Betulin and Its Derivatives Reduce Inflammation and COX-2 Activity in Macrophages

Abstract

Betulin is a heavily studied natural compound for its use as an anticancer or pro-regenerative agent. The structural similarity between betulin to steroids gives rise to the idea that the substance may as well act as an anti-inflammatory drug. This study is the first to describe the anti-inflammatory properties of betulinic acid, betulin, and its derivatives with amino acids 1,4-diaminebutane (Dab), 1,3-diaminepropane (Dap), Ornithine (Orn), and lysine (Lys) on murine macrophages from lymphoma site. The compounds were compared to dexamethasone. To establish the response of the macrophages to the natural compounds, we tested the viability as well as sensitivity to the inflammatory signaling (IFNγR). IL-6 secretory properties and HSP-70 content in the cells were examined. Furthermore, we characterized the effects of compounds on the inhibition of cyclooxygenase-2 (COX-2) activity both in the enzymatic assays and molecular docking studies. Then, the changes in COX-2 expression after betulin treatment were assessed. Betulin and betulinic acid are the low-cytotoxicity compounds with the highest potential to decrease inflammation via reduced IL-6 secretion. To some extent, they induce the reorganization of IFNγR with nearly no effect on COX-2 activity. Conversely, Bet-Orn and Bet-Lys are highly cytotoxic and induce the aggregation of IFNγR. Besides, Bet-Lys reduces the activity of COX-2 to a higher degree than dexamethasone. Bet-Orn is the only one to increase the HSP-70 content in the macrophages. In case of IL-6 reduction, all compounds were more potent than dexamethasone.

Genome-Wide Investigation of Oxidosqualene Cyclase Genes Deciphers the Genetic Basis of Triterpene Biosynthesis in Tea Plants

“…This is consistent with previous research that observed the loss of β-amyrin synthesis upon equivalent mutations of Tyr to aliphatic residues (Ala, Val, Leu, and Ile) or His in the β-amyrin synthase from Euphorbia tirucalli (EtAS). 40 Intriguingly, the CsOSC1 Y261H mutant generated trace amounts of two unknown lupane derivatives (products 2 and 6) in addition to lupeol (8) and ψ-taraxasterol (9) in a ratio of 6:2:0.5:0.6, without any dammarane-type triterpene production (Figures 6A,E, S7 and Table S8). This result stands in contrast to prior studies where His mutants predominantly generated tetracyclic dammaradienols.…”

“…16 The adjacent M259T mutation similarly reduced enzyme activity but maintained the wild-type product profile (Figure 6B,6F). Interestingly, the CsOSC6 M259T/W260L double mutant showed altered enzyme specificity, affording lupeol (8), two unidentified products (products 10 and 12), β-amyrin (5), and α-amyrin (7) at a ratio of 22:8:8:5:11, with lupeol as the major product. Product 10 was identified as a lanostane derivative, while product 12 was considered a lupane derivative by comparison with standards (Figures 6B,F, S8 and Table S8).…”

“…Triterpenoids represent a vast and structurally diverse class of natural products derived from C30 skeletons, with an estimated 20,000 structures found in nature. , Over 200 unique triterpene skeletons originating from natural sources or enzymatic reactions have been reported, with tetracyclic and pentacyclic triterpenoids being the most prevalent. , This remarkable structural diversity gives rise to a myriad of biological and pharmacological properties, such as anti-inflammatory, anticancer, antimicrobial, and neuroprotective activities . Prominent examples include oleanolic acid and betulinic acid, renowned for their potent anti-inflammatory and anticancer properties, and glycyrrhizin, a saponin from licorice root, with antiviral and hepatoprotective effects. − QS-21, a triterpene glycoside, has garnered significant attention as an immunological adjuvant in vaccine formulations . Consequently, triterpenes and their glycosides (also called saponins) have emerged as promising therapeutics, especially in preventative and curative healthcare .…”

Exploring the Action Mechanism and Validation of the Key Pathways of Dendrobium officinale Throat-clearing Formula for the Treatment of Chronic Pharyngitis Based on Network Pharmacology

“…The 10 compounds with the most connected targets in the order of degree were chrysanthenone, 3-methyl-6,7,8-trihydropyrrolo [ 1 ,2-a] pyramid ine-2-one, thymol betulin, tetrahydropalmatine, hydroginkgolinic acid, caryophyllene, alpha-pinene, beta-pinene, and camphene. Literature research revealed that among the active ingredients obtained through screening, thymol [ 42 ], betulinol [ 43 ], jensoethol [ 44 ], fenugreek ethereal [ 45 , 46 ], and gastrodene exhibited certain anti-inflammatory, antibacterial, and restoring autophagic activities. According to the PPI network diagram, the top 10 core targets were TNF, IL-6, IL-1β, AKT1, TP53, STAT3, INS, TLR4, IL-10, and EGRF.…”

Tuning of the Anti-Breast Cancer Activity of Betulinic Acid via Its Conversion to Ionic Liquids

“…Betulinic acid (BA) is a lupane-type pentacyclic triterpene that is found in the bark of several plants and is industrially isolated from plants of Betula species [ 12 ]. It has shown great pharmacological potential due to its wide variety of biological activities, including anti-tumor, anti-inflammatory, anti-oxidative, anti-diabetic, anti-malarial, antibacterial, antiviral, antifungal, and some other properties [ 12 , 13 , 14 , 15 ]. Among these, the anti-tumor properties of BA have been studied the most extensively.…”