Icariin modulates the sirtuin/NF‑κB pathway and exerts anti‑aging effects in human lung fibroblasts

Xu,Changqing; Huang,Xuqing; Tong,Yueyang; Feng,Xiaocheng; Wang,Yan; Wang,Cancan; Jiang,Yuyue

doi:10.3892/mmr.2020.11458

Icariin modulates the sirtuin/NF‑κB pathway and exerts anti‑aging effects in human lung fibroblasts

Authors:
- Changqing Xu
- Xuqing Huang
- Yueyang Tong
- Xiaocheng Feng
- Yan Wang
- Cancan Wang
- Yuyue Jiang
View Affiliations

Affiliations: Department of Respiration, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China, Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
Published online on: August 24, 2020 https://doi.org/10.3892/mmr.2020.11458
Pages: 3833-3839
Copyright: © Xu 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

Icariin (ICA) has been used as a promising anti‑aging drug; however, its underlying molecular mechanism is yet to be elucidated. The present study aimed to determine the anti‑aging molecular mechanisms of ICA. D‑galactose (D‑gal) was used to generate a cell aging model. IMR‑90 human lung fibroblasts were pretreated with different concentrations of ICA (1, 2, 4, 8 and 16 µmol/l) for 6 h and subsequently incubated with D‑gal (200 mmol/l) at 37˚C for 72 h. Senescence of IMR‑90 cells was assessed by senescence‑associated‑β‑galactosidase (SA‑β‑Gal) staining assay. Cell viability, and the expression levels of p53/p21, sirtuin (SIRT) 1/6 and p50/p65 were determined via the MTT assay and western blotting respectively. The results demonstrated that D‑gal notably increased the proportion of SA‑β‑Gal‑positive cells and decreased the viability of IMR‑90 cells; however, pretreatment with ICA reversed the effects of D‑gal on IMR‑90 cells in a concentration‑dependent manner. Furthermore, it was also demonstrated that the activation of p53/p21 and nuclear factor‑κB (NF‑κB) signaling, and downregulation of SIRT1/6 may be involved in IMR‑90 cells, in D‑gal‑induced aging and ICA may effectively prevent IMR‑90 cells from these changes induced by D‑gal. Taken together, the results of the present study suggest that the anti‑aging molecular mechanisms of ICA may be associated with the regulation of the SIRT1/NF‑κB pathway.

View Figures

View References

1	Wang Z, Hu S, Sang S, Luo L and Yu C: Age-period-cohort analysis of stroke mortality in China: Data from the global burden of disease study 2013. Stroke. 48:271–275. 2017. View Article : Google Scholar : PubMed/NCBI
2	Li X, Sun L, Zhang W, Li H, Wang S, Mu H, Zhou Q, Zhang Y, Tang Y, Wang Y, et al: Association of serum glycine levels with metabolic syndrome in an elderly Chinese population. Nutr Metab (Lond). 15:892018. View Article : Google Scholar : PubMed/NCBI
3	Lu H, Guo Z, Liu J, Zhang H, Zhao W, Wu Y, Ni J, Liu W, Tu J, Wang J, et al: Trends in stroke incidence among elderly low-income residents of rural China: A population-based study from 1992 to 2016. Aging (Albany NY). 10:3438–3449. 2018. View Article : Google Scholar : PubMed/NCBI
4	Panicker N, Saminathan H, Jin H, Neal M, Harischandra DS, Gordon R, Kanthasamy K, Lawana V, Sarkar S, Luo J, et al: Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson's disease. J Neurosci. 35:10058–10077. 2015. View Article : Google Scholar : PubMed/NCBI
5	Toosizadeh N, Harati H, Yen TC, Fastje C, Mohler J, Najafi B and Dohm M: Paravertebral spinal injection for the treatment of patients with degenerative facet osteoarthropathy: Evidence of motor performance improvements based on objective assessments. Clin Biomech (Bristol, Avon). 39:100–108. 2016. View Article : Google Scholar : PubMed/NCBI
6	Gondard E, Soto-Montenegro ML, Cassol A, Lozano AM and Hamani C: Transcranial direct current stimulation does not improve memory deficits or alter pathological hallmarks in a rodent model of Alzheimer's disease. J Psychiatr Res. 114:93–98. 2019. View Article : Google Scholar : PubMed/NCBI
7	Sun K, Yang P, Zhao R, Bai Y and Guo Z: Matrine attenuates d-galactose-induced aging-related behavior in mice via inhibition of cellular senescence and oxidative stress. Oxid Med Cell Longev. 2018:71086042018. View Article : Google Scholar : PubMed/NCBI
8	Wang LF, Cao Q, Wen K, Xiao YF, Chen TT, Guan XH, Liu Y, Zuo L, Qian YS, Deng KY and Xin HB: CD38 deficiency alleviates d-galactose-induced myocardial cell senescence through NAD(+)/sirt1 signaling pathway. Front Physiol. 10:11252019. View Article : Google Scholar : PubMed/NCBI
9	Wang JL, Liu B, Zhang C, Wang XM, Zhen D, Huang XM, Chen W and Gao JM: Effects of icariin on ovarian function in d-galactose-induced aging mice. Theriogenology. 125:157–167. 2019. View Article : Google Scholar : PubMed/NCBI
10	Sze SC, Tong Y, Ng TB, Cheng CL and Cheung HP: Herba epimedii: Anti-oxidative properties and its medical implications. Molecules. 15:7861–7870. 2010. View Article : Google Scholar : PubMed/NCBI
11	Li XA, Ho YS, Chen L and Hsiao WL: The protective effects of icariin against the homocysteine-induced neurotoxicity in the primary embryonic cultures of rat cortical neurons. Molecules. 21:15572016. View Article : Google Scholar
12	Pei LK, Guo BL, Sun SQ and Huang WH: Study on the identification of some species of Herba Epimedii with FTIR. Guang Pu Xue Yu Guang Pu Fen Xi. 28:55–60. 2008.(In Chinese). PubMed/NCBI
13	Shen CY, Jiang JG, Yang L, Wang DW and Zhu W: Anti-ageing active ingredients from herbs and nutraceuticals used in traditional Chinese medicine: Pharmacological mechanisms and implications for drug discovery. Br J Pharmacol. 174:1395–1425. 2017. View Article : Google Scholar : PubMed/NCBI
14	Hu ZW, Shen ZY and Huang JH: Experimental study on effect of epimedium flavonoids in protecting telomere length of senescence cells HU. Zhongguo Zhong Xi Yi Jie He Za Zhi. 24:1094–1097. 2004.(In Chinese). PubMed/NCBI
15	Cai WJ, Zhang XM and Huang JH: Effect of epimedium flavonoids in retarding aging of C. elegans. Zhongguo Zhong Xi Yi Jie He Za Zhi. 28:522–525. 2008.(In Chinese). PubMed/NCBI
16	Zhang SQ, Cai WJ, Huang JH, Wu B, Xia SJ, Chen XL, Zhang XM and Shen ZY: Icariin, a natural flavonol glycoside, extends healthspan in mice. Exp Gerontol. 69:226–235. 2015. View Article : Google Scholar : PubMed/NCBI
17	Zhang B, Wang G, He J, Yang Q, Li D, Li J and Zhang F: Icariin attenuates neuroinflammation and exerts dopamine neuroprotection via an Nrf2-dependent manner. J Neuroinflammation. 16:922019. View Article : Google Scholar : PubMed/NCBI
18	Sanz G, Singh M, Peuget S and Selivanova G: Inhibition of p53 inhibitors: progress, challenges and perspectives. J Mol Cell Biol. 11:586–599. 2019. View Article : Google Scholar : PubMed/NCBI
19	Wu D and Prives C: Relevance of the p53-MDM2 axis to aging. Cell Death Differ. 25:169–179. 2018. View Article : Google Scholar : PubMed/NCBI
20	Ou HL and Schumacher B: DNA damage responses and p53 in the aging process. Blood. 131:488–495. 2018. View Article : Google Scholar : PubMed/NCBI
21	Lessel D, Wu D, Trujillo C, Ramezani T, Lessel I, Alwasiyah MK, Saha B, Hisama FM, Rading K, Goebel I, et al: Dysfunction of the MDM2/p53 axis is linked to premature aging. J Clin Invest. 127:3598–3608. 2017. View Article : Google Scholar : PubMed/NCBI
22	Marudamuthu AS, Shetty SK, Bhandary YP, Karandashova S, Thompson M, Sathish V, Florova G, Hogan TB, Pabelick CM, Prakash YS, et al: Plasminogen activator inhibitor-1 suppresses profibrotic responses in fibroblasts from fibrotic lungs. J Biol Chem. 290:9428–9441. 2015. View Article : Google Scholar : PubMed/NCBI
23	Jiang C, Liu G, Luckhardt T, Antony V, Zhou Y, Carter AB, Thannickal VJ and Liu RM: Serpine 1 induces alveolar type II cell senescence through activating p53-p21-Rb pathway in fibrotic lung disease. Aging Cell. 16:1114–1124. 2017. View Article : Google Scholar : PubMed/NCBI
24	Müllers E, Silva Cascales H, Burdova K, Macurek L and Lindqvist A: Residual Cdk1/2 activity after DNA damage promotes senescence. Aging Cell. 16:575–584. 2017. View Article : Google Scholar : PubMed/NCBI
25	De U, Son JY, Jeon Y, Ha SY, Park YJ, Yoon S, Ha KT, Choi WS, Lee BM, Kim IS, et al: Plumbagin from a tropical pitcher plant (Nepenthes alata Blanco) induces apoptotic cell death via a p53-dependent pathway in MCF-7 human breast cancer cells. Food Chem Toxicol. 123:492–500. 2019. View Article : Google Scholar : PubMed/NCBI
26	Wheaton K: Caveolar vesicles generate DNA damage and perpetuate cellular aging. Cell Res. 21:993–994. 2011. View Article : Google Scholar : PubMed/NCBI
27	Wheaton K, Sampsel K, Boisvert FM, Davy A, Robbins S and Riabowol K: Loss of functional caveolae during senescence of human fibroblasts. J Cell Physiol. 187:226–235. 2001. View Article : Google Scholar : PubMed/NCBI
28	Bai L, Deng X, Li J, Wang M, Li Q, An W, A D and Cong YS: Regulation of cellular senescence by the essential caveolar component PTRF/Cavin-1. Cell Res. 21:1088–1101. 2011. View Article : Google Scholar : PubMed/NCBI
29	Ding L, Zeng Q, Wu J, Li D, Wang H, Lu W, Jiang Z and Xu G: Caveolin-1 regulates oxidative stress-induced senescence in nucleus pulposus cells primarily via the p53/p21 signaling pathway in vitro. Mol Med Rep. 16:9521–9527. 2017. View Article : Google Scholar : PubMed/NCBI
30	Tennen RI and Chua KF: Chromatin regulation and genome maintenance by mammalian SIRT6. Trends Biochem Sci. 36:39–46. 2011. View Article : Google Scholar : PubMed/NCBI
31	de Oliveira RM, Pais TF and Outeiro TF: Sirtuins: Common targets in aging and in neurodegeneration. Curr Drug Targets. 11:1270–1280. 2010. View Article : Google Scholar : PubMed/NCBI
32	Carew JS, Giles FJ and Nawrocki ST: Histone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 269:7–17. 2008. View Article : Google Scholar : PubMed/NCBI
33	Chuang PY, Cai W, Li X, Fang L, Xu J, Yacoub R, He JC and Lee K: Reduction in podocyte SIRT1 accelerates kidney injury in aging mice. Am J Physiol Renal Physiol. 313:F621–F628. 2017. View Article : Google Scholar : PubMed/NCBI
34	Tran D, Bergholz J, Zhang H, He H, Wang Y, Zhang Y, Li Q, Kirkland JL and Xiao ZX: Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell. 13:669–678. 2014. View Article : Google Scholar : PubMed/NCBI
35	Chen Y, Sun T, Wu J, Kalionis B, Zhang C, Yuan D, Huang J, Cai W, Fang H and Xia S: Icariin intervenes in cardiac inflammaging through upregulation of SIRT6 enzyme activity and inhibition of the NF-kappa B pathway. Biomed Res Int. 2015:8959762015.PubMed/NCBI
36	Salminen A, Ojala J, Huuskonen J, Kauppinen A, Suuronen T and Kaarniranta K: Interaction of aging-associated signaling cascades: Inhibition of NF-kappaB signaling by longevity factors FoxOs and SIRT1. Cell Mol Life Sci. 65:1049–1058. 2008. View Article : Google Scholar : PubMed/NCBI
37	Tilstra JS, Robinson AR, Wang J, Gregg SQ, Clauson CL, Reay DP, Nasto LA, St Croix CM, Usas A, Vo N, et al: NF-kB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest. 122:2601–2612. 2012. View Article : Google Scholar : PubMed/NCBI
38	Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY and Chua KF: SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell. 136:62–74. 2009. View Article : Google Scholar : PubMed/NCBI