ACY-1215 exhibits anti-inflammatory and chondroprotective effects in human osteoarthritis chondrocytes via inhibition of STAT3 and NF-κB signaling pathways

Cheng, Chao; Shan, Wenshan; Huang, Wei; Ding, Zhide; Cui, Guanjun; Liu, Fuen; Lü, Wei; Xu, Jiegou; He, Wei; Yin, Zongsheng

doi:10.1016/j.biopha.2018.11.017

Cited by 39 publications

(30 citation statements)

References 45 publications

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“…However, nonselective HDAC inhibition may lead to potentially toxic and side effects due to the extensive acetylation of intracellular molecules. Therefore, selective HDACis may be safer and have lower side effects than nonselective HDACis (Prince et al, 2009; Cheng et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomic Analysis Reveals the Sites Related to Acetylation and Mechanism of ACY-1215 in Acute Liver Failure Mice

Zhang

Wang

et al. 2019

Front. Pharmacol.

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Background: ACY-1215 is a well-known selective histone deacetylase 6 (HDAC6) inhibitor, and it has been considered as a potential therapeutic drug in inflammatory diseases, including acute liver failure (ALF). However, little is known about the impact of ACY-1215 treatment on histone lysine acetylation and proteome in ALF. In this study, we aim to investigate whether ACY-1215 has inhibitory effects and mechanism on the necrosis of hepatocytes; moreover, the impact of ACY-1215 treatment on histone lysine acetylation still needs further elucidation. Methods: Male C57/BL6 mice were divided into normal, model, and ACY-1215 groups. ACY-1215 (25 mg/kg) and same amounts of saline were injected intraperitoneally to the mice before the establishment of ALF model induced by lipopolysaccharide (LPS) (100 µg/kg) combined with D-gal (400 mg/kg). All animals were sacrificed after 24 h. In this study, detection programs, including quantitative proteomic analysis, transmission electron microscopy (TEM) micrographs, pathological staining, protein expression, the detection of reactive oxygen species (ROS) as well as glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) measurement. Results: The function of liver and the necrosis of hepatocytes in ALF mice were significantly normalized by ACY-1215 pretreatment. The quantitative proteomic analysis revealed that ACY-1215-restrained oxidative phosphorylation normalized the function respiratory electron-transport chain in the mitochondria. Moreover, pretreatment of ACY-1215 not only normalized the structure of mitochondria but also inhibited the generation of reactive oxygen species (ROS). Conclusions: ACY-1215 was able to inhibit necrosis of hepatocytes in ALF mice through regulating the mitochondrial-mediated oxidative stress, and we identified the common sites related to acetylation level.

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Section: Introductionmentioning

confidence: 99%

Quantitative Proteomic Analysis Reveals the Sites Related to Acetylation and Mechanism of ACY-1215 in Acute Liver Failure Mice

Zhang

Wang

et al. 2019

Front. Pharmacol.

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“…In the presence of RU-486 (GR inhibitor), HDAC6 expression in MSCs is decreased which indicates that GR could regulate HDAC6 expression. In addition, tubacin (HDAC6 inhibitor) can weaken the complex formation between GR and HDAC6 ( 18 ). The association between HDAC6 and GR in the pathogenesis of GC-induced secondary osteoporosis will be investigated in a future study.…”

Section: Discussionmentioning

confidence: 99%

“…However, the specific role of HDAC6 in Dex-induced proliferation and differentiation of preosteoblasts remains to be elucidated. Ricolinostat (ACY-1215; an HDAC6 inhibitor) has been demonstrated to reduce inflammatory damage in osteoarthritis ( 18 ). However, further studies are required to determine whether it has any effect in osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

ACY‑1215, a HDAC6 inhibitor, decreases the dexamethasone‑induced suppression of osteogenesis in MC3T3‑E1 cells

Wang

Chen

et al. 2020

Mol Med Rep

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Glucocorticoid-induced osteoporosis is the commonest form of drug-induced osteoporosis. Histone deacetylase 6 (HDAC6) is involved in the differentiation from mesenchymal stem cells to osteoblasts. However, the role of ricolinostat (ACY-1215, HDAC6 inhibitor) in the dexamethasone (Dex)-induced proliferation and differentiation of preosteoblasts remains to be elucidated. The protein expression and mRNA expression levels of HDAC6, osteopontin (OPN), runt-related transcription factor 2 (Runx2), osterix (Osx), collagen I (COL1A1) and glucocorticoid receptor (GR) in MC3T3-E1 cells were analyzed by western blot analysis and reverse transcription-quantitative PCR analysis. The cell viability was detected by CCK-8 assay. The alkaline phosphatase (ALP) activity and capacity of mineralization was determined by ALP assay kit and alizarin red staining. HDAC6 expression was increased in patient serum and Dex-induced MC3T3-E1 cells at a certain concentration range; 1 µM Dex was selected for further experimentation. Cell viability was decreased after Dex induction and restored following ACY-1215 treatment. The ALP activity and capability for mineralization was decreased when MC3T3-E1 cells were induced by 1 µM Dex and was gradually improved by the treatment of ACY-1215 at 1, 5 and 10 mM. The expression of OPN, Runx2, Osx and COL1A1 was similar, with the changes of capability for mineralization. Furthermore, GR expression was increased in Dex-induced MC3T3-E1 cells. ACY-1215 promoted the GR expression in MC3T3-E1 cells from 1–5 mM while GR receptor expression was increased with 10 mM ACY-1215 treatment. In conclusion, ACY-1215 reversed the Dex-induced suppression of proliferation and differentiation of MC3T3-E1 cells.

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“…Little is known on the role of HDAC5 in cartilage development and OA progression. HDAC5 acts as a co-activator of HDAC4 to inhibit chondrocyte hypertrophy through parathyroid hormone-related protein (PTHrP), which blocks the Mef2/Runx2 signaling pathway ( Cheng et al, 2019 ).…”

Section: Hdacs and Signaling Pathways In Cartilage Development And Oamentioning

confidence: 99%

“…Ricolinostat (ACY-1215) is a selective HDAC6 inhibitor that has anti-inflammatory and chondroprotective properties. ACY-1215 inhibits MMP1 and MMP13 expression by down regulating NF-κB and STAT3 activity in primary human chondrocyte stimulated with IL-1β ( Cheng et al, 2019 ).…”

Section: Hdac Inhibitors and Oa Treatmentmentioning

confidence: 99%

The Role of HDACs and HDACi in Cartilage and Osteoarthritis

Zhang

Yang

et al. 2020

Front. Cell Dev. Biol.

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Epigenetics plays an important role in the pathogenesis and treatment of osteoarthritis (OA). In recent decades, HDAC family members have been associated with OA. This paper aims to describe the different role of HDACs in the pathogenesis of OA through interaction with microRNAs and the regulation of relevant signaling pathways. We found that HDACs are involved in cartilage and chondrocyte development but also play a crucial role in OA. However, the distinct HDAC mechanism in the pathogenesis and treatment of OA require further investigation. Furthermore, HDAC inhibitors (HDACi) can protect cartilage from disease, which may represent a potential therapeutic approach against OA.

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ACY-1215 exhibits anti-inflammatory and chondroprotective effects in human osteoarthritis chondrocytes via inhibition of STAT3 and NF-κB signaling pathways

Cited by 39 publications

References 45 publications

Quantitative Proteomic Analysis Reveals the Sites Related to Acetylation and Mechanism of ACY-1215 in Acute Liver Failure Mice

Quantitative Proteomic Analysis Reveals the Sites Related to Acetylation and Mechanism of ACY-1215 in Acute Liver Failure Mice

ACY‑1215, a HDAC6 inhibitor, decreases the dexamethasone‑induced suppression of osteogenesis in MC3T3‑E1 cells

The Role of HDACs and HDACi in Cartilage and Osteoarthritis

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