrf2 crosstalk in methamphetamine-induced chronic pulmonary toxicity. Oxidative Med Cell Longev 2017:4310475

    Google Scholar 

  • Wang YY, Zhu J, Ma H, Ding ZC, Li L, Yan JK (2019) Antidiabetic activity of a polysaccharide-protein complex from Asian Clam (Corbicula fluminea) in streptozotoxin-induced diabetic rats and its underlying mechanism. Food Funct 10:5574–5586

  • Xie N, Wu C, Wang C, Cheng X, Zhang L, Zhang H, Lian Y (2017) Inhibition of the mitochondrial calcium uniporter inhibits Aβ-induced apoptosis by reducing reactive oxygen species-mediated endoplasmic reticulum stress in cultured microglia. Brain Res 1676:100–106

    Article  CAS  Google Scholar 

  • Yu WC, Chen YL, Hwang PA, Chen TH, Chou TC (2017) Fucoidan ameliorates pancreatic β-cell death and impaired insulin synthesis in streptozotocin-treated β cells and mice via a Sirt-1-dependent manner. Mol Nutr Food Res 61:1700136

  • Zhang R, Kang KA, Piao MJ, Maeng YH, Lee KH, Chang WY, You HJ, Kim JS, Kang SS, Hyun JW (2009) Cellular protection of morin against the oxidative stress induced by hydrogen peroxide. Chem Biol Interact 177:21–27

    Article  CAS  Google Scholar 

  • Zhang R, Qin M, Shi J, Tan L, Xu J, Tian Z, Wu Y, Li Y, Li Y, Wang N (2018) Molecular cloning and characterization of Pif gene from pearl mussel, Hyriopsis cumingii, and the gene expression analysis during pearl formation. 3 Biotech 8:214

    Article  Google Scholar 

Download references

Funding

This research was approved by the National Natural Science Foundation of China (81300673), Natural Science Foundation of Jiangsu Province, China (BK20130496), Startup Foundation for Advanced Talents of Jiangsu University (13JDG004 &13JDG006), and Cultivation Project for Young Core Teacher of Jiangsu University.

Author information

Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People’s Republic of China

    Rui Zhang, Jie Shi & Xiaonan Qiu

  2. School of Food and Biological Engineering, Jiangsu University, Zhenjiang, 212013, Jiangsu, People’s Republic of China

    Tingting Wang, Ruixia Liu, Yitian Li, Qing Gao & Ning Wang

Authors
  1. Rui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tingting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaonan Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruixia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yitian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qing Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ning Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rui Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Editor: Tetsuji Okamoto

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, R., Shi, J., Wang, T. et al. Apigetrin ameliorates streptozotocin-induced pancreatic β-cell damages via attenuating endoplasmic reticulum stress. In Vitro Cell.Dev.Biol.-Animal 56, 622–634 (2020). https://doi.org/10.1007/s11626-020-00478-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11626-020-00478-x

Keywords

Search

Navigation