Triterpenoid Acids Research Articles

Role of Pentacyclic Triterpenoid Acids in the Treatment of Bladder Cancer

Abstract: Bladder cancer carries a poor prognosis and has proven resistance to chemotherapy. Pentacyclic Triterpenoid Acids (PTAs) are natural bioactive compounds that have a well-known impact on cancer research because of their cytotoxic and chemopreventive activities. This review focuses on bladder cancer which can no longer be successfully treated by DNA damaging drugs. Unlike most of the existing drugs against bladder cancer, PTAs are non-toxic to normal cells. Collecting findings from both in vitro and in vivo studies, it has been concluded that PTAs may serve as promising agents in future bladder cancer therapy. In this review, the roles of various PTAs in bladder cancer have been explored, and their mechanisms of action in the treatment of bladder cancer have been described. Specific PTAs have been shortlisted from each of the chief skeletons of pentacyclic triterpenoids, which could be effective against bladder cancer because of their mode of action. This review thereby throws light on the multi targets and mechanisms of PTAs, which are responsible for their selective anticancer effects and provides guidelines for further research and development of new natural antitumor compounds.

A simplified HPLC-UV method for the analysis of triterpenoid acids from heritage apples (Malus domestica) from western North Carolina, USA

Background: Pentacyclic triterpenoid acids are common in a number of food and spice plant species. Apples (Malus domestica) are the most common human food source for these potentially beneficial phytochemicals. Pre-20th century heritage apples have long been grown in mountainous western North Carolina and may be a wide-ranging source of these phytochemicals. Objectives: Existing extraction and analytical methods were improved and used to assess the content of three triterpenoid acids in heritage apple cultivars grown in western North Carolina, USA.Methods: Apples from a local farmers market were collected during the fall apple season. Apple peels were freeze dried, ground, and extracted with ethanol thrice. Extracts were analyzed by HPLC against external standards for betulinic, oleanolic, and ursolic acids.Results: The improved method was used to extract and to analyze the triterpenoid acid levels in 16 heritage apple cultivars grown in the Appalachian region of western North Carolina. Total triterpenoid acids ranged from 2 to 29 mg/g dry weight of peels. Content did not vary by apple color or time of harvest. Russeted varieties contained noticeably less triterpenoids.Conclusions: An improved and simplified method was used for the analysis of heritage apple varieties in western North Carolinas. A wide range of values was found for these compounds of increasing interest in the human diet and in human health.Keywords:apples, phytochemicals, triterpenoids, ursolic acid, Appalachia

UHPLC-Q-Exactive Orbitrap MS/MS-based rapid identification of chemical components in substance benchmark of Kaixin San

Ultra-performance liquid chromatography-quadrupole-electrostatic field Orbitrap mass spectrometry(UHPLC-Q-Exactive Orbitrap MS/MS) was used for rapid identification of the chemical components in Kaixin San substance benchmark. The gradient elution was performed through a Waters ACQUITY~(TM) BEH C_(18) column(2.1 mm×150 mm, 1.7 μm) with water-acetonitrile as mobile phase, a column temperature of 30 ℃, a flow rate of 0.3 mL·min~(-1), and a sample size of 1 μL. The scanning was performed in the negative ion mode. The complex component groups in Kaixin San substance benchmark were quickly and accurately identified and clearly assigned based on the comparison of the retention time and MS data with those of the reference substance as well as the relative molecular weight of the same or similar components in the mass spectrum database and literature. A total of 77 compounds were identified, including 26 saponins, 13 triterpenoid acids, 20 oligosaccharide esters, 5 xanthones, and 13 other compounds. The qualitative method established in this study can systematically, accurately, and quickly identify the chemical components in Kaixin San substance benchmark, which can provide a basis for the further analysis of its active components in vivo and the establishment of its quality control system.

Isolation of Bioactive Pentacyclic Triterpenoid Acids from Olive Tree Leaves with Flash Chromatography

The present study reports on the use of the flash chromatography for the isolation and purification of oleanolic and maslinic acids from olive leaf extracts. Although the separation and identification of these acids is considered challenging due to the similarity in their structure, oleanolic and maslinic acids were detected, identified, and separated. Solubility prediction was used to help to match compatibility of extraction solvent with targeted triterpenoid acids. Aqueous washing was used, to first selectively remove unwanted interferents from the extraction solvent. The extracts obtained with different solvents and solvent mixtures were fractionated using flash chromatography and then analyzed. HPTLC chromatography was used to assess collected fractions as either semi-pure or pure, and to identify the fractions containing oleanolic and maslinic acids. The yields of oleanolic and maslinic acids reported here are significantly higher than yields obtained in previously reported isolations. The presence and purity of oleanolic and maslinic acid in collected fractions was confirmed by ATR-FTIR and NMR spectrometry.

Effective substance and mechanism of Ziziphi Spinosae Semen extract in treatment of insomnia based on serum metabolomics and network pharmacology

This study aims to study the effective substance and mechanism of Ziziphi Spinosae Semen extract in the treatment of insomnia based on serum metabolomics and network pharmacology. The rat insomnia model induced by p-chlorophenylalanine(PCPA) was established. After oral administration of Ziziphi Spinosae Semen extract, the general morphological observation, pentobarbital sodium-induced sleep test, and histopathological evaluation were carried out. The potential biomarkers of the extract in the treatment of insomnia were screened by ultra-high performance liquid chromatography-mass spectrometry(UHPLC-MS) combined with multivariate analysis, and the related metabolic pathways were further analyzed. The "component-target-pathway" network was constructed by ultra-high performance liquid chromatography coupled with quadrupole-Exactive mass spectrometry(UHPLC-Q-Exactive-MS/MS) combined with network pharmacology to explore the effective substances and mechanism of Ziziphi Spinosae Semen in the treatment of insomnia. The results of pentobarbital sodium-induced sleep test and histopathological evaluation(hematoxylin and eosin staining) showed that Ziziphi Spinosae Semen extract had good theraputic effect on insomnia. A total of 21 endogenous biomarkers of Ziziphi Spinosae Semen extract in the treatment of insomnia were screened out by serum metabolomics, and the metabolic pathways of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and nicotinate and nicotinamide metabolism were obtained. A total of 34 chemical constituents were identified by UHPLC-Q-Exactive-MS/MS, including 24 flavonoids, 2 triterpenoid saponins, 4 alkaloids, 2 triterpenoid acids, and 2 fatty acids. The network pharmacological analysis showed that Ziziphi Spinosae Semen mainly acted on target proteins such as dopamine D2 receptor(DRD2), 5-hydroxytryptamine receptor 1 A(HTR1 A), and alpha-2 A adrenergic receptor(ADRA2 A) in the treatment of insomnia. It was closely related to neuroactive ligand-receptor interaction, serotonergic synapse, and calcium signaling pathway. Magnoflorine, N-nornuciferine, caaverine, oleic acid, palmitic acid, coclaurine, betulinic acid, and ceanothic acid in Ziziphi Spinosae Semen may be potential effective compounds in the treatment of insomnia. This study revealed that Ziziphi Spinosae Semen extract treated insomnia through multiple metabolic pathways and the overall correction of metabolic disorder profile in a multi-component, multi-target, and multi-channel manner. Briefly, this study lays a foundation for further research on the mechanism of Ziziphi Spinosae Semen in treating insomnia and provides support for the development of innovative Chinese drugs for the treatment of insomnia.

Potential Mechanism of Maslinic Acid against Hypolipidemia Based on Network Pharmacology and Molecular Docking Integration Strategy

Maslinic acid is a pentacyclic triterpenoid acid. Recent research has shown that it has various biological activities such as anti-tumor, hypoglycaemic and hypolipidemic. Among them, the hypolipidemic effect is prominent and this study aims to further explore its mechanism of action in the treatment of hyperlipidemia. The chemical structure of maslinic acid was obtained from PubChem. Based on its chemical structure, the bioavailability and drug-like properties of maslinic acid were analyzed using Swiss absorption, distribution, metabolism and excretion and its potential targets were obtained from SwissTargetPrediction and PharmMapper. Then, the differentially expressed genes between hyperlipidemia patients and the health group were analyzed through the gene expression omnibus data set, and the related targets of hyperlipidemia were complemented using DrugBank, online Mendelian inheritance in man, GeneCards, DisGeNET and therapeutic target databases. Then, the protein-protein interaction network was constructed, the CytoNCA plugin and VarElect were used to screen core targets and metascape was used to systematically analyze the core targets and explore the mechanism. Finally, molecular docking showcased the interaction model. A total of 288 maslinic acid targets and 289 hyperlipidemia-related targets were collected and 18 potential therapeutic targets were found. The enrichment analysis results further systematically explained the effect of maslinic acid on hyperlipidemia. Maslinic acid can treat hyperlipidemia through complex interactions in which the regulation of core genes including albumin, peroxisome proliferator activated receptor alpha and apolipoprotein, and the regulation of peroxisome proliferator activated receptor signaling pathway play a major role.

In silico studies of interactions of peptide-conjugated cholesterol metabolites and betulinic acid with EGFR, LDR, and N-terminal fragment of CCKA receptors.

In this work, we designed three new ligands by conjugating cholesterol metabolites 3-hydroxy-5-cholestenoic acid (3-HC) and 3-oxo-4-cholestenoic acid (3-OC) and the natural tri-terpenoid betulinic acid with the tumor-targeting peptide YHWYGYTPQNVI. Molecular interactions with the unconjugated peptide and the conjugates were examined with three receptors that are commonly overexpressed in pancreatic adenocarcinoma cells using ligand docking and molecular dynamics. This study demonstrated the utility of the designed conjugates as a valuable scaffold for potentially targeting EGFR and LDLR receptors. Our results indicate that the conjugates showed strong binding affinities and formation of stable complexes with EGFR, while the unconjugated peptide, BT-peptide conjugate, an 3-HC-peptide conjugate showed the formation of fairly stable complexes with LDLR receptor. For EGFR, two receptor kinase domains were explored. Interactions with the N-terminal domain of CCKA-R were relatively weaker. For LDLR, binding occurred in the beta-propeller region. For the N-terminal fragment of CCKA-R, the conjugates induced significant conformational changes in the receptor. The molecular dynamic simulations for 100ns demonstrate that BT-peptide conjugates and the unconjugated peptide had the highest binding and formed the most stable complexes with EGFR. RMSD and trajectory analyses indicate that these molecules transit to a dynamically stable configuration in most cases within 60ns. NMA analysis indicated that amongst the conjugates that showed relatively higher interactions with the respective receptors, the highest potential for deformability was seen for the N-terminal-47 amino acid region of the CCKA-R receptor with and the lowest for the LDLR-receptor. Thus, the newly designed compounds may be evaluated in the future toward developing drug delivery materials for targeting tumor cells overexpressing LDLR or EGFR.

A clickable photoaffinity probe of betulinic acid identifies tropomyosin as a target

Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge, unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.

The triterpenoids and sesquiterpenoids from the plant of Agrimonia pilosa

A phytochemistry of the whole plant of Agrimonia pilosa led to the discovery of two new nortriterpenoids, agrimonorterpenes A and B (1 and 2), together with one known triterpenoid fupenzic acid (3) and seven known sesquiterpenoids (4–10). The new structures were determined as 19α-hydroxy-2-oxo-nor-A (3)-urs-11,12-dien-28-oic acid (1) and 2, 19β-dihydroxy-3-oxo-23-noroleana-1, 4, 12-trien-28-oic acid (2) by the spectroscopic data of UV, IR, HR-ESI-MS, and NMR. Notably, the structure of 1 possessed a rare five-membered A- ring. And this is the first time to discover the sesquiterpenoids (4–10) from A. pilosa. Compound 3 displayed the selective cytotoxicity against HCT116, BGC823, and HepG2 cell lines with the IC50 values of 16.31 μM, 21.94 μM, and 23.40 μM, respectively.

Efficacy of Ursolic Acid-Enriched Water-Soluble and Not Cytotoxic Nanoparticles against Enterococci.

Ursolic acid (UA), a pentacyclic triterpenoid acid found in many medicinal plants and aromas, is known for its antibacterial effects against multi-drug-resistant (MDR) Gram-positive bacteria, which seriously threaten human health. Unfortunately, UA water-insolubility, low bioavailability, and systemic toxicity limit the possibilities of its application in vivo. Consequently, the beneficial activities of UA observed in vitro lose their potential clinical relevance unless water-soluble, not cytotoxic UA formulations are developed. With a nano-technologic approach, we have recently prepared water-soluble UA-loaded dendrimer nanoparticles (UA-G4K NPs) non-cytotoxic on HeLa cells, with promising physicochemical properties for their clinical applications. In this work, with the aim of developing a new antibacterial agent based on UA, UA-G4K has been tested on different strains of the Enterococcus genus, including marine isolates, toward which UA-G4K has shown minimum inhibitory concentrations (MICs) very low (0.5–4.3 µM), regardless of their resistance to antibiotics. Time-kill experiments, in addition to confirming the previously reported bactericidal activity of UA against E. faecium, also established it for UA-G4K. Furthermore, cytotoxicity experiments on human keratinocytes revealed that nanomanipulation of UA significantly reduced the cytotoxicity of UA, providing UA-G4K NPs with very high LD50 (96.4 µM) and selectivity indices, which were in the range 22.4–192.8, depending on the enterococcal strain tested. Due to its physicochemical and biological properties, UA-G4K could be seriously evaluated as a novel oral-administrable therapeutic option for tackling difficult-to-treat enterococcal infections.

Identifying the Effect of Ursolic Acid Against Triple-Negative Breast Cancer: Coupling Network Pharmacology With Experiments Verification.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with complex heterogeneity, high invasiveness, and long-term poor prognosis. With the development of molecular pathology and molecular genetics, the gene map of TNBC with distinctive biological characteristics has been outlined more clearly. Natural plant extracts such as paclitaxel, vinblastine, colchicine etc., have occupied an important position in the treatment of hormone-independent breast cancer. Ursolic acid (UA), a triterpenoid acid compound derived from apple, pear, loquat leaves, etc., has been reported to be effective in a variety of cancer treatments, but there are few reports on the treatment of TNBC. This study performed comprehensive bioinformatics analysis and in vitro experiments to identify the effect of UA on TNBC treatment and its potential molecular mechanism. Our results showed that UA could not only reduce the proliferation, migration, and invasion in MDA-MB-231 and MDA-MB-468 cell lines with a dose-dependent manner but also induce cell cycle arrest and apoptosis. Meanwhile, we collected the gene expression data GSE45827 and GSE65194 from GEO for comparison between TNBC and normal cell type and obtained 724 DEGs. Subsequently, PLK1 and CCNB1 related to TNBC were screened as the key targets via topological analysis and molecular docking, and gene set enrichment analysis identified the key pathway as the p53 signaling pathway. In addition, quantitative real-time PCR and western blot verified the key genes were PLK1 and CCNB1. In vivo and in vitro experiments showed that UA could inhibit the growth of TNBC cells, and down-regulate the protein expression levels of PLK1 and CCNB1 by mediating p53 signaling pathway. These findings provide strong evidence for UA intervention in TNBC via multi-target therapy.

Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer.

Ursolic acid (UA) is a triterpenoid phytochemical with a strong anticancer effect. The metabolic rewiring, epigenetic reprogramming, and chemopreventive effect of UA in prostate cancer (PCa) remain unknown. Herein, we investigated the efficacy of UA in PCa xenograft, and its biological effects on cellular metabolism, DNA methylation, and transcriptomic using multi-omics approaches. The metabolomics was quantified by liquid-chromatography-mass spectrometry (LC-MS) while epigenomic CpG methylation in parallel with transcriptomic gene expression was studied by next-generation sequencing technologies. UA administration attenuated the growth of transplanted human VCaP-Luc cells in immunodeficient mice. UA regulated several cellular metabolites and metabolism-related signaling pathways including S-adenosylmethionine (SAM), methionine, glucose 6-phosphate, CDP-choline, phosphatidylcholine biosynthesis, glycolysis, and nucleotide sugars metabolism. RNA-seq analyses revealed UA regulated several signaling pathways, including CXCR4 signaling, cancer metastasis signaling, and NRF2-mediated oxidative stress response. Epigenetic reprogramming study with DNA Methyl-seq uncovered a list of differentially methylated regions (DMRs) associated with UA treatment. Transcriptome-DNA methylome correlative analysis uncovered a list of genes, of which changes in gene expression correlated with the promoter CpG methylation status. Altogether, our results suggest that UA regulates metabolic rewiring of metabolism including SAM potentially driving epigenetic CpG methylation reprogramming, and transcriptomic signaling resulting in the overall anticancer chemopreventive effect.

Untargeted Metabolomics and Targeted Quantitative Analysis of Temporal and Spatial Variations in Specialized Metabolites Accumulation in Poria cocos (Schw.) Wolf (Fushen).

Poria cocos (Schw.) Wolf is a saprophytic fungus that grows around the roots of old, dead pine trees. Fushen, derived from the sclerotium of P. cocos but also containing a young host pine root, has been widely used as a medicine and food in China, Japan, Korea, Southeast Asian countries, and some European countries. However, the compound variations at the different growth periods and in the different parts of Fushen have not previously been investigated. In this study, an untargeted metabolomics approach based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) and targeted quantitative analysis was utilized to characterize the temporal and spatial variations in the accumulation of specialized metabolites in Fushen. There were 119 specialized metabolites tentatively identified using the UPLC-Q/TOF-MS. The nine growth periods of Fushen were divided into four groups using partial least squares discrimination analysis (PLS-DA). Four different parts of the Fushen [fulingpi (FP), the outside of baifuling (BO), the inside of baifuling (BI), and fushenmu (FM)] were clearly discriminated using a PLS-DA and orthogonal partial least squares discrimination analysis (OPLS-DA). Markers for the different growth periods and parts of Fushen were also screened. In addition, the quantitative method was successfully applied to simultaneously determine 13 major triterpenoid acids in the nine growth periods and four parts. The quantitative results indicated that the samples in January, March, and April, i.e., the late growth period, had the highest content levels for the 13 triterpenoid acids. The pachymic acid, dehydropachymic acid, and dehydrotumulosic acid contents in the FM were higher than those in other three parts in March, whereas the poricoic acid B, poricoic acid A, polyporenic acid C, dehydrotratrametenolic acid, dehydroeburicoic acid, and eburicoic acid in FP were higher beginning in October. These findings reveal characteristics in temporal and spatial distribution of specialized metabolites in Fushen and provide guidance for the identification of harvesting times and for further quality evaluations.

Triterpenoid acids from medicinal mushroom Inonotus obliquus (Chaga) alleviate hyperuricemia and inflammation in hyperuricemic mice: Possible inhibitory effects on xanthine oxidase activity.

The purpose of this study was to explore the hypouricemic effect in hyperuricemia mice of triterpenoid acids from Inonotus obliquus (TAIO), and decipher of the underlying xanthine oxidase inhibitory mechanism. Measurement of xanthine oxidase (XO) inhibitory activity was assayed. Organ indexes and serum biochemical indicators were measured in potassium oxonate-induced hyperuricemia mice. Studies showed that TAIO had the strong inhibitory effect on XO activity, and its inhibition type was mixed and reversible. In vivo, TAIO decreased efficiently uric acid level, hepatic XO, serum blood urea nitrogen activities in hyperuricemia mice. Indicating that TAIO may ameliorate kidney damage and relieve inflammation in hyperuricemic mice, and had the inhibitory effect on XO activity. Furthermore, eight triterpenoids were identified by Ultra performance liquid chromatography electrospray quadrupole time of flight mass spectrometry. These findings proved that triterpenoids from Inonotus obliquus would have potential biological characteristics and effect on controlling hyperuricemia and gout as an active supplement. PRACTICAL APPLICATIONS: There are a large amount of evidence indicating that hyperuricemia and gout are related to the hypertension and obesity. And gout and hyperuricemia are also possible connection with cardiovascular disease and metabolic syndrome. Currently, xanthine oxidase is the target of many kinds of chemical drugs at present, but the therapeutic drugs used in clinical medicine will produce more or less side effects. Therefore, the aim of this study was to explore the material basis of effective substances for reducing uric acid in Inonotus obliquus and to evaluate its effect. This study can provide a promising application of Inonotus obliquus in the fields of functional foods or medicines for gout and hyperuricemia.

Screening Anti-Inflammatory Effects of Flavanones Solutions

There are a large number of remedies in traditional medicine focused on relieving pain and inflammation. Flavanones have been a potential source in the search for leading compounds and biologically active components, and they have been the focus of much research and development in recent years. Eysenhardtia platycarpa is used in traditional medicine for the treatment of kidney diseases, bladder infections, and diabetes mellitus. Many compounds have been isolated from this plant, such as flavones, flavanones, phenolic compounds, triterpenoid acids, chalcones, sugars, and fatty acids, among others. In this paper, natural flavanone 1 (extracted from Eysenhardtia platycarpa) as lead compound and flavanones 1a–1d as its structural analogues were screened for anti-inflammatory activity using Molinspiration® and PASS Online in a computational study. The hydro alcoholic solutions (FS) of flavanones 1, 1a–1d (FS1, FS1a–FS1d) were also assayed to investigate their in vivo anti-inflammatory cutaneous effect using two experimental models, a rat ear edema induced by arachidonic acid (AA) and a mouse ear edema induced by 12-O-tetradecanoylphorbol acetate (TPA). Histological studies and analysis of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were also assessed in AA-inflamed rat ear tissue. The results showed that the flavanone hydro alcoholic solutions (FS) caused edema inhibition in both evaluated models. This study suggests that the evaluated flavanones will be effective when used in the future in skin pathologies with inflammation, with the results showing 1b and 1d to be the best.

Ethyl Acetate Fraction and Isolated Phenolics Derivatives from Mandevilla moricandiana Identified by UHPLC-DAD-ESI-MSn with Pharmacological Potential for the Improvement of Obesity-Induced Endothelial Dysfunction.

Endothelial dysfunction in obesity plays a key role in the development of cardiovascular diseases, and it is characterized by increased vascular tonus and oxidative stress. Thus, this study aimed to investigate the vasodilatory and antioxidant activities of Mandevilla moricandiana ethyl acetate fraction and subfractions. Vascular effects were investigated on aorta isolated from control and monosodium glutamate (MSG) induced-obese Wistar rats, and antioxidant activity was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) methods. The ethyl acetate fraction (MMEAF) induced a concentration-dependent vasodilation on aortic rings through the NO pathway, with the involvement of histamine H1 and estrogen ERα receptors and showed potent antioxidant activity. In aorta of MSG obese rats, maximal relaxation to acetylcholine was increased in the presence of MMEAF (3 µg/mL), indicating that MMEAF ameliorated obesity-induced endothelial dysfunction. Quercetin and kaempferol aglycones and their correspondent glycosides, as well as caffeoylquinic acid derivatives, A-type procyanidin trimer, ursolic and oleanolic triterpenoid acids were identified in subfractions from MMEAF and seem to be the metabolites responsible for the vascular and antioxidant activities of this fraction.

Garland, Flower, and Petals via a Hierarchical Self-Assembly of Ursane-Type Triterpenoid Uvaol.

Uvaol, a 6-6-6-6-6 pentacyclic dihydroxy ursane-type triterpenoid, is isolable from different parts of plants Plumeria rubra, Olea europaea, Nerium oleander, Lavandula pedunculta, and Malus domestica. It is also obtained by a one-step reduction of naturally occurring triterpenoid ursolic acid. Herein, we report the first self-assembly properties of uvaol in different neat organic liquids and aqueous organic binary liquid mixtures. Spontaneous self-assembly of uvaol in different neat liquids and binary liquid mixtures yielded garland, flower, and petal-like porous superstructures of nano- to micrometer dimensions. Utilization of self-assemblies has been demonstrated in generation of anticancer drug conjugates and the removal of carcinogenic and toxic chemicals.

Molecular insight into isoform specific inhibition of PI3K-\u03b1 and PKC-\u03b7 with dietary agents through an ensemble pharmacophore and docking studies

Dietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, β-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from − 11.5 to − 8.5 kcal mol−1. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents.

The Identification of New Triterpenoids in Eucalyptus globulus Wood.

Eight polyhydroxy triterpenoid acids, hederagenin, (4α)-23-hydroxybetulinic acid, maslinic acid, corosolic acid, arjunolic acid, asiatic acid, caulophyllogenin, and madecassic acid, with 2, 3, and 4 hydroxyl substituents, were identified and quantified in the dichloromethane extract of Eucalyptus globulus wood by comparing their GC-retention time and mass spectra with standards. Two other triterpenoid acids were tentatively identified by analyzing their mass spectra, as (2α)-2-hydroxybetulinic acid and (2α,4α)-2,23-dihydroxybetulinic acid, with 2 and 3 hydroxyl substituents. Two MS detectors were used, a quadrupole ion trap (QIT) and a quadrupole mass filter (QMF). The EI fragmentation pattern of the trimethylsilylated polyhydroxy structures of these triterpenoid acids is characterized by the sequential loss of the trimethylsilylated hydroxyl groups, most of them by the retro-Diels-Alder (rDA) opening of the C ring with a π-bond at C12-C13. The rDA C-ring opening produces ions at m/z 320 (or 318) and m/z 278 (or 277, 276, 366). Sequential losses of the hydroxyl groups produce ions with m/z from [M - 90] to [M - 90*y], where y is the number of hydroxyl substituents present (from 2 to 4). Moreover, specific cleavage in ring E was observed, passing from m/z 203 to m/z 133 and conducting other major fragments such as m/z 189.

The triterpenoid ursolic acid ameliorates stress in Caenorhabditis elegans by affecting the depression-associated genes skn-1 and prdx2

IntroductionDepression is one of the leading causes of death worldwide. Lower antioxidant concentrations and increased oxidative stress levels contribute to the development of depression. Effective and tolerable medications are urgently needed. Nrf2 and PRDX2 are promising targets in the treatment of oxidative stress and, therefore, promising for the development of novel antidepressants. Ursolic acid (UA), a natural triterpenoid found in various plants is known to exert neuroprotective and antioxidant effects. Skn-1 (which corresponds to human Nrf2) and prdx2 deficient mutants of the nematode Caenorhabditis elegans are suitable models to study the effect of UA on these targets. Additionally, stress assays are used to mimic stress or depressed state. MethodsWe examined the antioxidant activity of UA in Caenorhabditis elegans wildtype and skn-1- and prdx2-deficient strains by H2DCF-DA and juglone assays as well as osmotic and heat stress assays. Additionally, we analyzed the binding of UA to human PRDX2 and Skn-1 proteins by molecular docking and microscale thermophoresis. ResultsUA exerted strong antioxidant activities. Additionally, induction of stress resistance towards osmotic and heat stress was observed. qRT-PCR revealed that UA upregulated the gene expression of skn-1 and prdx2. Molecular docking studies supported these findings. ConclusionOur findings implicate that the strong antioxidant activity of UA may exert anti-depressive effects by its interaction with the Skn-1 transcription factor, which is part of a detoxification network, and the antioxidant PRDX2 protein, which protects the organism from the detrimental effects of radical oxygen species.