<em>Lycium barbarum</em> Polysaccharide Inhibited Hypoxia-Inducible Factor 1 in COPD Patients

Li-Jun Chen

Wang Xu

Ya-Ping Li

Li-Ting

Chao Chen+4 authors

^{Department of Respiratory and Critical Medicine, The First People's Hospital of Yinchuan City, Yinchuan, Ningxia, People’s Republic of China}

^{Department of Respiratory and Critical Medicine, The Second Affiliated Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China}

^{Department of Respiratory Medicine, Weihai Municipal Hospital of Shandong Province, Weihai, Shandong, People’s Republic of China}

^{Department of Clinical Institute, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China}

Correspondence: Li-Jun Chen Department of Respiratory and Critical Medicine, The Second Affiliated Hospital of Ningxia Medical University, No. 2, Liqun West Street, Xingqing District, Yinchuan, Ningxia, 750001, People’s Republic of China, Phone: Tel +86-13895016600, Fax: Fax +86-951-6192235, Email ycchenlj@163.com

Received 2020 Mar 16; Accepted 2020 Jun 12.

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Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease characterized by irreversible airflow obstruction. Pathogenic mechanisms underlying COPD remain largely unknown.

Objective

The current study was designed to explore serum concentration of hypoxia-inducible factor 1α (HIF-1α) in stable COPD patients and the potential effect of Lycium barbarum polysaccharides (LBP) on HIF-1α protein expression.

Methods

Serum HIF-1α was quantified by ELISA in 102 stable COPD patients before and after 2-week orally taken LBP (100 mL/time, twice daily, 5–15 mg/mL). Correlation of serum LBP and lung function (FEV1%) or blood gas (PO₂ and PCO₂) was also analyzed. As a control, 105 healthy subjects were also enrolled into this study.

Results

Serum concentration of HIF-1α was significantly higher in the stable COPD patients (37.34 ± 7.20 pg/mL) than that in the healthy subjects (29.55 ± 9.66 pg/mL, P<0.001). Oral administration of LBP (5 mg/mL, 100 mL, twice daily for 2 weeks) not only relieved COPD symptoms but also significantly reduced serum HIF-1α concentration (36.94 ± 9.23 vs 30.49 ± 6.42 pg/mL, P<0.05). In addition, level of serum HIF-1α concentration was significantly correlated with PCO₂ (r = 0.283, P<0.001), but negatively and significantly correlated with PO₂ (r = −0.490, P=0.005) or FEV1%(r = −0.420, P=0.018).

Conclusion

These findings suggested that activation of HIF-1 signaling pathway may be involved in the pathophysiology of COPD and that stabilization of serum HIF-1α concentration by LBP might benefit the stable COPD patients.

Keywords: chronic obstructive pulmonary disease, COPD, hypoxia-induced factor 1, HIF-1, Lycium barbarum polysaccharides, LBP

Abstract

Note: * indicates the difference compared with the medium dose group is statistically significant.

Funding Statement

This study was supported by the Key Project of Ningxia Natural Science Foundation (Nos. NZ16217, NZ13175).

Funding Statement

References

1. Vestbo J, Hurd SS, Rodriguez-Roisin R. The 2011 revision of the global strategy for the diagnosis, management and prevention of COPD (GOLD)–why and what?Clin Respir J. 2012;6(4):208–214. doi:10.1111/crj.12002 [] [[PubMed]
2. Fullerton DG, Gordon SB, Calverley PM. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;374(9706):1964–1965;author reply 1965–1966. doi:10.1016/S0140-6736(09)62116-4 [] [[PubMed]
3. Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med. 2014;35(1):71–86. doi:10.1016/j.ccm.2013.10.004 [] [[PubMed]
4. Semenza GL. Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol. 2014;76:39–56. doi:10.1146/annurev-physiol-021113-170322 ] [
5. Zhao X, Gao S, Ren H, et al. Hypoxia-inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin. Cancer Res. 2014;74(9):2455–2464. doi:10.1158/0008-5472.CAN-13-3009 [] [[PubMed]
6. Gui D, Li Y, Chen X, Gao D, Yang Y, Li X. HIF1 signaling pathway involving iNOS, COX2 and caspase9 mediates the neuroprotection provided by erythropoietin in the retina of chronic ocular hypertension rats. Mol Med Rep. 2015;11(2):1490–1496. doi:10.3892/mmr.2014.2859 [] [[PubMed]
7. Szkandera J, Knechtel G, Stotz M, et al. Association of hypoxia-inducible factor 1-alpha gene polymorphisms and colorectal cancer prognosis. Anticancer Res. 2010;30(6):2393–2397. [[PubMed]
8. Yu ZG, Wang BZ, Cheng ZZ. The association of genetic polymorphisms of hypoxia inducible factor-1 alpha and vascular endothelial growth factor with increased risk of chronic obstructive pulmonary disease: a case-control study. Kaohsiung J Med Sci. 2017;33(9):433–441. doi:10.1016/j.kjms.2017.05.014 [] [[PubMed]
9. Fu X, Zhang F. Role of the HIF-1 signaling pathway in chronic obstructive pulmonary disease. Exp Ther Med. 2018;16(6):4553–4561. doi:10.3892/etm.2018.6785 ] [
10. Cheng J, Zhou ZW, Sheng HP, et al. An evidence-based update on the pharmacological activities and possible molecular targets of Lycium barbarum polysaccharides. Drug Des Devel Ther. 2015;9:33–78. doi:10.2147/DDDT.S72892 ] [
11. Deng HB, Cui DP, Jiang JM, Feng YC, Cai NS, Li DD. Inhibiting effects of Achyranthes bidentata polysaccharide and Lycium barbarum polysaccharide on nonenzyme glycation in D-galactose induced mouse aging model. Biomed Environ Sci. 2003;16(3):267–275. [[PubMed]
12. Luo Q, Cai Y, Yan J, Sun M, Corke H. Hypoglycemic and hypolipidemic effects and antioxidant activity of fruit extracts from Lycium barbarum. Life Sci. 2004;76(2):137–149. doi:10.1016/j.lfs.2004.04.056 [] [[PubMed]
13. Shi GJ, Zheng J, Wu J, et al. Protective effects of Lycium barbarum polysaccharide on male sexual dysfunction and fertility impairments by activating hypothalamic pituitary gonadal axis in streptozotocin-induced type-1 diabetic male mice. Endocr J. 2017;64(9):907–922. doi:10.1507/endocrj.EJ16-0430 [] [[PubMed]
14. Kwok SS, Bu Y, Lo AC, et al. A systematic review of potential therapeutic use of Lycium barbarum polysaccharides in disease. Biomed Res Int. 2019;2019:4615745. doi:10.1155/2019/4615745 ] [
15. Lee JW, Ko J, Ju C, Eltzschig HK. Hypoxia signaling in human diseases and therapeutic targets. Exp Mol Med. 2019;51(6):68. doi:10.1038/s12276-019-0235-1 ] [
16. Gan L, Hua Zhang S, Liang Yang X, Bi Xu H. Immunomodulation and antitumor activity by a polysaccharide-protein complex from Lycium barbarum. Int Immunopharmacol. 2004;4(4):563–569. doi:10.1016/j.intimp.2004.01.023 [] [[PubMed]
17. Zhang M, Tang X, Wang F, Zhang Q, Zhang Z. Characterization of Lycium barbarum polysaccharide and its effect on human hepatoma cells. Int J Biol Macromol. 2013;61:270–275. doi:10.1016/j.ijbiomac.2013.06.031 [] [[PubMed]
18. Bo R, Sun Y, Zhou S, et al. Simple nanoliposomes encapsulating Lycium barbarum polysaccharides as adjuvants improve humoral and cellular immunity in mice. Int J Nanomedicine. 2017;12:6289–6301. doi:10.2147/IJN.S136820 ] [
19. Zhang XR, Qi CH, Cheng JP, et al. Lycium barbarum polysaccharide LBPF4-OL may be a new Toll-like receptor 4/MD2-MAPK signaling pathway activator and inducer. Int Immunopharmacol. 2014;19(1):132–141. doi:10.1016/j.intimp.2014.01.010 [] [[PubMed]
20. Teng P, Li Y, Cheng W, Zhou L, Shen Y, Wang Y. Neuroprotective effects of Lycium barbarum polysaccharides in lipopolysaccharide-induced BV2 microglial cells. Mol Med Rep. 2013;7(6):1977–1981. doi:10.3892/mmr.2013.1442 [] [[PubMed]
21. Xin YF, Wan LL, Peng JL, Guo C. Alleviation of the acute doxorubicin-induced cardiotoxicity by Lycium barbarum polysaccharides through the suppression of oxidative stress. Food Chem Toxicol. 2011;49(1):259–264. doi:10.1016/j.fct.2010.10.028 [] [[PubMed]
22. CTS. Guidelines of COPD for primary doctors. Chin J Gen Pract. 2018;11(17):856–870. [PubMed]
23. Yasuo M, Mizuno S, Kraskauskas D, et al. Hypoxia inducible factor-1alpha in human emphysema lung tissue. Eur Respir J. 2011;37(4):775–783. doi:10.1183/09031936.00022910 [] [[PubMed]
24. Zhang HX, Yang JJ, Zhang SA, et al. HIF-1alpha promotes inflammatory response of chronic obstructive pulmonary disease by activating EGFR/PI3K/AKT pathway. Eur Rev Med Pharmacol Sci. 2018;22(18):6077–6084. doi:10.26355/eurrev_201809_15946 [] [[PubMed]
25. Mo JH, Kim JH, Lim DJ, Kim EH. The role of hypoxia-inducible factor 1alpha in allergic rhinitis. Am J Rhinol Allergy. 2014;28(2):e100–e106. doi:10.2500/ajra.2014.28.4025 [] [[PubMed]
26. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–732. doi:10.1038/nrc1187 [] [[PubMed]
27. Li J, Xu Y, Jiao H, Wang W, Mei Z, Chen G. Sumoylation of hypoxia inducible factor-1alpha and its significance in cancer. Sci China Life Sci. 2014;57(7):657–664. doi:10.1007/s11427-014-4685-3 [] [[PubMed]
28. Karpel-Massler G, Westhoff MA, Kast RE, et al. Simultaneous Interference with HER1/EGFR and RAC1 signaling drives cytostasis and suppression of survivin in human glioma cells in vitro. Neurochem Res. 2017;42(5):1543–1554. doi:10.1007/s11064-017-2213-0 [] [[PubMed]
29. York ER, Varella-Garcia M, Bang TJ, Aisner DL, Camidge DR. Tolerable and effective combination of full-dose crizotinib and osimertinib targeting MET amplification sequentially emerging after T790M positivity in EGFR-mutant non-small cell lung cancer. J Thorac Oncol. 2017;12(7):e85–e88. doi:10.1016/j.jtho.2017.02.020 [] [[PubMed]
30. Tosuner Z, Bozkurt SU, Kilic T, Yilmaz B. The role of EGFR, hepatocyte growth factor receptor (c-Met), c-ErbB2 (HER2-neu) and clinicopathological parameters in the pathogenesis and prognosis of chordoma. Turk Patoloji Derg. 2017;33(2):112–120. doi:10.5146/tjpath.2016.01378 [] [[PubMed]
31. Kiers D, Wielockx B, Peters E, et al. Short-term hypoxia dampens inflammation in vivo via enhanced adenosine release and adenosine 2B receptor stimulation. EBioMedicine. 2018;33:144–156. doi:10.1016/j.ebiom.2018.06.021 ] [
32. Bowser JL, Lee JW, Yuan X, Eltzschig HK. The hypoxia-adenosine link during inflammation. J Appl Physiol. 2017;123(5):1303–1320. doi:10.1152/japplphysiol.00101.2017 ] [
33. Riegel AK, Faigle M, Zug S, et al. Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation. Blood. 2011;117(8):2548–2555. doi:10.1182/blood-2010-10-313957 ] [
34. Yuan X, Lee JW, Bowser JL, Neudecker V, Sridhar S, Eltzschig HK. Targeting hypoxia signaling for perioperative organ injury. Anesth Analg. 2018;126(1):308–321. doi:10.1213/ANE.0000000000002288 ] [
35. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23(24):9361–9374. doi:10.1128/MCB.23.24.9361-9374.2003 ] [
36. Sheng W, Fan W. Effect of Lycium barbarum polysaccharide on ability of hypoxia and anti-fatigue in mice. J Xinxiang Med Coll. 2011;28(3):298–300. [PubMed]
37. Li X, Wang B, Liu J, Zhang S. Study of effect of LBP on antihypoxia in mice. J Huazhong Agricl Univ. 1999;18(3):283–285. [PubMed]
38. Zhu Y, Sun Y, Guan W, et al. Lycium barbarum polysaccharides enhances SIRT1 expression and decreases MMP-9 and HIF-1a expression in hypoxic pulmonary vascular smooth muscle cells. Chin J Cell Mol Immunol. 2016;7(7):906–940. [[PubMed]
39. Chen W, Cheng X, Chen J, et al. Lycium barbarum polysaccharides prevent memory and neurogenesis impairments in scopolamine-treated rats. PLoS One. 2014;9(2):e88076. doi:10.1371/journal.pone.0088076 ] [
40. Kou L, Du M, Zhang C, et al. Polysaccharide purified from Lycium barbarum protects differentiated PC12 cells against LGlu-induced toxicity via the mitochondria-associated pathway. Mol Med Rep. 2017;16(4):5533–5540. doi:10.3892/mmr.2017.7289 [] [[PubMed]
41. Ho YS, Yu MS, Lai CS, So KF, Yuen WH, Chang RC. Characterizing the neuroprotective effects of alkaline extract of Lycium barbarum on beta-amyloid peptide neurotoxicity. Brain Res. 2007;1158:123–134. doi:10.1016/j.brainres.2007.04.075 [] [[PubMed]
42. Ho YS, Yu MS, Yik SY, So KF, Yuen WH, Chang RC. Polysaccharides from wolfberry antagonizes glutamate excitotoxicity in rat cortical neurons. Cell Mol Neurobiol. 2009;29(8):1233–1244. doi:10.1007/s10571-009-9419-x [] [[PubMed]
43. Chiu K, Chan HC, Yeung SC, et al. Modulation of microglia by wolfberry on the survival of retinal ganglion cells in a rat ocular hypertension model. J Ocul Biol Dis Infor. 2009;2(2):47–56. doi:10.1007/s12177-009-9023-9 ] [
44. Zhu C, Zhang S. The antitumor and immunoenhancement activity of Lycium barbarum polysaccharides in hepatoma H-22-bearing mice. Acta Nutr Sin. 2006;28:182–183. [PubMed]
45. Zhu J, Zhao LH, Zhao XP, Chen Z. Lycium barbarum polysaccharides regulate phenotypic and functional maturation of murine dendritic cells. Cell Biol Int. 2007;31(6):615–619. doi:10.1016/j.cellbi.2006.12.002 [] [[PubMed]
46. Sheng B, Zhao X, Liang K. Regulatory effect of Lycium barbarum on immunity in over 60 seniors. Pharmacol Clin Chin Mater Med. 1988;4(2):43–44. [PubMed]
47. Mu B, Liu X, Xiong J, Gou A. Acute toxicity and mutagenicity of Lycium barbarum polysaccharides. J Environ Occup Med. 2002;19(2):201–202. [PubMed]
48. Li W, Dai S, Shao W. Effect of oral administration of Lycium barbarum on superoxide dismutase, Hb, and LPD in seniors. Chin Traditional Herbal Drugs. 1991;22(6):25–26. [PubMed]