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In the olive oil industry, a pit fraction is collected from olive pomace and split into a clean pit fraction and a residual olive skin-rich fraction, which does not an industrial application. Therefore, in this work, microwave-assisted extraction (MAE) was applied to obtain high-value triterpene acids (maslinic acid and oleanolic acid) from this biomass using the renewable solvent ethanol. The response surface methodology was used to gain a deeper understanding of how the solvent (ethanol–water, 50–100% v/v), time (4–30 min), and temperature (50–120 °C) affect the extraction performance, as well as the energy required for the process. The effect of milling was also studied and the solid-to-liquid ratio was also evaluated, and overall, a good compromise was found at 10% (w/v) using the raw sample (unmilled biomass). The optimised conditions were applied to residual olive skin sourced from various industries, yielding up to 5.1 g/100 g and 2.2 g/100 g dry biomass for maslinic acid and oleanolic acid, respectively. In conclusion, the residual olive skin is a promising natural source of these triterpene acids, which can be extracted using MAE, releasing extracted solids rich in polymeric carbohydrates and lignin that can be valorised under a holistic biorefinery process.

Oleanolic acid (OLA) has beneficial health effects in animals, but in vivo efficacy in monogastric animals is questioned due to its low bioavailability. To gain further insight on the nutritional effects of OLA it was administered as part of a diet. We investigated digestibility and plasma OLA in pigs and the associated influence on growth, organs, digestibility of nutrients and plasma biochemical profile. Twenty-four crossbred barrows (23.7 ± 1.0 kg BW) were assigned one of three treatments: Control (basal diet without OLA), OLA-1 (basal diet with 260 mg/free OLA) and OLA-2 (basal diet with 260 mg/kg cyclodextrin-OLA). Diets included chromium oxide to estimate digestibility. Blood samples were collected on day 14 for OLA analysis and feces on days 22–24 for determining digestibility. Pigs were slaughtered on day 31 (39.9 ± 2.43 kg BW) and their blood collected for analysis. Growth and organ weights were not affected (p > 0.05). OLA-1 decreased apparent total tract digestibility (ATTD) of energy (p < 0.05). OLA-2 increased ATTD of dry and organic matter compared with Control pigs (p < 0.05). OLA-1 increased plasma calcium and alkaline phosphatase (p < 0.05). Ileal digestibility of OLA was not affected (0.88), although OLA ATTD increased in OLA-1 compared to Control pigs (0.75 vs. 0.82; p < 0.05). OLA-1 and OLA-2 increased plasma OLA compared to Control pigs (p < 0.05 and p = 0.083). In conclusion, although the OLA was digested and absorbed, plasma concentration was low (4.29 µg/L), and pig growth, organs and plasma parameters were not affected.

Cranberry fruit extracts have been shown to inhibit expression of pro-inflammatory cytokines in THP-1 cells and reduce colonic tumor burden and tissue inflammation in a mouse model of colitis. These activities are attributed to both the triterpenoid and polyphenol constituents of the fruit. The pentacyclic triterpenoids ursolic acid (UA), oleanolic acid (OA), corosolic acid (CA), maslinic acid (MA), and esters of UA and OA occur in the waxy layer of cranberry peel, and their content in cranberry products is likely to vary with the fruit source and processing methods. UPLC-MS (ultra performance liquid chromatography-mass spectrometry) was applied to determine the four triterpenoid acids and their esters in cranberry products and raw materials. Cranberry pomace, a side stream in juice production, was a rich source at 64,090 µg total triterpenoids/g DW. Cranberry juice beverages ranged from 0.018 to 0.26 µg/g of product, fruit samples ranged from 6542 to 17,070 µg/g DW, and whole berry products contained up to 2665 µg/g DW. Free UA was the most plentiful triterpenoid in all samples. These analyses illustrate the potential value of an underutilized side stream in cranberry juice production and highlight potential benefits of whole fruit products.

Oleanolic acid, a naturally occurring triterpenoid compound, has garnered significant attention in the scientific community due to its diverse pharmacological properties. Continuing our previous work on the synthesis of oleanolic acid dimers (OADs), a simple, economical, and safe acetylation reaction was performed. The newly obtained derivatives (AcOADs, 3a–3n) were purified using two methods. The structures of all acetylated dimers (3a–3n) were determined based on spectral methods (IR, NMR). For all AcOADs (3a–3n), the relationship between the structure and the expected directions of pharmacological activity was determined using a computational method (QSAR computational analysis). All dimers were also tested for their cytotoxic activity on the SKBR-3, SKOV-3, PC-3, and U-87 cancer cell lines. HDF cell line was applied to evaluate the Selectivity Index of the tested compounds. All cytotoxic tests were performed with the application of the MTT assay. Finally, all dimers of oleanolic acid were subjected to DPPH and CUPRAC tests to evaluate their antioxidant activity. The obtained results indicate a very high level of cytotoxic activity (IC50 for most AcOADs below 5.00 µM) and a fairly high level of antioxidant activity (Trolox equivalent in some cases above 0.04 mg/mL).

Eriobotrya japonica (E. japonica) leaves have been used as an herbal traditional medicine in China and Japan owing to their anti-inflammatory and protective effects against skin conditions and allergy symptoms. These beneficial effects are likely mediated by the various triterpenoids present in E. japonica leaves. However, the efficacy of E. japonica leaves in the treatment of allergic rhinitis has not been evaluated in humans. Therefore, in the present study, a randomized, controlled, double-blind trial was performed on healthy adults of age >20 (n = 27) who were randomly assigned to receive either 2.5 g of placebo or E. japonica leaf supplements once daily for 4 weeks. The Japanese Allergic Rhinitis Quality of Life Standard Questionnaire (JRQLQ), dermatological allergy symptoms, Dermatology Life Quality Index, and skin condition parameters were assessed at baseline and after 4 weeks. Significant differences were observed in the variability of the itchy nose, itchy eyes, and eye symptoms between the E. japonica supplementation and placebo groups after 4 weeks. Arm skin transepidermal water loss was improved only in the E. japonica supplementation group. This study suggests that E. japonica leaves can be used as a functional food ingredient to relieve allergic symptoms.

Cancer is a global health problem, with the incidence rate estimated to reach 40% of the population by 2030. Although there are currently several therapeutic methods, none of them guarantee complete healing. Plant-derived natural products show high therapeutic potential in the management of various types of cancer, with some of them already being used in current practice. Among different classes of phytocompounds, pentacyclic triterpenoids have been in the spotlight of research on this topic. Ursolic acid (UA) and its structural isomer, oleanolic acid (OA), represent compounds intensively studied and tested in vitro and in vivo for their anticancer and chemopreventive properties. Since natural compounds can rarely be used in practice as such due to their characteristic physico-chemical properties, to tackle this problem, their derivatization has been attempted, obtaining compounds with improved solubility, absorption, stability, effectiveness, and reduced toxicity. This review presents various UA and OA derivatives that have been synthesized and evaluated in recent studies for their anticancer potential. It can be observed that the most frequent structural transformations were carried out at the C-3, C-28, or both positions simultaneously. It has been demonstrated that conjugation with heterocycles or cinnamic acid, derivatization as hydrazide, or transforming OH groups into esters or amides increases anticancer efficacy.

Triterpene acids are a class of pentacyclic natural carboxylic compounds endowed with a variety of biological activities including antitumor, antimicrobial, and hepatoprotective effects. In this work, several oleanolic acid derivatives were synthesized by structurally modifying them on the C-3 position. All synthesized derivatives were evaluated for possible antibacterial and antiviral activity, and among all the epimers, 6 and 7 demonstrated the best biological activities. Zone-of-inhibition analyses were conducted against two strains, E. coli as a Gram-negative and S. aureus as a Gram-positive model. Subsequently, experiments were performed using the microdilution method to determine the minimum inhibitory concentration (MIC). The results showed that only the derivative with reduced hydrogen bonding ability on ring A possesses remarkable activity toward E. coli. The conversion from acid to methyl ester implies a loss of activity, probably due to a reduced affinity with the bacterial membrane. Before the antiviral activity, the cytotoxicity of triterpenes was evaluated through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Samples 6 and 7 showed less than 50% cytotoxicity at 0.625 and 1 mg/mL, respectively. The antiviral activity against SARS-CoV-2 and PV-1 did not indicate that triterpene acids had any inhibitory capacity in the sub-toxic concentration range.

The nutritional composition of food for animal production can be enhanced using olive tree and plant by-products due to their high content of bioactive compounds such as pentacyclic triterpenes. Here, we present a novel application of near-infrared spectroscopy (NIRS) for the prediction of the total or individual [maslinic acid (MA), oleanolic acid (OA), and uvaol (UO)] pentacyclic triterpene concentrations in a feed additive obtained from a plant mixture. The oxygen radical absorbance capacity of these types of samples demonstrated the existence of a high antioxidant capacity. The conventional determination methods of pentacyclic triterpene concentration are costly, labor-intensive, and not practical for analyzing several lines within a limited timeframe at the factory level. The optimal regression model developed in our work demonstrated high correlation values for the calibration and validation sets, along with a high residual prediction deviation value. We used 63 samples for the development of the model. The NIRS method can be applied directly to dried powder and makes extraction and high-performance liquid chromatography (HPLC) analysis unnecessary. Our results also demonstrate that NIRS can accurately quantify pentacyclic triterpenes even at low concentrations in food additives. It can be used at the factory level to directly determine the pentacyclic triterpene concentrations in the additive powder at the same time that the powder is produced.

The presented work aimed to explore the potential of oleanolic acid dimers (OADs): their cytostatic and antioxidant activities, molecular docking, pharmacokinetics, and ADMETox profile. The cytostatic properties of oleanolic acid (1) and its 14 synthesised dimers (2a–2n) were evaluated against 10 tumour types and expressed as IC50 values. Molecular docking was performed with the CB-Dock2 server. Antioxidant properties were evaluated with the CUPRAC method. ADMETox properties were evaluated with the ADMETlab Manual (2.0) database. The results indicate that the obtained OADs can be effective cytostatic agents, for which the IC50 not exceeded 10.00 for many tested cancer cell lines. All OADs were much more active against all cell lines than the mother compound (1). All dimers can inhibit the interaction between the 1MP8 protein and cellular proteins with the best results for compounds 2f and 2g with unsaturated bonds within the linker. An additional advantage of the tested OADs was a high level of antioxidant activity, with Trolox equivalent for OADs 2c, 2d, 2g–2j, 2l, and 2m of approximately 0.04 mg/mL, and beneficial pharmacokinetics and ADMETox properties. The differences in the DPPH and CUPRAC assay results obtained for OADs may indicate that these compounds may be effective antioxidants against different radicals.

Natural products have always played an important role in pharmacotherapy, helping to control pathophysiological processes associated with human disease. Thus, natural products such as oleanolic acid (OA), a pentacyclic triterpene that has demonstrated important activities in several disease models, are in high demand. The relevant properties of this compound have motivated re-searchers to search for new analogues and derivatives using the OA as a scaffold to which new functional groups have been added or modifications have been realized. OA and its derivatives have been shown to be effective in the treatment of inflammatory processes, triggered by chronic diseases or bacterial and viral infections. OA and its derivatives have also been found to be effective in diabetic disorders, a group of common endocrine diseases characterized by hyperglycemia that can affect several organs, including the liver and brain. This group of compounds has been reported to exhibit significant bioactivity against cancer processes in vitro and in vivo. In this review, we summarize the bioactive properties of OA and its derivatives as anti-inflammatory, anti-bacterial, antiviral, anti-diabetic, hepatoprotective, neuroprotective, and anticancer agents.

The main type of saponins occurring in the root of Platycodon grandiflorus (Jacq.) A. DC. are oleanolic acid glycosides. The CYP716 gene family plays a major role in catalyzing the conversion of β-amyrin into oleanolic acid. However, studies on the CYP716 genes in P. grandiflorus are limited, and its evolutionary history remains poorly understood. In this study, 22 PgCYP716 genes were identified, distributed among seven subfamilies. Cis-acting elements of the PgCYP716 promoters were mainly involved in plant hormone regulation and responses to abiotic stresses. PgCYP716A264, PgCYP716A391, PgCYP716A291, and PgCYP716BWv3 genes were upregulated in the root and during saponin accumulation, as shown by RNA-seq analysis, suggesting that these four genes play an important role in saponin synthesis. The results of subcellular localization indicated that these four genes encoded membrane proteins. Furthermore, the catalytic activity of these four genes was proved in the yeast, which catalyzed the conversion of β-amyrin into oleanolic acid. We found that the content of β-amyrin, platycodin D, platycoside E, platycodin D3, and total saponins increased significantly when either of the four genes was over expressed in the transgenic hair root. In addition, the expression of PgSS, PgGPPS2, PgHMGS, and PgSE was also upregulated while these four genes were overexpressed. These data support that these four PgCYP716 enzymes oxidize β-amyrin to produce oleanolic acid, ultimately promoting saponin accumulation by activating the expression of upstream pathway genes. Our results enhanced the understanding of the functional variation among the PgCYP716 gene family involved in triterpenoid biosynthesis and provided a theoretical foundation for improving saponin content and enriching the saponin biosynthetic pathway in P. grandiflorus.

The present work aimed to obtain a set of oleanolic acid derivatives with a high level of cytotoxic and antioxidant activities and a low level of toxicity by applying an economical method. Oleanolic acid was alkylated with α,ω-dihalogenoalkane/α,ω-dihalogenoalkene to obtain 14 derivatives of dimer structure. All of the newly obtained compounds were subjected to QSAR computational analysis to evaluate the probability of the occurrence of different types of pharmacological activities depending on the structure of the analysed compound. All dimers were tested for cytotoxicity activity and antioxidant potential. The cytotoxicity was tested on the SKBR-3, SKOV-3, PC-3, and U-87 cancer cell lines with the application of the MTT assay. The HDF cell line was applied to evaluate the tested compounds’ Selectivity Index. The antioxidant test was performed with a DPPH assay. Almost all triterpene dimers showed a high level of cytotoxic activity towards selected cancer cell lines, with an IC50 value below 10 µM. The synthesised derivatives of oleanolic acid exhibited varying degrees of antioxidant activity, surpassing that of the natural compound in several instances. Employing the DPPH assay, compounds 2a, 2b, and 2f emerged as promising candidates, demonstrating significantly higher Trolox equivalents and highlighting their potential for pharmaceutical and nutraceutical applications. Joining two oleanolic acid residues through their C-17 carboxyl group using α,ω-dihalogenoalkanes/α,ω-dihalogenoalkenes resulted in the synthesis of highly potent cytotoxic agents with favourable SIs and high levels of antioxidant activity.

Oleanolic acid (OA) is a vegetable chemical that is present naturally in a number of edible and medicinal botanicals. It has been extensively studied by medicinal chemists and scientific researchers due to its biological activity against a wide range of diseases. A significant number of researchers have synthesized a variety of analogues of OA by modifying its structure with the intention of creating more potent biological agents and improving its pharmaceutical properties. In recent years, chemical and enzymatic techniques have been employed extensively to investigate and modify the chemical structure of OA. This review presents recent advancements in medical chemistry for the structural modification of OA, with a special focus on the biotransformation, semi-synthesis and relationship between the modified structures and their biopharmaceutical properties.

Repetitive motion or exercise is associated with oxidative stress and muscle inflammation, which can lead to declining grip strength and muscle damage. Oleanolic acid and ursolic acid have anti-inflammatory and antioxidant properties and can be extracted from Chaenomeles speciosa through ultrasonic sonication. We investigated the association between grip strength declines and muscle damage induced by lambda carrageenan (LC) injection and exercise exposure in rats. We also assessed the reparative effects of transdermal pretreatment and post-treatment with C. speciosa extracts (CSEs) by using a supersonic atomizer. The half-maximal inhibitory concentration (IC50) of CSEs for cells was 10.5 mg/mL. CSEs significantly reduced the generation of reactive oxygen species and inflammatory factors (interleukin [IL]-6 and IL-1β) in in vitro cell tests. Rats subjected to LC injection and 6 weeks of exercise exhibited significantly increased inflammatory cytokine levels (IL-1β, TNF-α, and IL-6). Hematoxylin and eosin staining revealed inflammatory cell infiltration and evident muscle damage in the gastrocnemius muscle, which exhibited splitting and the appearance of the endomysium and perimysium. The treated rats’ grip strength significantly declined. Following treatment with CSEs, the damaged muscles exhibited decreased IL-1β, TNF-α, and IL-6 levels and normal morphologies. Moreover, grip strength significantly recovered. Pretreatment with CSEs yielded an immediate and significant increase in grip strength, with an increase of 180% and 165% occurring in the rats exposed to LC injection and exercise within the initial 12 h period, respectively, compared with the control group. Pretreatment with CSEs delivered transdermally using a supersonic atomizer may have applications in sports medicine and training or competitions.

For the first time, a synthetic analogue of natural (5Z,9Z)-dienoic acid has been synthesized in the form of a hybrid molecule containing a fragment of oleanolic acid and (5Z,9Z)-tetradeca-5.9-dienedicarboxylic acid, synthesized using a new reaction of Ti-catalyzed homo-cyclomagnesiation 1,2-dienes. The high cytotoxic activity of (5Z,9Z)-14-[(3,28-dioxoolean-12-en-28-yl)oxy]tetradeca-5,9-dienoic acid against tumor cells Jurkat, K562, U937 and HL60 was established. This compound is also an inducer of apoptosis, affects the cell cycle and inhibits human topoisomerase I.

Probiotic biofilms have been beneficial in the fight against infections, restoring the equilibrium of the host’s gut microbiota, and enhancing host health. They are considered a novel strategy for probiotic gut colonization. In this case, we evaluated the effects of various active substances from traditional Chinese medicine on Escherichia coli Nissle 1917 (EcN) to determine if they promote biofilm formation. It was shown that 8–64 μg/mL of oleanolic acid increased the development of EcN biofilm. Additionally, we observed that oleanolic acid can effectively suppress biofilm formation in pathogenic bacteria such as Salmonella and Staphylococcus aureus. Next, we assessed the amount of EcN extracellular polysaccharides, the number of live bacteria, their metabolic activity, the hydrophobicity of their surface, and the shape of their biofilms using laser confocal microscopy. Through transcriptome analysis, a total of 349 differentially expressed genes were identified, comprising 134 upregulated and 215 downregulated genes. GO functional enrichment analysis and KEGG pathway enrichment analysis revealed that oleanolic acid functions are through the regulation of bacterial motility, the iron absorption system, the two-component system, and adhesion pathways. These findings suggest that the main effects of oleanolic acid are to prevent bacterial motility, increase initial adhesion, and encourage the development of EcN biofilms. In addition, oleanolic acid interacts with iron absorption to cooperatively control the production of EcN biofilms within an optimal concentration range. Taking these results together, this study suggests that oleanolic acid may enhance probiotic biofilm formation in the intestines, presenting new avenues for probiotic product development.

The growing interest in oleanolic acid (OA) as a triterpenoid with remarkable health benefits prompts an emphasis on its efficient use in pharmaceutical research. OA exhibits a range of pharmacological effects, including antidiabetic, anti-inflammatory, immune-enhancing, gastroprotective, hepatoprotective, antitumor, and antiviral properties. While OA demonstrates diverse pharmacological effects, optimizing its therapeutic potential requires overcoming significant challenges. In the field of pharmaceutical research, the exploration of efficient drug delivery systems is essential to maximizing the therapeutic potential of bioactive compounds. Efficiently delivering OA faces challenges, such as poor aqueous solubility and restricted bioavailability, and to unlock its full therapeutic efficacy, novel formulation strategies are imperative. This discussion thoroughly investigates different approaches and advancements in OA drug delivery systems with the aim of enhancing the biopharmaceutical features and overall efficacy in diverse therapeutic contexts.

In our previous study, two oleanane-type pentacyclic triterpenoids (oleanolic acid and maslinic acid) were reported to affect the N-glycosylation and intracellular trafficking of intercellular adhesion molecule-1 (ICAM-1). The present study was aimed at investigating the structure–activity relationship of 13 oleanane-type natural triterpenoids with respect to the nuclear factor κB (NF-κB) signaling pathway and the expression, intracellular trafficking, and N-glycosylation of the ICAM-1 protein in human lung adenocarcinoma A549 cells. Hederagenin, echinocystic acid, erythrodiol, and maslinic acid, which all possess two hydroxyl groups, decreased the viability of A549 cells. Celastrol and pristimerin, both of which possess an α,β-unsaturated carbonyl group, decreased cell viability but more strongly inhibited the interleukin-1α-induced NF-κB signaling pathway. Oleanolic acid, moronic acid, and glycyrrhetinic acid interfered with N-glycosylation without affecting the cell surface expression of the ICAM-1 protein. In contrast, α-boswellic acid and maslinic acid interfered with the N-glycosylation of the ICAM-1 protein, which resulted in the accumulation of high-mannose-type N-glycans. Among the oleanane-type triterpenoids tested, α-boswellic acid and maslinic acid uniquely interfered with the intracellular trafficking and N-glycosylation of glycoproteins.

Periodontal disease is caused by oral pathogenic bacteria and is associated with systemic disease and frailty. Therefore, its prevention is crucial in extending healthy life expectancy. This study aimed to evaluate the effect of orally administered oleanolic acid, extracted from wine pomace, on periodontopathic bacterial growth in healthy individuals. In this randomized, placebo-controlled, double-blind, parallel-group comparison study, 84 healthy adults were assigned to a placebo (n = 29), low-dose (n = 29, 9 mg oleanolic acid), or high-dose (n = 26, 27 mg oleanolic acid) groups. The number of oral bacteria in their saliva, collected before and 5 h after administration, was determined using the polymerase chain reaction-invader technique. The proportion of periodontopathic bacteria among the total oral bacteria in the saliva was calculated. Oleanolic acid significantly decreased the proportion of Porphyromonas gingivalis among the total oral bacteria in a dose-dependent manner (p = 0.005 (low-dose) and p = 0.003 (high-dose) vs. placebo, Williams’ test). Moreover, high-dose oleanolic acid decreased the proportion of Tannerella forsythia (p = 0.064 vs. placebo, Williams’ test). Periodontopathic bacteria are closely associated with the development and progression of periodontal disease; thus, the continuous daily intake of oleanolic acid derived from pomace may be helpful in maintaining a healthy oral microbiome by controlling the proportion of periodontopathic bacteria.

In this study, the synthesis and biological activities of previously and newly synthesized oleanolic acid derivatives containing seven-membered cyclic amines at the C28 position were described. The obtained compounds were fully characterized via 1H and 13C NMR spectroscopy, and the bioactivity was evaluated by Ellman’s method. Among the tested compounds, 2,3-indolo-oleanolic acid was found to be the most active compound with an IC50 value of 0.78 µM against acetylcholinesterase. These results are significant due to the fact that research on the inhibition of acetylcholinesterase and butyrylcholinesterase enzymes by oleanolic acid, in particular indoloderivatives, is limited.

Metabolic syndromes (MetS) and related cardiovascular diseases (CVDs) pose a serious threat to human health. MetS are metabolic disorders characterized by obesity, dyslipidemia, and hypertension, which increase the risk of CVDs’ initiation and development. Although there are many availabile drugs for treating MetS and related CVDs, some side effects also occur. Considering the low-level side effects, many natural products have been tried to treat MetS and CVDs. A five-cyclic triterpenoid natural product, oleanolic acid (OA), has been reported to have many pharmacologic actions such as anti-hypertension, anti-hyperlipidemia, and liver protection. OA has specific advantages in the treatment of MetS and CVDs. OA achieves therapeutic effects through a variety of pathways, attracting great interest and playing a vital role in the treatment of MetS and CVDs. Consequently, in this article, we aim to review the pharmacological actions and potential mechanisms of OA in treating MetS and related CVDs.

Saponins, both steroidal and triterpenoid, exhibit distinct bioactivities. However, they are not commonly found together in natural sources; instead, sources tend to be rich in one type or another and mainly in the form of saponins rather than the sapogenin aglycones. Developing co-extracts containing both saponin or sapogenin types would be a strategy to harness their respective bioactivities, yielding multibioactive extracts. Therefore, this study evaluates the bioactivity (hypolipidemic, antioxidant, and anti-inflammatory activities) of co-extracts from fenugreek seeds (steroidal-rich saponins) and quinoa husk (triterpenoid-rich saponins), co-extracted at varying proportions, alongside their respective sapogenin-rich hydrolysates. Pancreatic lipase inhibition increased with fenugreek content in co-extracts, especially in sapogenin-rich variants. The latter substantially interfered with cholesterol bioaccessibility (90% vs. 15% in sapogenin-rich extracts). Saponin-rich co-extracts exhibited reduced cytokine release with increased fenugreek content, while sapogenin-rich counterparts showed greater reductions with higher quinoa husk content. Limited cellular antioxidant activities were observed in all extracts, with improved post-hydrolysis bioactivity. Therefore, simultaneous co-extraction of steroidal and triterpenoid sources, such as fenugreek and quinoa husk, as well as their subsequent hydrolysis, are innovative strategies for obtaining multibioactive natural extracts.

(1) Background: The aim of the presented work was to obtain a set of oleanolic acid derivatives with a high level of anticancer activity and a low level of toxicity by applying an economic method. Three types of oleanolic acid derivatives were obtained: (i) derivatives of methyl oleanonate oxime, (ii) derivatives of methyl oleanonate oxime with an additional 11-oxo function, and (iii) derivatives of morpholide of oleanonic acid oxime. (2) Methods: The above oximes were acylated with aliphatic or aromatic carboxylic acid. The newly obtained compounds were subjected to ADMETox analysis and were also tested for cytotoxicity activity on the HeLa, KB, MCF-7, A-549, and HDF cell lines with the MTT assay. (3) Results: Among the tested acylated oximes of oleanolic acid, some derivatives, particularly those with two nitro groups attached to the aromatic ring, proved to be the most potent cytotoxic agents. These triterpene derivatives significantly inhibited the growth of the HeLa, KB, MCF-7, and A-549 cancer cell lines in micromolar concentrations. (4) Conclusions: The introduction of different moieties, particularly the 3,5-dinitro group, resulted in the synthesis of highly potent cytotoxic agents with favorable SI and ADMETox parameters.

Sapogenins are the non-sugar parts of saponins (aglycones), high-molecular-weight glycosides linked to one or more sugar side chains. This group of compounds presents many properties, e.g., the potent properties of reducing surface tension and foaming properties, as evidenced by the amphipathic nature of these substances. They are used in the cosmetics industry, the washing and detergent industry, and the food industry. In addition, they have many healing properties. They lower blood cholesterol but are also used to synthesize steroid drugs or hormones. As reported in the literature, saponins also show antitumor activity, leading to cell cycle inhibition and apoptosis of various neoplastic cells. In this study, the influence of two sapogenins: asiatic acid (AA) and oleanolic acid (OA), on the properties of monolayers made of phosphatidylcholine (DPPC) was investigated. The method used in these studies was the Langmuir method with Brewster angle microscopy. The interactions between the tested compounds in mixed monolayers were described. Using mathematical equations, we established that oleanolic acid and asiatic acid formed complexes with DPPC at 1:1 ratios, characterized by high stability constants. We derived the parameters characterizing the formed complexes and described the phase transitions that occur during the formation of pure and mixed monolayers.

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.

The aim of this work was to evaluate the vasorelaxant and antihypertensive effects of a standardized precipitate of the hydroalcoholic extract from Agastache mexicana (PPAm), comprising ursolic acid, oleanolic acid, acacetin, luteolin and tilianin, among others. In the ex vivo experiments, preincubation with L-NAME (nonspecific inhibitor of nitric oxide synthases) reduced the relaxation induced by PPAm; nevertheless, preincubation with indomethacin (nonspecific inhibitor of cyclooxygenases) did not generate any change in the vasorelaxation, and an opposed effect was observed to the contraction generated by CaCl2 addition. Oral administration of 100 mg/kg of PPAm induced a significant acute decrease in diastolic (DBP) and systolic (SBP) blood pressure in spontaneously hypertensive rats, without changes in heart rate. Additionally, PPAm showed a sustained antihypertensive subacute effect on both DBP and SBP for 10 days compared to the control group. On the other hand, human umbilical vein cells treated with 10 µg/mL of PPAm showed a significant reduction (p < 0.05) in intracellular adhesion molecule-1, compared to the control, but not on vascular cell adhesion molecule-1. In conclusion, PPAm induces a significant antihypertensive effect in acute- and subacute-period treatments, due to its direct vasorelaxant action on rat aortic rings through NO production and Ca2+ channel blockade.

In the olive oil industry, a pit fraction is collected from olive pomace and split into a clean pit fraction and a residual olive skin-rich fraction, which does not an industrial application. Therefore, in this work, microwave-assisted extraction (MAE) was applied to obtain high-value triterpene acids (maslinic acid and oleanolic acid) from this biomass using the renewable solvent ethanol. The response surface methodology was used to gain a deeper understanding of how the solvent (ethanol-water, 50-100% v / v ), time (4-30 min), and temperature (50-120 °C) affect the extraction performance, as well as the energy required for the process. The effect of milling was also studied and the solid-to-liquid ratio was also evaluated, and overall, a good compromise was found at 10% ( w / v ) using the raw sample (unmilled biomass). The optimised conditions were applied to residual olive skin sourced from various industries, yielding up to 5.1 g/100 g and 2.2 g/100 g dry biomass for maslinic acid and oleanolic acid, respectively. In conclusion, the residual olive skin is a promising natural source of these triterpene acids, which can be extracted using MAE, releasing extracted solids rich in polymeric carbohydrates and lignin that can be valorised under a holistic biorefinery process.

Cranberry fruit extracts have been shown to inhibit expression of pro-inflammatory cytokines in THP-1 cells and reduce colonic tumor burden and tissue inflammation in a mouse model of colitis. These activities are attributed to both the triterpenoid and polyphenol constituents of the fruit. The pentacyclic triterpenoids ursolic acid (UA), oleanolic acid (OA), corosolic acid (CA), maslinic acid (MA), and esters of UA and OA occur in the waxy layer of cranberry peel, and their content in cranberry products is likely to vary with the fruit source and processing methods. UPLC-MS (ultra performance liquid chromatography-mass spectrometry) was applied to determine the four triterpenoid acids and their esters in cranberry products and raw materials. Cranberry pomace, a side stream in juice production, was a rich source at 64,090 µg total triterpenoids/g DW. Cranberry juice beverages ranged from 0.018 to 0.26 µg/g of product, fruit samples ranged from 6542 to 17,070 µg/g DW, and whole berry products contained up to 2665 µg/g DW. Free UA was the most plentiful triterpenoid in all samples. These analyses illustrate the potential value of an underutilized side stream in cranberry juice production and highlight potential benefits of whole fruit products., Competing Interests: The authors declare that this study received funding from Ocean Spray Cranberries, Inc., and the role of the company was to provide research materials and funding to support the study. Authors I. P.-R. and C. K. were employed by the company Ocean Spray Cranberries, Inc. I. P.-R. participated in the initial study design. I. P.-R. and C.K. participated in the review and editing of the manuscript and agreed to its publication. Author C. N., as principal investigator, received funding from Ocean Spray Cranberries, Inc. to support this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Using oleanolic acid as a starting compound, a series of new oleanane-type triterpenic derivatives were synthesized via O-acylation (with nicotinic, isonicotinic, and methoxycinnamic acid acyl chlorides), N-amidation (with cyclic- or polyamines), the Mannich reaction (with secondary cyclic amines), and Claisen–Schmidt condensation (with aromatic aldehydes), and their potencies as treatments for immunometabolic disorders were investigated. The compounds were evaluated against α-glucosidase and PTP1B enzymes and LPS-stimulated murine macrophages. It was found that the target compounds are highly effective α-glucosidase inhibitors but lack activity against PTP1B. A leading compound, N-methylpiperazine methylated 2,3-indolo-oleanolic propargyl amide 15, is also a micromolar inhibitor of NO synthesis in LPS-stimulated macrophages and suppresses oxidative bursts in neutrophils with similar efficiency. These results, in addition to its ability to stimulate glucose uptake in rat fibroblasts and improve maltose tolerance in rats, allow us to consider compound 15 a promising prototype drug for the treatment of immunometabolic defects in type 2 diabetes.

Biologically active compounds present in the diet can interact with biological membranes (such as cell membranes), changing their properties. Their mutual interactions can influence their respective activities. In this study, we analyzed the interactions of oleanolic acid and phenolic compounds such as apigenin, rutin, resveratrol and ferulic acid with phosphatidylcholine membranes. Spectroscopic methods (fluorescence spectroscopy, dynamic light scattering) and machine learning were applied. The results of structural studies were compared with the antioxidant activity of the investigated substances in lipid membranes. In liposomes loaded with oleanolic acid, the pro-oxidant activity of resveratrol arises from changes in membrane structure, leading to an increased exposure of its hydrophilic region to external radicals. A similar mechanism may be involved in the pro-oxidant action of oleanolic acid. By contrast, apigenin, rutin and ferulic acid are present at the membrane surface. Their presence in this region protects the bilayer from radicals generated in the aqueous phase. Lower antioxidant activity observed in the case of ferulic aid is probably related to weaker interactions of this compound with the membrane, compared to the investigated flavonoids. Appropriate machine learning models for predicting oleanolic acid and phenolic compounds have been developed for the future application of intelligent predictive systems to optimizing manufacturing processes involving liposomes. The most effective regression model turned out to be the MLP 1:1-100-50-50-6:1, identifying resveratrol with a determination index of 0.83.

Background and objectives: Oleanolic acid (OA) is a penta-cyclic triterpene with diverse bioactivities such as anticarcinogenic, antiviral, antimicrobial, hepatoprotective, anti-atherosclerotic, hypolipidemic, and gastroprotective. However, its effects on hepatorenal damage remain unclear. The protective activity of OA, separated from Viscum schimperi (Loranthaceae), against TAA (thioacetamide)-produced acute hepatic and renal damage was explored. Materials and Methods: Mice were treated with OA for 7 days before TAA (200 mg/kg, i.p.). Serum indices of hepatorenal injury, pathological lesions, molecular biological indexes, and inflammatory/apoptotic genes were estimated. Results: The tissues of both organs were greatly affected by the TAA injection. That was evident through increased serum markers of hepato-renal injury as well as remarkable histopathological lesions. TAA-induced injury was associated with oxidative and inflammatory responses in both organs as there was an elevation of oxidative stress parameters (4-HNE (4-hydroxy-nonenal), MDA (malondialdehyde), NOx (nitric oxide)), decline of antioxidants (reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC)), and an increase in the gene expression/level of inflammatory mediators (interleukins (1β&6)). The inflammatory response was linked to a significant activation of NF-κB (nuclear-factor kappa-B)/TNF-α (tumor-necrosis factor-alpha) signaling. The inflammatory response in both organs was accompanied by apoptotic changes, including a rise in the gene expression and level of apoptotic parameters (caspase-3 and Bax) along with a decline in Bcl-2 (anti-apoptotic parameter) gene expression and level. These pathogenic events were found to be closely related to the suppression of the antioxidant signaling pathway, Nrf2 (nuclear-factor erythroid 2–related factor-2)/SIRT1 (sirtuin-1)/HO-1 (heme-oxygenase 1). On the other hand, OA significantly ameliorated TAA-induced injury in both organs. On the other hand, OA counterpoised the inflammatory response as it ameliorated NF-κB/TNF-α signaling and cytokine release. OA enhanced Nrf2/SIRT1/HO-1 signaling and counteracted apoptotic damage. Conclusions: OA showed anti-inflammation and antiapoptotic capacities that effectively suppressed TAA-induced acute hepatorenal damage.

Sonodynamic therapy (SDT) is a non-invasive therapeutic modality in cancer treatment that combines low-intensity ultrasound (US) and sonosensitizers. Tumor cells are destroyed through the synergistic effects of ultrasound and a chemical sonosensitizer. This study focused on the synthesis and in vitro evaluation of the sonodynamic effect of natural curcumin, triterpene oleanolic acid, and their semi-synthetic derivatives on tongue cancer SCC-25 and hypopharyngeal FaDu cell lines. The combination of the tested compounds with sonication showed a synergistic increase in cytotoxicity. In the group of oleanolic acid derivatives, oleanoyl hydrogen succinate (6) showed the strongest cytotoxic effect both in the SCC-25 and FaDu cell lines. Comparing curcumin (4) and its pyrazole derivative (5), curcumin showed a better cytotoxic effect on SCC-25 cells, while curcumin pyrazole was more potent on FaDu cells. The highest sonotherapeutic activity, compared to its individual components, was demonstrated by a structural linker mode hybrid containing both curcumin pyrazole-oleanoyl hydrogen succinate units within one complex molecule (7). This study can be beneficial in the context of new perspectives in the search for effective sonosensitizers among derivatives of natural organic compounds.

As part of the valorization of agricultural waste into bioactive compounds, a series of structurally novel oleanolic acid ((3β-hydroxyolean-12-en-28-oic acid, OA-1)-phtalimidines (isoindolinones) conjugates 18a–u bearing 1,2,3-triazole moieties were designed and synthesized by treating an azide 4 previously prepared from OA-1 isolated from olive pomace (Olea europaea L.) with a wide range of propargylated phtalimidines using the Cu(I)-catalyzed click chemistry approach. OA-1 and its newly prepared analogues, 18a–u, were screened in vitro for their antibacterial activity against two Gram-positive bacteria, Staphylococcus aureus and Listeria monocytogenes, and two Gram-negative bacteria, Salmonella thyphimurium and Pseudomonas aeruginosa. Attractive results were obtained, notably against L. monocytogenes. Compounds 18d, 18g, and 18h exhibited the highest antibacterial activity when compared with OA-1 and other compounds in the series against tested pathogenic bacterial strains. A molecular docking study was performed to explore the binding mode of the most active derivatives into the active site of the ABC substrate-binding protein Lmo0181 from L. monocytogenes. Results showed the importance of both hydrogen bonding and hydrophobic interactions with the target protein and are in favor of the experimental data.

Curcumin and oleanolic acid are natural compounds with high potential in medicinal chemistry. These products have been widely studied for their pharmacological properties and have been structurally modified to improve their bioavailability and therapeutic value. In the present study, we discuss how these compounds are utilized to develop bioactive hybrid compounds that are intended to target cancer cells. Using a bifunctional linker, succinic acid, to combine curcumin and triterpenoic oleanolic acid, several hybrid compounds were prepared. Their cytotoxicity against different cancer cell lines was evaluated and compared with the activity of curcumin (the IC50 value (24 h), for MCF7, HeLaWT and HT-29 cancer cells for KS5, KS6 and KS8 compounds was in the range of 20.6–94.4 µM, in comparison to curcumin 15.6–57.2 µM). Additionally, in silico studies were also performed. The computations determined the activity of the tested compounds towards proteins selected due to their similar binding modes and the nature of hydrogen bonds formed within the cavity of ligand−protein complexes. Overall, the curcumin-triterpene hybrids represent an important class of compounds for the development of effective anticancer agents also without the diketone moiety in the curcumin molecule. Moreover, some structural modifications in keto-enol moiety have led to obtaining more information about different chemical and biological activities. Results obtained may be of interest for further research into combinations of curcumin and oleanolic acid derivatives.

In the field of research on medicinal plants from the Armenian flora, the phytochemical study of two Scabiosa L. species, S. caucasica M. Bieb. and S. ochroleuca L. (Caprifoliaceae), has led to the isolation of five previously undescribed oleanolic acid glycosides from an aqueous-ethanolic extract of the roots: 3-O-α-L-rhamnopyranosyl-(1→3)-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→4)-β-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid 28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester, 3-O-β-D-xylopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→4)-β-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid 28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester, 3-O-β-D-xylopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→4)-β-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid, 3-O-β-D-xylopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-D-xylopyranosyl-(1→4)-β-D-glucopyranosyl-(1→4)-β-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid 28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester, 3-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1→4)-β-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyloleanolic acid 28-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester. Their full structural elucidation required extensive 1D and 2D NMR experiments, as well as mass spectrometry analysis. For the biological activity of the bidesmosidic saponins and the monodesmosidic saponin, their cytotoxicity on a mouse colon cancer cell line (MC-38) was evaluated.

The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12β-O-(γ-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure–activity relationship (SAR) and identified the most potent compound, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg·Kg−1) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of 10b extends into the H11–H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12β-alkonate. These findings suggest that 12-glutamyl OA derivative 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH).

Breast cancer is one of the most frequently observed malignancies worldwide and represents a heterogeneous group of cancers. For this reason, it is crucial to properly diagnose every single case so a specific and efficient therapy can be adjusted. One of the most critical diagnostic parameters evaluated in cancer tissue is the status of the estrogen receptor (ER) and epidermal growth factor receptor (EGFR). Interestingly, the expression of the indicated receptors may be used in a personalized therapy approach. Importantly, the promising role of phytochemicals in the modulation of pathways controlled by ER and EGFR was also demonstrated in several types of cancer. One such biologically active compound is oleanolic acid, but due to poor water solubility and cell membrane permeability that limits its use, alternative derivative compounds were developed. These are HIMOXOL and Br-HIMOLID, which were demonstrated to be capable of inducing apoptosis and autophagy or diminishing the migratory and invasive potential of breast cancer cells in vitro. In our study, we revealed that proliferation, cell cycle, apoptosis, autophagy, and also the migratory potential of HIMOXOL and Br-HIMOLID in breast cancer cells are mediated by ER (MCF7) and EGFR (MDA-MB-231) receptors. These observations make the studied compounds interesting in the context of anticancer strategies.

8-Aminoquinoline amides of 3-oxo-olean-12-en-28-oic acid and 3-oxo-urs-12-en-28-oic acid were obtained and characterized by 1H, 13C-NMR and single crystal X-ray analysis. The used triterpenoic acids are oxidized forms of naturally occurring oleanolic acid and ursolic acids. Such types of derivatives are known for their anticancer and antiviral activities. On the other hand, 8-aminoquinoline amides are frequently used for transition metal complexation that is applicable for both C-H activation processes and biological activity studies.

Efficient and mild synthetic routes for bioactive natural product derivatives are of current interest for drug discovery. Herein, on the basis of the pharmacophore hybrid strategy, we report a two-step protocol to obtain a series of structurally novel oleanolic acid (OA)-dithiocarbamate conjugates in mild conditions with high yields. Moreover, biological evaluations indicated that representative compound 3e exhibited the most potent and broad-spectrum antiproliferative effects against Panc1, A549, Hep3B, Huh-7, HT-29, and Hela cells with low cytotoxicity on normal cells. In terms of the IC50 values, these OA-dithiocarbamate conjugates were up to 30-fold more potent than the natural product OA. These compounds may be promising hit compounds for the development of novel anti-cancer drugs.

One of several promising strategies for increasing the bioavailability and therapeutic potential of high-lipophilic biologically active compounds is gold nanoparticle formulation. The current study describes the synthesis and biological antimelanoma evaluation of three triterpen-functionalized gold nanoparticles, obtained using our previously reported antimelanoma benzotriazole-triterpenic acid esters. Functionalized gold nanoparticle (GNP) formation was validated through UV-VIS and FTIR spectroscopy. The conjugate’s cytotoxic effects were investigated using HaCaT healthy keratinocytes and A375 human melanoma cells. On A375 cells, all three conjugates demonstrated dose-dependent cytotoxic activity, but no significant cytotoxic effects were observed on normal HaCaT keratinocytes. GNP-conjugates were found to be more cytotoxic than their parent compounds. After treatment with all three GNP-conjugates, 4,6′-diamidino-2-phenylindole (DAPI) staining revealed morphological changes consistent with apoptosis in A375 melanoma cells. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed that the triterpene-GNP conjugate treated A375 melanoma cells had a fold change increase in Bcl-2-associated X protein (BAX) expression and a fold change decrease in B-cell lymphoma 2 (Bcl-2) expression. In A735 melanoma cells, high-resolution respirometry studies revealed that all three GNP-conjugates act as selective inhibitors of mitochondrial function. Furthermore, by examining the effect on each mitochondrial respiratory rate, the results indicate that all three conjugates are capable of increasing the production of reactive oxygen species (ROS), an apoptosis trigger in cancer cells.

Cancer is a global health problem, with the incidence rate estimated to reach 40% of the population by 2030. Although there are currently several therapeutic methods, none of them guarantee complete healing. Plant-derived natural products show high therapeutic potential in the management of various types of cancer, with some of them already being used in current practice. Among different classes of phytocompounds, pentacyclic triterpenoids have been in the spotlight of research on this topic. Ursolic acid (UA) and its structural isomer, oleanolic acid (OA), represent compounds intensively studied and tested in vitro and in vivo for their anticancer and chemopreventive properties. Since natural compounds can rarely be used in practice as such due to their characteristic physico-chemical properties, to tackle this problem, their derivatization has been attempted, obtaining compounds with improved solubility, absorption, stability, effectiveness, and reduced toxicity. This review presents various UA and OA derivatives that have been synthesized and evaluated in recent studies for their anticancer potential. It can be observed that the most frequent structural transformations were carried out at the C-3, C-28, or both positions simultaneously. It has been demonstrated that conjugation with heterocycles or cinnamic acid, derivatization as hydrazide, or transforming OH groups into esters or amides increases anticancer efficacy.

The main type of saponins occurring in the root of Platycodon grandiflorus (Jacq.) A. DC. are oleanolic acid glycosides. The CYP716 gene family plays a major role in catalyzing the conversion of β-amyrin into oleanolic acid. However, studies on the CYP716 genes in P. grandiflorus are limited, and its evolutionary history remains poorly understood. In this study, 22 PgCYP716 genes were identified, distributed among seven subfamilies. Cis -acting elements of the PgCYP716 promoters were mainly involved in plant hormone regulation and responses to abiotic stresses. PgCYP716A264 , PgCYP716A391 , PgCYP716A291 , and PgCYP716BWv3 genes were upregulated in the root and during saponin accumulation, as shown by RNA-seq analysis, suggesting that these four genes play an important role in saponin synthesis. The results of subcellular localization indicated that these four genes encoded membrane proteins. Furthermore, the catalytic activity of these four genes was proved in the yeast, which catalyzed the conversion of β-amyrin into oleanolic acid. We found that the content of β-amyrin, platycodin D, platycoside E, platycodin D3, and total saponins increased significantly when either of the four genes was over expressed in the transgenic hair root. In addition, the expression of PgSS , PgGPPS2 , PgHMGS , and PgSE was also upregulated while these four genes were overexpressed. These data support that these four PgCYP716 enzymes oxidize β-amyrin to produce oleanolic acid, ultimately promoting saponin accumulation by activating the expression of upstream pathway genes. Our results enhanced the understanding of the functional variation among the PgCYP716 gene family involved in triterpenoid biosynthesis and provided a theoretical foundation for improving saponin content and enriching the saponin biosynthetic pathway in P. grandiflorus .

Like other pentacyclic triterpenoids, oleanolic acid, a natural plant metabolite prevalent in plant peels, stems, and leaves, is regarded as a possible drug candidate. A growing number of studies have shown that oleanolic acid exhibits a variety of beneficial properties, including antiviral, anti-inflammatory, antioxidant, anticancer, and hepatoprotective effects. Additionally, the rapid advance of nanotechnology has dramatically improved oleanolic acid’s bioavailability and minimized its disadvantages, leading to unexpected changes in its pharmacological activity and use. Therefore, our aim was to review the progress of research on the distribution and biological properties of oleanolic acid in plants and to discuss new pharmaceutical approaches for oleanolic acid.

Oleanolic acid (OLA) and oleic acid (OA) are ubiquitous in the plant kingdom, exhibiting a therapeutic effect on human health, and are components of novel pharmaceutical formulations. Since OLA has limited solubility, the utilization of nanotechnology-based drug delivery systems enhancing bioavailability is highly advantageous. We report on the interfacial behavior of the OLA:OA system at various molar ratios, using the Langmuir technique to assess the dependence of the molar composition on miscibility and rheological properties affecting film stability. Specifically, we evaluate the interfacial properties (morphology, thermodynamics, miscibility, and viscoelasticity) of the OLA:OA binary system in various molar ratios, and indicate how the OLA:OA system exhibits the most favorable molecular interactions. We apply the Langmuir monolayer technique along with the complementary techniques of Brewster angle microscopy, dilatational interfacial rheology, and excess free energy calculations. Results demonstrate that the properties of mixed monolayers depend on OLA:OA molar ratio. Most of the systems (OLA:OA 2:1, 1:1, 1:5) are assumed to be immiscible at surface pressures >10 mN/m. Moreover, the OLA:OA 1:2 is immiscible over the entire surface pressure range. However, the existence of miscibility between molecules of OLA and OA in the 5:1 for every surface pressure tested suggests that OA molecules incorporate into the OLA lattice structure, improving the stability of the mixed film. The results are discussed in terms of providing physicochemical insights into the behavior of the OLA:OA systems at the interface, which is of high interest in pharmaceutical design.

A series of sixteen A-ring modified (2,3-indolo-, 2-benzylidene) oleanonic acid derivatives, holding some cyclic amines, linear polyamines and benzylaminocarboxamides at C28, has been synthesized and screened for antiviral activity against influenza A/PuertoRico/8/34 (H1N1) and Dengue virus serotypes of DENV-1, -2, -3, -4. It was found that 28-homopiperazine 2 and 3-N-phthalyl 22 amides of oleanonic acid demonstrated high potency with selectivity index SI 27 (IC50 21 μM) and 42 (IC50 12 μM). Oleanonic acid aminoethylpiperazine amide 6 and C-azepano-erythrodiol 23 appeared to be the most effective compounds against DENV-1 (IC50′s 67 and 107 μM) and -2 (IC50′s 86 and 68 μM correspondingly) serotypes.

Repetitive motion or exercise is associated with oxidative stress and muscle inflammation, which can lead to declining grip strength and muscle damage. Oleanolic acid and ursolic acid have anti-inflammatory and antioxidant properties and can be extracted from Chaenomeles speciosa through ultrasonic sonication. We investigated the association between grip strength declines and muscle damage induced by lambda carrageenan (LC) injection and exercise exposure in rats. We also assessed the reparative effects of transdermal pretreatment and post-treatment with C. speciosa extracts (CSEs) by using a supersonic atomizer. The half-maximal inhibitory concentration (IC 50 ) of CSEs for cells was 10.5 mg/mL. CSEs significantly reduced the generation of reactive oxygen species and inflammatory factors (interleukin [IL]-6 and IL-1β) in in vitro cell tests. Rats subjected to LC injection and 6 weeks of exercise exhibited significantly increased inflammatory cytokine levels (IL-1β, TNF-α, and IL-6). Hematoxylin and eosin staining revealed inflammatory cell infiltration and evident muscle damage in the gastrocnemius muscle, which exhibited splitting and the appearance of the endomysium and perimysium. The treated rats' grip strength significantly declined. Following treatment with CSEs, the damaged muscles exhibited decreased IL-1β, TNF-α, and IL-6 levels and normal morphologies. Moreover, grip strength significantly recovered. Pretreatment with CSEs yielded an immediate and significant increase in grip strength, with an increase of 180% and 165% occurring in the rats exposed to LC injection and exercise within the initial 12 h period, respectively, compared with the control group. Pretreatment with CSEs delivered transdermally using a supersonic atomizer may have applications in sports medicine and training or competitions.

Oleanolic acid (OA) is an active ingredient of the traditional Chinese medicine (TCM) Fructus ligustri lucidi (FLL). Its clinical use is restricted because it is water-insoluble and has limited dosage forms of administration at present. Hence, the FFL dropping pills were prepared by the hot-melt method of solid dispersion technology. A 23 factorial design was used to examine the effects of the materials used to prepare the dropping pills (e.g., different ratios of PEG4000 and PEG6000, FLL extract loading, and percentage of Tween 80) on parameters such as dropping pill roundness, weight variation, and disintegration time. Moreover, 23 full factorial design was utilized to search for the optimal formulation for dissolution experiments. The results showed that the percentage of Tween 80 demonstrated significant effects on dropping pill roundness, weight variation, and disintegration time; FLL extract loading affected roundness and weight variation; and different ratios of PEG4000 and PEG6000 only affected disintegration time. The optimal formulation of the dropping pills released 70% of the drug after 30 min of dissolution release, which was faster than commercially available FLL Chinese medicines. Furthermore, the amount released was higher than that of commercially available formulations. In this study, a solid dispersion technique was used to successfully produce FLL dropping pills. In addition to improving the water insolubility of FLL and increasing the dissolution release percentage of the drug, we increased the application value of FLL and reduced the issues of traditional administration dosage forms.

Using the bioresources of the Regional Specialised Collection of Alkanotrophic Microorganisms (acronym IEGM, Perm, Russia; WFCC # 285), R. rhodochrous IEGM 757 was selected, which catalyzed the C5, C22, and C23 functionalization of pentacyclic triterpenoid oleanolic acid (OA, 3β-hydroxyolean-12-en-28-oic acid, 1.0 g/L) to form a new 5α,22α-dihydroxy derivative of gypsogenic acid (3β,5α,22α-trihydroxyolean-12-ene-23,28-dioic acid) for 5 days. In silico analysis showed that, compared to the native triterpenoid, the OA metabolite may be more soluble in water and less ecotoxic, act as an apoptosis agonist and insulin promoter, and have chemopreventive and analgesic effects. Phase-contrast, fluorescent, scanning, and transmission electron microscopy and X-ray spectroscopy demonstrated the high resistance of R. rhodochrous IEGM 757 to OA. This creates opportunities for further research and development of a method for the production of the OA metabolite. New-generation sequencing of the R. rhodochrous IEGM 757 whole genome, annotation and bioinformatics analysis of the obtained sequences, and real-time PCR were applied. As a result, 24 genes encoding CYP450 enzymes were found, which are highly likely to be involved in the process of OA oxidation.

Cancer has been a major health problem in the world in the past decades. It is urgent to develop new, effective and safe drugs for the treatment of cancer. There are many pentacyclic triterpenoids with positive anti-tumor activity and safety in nature. Oleanolic acid (OA), as one of the pentacyclic triterpenoids, also has broad biological activities including liver protection, anti-inflammatory, hypoglycemic, antiviral and anti-tumor. Therefore, to investigate its anti-tumor activity and mechanism, many OA derivatives have been developed. Some derivatives are less toxic to normal hepatocytes, which may be due to the strong liver protection ability of OA. However, the poor water solubility of OA is one of the main reasons for the weak anti-tumor activity. It is reported that some OA derivatives could enhance solubility by chemically linking some hydrophilic groups to improve anti-tumor activity. This review not only summarizes the highly water-soluble OA derivatives that can improve anti-tumor activity reported in recent years, but also introduces their possible anti-tumor mechanisms.

The interplay between steroids and triterpenoids, compounds sharing the same biosynthetic pathway but exerting distinctive functions, is an important part of the defense strategy of plants, and includes metabolic modifications triggered by stress hormones such as jasmonic acid. Two experimental models, Calendula officinalis hairy root cultures and greenhouse cultivated plants (pot plants), were applied for the investigation of the effects of exogenously applied jasmonic acid on the biosynthesis and accumulation of steroids and triterpenoids, characterized by targeted GC-MS (gas chromatography-mass spectroscopy) metabolomic profiling. Jasmonic acid elicitation strongly increased triterpenoid saponin production in hairy root cultures (up to 86-fold) and their release to the medium (up to 533-fold), whereas the effect observed in pot plants was less remarkable (two-fold enhancement of saponin biosynthesis after a single foliar application). In both models, the increase of triterpenoid biosynthesis was coupled with hampering the biomass formation and modifying the sterol content, involving stigmasterol-to-sitosterol ratio, and the proportions between ester and glycoside conjugates. The study revealed that various organs in the same plant can react differently to jasmonic acid elicitation; hairy root cultures are a useful in vitro model to track metabolic changes, and enhanced glycosylation (of both triterpenoids and sterols) seems to be important strategy in plant defense response.