Erxian Decoction Attenuates TNF-α Induced Osteoblast Apoptosis by Modulating the Akt/Nrf2/HO-1 Signaling Pathway

Abstract

Erxian decoction (EXD), a traditional Chinese medicine formula, has been used for treatment of osteoporosis for many years. The purpose of this study was to investigate the pharmacological effect of EXD in preventing osteoblast apoptosis and the underlying mechanism of prevention. Putative targets of EXD were predicted by network pharmacology, and functional and pathway enrichment analyses were also performed. Evaluations of bone mineral density, serum estradiol level, trabecular area fraction, serum calcium levels, and tumor necrosis factor (TNF)-α levels in ovariectomized rats, as well as cell proliferation assays, apoptosis assays, and western blotting in MC3T3-E1 osteoblasts were performed for further experimental validation. Ninety-three active ingredients in the EXD formula and 259 potential targets were identified. Functional and pathway enrichment analyses indicated that EXD significantly influenced the PI3K-Akt signaling pathway. In vivo experiments indicated that EXD treatment attenuated bone loss and decreased TNF-α levels in rats with osteoporosis. In vitro experiments showed that EXD treatment increased cell viability markedly and decreased levels of caspase-3 and the rate of apoptosis. It also promoted phosphorylation of Akt, nuclear translocation of transcription factor NF-erythroid 2-related factor (Nrf2), and hemeoxygenase-1 (HO-1) expression in TNF-α-induced MC3T3-E1 cells. Our results suggest that EXD exerted profound anti-osteoporosis effects, at least partially by reducing production of TNF-α and attenuating osteoblast apoptosis via Akt/Nrf2/HO-1 signaling pathway.

Investigating the pharmacological mechanisms of SheXiang XinTongNing against coronary heart disease based on network pharmacology

“…It coincides well with the holistic ideas of 'network target, multicomponent therapeutics' of TCM and contributes greatly to the prediction of potential drugs and the screening of the components, targets as well as pathways of drugs [19]. In previous study, the network pharmacology has been used in elucidating the key components and mechanisms of TCM involved in their therapeutic effects, such as the mechanisms of Erxian Decoction against TNF-α induced osteoblast apoptosis [20], the mechanisms of Huayu-Qiangshen-Tongbi formula on rheumatoid arthritis [21], the anticancer mechanisms of Compound Kushen Injection against hepatocellular carcinoma [22].…”

Theaflavin-3,3′-Digallate Promotes the Formation of Osteoblasts Under Inflammatory Environment and Increases the Bone Mass of Ovariectomized Mice

“…When osteoblast precursor cells differentiate into osteoblasts, the transcription factor Runx2 is upregulated to promote the osteoblast lineage ( Vimalraj et al, 2015 ). Studies have shown that high concentration of TNF-α can induce osteoblast apoptosis ( Wang et al, 2019 ), while low concentration of TNF-α inhibits osteoblast differentiation and reduces the activity of ALP ( Bu et al, 2009 ; Yu et al, 2019 ). This effect may explain the inhibition of bone formation in chronic inflammation.…”

Cytoprotective effects of fermented oyster extracts against oxidative stress-induced DNA damage and apoptosis through activation of the Nrf2/HO-1 signaling pathway in MC3T3-E1 osteoblasts

“…For example, loss of Nrf2 increases the susceptibility of bone loss due to increased oxidative stress (Liu et al, 2019[ 43 ]; Pellegrini et al, 2017[ 46 ]; Ibáñez et al, 2014[ 26 ]); and in contrast, loss of Nrf2 accelerates bone loss, by promoting RANKL-induced osteoclast differentiation or upregulating RANKL (Hyeon et al, 2013[ 25 ]; Rana et al, 2012[ 49 ]). In addition, various natural products have been reported to have antioxidant properties through the activation of Nrf2/HO-1 signaling pathway, to protect osteoblast apoptosis caused by oxidative injury (Jin et al, 2020[ 30 ]; Wang et al, 2019[ 55 ]; Cheng et al, 2019[ 8 ]; Han et al, 2019[ 22 ], 2017[ 20 ]). Therefore, the effect of FO on the expression of Nrf2 was explored, and the results of Western blot analysis showed that the expression of p-Nrf2 protein was markedly upregulated, meaning that Nrf2 was activated in FO-treated MC3T3-E1 cells.…”