nach oben

Journal of Bone and Mineral Metabolism

Erschienen in:

01.02.2022 | Original Article

Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3β/Nrf2 pathway

verfasst von: Xiaolei Sun, Tianshuang Xia, Shiyao Zhang, Jiabao Zhang, Lingchuan Xu, Ting Han, Hailiang Xin

Erschienen in: Journal of Bone and Mineral Metabolism | Ausgabe 3/2022

Einloggen, um Zugang zu erhalten

Abstract

Introduction

Osteoporosis is closely related to iron metabolism. This study aimed to investigate whether hops extract (HLE) and its active component xanthohumol (XAN) could ameliorate bone loss caused by iron overload, and explored its potential mechanism.

Materials and methods

Iron overload mice induced by iron dextran (ID) were used in vivo, and were treated with HLE and XAN for 3 months. Bone micro-structure and bone morphology parameters were determined by Micro-CT and TRAP staining. Bone metabolism markers and oxidation indexes in serum and bone tissue were evaluated. For in vitro experiment, bone formation indexes were determined. Moreover, the expression of key proteins in protein kinase B (Akt)/glycogen synthetase kinase 3β (GSK3β)/nuclear factor E2-related (Nrf2) pathway was evaluated by Western blotting.

Results

HLE and XAN effectively improved the bone micro-structure of the femur in mice, altered bone metabolism biomarkers, and regulated the expression of proteins related to bone metabolism. Additionally, they significantly promoted cell proliferation, runt-related gene 2 (Runx2) expression, and increased ALP activity in ID-induced osteoblasts. Moreover, HLE and XAN markedly inhibited the increase of oxidative stress caused by iron overload in vivo and in vitro. Further studies showed that they significantly up-regulated the expression of p-Akt, p-GSK3β, nuclear-Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1) in ID-induced osteoblasts.

Conclusion

These findings indicated hops and xanthohumol could ameliorate bone loss induced by iron overload via activating Akt/GSK3β/Nrf2 pathway, which brought up a novel sight for senile osteoporosis therapy.

Li Y, Lu SS, Tang GY, Hou M, Tang Q, Zhang XN, Chen WH, Chen G, Xue Q, Zhang CC, Zhang JF, Chen Y, Xu XY (2014) Effect of Morinda officinalis capsule on osteoporosis in ovariectomized rats. Chin J Nat Med 12:204–212PubMed

Lin J, Zhu J, Wang Y, Zhang N, Gober HJ, Qiu X, Li D, Wang L (2017) Chinese single herbs and active ingredients for postmenopausal osteoporosis: from preclinical evidence to action mechanism. Biosci Trends 11:496–506PubMedCrossRef

Abbassy HA, Elwafa R, Omar OM (2019) Bone mineral density and vitamin d receptor genetic variants in egyptian children with beta thalassemia major on vitamin D supplementation. Mediterr J Hematol Infect Dis 11:e2019013PubMedPubMedCentralCrossRef

Cheng Q, Zhang X, Jiang J, Zhao G, Wang Y, Xu Y, Xu X, Ma H (2017) Postmenopausal iron overload exacerbated bone loss by promoting the degradation of type I collagen. Biomed Res Int 2017:1345193PubMedPubMedCentral

Xu G, Li X, Zhu Z, Wang H, Bai X (2021) Iron overload induces apoptosis and cytoprotective autophagy regulated by ROS generation in Mc3t3-E1 cells. Biol Trace Elem Res 199:3781–3792PubMedCrossRef

Yarjanli Z, Ghaedi K, Esmaeili A, Rahgozar S, Zarrabi A (2017) Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci 18:51PubMedPubMedCentralCrossRef

Zhao GY, Di DH, Wang B, Huang X, Xu YJ (2015) Effects of mouse hepcidin 1 treatment on osteoclast differentiation and intracellular iron concentration. Inflammation 38:718–727PubMedCrossRef

Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283:65–87PubMedCrossRef

Qi J, Hu KS, Yang HL (2015) Roles of TNF-alpha, GSK-3beta and RANKL in the occurrence and development of diabetic osteoporosis. Int J Clin Exp Pathol 8:11995–12004PubMedPubMedCentral

10.

Noh T, Gabet Y, Cogan J, Shi Y, Tank A, Sasaki T, Criswell B, Dixon A, Lee C, Tam J, Kohler T, Segev E, Kockeritz L, Woodgett J, Muller R, Chai Y, Smith E, Bab I, Frenkel B (2009) Lef1 haploinsufficient mice display a low turnover and low bone mass phenotype in a gender- and age-specific manner. PLoS ONE 4:e5438PubMedPubMedCentralCrossRef

11.

Ge XH, Shao L, Zhu GJ (2018) Oxymatrine attenuates brain hypoxic-ischemic injury from apoptosis and oxidative stress: role of p-Akt/GSK3beta/HO-1/Nrf-2 signaling pathway. Metab Brain Dis 33:1869–1875PubMedCrossRef

12.

Rana AK, Singh D (2018) Targeting glycogen synthase kinase-3 for oxidative stress and neuroinflammation: opportunities, challenges and future directions for cerebral stroke management. Neuropharmacology 139:124–136PubMedCrossRef

13.

Dai P, Mao Y, Sun X, Li X, Muhammad I, Gu W, Zhang D, Zhou Y, Ni Z, Ma J, Huang S (2017) Attenuation of oxidative stress-induced osteoblast apoptosis by curcumin is associated with preservation of mitochondrial functions and increased Akt-GSK3beta signaling. Cell Physiol Biochem 41:661–677PubMedCrossRef

14.

Kim MB, Kang H, Li Y, Park YK, Lee JY (2021) Fucoxanthin inhibits lipopolysaccharide-induced inflammation and oxidative stress by activating nuclear factor E2-related factor 2 via the phosphatidylinositol 3-kinase/Akt pathway in macrophages. Eur J Nutr 60:3315–3324PubMedCrossRef

15.

Rana T, Schultz MA, Freeman ML, Biswas S (2012) Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL. Free Radic Biol Med 53:2298–2307PubMedCrossRef

16.

Aghamiri V, Mirghafourvand M, Mohammad-Alizadeh-Charandabi S, Nazemiyeh H (2016) The effect of Hop (Humulus lupulus L.) on early menopausal symptoms and hot flashes: a randomized placebo-controlled trial. Complement Ther Clin Pract 23:130–135PubMedCrossRef

17.

Sasaoka N, Sakamoto M, Kanemori S, Kan M, Tsukano C, Takemoto Y, Kakizuka A (2014) Long-term oral administration of hop flower extracts mitigates Alzheimer phenotypes in mice. PLoS ONE 9:e87185PubMedPubMedCentralCrossRef

18.

Zanoli P, Zavatti M (2008) Pharmacognostic and pharmacological profile of Humulus lupulus L. J Ethnopharmacol 116:383–396PubMedCrossRef

19.

Suh KS, Chon S, Choi EM (2018) Cytoprotective effects of xanthohumol against methylglyoxal-induced cytotoxicity in MC3T3-E1 osteoblastic cells. J Appl Toxicol 38:180–192PubMedCrossRef

20.

Xia TS, Lin LY, Zhang QY, Jiang YP, Li CH, Liu XY, Qin LP, Xin HL (2021) Humulus lupulus L. extract prevents ovariectomy-induced osteoporosis in mice and regulates activities of osteoblasts and osteoclasts. Chin J Integr Med 27:31–38PubMedCrossRef

21.

Jeong HM, Han EH, Jin YH, Choi YH, Lee KY, Jeong HG (2011) Xanthohumol from the hop plant stimulates osteoblast differentiation by RUNX2 activation. Biochem Biophys Res Commun 409:82–89PubMedCrossRef

22.

Zhao L (2016) Anti-osteoporosis mechanism of curculigoside and its transport charayeristics in human intestinal Caco-2 cell line. Shanghai Jiaotong University

23.

Zhu YM (1989) Medicinal flora of Inner Mongolia. Inner Mongolia Peoples Publishing House

24.

He YQ, Zhao L, Shen Y, Han T, Zhang JH, Xin HL, Zhang QY (2018) Effects of icariin on bone metabolism in iron overload mice. Acta Pharmaceutica Sinica 53:1100–1107

25.

Wang S, Cao K, Liao Y, Zhang W, Zheng J, Li X, Huang M, Zhong Y, Hu X, Chen D, Wang Y (2021) CDCA2 protects against oxidative stress by promoting BRCA1-NRF2 signaling in hepatocellular carcinoma. Oncogene 40:4368–4383PubMedCrossRef

26.

Zhang MM (2014) Expert consensus of clinical application of the bone metabolic and biochemical markers, by Osteoporosis Committee of Chinese Gerontological Society. Chin J Osteoporos 20:1263–1272

27.

Liu H, Yue X, Zhang G (2021) Downregulation of miR146a inhibits osteoporosis in the jaws of ovariectomized rats by regulating the Wnt/betacatenin signaling pathway. Int J Mol Med 47:1PubMed

28.

Xu X, Zhang Z, Wang W, Yao H, Ma X (2017) Therapeutic effect of cistanoside A on bone metabolism of ovariectomized mice. Molecules 22:197PubMedCentralCrossRef

29.

Miller PD (2005) Bone density and markers of bone turnover in predicting fracture risk and how changes in these measures predict fracture risk reduction. Curr Osteoporos Rep 3:103–110PubMedCrossRef

30.

Guo Z, Peng YW, Sun K, Lin JM, Guo JC, Wang GC, Guo FJ (2020) Research progress of iron metabolism and its relationship with osteoarthritis. Orthopaedics 11:457–462

31.

Wei YW, Liu D, Fu P, Li SY, Gao YF, Qian G (2018) The effect of serum ferritin and serum hepcidin on senile patients with essential hypertension and osteoporosis. Chin J Osteoporos 24:87–90

32.

Lu W, Xiong XX, Fan SH (2020) Effects of hepcidin on serum iron content and bone mineral density in rats with primary osteoporosis. Contemp Med 26:139–141

33.

Lv MM, Zheng ZY, Zhang YL, Yue RC, Hu HX (2021) Ferroptosis pathway and process in cardiovascular disease. Chin General Pract 24:3769–3773

34.

Magtanong L, Ko PJ, Dixon SJ (2016) Emerging roles for lipids in non-apoptotic cell death. Cell Death Differ 23:1099–1109PubMedPubMedCentralCrossRef

35.

Liu G, Men P, Kenner GH, Miller SC (2008) Therapeutic effects of an oral chelator targeting skeletal tissue damage in experimental postmenopausal osteoporosis in rats. Hemoglobin 32:181–190PubMedCrossRef

36.

Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73:3221–3247PubMedPubMedCentralCrossRef

37.

Fão L, Mota SI, Rego AC (2019) Shaping the Nrf2-ARE-related pathways in Alzheimer’s and Parkinson’s diseases. Age Res Rev 54:100942CrossRef

38.

Henderson J, Dayalan Naidu S, Dinkova-Kostova AT, Przyborski S, Stratton R, Reilly OS (2021) The cell-permeable derivative of the immunoregulatory metabolite itaconate, 4-octyl itaconate is anti-fibrotic in systemic sclerosis. Cells 10:2053PubMedPubMedCentralCrossRef

39.

Sharawy MH, El-Kashef DH, Shaaban AA, El-Agamy DS (2021) Anti-fibrotic activity of sitagliptin against concanavalin A-induced hepatic fibrosis. Role of Nrf2 activation/NF-κB inhibition. Int Immunopharmacol 100:108088PubMedCrossRef

40.

Duranti G, Maldini M, Crognale D, Horner K, Dimauro I, Sabatini S, Ceci R (2021) Moringa oleifera leaf extract upregulates Nrf2/HO-1 expression and ameliorates redox status in C2C12 skeletal muscle cells. Molecules (Basel, Switzerland) 26:5041CrossRef

41.

Tsay J, Yang Z, Ross FP, Cunningham-Rundles S, Lin H, Coleman R, Mayer-Kuckuk P, Doty SB, Grady RW, Giardina PJ, Boskey AL, Vogiatzi MG (2010) Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood 116:2582–2589PubMedPubMedCentralCrossRef

Titel: Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3β/Nrf2 pathway
verfasst von: Xiaolei Sun
Tianshuang Xia
Shiyao Zhang
Jiabao Zhang
Lingchuan Xu
Ting Han
Hailiang Xin
Publikationsdatum: 01.02.2022
Verlag: Springer Nature Singapore
Erschienen in: Journal of Bone and Mineral Metabolism / Ausgabe 3/2022
Print ISSN: 0914-8779
Elektronische ISSN: 1435-5604
DOI: https://doi.org/10.1007/s00774-021-01295-2

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3β/Nrf2 pathway

Abstract

Introduction

Materials and methods

Results

Conclusion

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

Nach Herzinfarkt mit Typ-1-Diabetes schlechtere Karten als mit Typ 2?

15% bedauern gewählte Blasenkrebs-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Innere Medizin

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Introduction

Materials and methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2022

Bone markers and bone mineral density associates with periodontitis in females with poly-cystic ovarian syndrome

Sexual dimorphism in the relation between sex hormones and osteoporosis in patients with type 2 diabetes mellitus

Relationship between oseteoporosis with fatty infiltration of paraspinal muscles based on QCT examination

Polypharmacy and bone fracture risk

Folate ameliorates homocysteine-induced osteoblast dysfunction by reducing endoplasmic reticulum stress-activated PERK/ATF-4/CHOP pathway in MC3T3-E1 cells

p53 deficiency promotes bone regeneration by functional regulation of mesenchymal stromal cells and osteoblasts

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

Nach Herzinfarkt mit Typ-1-Diabetes schlechtere Karten als mit Typ 2?

15% bedauern gewählte Blasenkrebs-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Innere Medizin