Harnessing Oleanolic Acid and Its Derivatives as Modulators of Metabolic Nuclear Receptors.

Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to these NRs modulation, OA showed prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.

Use of Euphorbia balsamifera Extract in Precursor Fabrication of Silver Nanoparticles for Efficient Removal of Bromocresol Green and Bromophenol Blue Toxic Dyes.

Silver nanoparticles (Ag-NPs) are attracting great attention for their use in various applications, along with methods for their green and facile production. In this study, we present a new eco-friendly approach based on the use of Euphorbia balsamifera extract (EBE) in the green synthesis of silver nanoparticles (Ag-NPs), which are then applied as a reducing and stabilizing agent for the efficient removal of water-based reactive dyes such as bromocresol green (BCG) and bromophenol blue (BPB). The as-prepared Ag-NPs are quasi-spherical in shape, with an average diameter of 20-34 nm. Diverse characterization methods, including X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Brunauer-Emmett-Teller (BET) analysis, were used to analyze these Ag-NPs. The results reveal that water-soluble biomolecules in the Euphorbia balsamifera extract play an important role in the formation of the Ag-NPs. The removal of toxic dyes was studied under varied operational parameters such as Ag-NP dosage, initial dye concentration, pH, stirring time, and temperature. Under the optimum investigated conditions, nearly 99.12% and 97.25% of the bromocresol green and bromophenol blue dyes, respectively, were removed. Both BCG and BPB adsorption were found to adhere to pseudo-second-order kinetics (r22 = 1 and 0.995) and fit the Langmuir isotherm models well (R12 = 0.998 and 0.994), with maximal monolayer adsorption capacities of 20.40 and 41.03 mg/g, respectively. Their adsorption processes were observed to be intrinsically endothermic. The results confirm the potential of the Euphorbia balsamifera extract as a low-cost, nontoxic, and eco-friendly natural resource for the synthesis of Ag-NPs that may be useful in the remediation of hazardous dye-contaminated water sources.

In vitro acetylcholinesterase, tyrosinase inhibitory potentials of secondary metabolites from Euphorbia schimperiana and Euphorbia balsamifera.

Acetylcholinesterase, tyrosinase, and α-glucosidase inhibition activities of Euphorbia schimperiana and Euphorbia balsamifera extracts, fractions, and available pure compounds were evaluated for the first time. Acetylcholinesterase assay revealed a significant inhibitory activity of E. balsamifera total extract and n-hexane fraction with 47.7% and 43.3%, respectively, compared to the reference drug, which was 75%. The n-butanol fraction demonstrated tyrosinase inhibitory activity for E. balsamifera and E. schimperiana with 36.7% and 29.7%, respectively, compared to 60% for the reference drug. Quercetin-3-O-α-glucuronide, quercetin-3-O-ß-D-glucuronide-methyl ester, quercetin-3-O-α-L-rhamnoside, 3,3'-di-O-methyl ellagic acid, 3,3'-di-O-methyl-ellagic acid-4-ß-D-xylopyranoside, and 4-O-ethyl gallic acid were identified from E. schimperiana while quercetin-3-O-glucopyranoside and isoorientin were determined from E. balsamifera. The AChE inhibitory effect of pure compounds exhibited promising activity, where 4-O-ethylgallic acid demonstrated 51.1%, while the highest tyrosinase inhibition was demonstrated by isoorientin with 50.6% compared to the reference drug (60%). Finally, a molecular docking study was performed for the most promising AChE and tyrosinase inhibitors. The extracts, fractions, and isolated compounds showed no α-glucosidase inhibitory activity.

Isolation of diverse bioactive compounds from Euphorbia balsamifera: Cytotoxicity and antibacterial activity studies.

Antibacterial and cytotoxic activities of Euphorbia balsamifera, fractions and pure compounds were evaluated. The cytotoxic assays for HCT116, HePG2 and MCF7 showed a significant IC50: 54.7 and 76.2 µg/mL of non-polar fraction "n-hexane" against HCT116 and HePG2, respectively. Antibacterial results revealed that plant fractions exhibited significant potential against the tested pathogens than the total extract where n-butanol and ethyl acetate fractions showed significant antibacterial activity (P < 0.05) against tested bacterial strains. Isolation and structure determination of compounds from n-hexane and n-butanol fractions were performed. From n-hexane fraction, 29-nor-cycloartanol (1), lanost-8-en-3-ol (2a), cycloartanol (2b) and kampferol-3,4'-dimethyl ether (3) were isolated and structurally identified, along with 24 compounds were tentatively identified by GC-MS. From the polar n-butanol fraction, 4-O-ß-D-glucopyranosyl-2-hydroxy-6-methoxyacetophenone (4), 4-O-α-L-rhamnosyl-(1 â†’ 6)-ß-D-glucopyranosyl-2-hydroxy-6methoxy-acetophenone (5), quercetin-3-O-glucopyranoside (6) and isoorientin (7) were assigned. Structures of the obtained compounds were determined by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. Except compounds 1 and 5, all reported compounds announced antibacterial efficiency. Compound 2 showed selectively the highest activity against Enterococcus faecalis (22 ± 0.13 mm), meanwhile 4-O-ß-D-glucopyranosyl-2-hydroxy-6-methoxyacetophenone (4) showed broadly the highest antibacterial activity with MIC of 1.15-1.88 mg/mL against the test Gram-positive and Gram-negative bacteria. Cytotoxic assays indicated that kampferol-3,4'-dimethyl ether (3) exhibited the highest activity with matching IC50 values to doxorubicin; 111.46, 42.67 and 44.90 µM against HCT116, HePG2 and MCF7, respectively, however, it is toxic on retina normal cell line RPE1.