**1. Introduction**

Inflammation is a defensive mechanism that responds to foreign substances or pathogens. During inflammatory reactions, prostaglandin E2 (PGE2) and nitric oxide (NO) are the crucial proinflammatory mediators. Cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), the key enzymes responsible for the production of inflammatory PGE2 and NO, have been identified in activated macrophages [1–3]. Lipopolysaccharide (LPS; a pathogen- and host-derived molecule) stimulates macrophages to, in turn, upregulate inflammatory mediators such as PGE2, tumor necrosis factor alpha (TNF-α), proinflammatory cytokines (e.g., interleukin (IL)-1, IL-6, IL-8, and IL-10), reactive oxygen species (ROS), and NO [1,4–6]. Upregulation of various types of inflammatory mediators leads to acute and chronic inflammation, which is associated with many chronic diseases such as gout, arthritis, diabetes, cancer, atherosclerosis, and neurodegenerative disease [1,2,7,8]. Therefore, inhibition of secretion and synthesis of these inflammatory mediators is a potential therapeutic treatment of inflammation-associated diseases.

**Citation:** Mangmool, S.; Limpichai, C.; Han, K.K.; Reutrakul, V.; Anantachoke, N. Anti-Inflammatory Effects of *Mitrephora sirikitiae* Leaf Extract and Isolated Lignans in RAW 264.7 Cells. *Molecules* **2022**, *27*, 3313. https://doi.org/10.3390/ molecules27103313

Academic Editor: Nour Eddine Es-Safi

Received: 23 April 2022 Accepted: 20 May 2022 Published: 21 May 2022

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*Mitrephora sirikitiae* Weeras., Chalermglin & R.M.K. Saunders (Annonaceae), an endemic plant called Mahaphrom Rachini in Thai, was found for the first time in the Mae Surin Waterfall National Park, Mae Hong Sorn Province, Thailand in 2004 [9]. Recently, we reported anticancer activities of the methanol extracts of *M. sirikitiae* leaves and stems, as well as their isolated compounds (e.g., lignans, dihydrobenzofuran lignan, alkaloids, and diterpenoids) against various types of cancer cells. It was found that lignans, including (−)-epieudesmin (**1**), (−)-phylligenin (**2**), 2-(3,4-dimethoxyphenyl)-6- (3,5-dimethoxyphenyl)-3,7-dioxabicyclo[3.3.0]octane (**3**), magnone A (**4**), mitrephoran (**5**), and 3 ,4-*O*-dimethylcedrusin (**6**), were the main secondary metabolites in *M. sirikitiae* leaves [10]. Lignans are polyphenols that possess various pharmacological activities such as antioxidant, anti-inflammatory, antimicrobial, and anticancer activities [11–13]. Lignanrich plant extracts and their lignans have been revealed for anti-inflammatory activities through inhibition of 15-lipooxygenase (15-LOX), COX-1, and COX-2 activities [14] and suppression of PGE2, NO, TNF-α, and IL-6 secretions [15–19], as well as downregulation of COX-2, iNOS, TNF-α, and IL-6 mRNA expression [15,16].

However, the anti-inflammatory properties of *M. sirikitiae* leaf extract are not fully understood. The cellular anti-inflammatory activities of the extract and isolated lignans from *M. sirikitiae* leaves on inhibition of LPS-induced upregulation of inflammatory mediators have not been defined. Therefore, we investigated the anti-inflammatory effects of methanol extract of *M. sirikitiae* leaves and its isolated lignans in LPS-induced secretion and synthesis of inflammatory mediators in RAW 264.7 macrophages.

### **2. Results and Discussion**
