Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling

Sun, Xiaoning; Zhang, Boya; Pan, Xuran; Huang, Hai; Xie, Ziang; Ma, Yan; Hu, Bin; Wang, Jiying; Chen, Zhijun; Shi, Peihua

doi:10.1096/fj.201900887rr

Cited by 53 publications

(47 citation statements)

References 32 publications

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“…In the ALI + OI group, mice were administered OI (50 mg/kg or 100 mg/kg) for three days. 16 On the third day, 2 h after the treatment with OI or DMSO, the mice were administered LPS (5 mg/kg) intratracheally. After 12 h, the mice were sacrificed, and the lung samples and bronchoalveolar lavage fluid (BALF) were harvested as described in a previous study.…”

Section: Methodsmentioning

confidence: 99%

<p>4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation</p>

Yang¹,

Chen²,

Zhang³

et al. 2020

DDDT

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Background Acute lung injury (ALI) is a fatal disease in the absence of pharmacological treatment. Oxidative stress and inflammation are closely related to ALI. Innate immune cells are the main source of reactive oxygen species (ROS). Macrophages play an extremely important role in ALI through the activation of inflammation and oxidative stress. Itaconate, a metabolite of tricarboxylic acid, has been reported to have strong antioxidant and anti-inflammatory effects. However, the role of itaconate in ALI is unclear. Herein, we use 4-octyl itaconate (OI), the cellular permeable derivate of itaconate, to study the effects of itaconate in vivo and in vitro. Methods We used OI to pretreat C57BL/6 mice and LPS-induced ALI models to illustrate the role of itaconate in acute lung injury. The mice were randomly divided into four groups: control group, OI (100 mg/kg) group, ALI Group, ALI + OI (50 mg/kg) group, and ALI + OI (100 mg/kg) group. RAW264.7 cells were used to further prove the role and mechanism of itaconate in vitro. Results According to the H&E staining of the lung, OI was observed to significantly reduce lung inflammation. The active oxygen content of tissues was also significantly reduced (P<0.05). OI reduced the accumulation of neutrophils and secretion of inflammatory factors in LPS-induced ALI (P<0.05). At the cellular level, OI also reduced oxidative stress and inflammation. Intervention with OI was also observed to upregulate the expression of nuclear factor erythroid 2-related factor-2 (Nrf-2) and Nrf-2 target genes in the lung tissue and RAW264.7 cells. Conclusion OI alleviates LPS-induced ALI. Moreover, the antioxidant and anti-inflammatory effects of OI might depend on the activation of Nrf-2. Therefore, OI might have therapeutic potential for the treatment of ALI.

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Section: Methodsmentioning

confidence: 99%

<p>4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation</p>

Yang¹,

Chen²,

Zhang³

et al. 2020

DDDT

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“… 22 Nrf2 genetic or pathological deficiencies correlate with increased susceptibility to OP in mice due to an insufficient antioxidative stress capacity, 23 , 24 while enhancing Nrf2 by various activators or agonists is protective against OP. 25 , 26 The Nrf2 promoter is characterized by CpG islands, and Nrf2 downregulation due to altered DNA methylation is observed in several aging-related pathological conditions, such as aging, cancer and neurodegenerative disease, 27 , 28 suggesting that epigenetic Nrf2 suppression might contribute to the initiation or progression of OP.…”

Section: Introductionmentioning

confidence: 99%

Nrf2 epigenetic derepression induced by running exercise protects against osteoporosis

Chen

Zhu

et al. 2021

Bone Res

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Osteoporosis (OP) is a common skeletal disease involving low bone mineral density (BMD) that often leads to fragility fracture, and its development is affected by multiple cellular pathologies and associated with marked epigenetic alterations of osteogenic genes. Proper physical exercise is beneficial for bone health and OP and reportedly possesses epigenetic modulating capacities; however, whether the protective effects of exercise on OP involve epigenetic mechanisms is unclear. Here, we report that epigenetic derepression of nuclear factor erythroid derived 2-related factor-2 (Nrf2), a master regulator of oxidative stress critically involved in the pathogenesis of OP, mediates the significant osteoprotective effects of running exercise (RE) in a mouse model of OP induced by ovariectomy. We showed that Nrf2 gene knockout (Nfe2l2−/−) ovariectomized mice displayed a worse BMD reduction than the controls, identifying Nrf2 as a critical antiosteoporotic factor. Further, femoral Nrf2 was markedly repressed with concomitant DNA methyltransferase (Dnmt) 1/Dnmt3a/Dnmt3b elevations and Nrf2 promoter hypermethylation in both patients with OP and ovariectomized mice. However, daily 1-h treadmill RE significantly corrected epigenetic alterations, recovered Nrf2 loss and improved the femur bone mass and trabecular microstructure. Consistently, RE also normalized the adverse expression of major osteogenic factors, including osteoblast/osteoclast markers, Nrf2 downstream antioxidant enzymes and proinflammatory cytokines. More importantly, the RE-conferred osteoprotective effects observed in the wild-type control mice were largely abolished in the Nfe2l2−/− mice. Thus, Nrf2 repression due to aberrant Dnmt elevation and subsequent Nrf2 promoter hypermethylation is likely an important epigenetic feature of the pathogenesis of OP, and Nrf2 derepression is essential for the antiosteoporotic effects of RE.

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“…ELISA results demonstrated that Sch had an anti‐oxidant effect when stimulated by RANKL (Figure 5F). Nrf2 functions as a transcriptional factor which regulates the expression of several anti‐oxidant and phase II detoxifying enzymes, hence decrease the production of ROS 9,11,12 . We then tested whether this compound could enhance the expression of Nrf2, the lynchpin factor in anti‐oxidant system, during osteoclast differentiation.…”

Section: Resultsmentioning

confidence: 99%

“…The mRNA expression levels were assessed by real‐time PCR system (Applied Biosystems). The specific primers we used are according to a previously report unless otherwise noted 11,12,18,19 . The primers are listed in Table .…”

Section: Methodsmentioning

confidence: 99%

Schisandrin A restrains osteoclastogenesis by inhibiting reactive oxygen species and activating Nrf2 signalling

Qian

Yin

et al. 2020

Cell Proliferation

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The activity of osteoclasts (OCs) and osteoblasts (OBs) is regulated precisely in the development of skeletal system. 1,2 Some disease such as osteoporosis, rheumatoid arthritis and Paget's disease are correlated with over-activation of OCs. 3 The differentiation and formation of mature osteoclasts depend on the two necessary signals: macrophage colony-stimulating (M-CSF) and receptor activator of NF-kB ligand (RANKL). M-CSF promotes the proliferation and survival of osteoclast precursors by activating the AKT and ERK1/2

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Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling

Cited by 53 publications

References 32 publications

<p>4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation</p>

<p>4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation</p>

Nrf2 epigenetic derepression induced by running exercise protects against osteoporosis

Schisandrin A restrains osteoclastogenesis by inhibiting reactive oxygen species and activating Nrf2 signalling

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