N-Acylethanolamine acid amidase (NAAA) inhibitor F215 as a novel therapeutic agent for osteoarthritis

Zhou, Pan; Xiang, Lei; Yang, Yunyun; Wu, Yuezhou; Hu, Ting; Liu, Xiaolong; Lin, Feitai; Xiu, Yanghui; Wu, Kan; Lu, Canzhong; Ren, Jie; Qiu, Yan; Li, Yuhang

doi:10.1016/j.phrs.2019.104264

Cited by 29 publications

(26 citation statements)

References 48 publications

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“…Western blot assay and RT-qPCR were performed as descriptions. 24,25 Cell Apoptosis Assay T cells were isolated from BALB/c mice spleens by nylon wool-elution, as described previously. 23 T cells were cultured with RPMI 1640 medium, HSC-CM, or shC3 HSC-CM in 12-well plates, respectively, and then stimulated with 1 μg/mL of anti-CD3 mAb and CD28 (R&D Systems, Minneapolis, MN, USA).…”

Section: Knockdown Of C3 In Hscsmentioning

confidence: 99%

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

Huang

et al. 2020

OTT

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Objective: Hepatic stellate cells (HSCs) are the important players in liver cirrhosis and liver cancer. They also act as critical mediators of immunosuppression in hepatocellular carcinoma (HCC). In this study, we hypothesized that HSCs promote HCC progression via C3. Methods: C3 in HSCs was knocked down using a shRNA retroviral plasmid. The conditioned medium from HSCs or shC3 HSCs (knockdown of C3 by shRNA in HSCs) was collected to detect their effects on bone marrow (BM) and T cells (including expansion and apoptosis) in vitro, and in an HCC in situ model in mice. Results: We found that HSCs promoted T-cell apoptosis and decreased their proliferation, inhibited dendritic cell (DC) maturation, and induced myeloid-derived suppressor cell (MDSC) expansion through the C3 pathway in vitro. In addition, the knockdown of C3 suppressed HSC-promoted HCC development in the orthotopic transplantation tumor model of HCC in mice. Conclusion: These findings provide more insights into the immunomodulatory roles of HSCs in HCC progression and indicate that modulation of the C3 pathway might be a novel therapeutic approach for liver cancer.

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Section: Knockdown Of C3 In Hscsmentioning

confidence: 99%

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

Huang

et al. 2020

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“…Fatty acid amide hydrolase (FAAH) and N -acylethanolamine acid amidase (NAAA) are the important enzymes in the degradation of FAEs. Pharmacological blocking of NAAA or FAAH increases endogenous FAE levels in rodent models, exhibiting analgesic and anti-inflammatory effects (Ahn et al, 2009; Bottemanne et al, 2018; Zhou et al, 2019). Inhibition of FAAH and NAAA showed no undesirable cardiovascular effects and gastrointestinal hemorrhaging as commonly seen with cyclo-oxygenase-2 (COX-2) inhibitors (Yang et al, 2015; Ren et al, 2017), and have become an alternative therapeutic strategy for inflammation-related diseases.…”

Section: Introductionmentioning

confidence: 99%

A New Use for an Old Drug: Carmofur Attenuates Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Inhibition of FAAH and NAAA Activities

Xiu

Zhou

et al. 2019

Front. Pharmacol.

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Acute lung injury (ALI), characterized by a severe inflammatory process, is a complex syndrome that can lead to multisystem organ failure. Fatty acid amide hydrolase (FAAH) and N -acylethanolamine acid amidase (NAAA) are two potential therapeutic targets for inflammation-related diseases. Herein, we identified carmofur, a 5-fluorouracil-releasing drug and clinically used as a chemotherapeutic agent, as a dual FAAH and NAAA inhibitor. In Raw264.7 macrophages, carmofur effectively reduced the mRNA expression of pro-inflammatory factors, including IL-1β, IL-6, iNOS, and TNF-α, and down-regulated signaling proteins of the nuclear transcription factor κB (NF-κB) pathway. Furthermore, carmofur significantly ameliorated the inflammatory responses and promoted resolution of pulmonary injury in lipopolysaccharide (LPS)-induced ALI mice. The pharmacological effects of carmofur were partially blocked by peroxisome proliferator-activated receptor-α (PPARα) antagonist MK886 and cannabinoid receptor 2 (CB2) antagonist SR144528, indicating that carmofur attenuated LPS-induced ALI in a PPARα- and CB2-dependent mechanism. Our study suggested that carmofur might be a novel therapeutic agent for ALI, and drug repurposing may provide us effective therapeutic strategies for ALI.

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“…As an age related disease, OA affects 240 million people globally, approximately 10% of men and 18% of women over 60 years old, and significantly affects the quality of life and healthcare in older population [3]. Currently, most of therapeutic strategies designed for OA are focused on relieving inflammation and pain [4]. In addition to joint replacement surgery, osteoarthritis is commonly considered as an incurable disease.…”

Section: Introductionmentioning

confidence: 99%

Protease-activated receptor 2 (PAR-2) antagonist AZ3451 as a novel therapeutic agent for osteoarthritis

Huang

et al. 2019

Aging

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Osteoarthritis (OA) is a highly prevalent joint disorder blamed for pain and disability in older individuals. It's commonly accepted that inflammation, apoptosis, autophagy and cellular senescence participate in the progress of OA. Protease activated receptor 2 (PAR2), a member of the G-protein coupled receptors, is involved in the regulation of various inflammation diseases. Previous studies have identified PAR2 as a potential therapeutic target for the treatment of OA. Here, we investigated the role of PAR2 antagonist AZ3451 in inflammation response, apoptosis, autophagy and cellular senescence during OA. We confirmed that PAR2 expression was significantly upregulated in OA articular cartilage tissues as well as in interleukin 1β (IL-1β) stimulated chondrocytes. We demonstrated AZ3451 could prevent the IL-1β-induced inflammation response, cartilage degradation and premature senescence in chondrocytes. Further study showed that AZ3451 attenuated chondrocytes apoptosis by activating autophagy in vitro. The P38/MAPK, NF-κB and PI3K/AKT/mTOR pathways were involved in the protective effect of AZ3451. In vivo, we found that intra-articular injection of AZ3451 could ameliorate the surgery induced cartilage degradation in rat OA model. Our work provided a better understanding of the mechanism of PAR2 in OA, and indicated that PAR2 antagonist AZ3451 might serve as a promising strategy for OA treatment.

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N-Acylethanolamine acid amidase (NAAA) inhibitor F215 as a novel therapeutic agent for osteoarthritis

Cited by 29 publications

References 48 publications

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

A New Use for an Old Drug: Carmofur Attenuates Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Inhibition of FAAH and NAAA Activities

Protease-activated receptor 2 (PAR-2) antagonist AZ3451 as a novel therapeutic agent for osteoarthritis

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