Four-Octyl Itaconate Protects Chondrocytes against H2O2-Induced Oxidative Injury and Attenuates Osteoarthritis Progression by Activating Nrf2 Signaling

Zhang, Peng; Wang, Xiaotong; Peng, Qiliang; Jin, Yesheng; Shi, Gaolong; Fan, Zhihai; Zhou, Zhiqiang

doi:10.1155/2022/2206167

Cited by 9 publications

(7 citation statements)

References 35 publications

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“…The anti-oxidative stress effects of composites were evaluated as previously reported [ 38 , 39 ]. Briefly, the cells were seeded in a 96-well plate at a density of 5 × 10 3 cells/well overnight.…”

Section: Methodsmentioning

confidence: 99%

Intracellular Delivery of Itaconate by Metal–Organic Framework-Anchored Hydrogel Microspheres for Osteoarthritis Therapy

Ren

Pan

et al. 2023

Pharmaceutics

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Treatment of osteoarthritis (OA) remains a significant clinical challenge. Itaconate (IA), an emerging regulator of intracellular inflammation and oxidative stress, may potentially be harnessed to treat OA. However, the short joint residence time, inefficient drug delivery, and cell-impermeable property of IA can seriously hamper the clinical translation. Herein, IA-encapsulated zeolitic imidazolate framework-8 (IA-ZIF-8) nanoparticles were self-assembled by zinc ions, 2-methylimidazole, and IA to render them pH-responsive. Subsequently, IA-ZIF-8 nanoparticles were firmly immobilized in hydrogel microspheres via one-step microfluidic technology. It was demonstrated in vitro experiments that IA-ZIF-8-loaded hydrogel microspheres (IA-ZIF-8@HMs) exhibited good anti-inflammatory and anti-oxidative stress effects by releasing pH-responsive nanoparticles into chondrocytes. Importantly, compared with IA-ZIF-8, IA-ZIF-8@HMs showed better performance in the treatment of OA due to their superior performance in sustained release. Thus, such hydrogel microspheres not only hold enormous potential for OA therapy, but also provide a novel avenue for cell-impermeable drugs by constructing appropriate drug delivery systems.

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Section: Methodsmentioning

confidence: 99%

Intracellular Delivery of Itaconate by Metal–Organic Framework-Anchored Hydrogel Microspheres for Osteoarthritis Therapy

Ren

Pan

et al. 2023

Pharmaceutics

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“…Group Ⅳ: SE + AKBA treatment group. On postpartum days 11, 13, and 15, rat pups of Groups III and Ⅳ underwent injection of sodium selenite (20 μmol/kg body weight) to generate a cataract model ( Zhang P. et al, 2022 ). In addition, Group Ⅱ and Group Ⅳ received AKBA intraperitoneally at doses of 20 mg/kg from day 11 to day 15 postpartum.…”

Section: Methodsmentioning

confidence: 99%

Acetyl-11-Keto-Beta Boswellic Acid (AKBA) Protects Lens Epithelial Cells Against H2O2-Induced Oxidative Injury and Attenuates Cataract Progression by Activating Keap1/Nrf2/HO-1 Signaling

Yang

Lin

et al. 2022

Front. Pharmacol.

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Age-related cataract (ARC) is one of the leading blinding eye diseases worldwide. Chronic oxidative stress and the apoptosis of human lens epithelial cells (HLECs) have been suggested to be the mechanism underlying cataract formation. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic triterpene with antioxidative and antiapoptotic effects. In this study, we investigated the potential effects of AKBA on oxidative-induced HLECs injury and cataract formation. H2O2 was used to simulate HLECs oxidative injury in vitro, and Na2SeO3 was applied to establish an in vivo cataract model. In our current study, a cell counting kit-8 (CCK-8) assay was performed to evaluate the effects of H2O2 and AKBA on cell viability in vitro. Intracellular reactive oxygen species (ROS) levels were measured with the ROS assay to verify the antioxidant capacity of AKBA. Apoptotic cells were detected and measured by TUNEL staining and flow cytometry, and quantitative real-time (qRT)-PCR and Western blotting were applied to examine the transcription and expression of apoptosis-related proteins. Furthermore, immunofluorescence staining was performed to locate factor-erythroid 2-related factor 2 (Nrf2), and the protein levels of Nrf2, kelch-like ECH-associated protein 1 (Keap1) and heme oxygenase-1 (HO-1) were determined by Western blotting. Finally, we observed the degree of lens opacity and performed hematoxylin-eosin (H&E) staining to assess the protective effect of AKBA on cataract formation in vivo. AKBA increased HLECs viability under H2O2 stimulation, decreased intracellular ROS levels and alleviated the cell apoptosis rate in vitro. AKBA significantly decreased the expression of caspase-3 and Bax and increased the content of Bcl-2. The results of immunofluorescence and immunohistochemical staining proved that the expression and nuclear translocation of Nrf2 were activated with AKBA treatment in vivo and in vitro. Moreover, computational docking results showed that AKBA could bind specifically to the predicted Keap1/Nrf2 binding sites. After AKBA activation, Nrf2 dissociates from the Nrf2/Keap1 complex, translocates into the nucleus, and subsequently promotes HO-1 expression. In addition, AKBA attenuated lens opacity in selenite-induced cataracts. Overall, these findings indicated that AKBA alleviated oxidative injury and cataract formation by activating the Keap1/Nrf2/HO-1 cascade. Therefore, our current study highlights that AKBA may serve as a promising treatment for ARC progression.

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“…OI and DMF have protective effects on the cartilage in OA. More specifically, OI-induced transcription of Nrf2 in chondrocytes results in the high expression of HO-1, NQO1, and GCLC, and the low secretion of IL-6, IL-10, MCP-1, and TNF-a, which can switch the prevention from cell death and apoptosis of chondrocytes via decreasing oxidative stress and inflammation responses, and put a brake on the progress of OA in vivo (224,225). Similarly, dimethyl fumarate (DMF) can suppress the production of MMP-1, MMP-3, and MMP-13 and the destruction of COL2 induced by TNF-a in OA, which appears to work by inhibiting JAK/STAT3 signaling (226).…”

Section: Potential Treatment Strategies For Oa Linking Nrf2 Activatio...mentioning

confidence: 99%

Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis

Wang

2022

Front. Immunol.

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Macrophages are the most abundant immune cells within the synovial joints, and also the main innate immune effector cells triggering the initial inflammatory responses in the pathological process of osteoarthritis (OA). The transition of synovial macrophages between pro-inflammatory and anti-inflammatory phenotypes can play a key role in building the intra-articular microenvironment. The pro-inflammatory cascade induced by TNF-α, IL-1β, and IL-6 is closely related to M1 macrophages, resulting in the production of pro-chondrolytic mediators. However, IL-10, IL1RA, CCL-18, IGF, and TGF are closely related to M2 macrophages, leading to the protection of cartilage and the promoted regeneration. The inhibition of NF-κB signaling pathway is central in OA treatment via controlling inflammatory responses in macrophages, while the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway appears not to attract widespread attention in the field. Nrf2 is a transcription factor encoding a large number of antioxidant enzymes. The activation of Nrf2 can have antioxidant and anti-inflammatory effects, which can also have complex crosstalk with NF-κB signaling pathway. The activation of Nrf2 can inhibit the M1 polarization and promote the M2 polarization through potential signaling transductions including TGF-β/SMAD, TLR/NF-κB, and JAK/STAT signaling pathways, with the regulation or cooperation of Notch, NLRP3, PI3K/Akt, and MAPK signaling. And the expression of heme oxygenase-1 (HO-1) and the negative regulation of Nrf2 for NF-κB can be the main mechanisms for promotion. Furthermore, the candidates of OA treatment by activating Nrf2 to promote M2 phenotype macrophages in OA are also reviewed in this work, such as itaconate and fumarate derivatives, curcumin, quercetin, melatonin, mesenchymal stem cells, and low-intensity pulsed ultrasound.

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Four-Octyl Itaconate Protects Chondrocytes against H2O2-Induced Oxidative Injury and Attenuates Osteoarthritis Progression by Activating Nrf2 Signaling

Cited by 9 publications

References 35 publications

Intracellular Delivery of Itaconate by Metal–Organic Framework-Anchored Hydrogel Microspheres for Osteoarthritis Therapy

Intracellular Delivery of Itaconate by Metal–Organic Framework-Anchored Hydrogel Microspheres for Osteoarthritis Therapy

Acetyl-11-Keto-Beta Boswellic Acid (AKBA) Protects Lens Epithelial Cells Against H2O2-Induced Oxidative Injury and Attenuates Cataract Progression by Activating Keap1/Nrf2/HO-1 Signaling

Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis

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