Mosloflavone-Resveratrol Hybrid TMS-HDMF-5z Exhibits Potent In Vitro and In Vivo Anti-Inflammatory Effects Through NF-κB, AP-1, and JAK/STAT Inactivation

Seo-Yeon Kim; Ahmed H E Hassan; Kyung-Sook Chung; Su-Yeon Kim; Hee-Soo Han; Hwi-Ho Lee; Seang-Hwan Jung; Kwang-Young Lee; Ji-Sun Shin; Eungyeong Jang; Seolmin Yoon; Yong Sup Lee; Kyung-Tae Lee

doi:10.3389/fphar.2022.857789

Mosloflavone-Resveratrol Hybrid TMS-HDMF-5z Exhibits Potent In Vitro and In Vivo Anti-Inflammatory Effects Through NF-κB, AP-1, and JAK/STAT Inactivation

Front Pharmacol. 2022 Apr 21:13:857789. doi: 10.3389/fphar.2022.857789. eCollection 2022.

Authors

Seo-Yeon Kim^{1

2}, Ahmed H E Hassan^{3

4}, Kyung-Sook Chung¹, Su-Yeon Kim^{1

2}, Hee-Soo Han^{1

2}, Hwi-Ho Lee¹, Seang-Hwan Jung¹, Kwang-Young Lee¹, Ji-Sun Shin¹, Eungyeong Jang^{5

6}, Seolmin Yoon^{2

3}, Yong Sup Lee^{2

3}, Kyung-Tae Lee^{1

2}

Affiliations

¹ Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, South Korea.
² Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, South Korea.
³ Medicinal Chemistry Laboratory, College of Pharmacy, Kyung Hee University, Seoul, South Korea.
⁴ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
⁵ Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
⁶ Department of Internal Medicine, Kyung Hee University Korean Medicine Hospital, Seoul, South Korea.

Abstract

TMS-HDMF-5z is a hybrid of the natural products mosloflavone and resveratrol. It was discovered to show potent inhibitory effects against lipopolysaccharide (LPS)-induced production of inflammatory mediators in RAW 264.7 macrophages. However, its mechanism of action is unknown. Hence this study aimed to demonstrate and explore in vitro and in vivo anti-inflammatory effects of TMS-HDMF-5z and its mechanism of action employing RAW 264.7 macrophages and carrageenan-induced hind paw edema. This work revealed that TMS-HDMF-5z suppressed the LPS-induced inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein, mRNA, and promoter binding levels and tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and interferon-β (IFN-β) at the mRNA expression in RAW 264.7 macrophages. The results showed that TMS-HDMF-5z reduced the transcription and DNA binding activities of nuclear factor-κB (NF-κB) through inhibiting nuclear translocation of p65 and phosphorylation of κB inhibitor α (IκBα), IκB kinase (IKK), and TGF-β activated kinase 1 (TAK1). Additionally, TMS-HDMF-5z attenuated the LPS-induced transcriptional and DNA binding activities of activator protein-1 (AP-1) by suppressing nuclear translocation of phosphorylated c-Fos, c-Jun, and activating transcription factor 2 (ATF2). TMS-HDMF-5z also reduced the LPS-induced phosphorylation of Janus kinase 1/2 (JAK1/2), signal transducers and activators of transcription 1/3 (STAT1/3), p38 mitogen-activated protein kinase (MAPK), and MAPK-activated protein kinase 2 (MK2). In rats, TMS-HDMF-5z alleviated carrageenan-induced hind paw edema through the suppressing iNOS and COX-2 via NF-κB, AP-1, and STAT1/3 inactivation. Collectively, the TMS-HDMF-5z-mediated inhibition of NF-κB, AP-1, and STAT1/3 offer an opportunity for the development of a potential treatment for inflammatory diseases.

Keywords: AP-1; NF-κB; TMS-HDMF-5z; carrageenan-induced edema; macrophages.