Pistagremic Acid Research Articles

Multi-target anticancer activity of compounds isolated from galls of Pistacia chinensis subsp. integerrima: A mechanistic investigation

The usage of Pistacia chinensis subsp. integerrima (J.L. Stewart) Rech. f. and its extracts in traditional medicine is well-documented, since this plant is known for its anti-infective, antidiabetic and antioxidant properties. Additionally, recent studies described the antiproliferative activity of its extracts on cancer cell models. Nevertheless, the mechanisms of action underlying this biological effect still have to be fully elucidated. In this study, we focused our attention on the characterization of the bioactivity profile of the flavonoids spinacetin (1) and patuletin (2) and of the triterpene pistagremic acid (3) extracted from the galls of P. integerrima. The compounds were tested in vitro against aldose reductase and thymidine phosphorylase, two targets that are attracting growing attention in the field of drug discovery due to their involvement in metabolism regulation and angiogenesis. Computational studies were used to rationalize experimental data, and the results support the potential of spinacetin (1) as a promising bioactive multi-target anticancer agent.

Antifungal and Antiproliferative Activity of Pistagremic Acid and Flavonoids Extracted from the Galls of Pistacia chinensis subsp. integerrima.

Pistacia chinensis subsp. integerrima (J.L. Stewart) Rech. f. is a plant known for its therapeutic applications in traditional medicine, which are related to its antimicrobial, anticancer, antioxidant, anti-inflammatory, analgesic, antidiarrheal, and muscle relaxant properties. The galls of P. chinensis are rich in triterpenes and flavonoids, and we here report the extraction of pistagremic acid (1), apigenin (2) and sakuranetin (3) from this source. The isolated compounds were tested against Aspergillus flavus, Candida albicans, Candida glabrata, Fusarium solani, Microsporum canis and Trichoderma longibrachiatum. The results highlighted the antimicrobial activity of flavonoids 2 and 3, suggesting that this class of molecules may be responsible for the effect related to the traditional use. On the other hand, when the compounds and the extract were tested for their antiproliferative activity on a panel of 4 human cancer cell lines, the triterpene pistagremic acid (1) showed a higher potential, thus demonstrating a different bioactivity profile. Structure-based docking and molecular dynamics simulations were used to help the interpretation of experimental results. Taken together, the here reported findings pave the way for the rationalization of the use of P. chinensis extracts, highlighting the contributions of the different components of galls to the observed bioactivity.

Ethnobotany, ethnopharmacology, phytochemistry, biological activities and toxicity of Pistacia chinensis subsp. integerrima: A comprehensive review.

Pistacia chinensis subsp. integerrima (J. L. Stewart ex Brandis) Rech. F. is a valuable medicinal plant used in south Asian communities for the treatment of asthma, diarrhea, diabetes, liver diseases, fever, pain and inflammation. This review critically evaluates the available information on P. integerrima's ethnobotany, ethnopharmacology, phytochemistry, pharmacology and toxicology. Electronic databases such as Google Scholar, PubMed, Springer Link, and so forth, books and theses were used to find relevant information about P. integerrima using keywords such as "Pistacia integerrima," "P. integerrima," "Ethnopharmacology," "Phytochemistry," "Traditional uses". A number of in vitro and in vivo pharmacological activities have been reported; however, the most promising and attractive activity observed was its role in Alzheimer, diabetes, convulsions, cancer, asthma, diabetes, diarrhea and as an immunomodulatory, analgesic and antiinflammatory. In addition, Pistagremic acid exerted anti-Alzheimer's activity based on a hitherto unknown mechanism through interference with the amyloidogenic pathway. Most of the pharmacological activities were linked with traditional uses. A range of compounds have been reported from P. integerrima extracts including triterpenes, volatile oils, flavonoids, fatty acids, phenolic, phytosterols, tannins and oligosaccharides as well as unknown triterpenes and flavonoids. Pistagremic acid, a novel triterpene, was attributed to most of the activities. in vivo toxicological studies in animal suggested a toxic dose of 1,500 mg kg-1 , for its methanolic extract. All reported pharmacological activities were carried out in vitro and a gap in research, that is, preclinical and clinical investigation exists. Its outstanding activity as an antiglycating agent is the most promising and a so far unique activity and needs further evaluation. In-depth research and clinical trials on human subjects in order to investigate P. integerrima pharmacological activity, clinical efficacy and safety are crucial next steps.

Muscle relaxant activities of pistagremic acid isolated from Pistacia integerrima.

The aim of the current work was to explore the muscle relaxant effect of pistagremic acid (PA) isolated from Pistacia integerrima in various animal paradigms. In a rotarod test, PA caused a significant (p<0.05) muscle relaxant potential in a dose-dependent manner. When studied in the inclined plane test, pretreatment with PA (5 and 10 mg/kg) caused promising activity (p<0.05) after treatment for 30, 60 and 90 min. The muscle relaxant potential of PA was strongly complimented by the traction and chimney tests, showing a dominant effect after 60 min of treatment. In conclusion, PA possesses strong muscle relaxant activity in various animal-based models.

Gastrointestinal Motility and Acute Toxicity of Pistagremic Acid Isolated from the Galls of Pistacia integerrima

Pistacia integerrima has many medicinal uses in therapeutic as well as folk medicine. P. integerrima has been used for the treatment of different ailments such as blood purifier, anti-inflammatory, and as remedy for gastrointestinal disorders such as vomiting and diarrhea, expectorant, cough, asthma and fever. The main objective of this research work was to evaluate the effect of pistagremic acid (PA) isolated from the galls of Pistacia integerima in acute toxicity and gastrointestinal (GIT) motility tests. Compound 1 namely pistagremic acid (PA) (at 10, 50, 100 mg/kg i.p) were assessed for their in-vivo gastrointestinal motility test using charcoal screening model. Results revealed that pretreatment of PA exhibited substantial safety in acute toxicity test up to the dose of 500 mg/kg p.o. However, when studied in charcoal meal GI transit test, PA caused significant (p < 0.05) attenuation of GIT motility and an increase in intestinal transit time, comparable to atropine (a muscarinic receptor blocking agent). In conclusion, PA displayed a strong dose-dependent reduction in GIT motility with considerable safety.

Reversal of Multidrug Resistance and Computational Studies of Pistagremic Acid Isolated from Pistacia integerrima.

Pistagremic acid (PA) is a bioactive triterpenoid isolated from various parts of Pistacia integerrima plants. The aim of this research was to investigate PA for reversion of multidrug resistant (MDR) mediated by P-glycoprotein using rhodamine-123 exclusion study on a multidrug resistant human ABCB1 (ATP-binding cassette, sub-family B, member 1) gene-transfected mouse T-lymphoma cell line in vitro. Results were similar to those with verapamil as a positive control. Docking studies of PA and standard Rhodamine123 were carried out against a P-gp crystal structure which showed satisfactory results. Actually, PA cannot bind exactly where co-crystallized ligand of P-gp is already present. However, the docking study predicted that if a compound gives a lesser score then it may have some potency. The docking scores of PA and Rhodamine were similar. Therefore, we can conclude that there are certain important chemical features of PA which are responsible for the inhibiting potency of P-gp.

Pistagremic acid, a novel β-secretase enzyme (BACE1) inhibitor from Pistacia integerrima Stewart

A new triterpenic compound named pistagremic acid (PA) was once again isolated from Pistaciaintegerrima. The β-secretase inhibition study was carried out. Compound PA was found significantly active against β-secretase enzyme (BACE1) with IC50 value of 350 ± 2 nM in comparison to the standard inhibitors [Asn670, Sta671, Val672]-amyloid-β/A4 precursor protein 770 fragment 662–675 (IC50 = 290.71 ± 1 nM). The selectivity of this compound was also evaluated against the acetylcholinesterase and butyrylcholinesterase enzymes. Interestingly compound PA was found to be inactive against them and showed selectivity towards β-secretase enzyme (BACE1).

In-vivo antinociceptive, anti-inflammatory and antipyretic activity of pistagremic acid isolated from Pistacia integerrima

The current study was designed to explore the antinociceptive, antiinflammatory and antipyretic activity of pistagremic acid (PA), isolated from Pistacia integerima bark in various animal paradigms. The results illustrated significant inhibition of noxious stimulation in acetic acid induced writhing test with maximum effect of 68% at 10mg/kg i.p. In tail immersion test, pretreatment with PA demonstrated marked activity during various assessment times in a dose dependent manner. The maximum pain inhibition was 59.46% at 10mg/kg i.p. after 90min of PA treatment. However, the injection of naloxone did not antagonize this induced effect. PA significantly ameliorated post carrageenan induced edema dose dependently during various stages of inflammation. The effect was most dominant (60.02%) after 3rd h of drug administration when examined for 5h. Similarly, it provoked dose dependent antipyretic effect in febrile mice with maximum of 60.04% activity at 10mg/kg i.p. after 3rd hour of PA post treatment. Furthermore, molecular docking was carried out to understand the binding mode of PA. From the docking study it was observed that PA fits well in the active site of COX-2 enzyme due to hydrogen and hydrophobic moiety interactions to the important active site of molecule.In conclusion, PA possesses strong peripheral and central antinociceptive activity independent of opioidergic effect which was augmented by its anti-inflammatory and antipyretic activities.

Pistagremic Acid, a Novel Antimicrobial and Antioxidant Isolated from Pistacia integerrima

In the present research, a new triterpenic compound was isolated from galls of Pistacia integerrima. The structure of this novel compound was identified using modern sophisticated spectroscopic techniques such as HR-EI-MS, FAB, 1D, and 2D NMR spectral data and single crystal X-ray diffraction methods. The compound was confirmed to be 2-methyl-6-(4,4,10,13,14-pentamethyl-3-O-2,3,4,5,6,7,10,11,12,13,14,15,16,-17-tetradecahydro-1H-cyclopenta[a]-phenanthren-17-yl)hept-2-enoic acid and named pistagremic acid, which has antimicrobial and antioxidant properties.

Density functional theory and phytochemical study of Pistagremic acid

We report here for the first time a comparative theoretical and experimental study of Pistagremic acid (P.A). We have developed a theoretical model for obtaining the electronic and spectroscopic properties of P.A. The simulated data showed nice correlation with the experimental data. The geometric and electronic properties were simulated at B3LYP/6-31 G (d, p) level of density functional theory (DFT). The optimized geometric parameters of P.A were found consistent with those from X-ray crystal structure. Differences of about 0.01 and 0.15Å in bond length and 0.19–1.30° degree in the angles, respectively; were observed between the experimental and theoretical data. The theoretical vibrational bands of P.A were found to correlate with the experimental IR spectrum after a common scaling factor of 0.963. The experimental and predicted UV–Vis spectra (at B3LYP/6-31+G (d, p)) have 36nm differences. This difference from experimental results is because of the condensed phase nature of P.A. Electronic properties such as Ionization Potential (I.P), Electron Affinities (E.A), co-efficient of highest occupied molecular orbital (HOMO), co-efficient of lowest unoccupied molecular orbital (LUMO) of P.A were estimated for the first time however, no correlation can be made with experiment. Inter-molecular interaction and its effect on vibrational (IR), electronic and geometric parameters were simulated by using Formic acid as model for hydrogen bonding in P.A.

Broad Spectrum Anticancer Activity of Pistagremic Acid

Background: Pistagremic acid; 3-methyl-7-(4,4,10,13,14-pentamethyl-3-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthr-en-17-yl)-oct-3-enoic acid was isolated from the chloroform fraction of Pistacia integerrima. Cytotoxic evaluation against NCI-60 DTP human tumor cell line was performed. Methods: The anticancer assays for this compound were performed in accordance with the protocol of the Drug Evaluation Branch, by the National Cancer Institute (NCI) Developmental Therapeutic Program (www.dtp.nci.nih.gov) to be screened for their anticancer activity in vitro. Results: It showed broad spectrum antiproliferative activity with an average GI50, and TGI, values 0.103 μM and 0.259 μM, respectively. It also showed significant LC50 value at the average 0.634 μM against all cell lines excluding K-562, RPMI-8226, NCI-H226, and NCI-H460 cell-lines. Conclusions: Pistagremic acid showed cytotoxicity for all tested cancer cell line, thus it may serve as a potential structure lead for the development of new anticancer drugs.

Pistagremic acid, a glucosidase inhibitor from Pistacia integerrima

Pistacia integerrima Stewart in traditionally used as folk remedy for various pathological conditions including diabetes. In order to identify the bioactive compound responsible for its folk use in diabetes, a phytochemical and biological study was conducted. Pistagremic acid (PA) was isolated from the dried galls extract of P. integerrima. Strong α-glucosidase inhibitory potential of PA was predicted using its molecular docking simulations against yeast α-glucosidase as a therapeutic target. Significant experimental α-glucosidase inhibitory activity of PA confirmed the computational predictions. PA showed potent enzyme inhibitory activity both against yeast (IC50: 89.12±0.12μM) and rat intestinal (IC50: 62.47±0.09μM) α-glucosidases. Interestingly, acarbose was found to be more than 12 times more potent an inhibitor against mammalian (rat intestinal) enzyme (having IC50 value 62.47±0.09μM), as compared to the microbial (yeast) enzyme (with IC50 value 780.21μM). Molecular binding mode was explored via molecular docking simulations, which revealed hydrogen bonding interactions between PA and important amino acid residues (Asp60, Arg69 and Asp 70 (3.11Å)), surrounding the catalytic site of the α-glucosidase. These interactions could be mainly responsible for their role in potent inhibitory activity of PA. PA has a strong potential to be further investigated as a new lead compound for better management of diabetes.

Pistagremic acid a new leishmanicidal triterpene isolated from Pistacia integerrima Stewart

The present study was designed to investigate the whole plant of Pistacia integerrima Stewart in order to examine the pharmacological basis of the use of the plant in folk medicine for the treatment of infectious diseases and disorder. Phytochemical and pharmacological studies led to the isolation of a new triterpene pistagremic acid (3-methyl-7-(4,4,10,13,14-pentamethyl-3-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-oct-3-enoic). Pistagremic acid showed significant leishmanicidal activity (IC50: 6.71 ± 0.09 µM) against Leishmania major (DESTO) promastigotes in comparison to standard compound amphotericin B (IC50: 0.21 ± 0.06 µM).