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Olech, M. Tormentic Acid. Encyclopedia. Available online: https://encyclopedia.pub/entry/11529 (accessed on 28 March 2024).
Olech M. Tormentic Acid. Encyclopedia. Available at: https://encyclopedia.pub/entry/11529. Accessed March 28, 2024.
Olech, Marta. "Tormentic Acid" Encyclopedia, https://encyclopedia.pub/entry/11529 (accessed March 28, 2024).
Olech, M. (2021, June 30). Tormentic Acid. In Encyclopedia. https://encyclopedia.pub/entry/11529
Olech, Marta. "Tormentic Acid." Encyclopedia. Web. 30 June, 2021.
Tormentic Acid
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Tormentic acid, also known as 2α,3β,19α-trihydroxyurs-2-en-28-oic acid (IUPAC Name: (1R,2R,4aS,6aR,6aS,6bR,8aR,10R,11R,12aR,14bS)-1,10,11-trihydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid), is a pentacyclic triterpene. Its biological activity e.g. anti-inflammatory, antidiabetic, antihyperlipidemic, hepatoprotective, cardioprotective, neuroprotective, anti-cancer, anti-osteoarthritic, antinociceptive, antioxidative, anti-melanogenic, cytotoxic, antimicrobial, and antiparasitic has been confirmed in in vitro and in vivo studies. This molecule and its derivatives can be found in various plant species and families (e.g. Rosaceae, Lamiaceae, Myrtaceae, Oleaceae, Urticaceae, Boraginaceae), including edibles and herbs. 

tormentic acid triterpenes pentacyclic triterpene CAS 13850-16-3 bioactivity plant metabolite tormentic acid derivatives

1. Introduction

Given the constantly growing number of diseases and the common phenomenon of drug resistance, scientists are forced to seek for more potent and less toxic treatments. Pentacyclic triterpenes represent a valuable group of compounds among natural metabolites. They are abundant in the plant kingdom and are found in various plant parts, including edibles (olive, strawberries, mango, rose fruits, apples, mulberry, quince), herbs, and herbal products. Therefore, the quantities of these compounds in human diet can be quite significant. The individual average human intake of triterpenes was determined to be approximately 250 mg per day in the Western world, and even 400 mg per day in the Mediterranean countries [1].
Pentacyclic triterpenes have been repeatedly proven to possess a broad spectrum of pharmacological activities. The health-beneficial properties of these compounds have been shown to include anti-inflammatory, anticancer, antidiabetic, cardio- and hepato-protective, antimicrobial, antiviral, antiparasitic, and other activities [2][3][4][5][6]. The affinity and spectrum of biological activity is associated with the diverse triterpene skeleton structure and connected substituents. Even structurally quite similar triterpenes may have different pharmacological potential, polarity, solubility, and bioavailability and can occur in unrelated plant species [1][7][8][9]. One of the pentacyclic triterpenes is 2α,3β,19α-trihydroxyurs-2-en-28-oic acid known as tormentic acid (TA).

2. Structure, Function, and Occurrence of TA

Tormentic acid, also known as 2α,3β,19α-trihydroxyurs-2-en-28-oic acid (IUPAC Name: (1R,2R,4aS,6aR,6aS,6bR,8aR,10R,11R,12aR,14bS)-1,10,11-trihydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid), is a compound classified as a pentacyclic triterpene. Triterpenes are synthesized via the mevalonic acid (MVA) pathway in cytosol by cyclization of the squalene molecule. Their skeleton is composed of six isoprene units (C5). Owing to the number of cyclic structures making up such compounds, there is a wide variety of triterpenes, including pentacyclic triterpenes. These can be further categorized into the oleanane, ursane, lupine, and hopane groups. Tormentic acid belongs to ursane-type pentacyclic triterpenes [10][11].
Tormentic acid has been found in various species and plant families (Table 1). Based on the collected data, it can be assumed that this compound is typical of the Rosaceae family. However, several species from Lamiaceae and Urticaceae were also reported to be sources of this compound. Moreover, TA was also found in nineteen other families including, e.g., Betulaceae, Boraginaceae, Compositae, Caryophyllaceae, Ericaceae, Oleaceae, Polygonaceae, Urticaceae, and Saxifragaceae. The presence of this triterpene was revealed in different aerial and underground plant organs [3][12][13][14][15][16][17][18][19][20][21][22].
Table 1. Confirmed botanical sources of tormentic acid (currently accepted botanical names (where applicable) according to www.theplantlist.org (accessed on 12 April 2021) are given in square brackets) and initial extrahent type used for elution of TA from plant material.

Plant Family

Species and Organ Investigated

Extraction Solvent

Ref.

Acanthaceae

Rostellularia procumbens (L.) Nees

[Justicia procumbens L.]

Whole plant

80% Ethanol

[23]

Aphloiaceae

Aphloia theiformis (Vahl) Benn.

Leaves

Methanol

[24]

Aphloiaceae

Aphloia theiformis (Vahl) Benn.

Leaves

70% Ethanol

[25]

Betulaceae

Betula schmidtii Regel

Twigs

80% Methanol

[12]

Bignoniaceae

Markhamia obtusifolia (Baker) Sprague

Leaves

Acetone

[26]

Bignoniaceae

Markhamia platycalyx (Baker) Sprague

[Markhamia lutea (Benth.) K.Schum.]

Leaves

95% Ethanol

[27]

Bignoniaceae

Markhamia tomentosa (Benth) K. Schum ex Engl.

Leaves

Ethanol

[16]

Boraginaceae

Anchusa italica Retz.

[Anchusa azurea Mill.]

Aerial parts

75% Ethanol

[15]

Boraginaceae

Arnebia euchroma (Royle) I.M.Johnst.

Roots

Methanol

[28]

Caprifoliaceae

Cephalaria tuteliana Kuș & Göktürk

Not specified

Methanol

[17]

Caryophyllaceae

Psammosilene tunicoides W.C. Wu & C. Y. Wu.

Roots

80% Ethanol

[29]

Compositae

Kleinia pendula (Forssk.) DC.

Fresh aerial parts

Methanol

[3]

Ericaceae

Rhododendron websterianum Rehder & E.H. Wilson

Fruits

95% Ethanol

[18]

Lamiaceae

Hyptis capitata Jacq.

Leaves and stems

Methanol

[30]

Lamiaceae

Isodon rubescens (Hemsl.) H.Hara

Whole plant

-

[31]

Lamiaceae

Lavandula luisieri (Rozeira) Riv.-Mart.

[Lavandula stoechas subsp. luisieri (Rozeira) Rozeira]

Flowering plant

Ethanol

[32]

Lamiaceae

Leptohyptis macrostachys (L’H’erit.), Harley and J.F.B. Pastore (previously Hyptis macrostachys Benth.)

Aerial parts

95% Ethanol

[33]

Lamiaceae

Ocimum gratissimum L.

Aerial parts

Methanol

[34]

Lamiaceae

Perilla frutescens L. Britton

Cell culture from leaves

Methanol

[35]

Lamiaceae

Perilla frutescens (L.) Britton var. acuta Kudo

Fresh leaves

Methanol

[36]

Lamiaceae

Perilla frutescens (L.) Britton

Leaves

Ethanol

[37][38]

Lamiaceae

Platostoma rotundifolium (Briq.) A. J. Paton

Aerial parts

Ethyl acetate

[39]

Lamiaceae

Salvia judaica Boiss.

Aerial parts

Ethanol

[40]

Lamiaceae

Salvia miltiorrhiza Bunge

Roots and aerial parts

Ethanol

[41]

Leguminosae

Campylotropis hirtella (Franch.) Schindl.

Roots

-

[42]

Malvaceae

Triumfetta cordifolia A.Rich.

Stems

Methylene: methanol (1:1)

[43]

Myrtaceae

Acca sellowiana (O.Berg) Burret

Callus culture from fruit pulp

Methanol

[44]

Myrtaceae

Callistemon citrinus (Curtis) Skeels

Leaves

Dichloromethane: Methanol (50:50, v/v)

Water: Ethanol (50:50, v/v)

[45]

Oleaceae

Ligustrum robustum (Roxb.) Blume

Not specified

70% Methanol

[19]

Oleaceae

Olea europaea L.

Cell-suspension cultures (callus induced from leaf stalk)

Methanol

[20]

Oleaceae

Olea europaea L.

(varieties Manzanilo, Picual, Koroneiki, and Coratina)

Fruits

Methanol

[46]

Oleaceae

Osmanthus fragrans Lour

Fruits

Methanol

[7]

Polygonaceae

Rumex japonicus Houtt.

Stems

80% Ethanol

[21]

Rosaceae

Agrimonia pilosa Ledeb.

Aerial parts

80% Ethanol

[47]

Rosaceae

Alchemilla faeroensis (J. Lange) Buser

Aerial parts

Ethanol

[48]

Rosaceae

Cotoneaster simonsii hort. ex Baker

Aerial parts (leaves and twigs)

Chloroform

[49]

Rosaceae

Crataegus pinnatifida Bunge

Leaves

80% Ethanol

[50]

Rosaceae

Cydonia oblonga Mill.

Seeds

Methanol

[51]

Rosaceae

Eriobotrya deflexa f. buisanesis

[Eriobotrya deflexa (Hemsl.) Nakai.]

Leaves

Methanol

[52]

Rosaceae

Eriobotrya fragrans Champ. ex Benth

Leaves

95% Ethanol

[53]

Rosaceae

Eriobotrya japonica (Thunb) Lindl.

Leaves

80% Methanol

[54]

Rosaceae

Eriobotrya japonica (Thunb.) Lindl.

Leaves

95% Ethanol

[55][56]

Rosacae

Eriobotrya japonica (Thunb.) Lindl

Cell suspension culture (callus induced from leaves)

Ethanol

[57]

Rosaceae

Eriobotrya japonica (Thunb.) Lindl.

Callus cultures induced from an axenic leaf

Ethanol

[58]

Rosaceae

Eriobotrya japonica (Thunb) Lindl.

Cell suspension culture (obtained from immature embryos)

95% Ethanol

[59]

Rosaceae

Eriobotrya japonica (Thunb.) Lindl.

Cell suspension culture (callus induced from leaves)

95% Ethanol

[4]

Rosaceae

Fragaria × ananassa Duch. var ‘Falandi’

Fresh fruit

95% Ethanol

[60]

Rosaceae

Fragaria × ananassa Duch. var ‘Hokouwase’

Green unripe fresh fruit

Methanol

[61]

Rosaceae

Geum japonicum auct.

[Geum macrophyllum Willd.]

Whole plant

Methanol

[62]

Rosaceae

Geum rivale L.

Flowering aerial parts

Chloroform: Methanol (9:1)

[63]

Rosaceae

Geum urbanum L.

Roots and aerial parts

Methanol

[64]

Rosaceae

Malus domestica Borkh varieties “Mela Rosa Marchigiana” and “Golden Delicious”

Pulp callus culture

Methanol

[65]

Rosaceae

Margyricarpus setosus Ruiz & Pav.

[Margyricarpus pinnatus (Lam.) Kuntze]

Aerial parts

Methanol

[66]

Rosaceae

Potentilla anserina L.

Roots

-

[67]

Rosaceae

Potentilla anserina L.

Roots

70% Ethanol

[68]

Rosaceae

Potentilla chinensis Ser.

Whole plant

95% Ethanol

[69]

Rosaceae

Potentilla fulgens

[Potentilla lineata Trevir.]

Roots

Methanol

[70]

Rosaceae

Poterium ancistroides Desf.

[Sanguisorba ancistroides (Desf.) Ces.]

Aerial parts

Ethyl acetate

[71]

Rosaceae

Poterium ancistroides Desf.

[Sanguisorba ancistroides (Desf.) Ces.]

Herb

Methanol

[72]

Rosaceae

Rosa nutkana C.Presl

Fruits

Methanol

[73]

Rosaceae

Rosa roxburghii

-

[74]

Rosaceae

Rosa rugosa Thunb.

Roots

Methanol

[75]

Rosaceae

Rubus chingii Hu

Roots and rhizomes

Ethanol

[76]

Rosaceae

Rubus crataegifolius Bunge

Leaves

Methanol

[77]

Rosaceae

Sanguisorba officinalis L.

Root

Cold water

Hot water

Methanol

[78]

Rosaceae

Sarcopoterium spinosum (L.) Spach.

Aerial parts

-

[79]

Rubiaceae

Knoxia valerianoides Thorel ex Pit.

[Knoxia roxburghii subsp. brunonis (Wall. ex G.Don) R.Bhattacharjee & Deb]

Roots

Ethanol

[80]

Sapotaceae

Tridesmostemon omphalocarpoides Engl.

Wood and stem bark

Dichloromethane: Methanol (1:1)

[81]

Saxifragaceae

Tiarella polyphylla D. Don

Whole plant

Methanol

[14]

Staphyleaceae

Euscaphis konishii Hayata

[Euscaphis japonica (Thunb.) Kanitz]

Twigs

95% Ethanol

[82]

Urticaceae

Cecropialyratiloba Miq.

[Cecropia pachystachya Trécul.)]

Roots

Methanol

[13]

Urticaceae

Cecropia pachystachya Trécul

Roots, root bark, stem and stem bark

Ethanol

[22]

Urticaceae

Debregeasia salicifolia D. Don.

[Debregeasia saeneb (Forssk.) Hepper & J.R.I.Wood]

Stems

Methanol

[5]

Urticaceae

Myrianthus arboreus P.Beauv

Stem bark

Methylated ethyl acetate

[83]

Urticaceae

Myrianthus arboreus P.Beauv

Root wood

Methylated spirit

[84]

Urticaceae

Myrianthus arboreus P.Beauv

Stems

Chloroform

[85]

Urticaceae

Myrianthus serratus (Trecul) Benth.

Trunk wood

Ethyl acetate

[86]

Urticaceae

Pourouma guianensis Aubl.

Leaves

Methanol

[87]

Urticaceae

Sarcochlamys pulcherrima (Roxb.) Gaudich.

Aerial parts

Methanol

[88]

Vochysiaceae

Vochysia divergens Pohl.

Stem bark

Ethanol

[89][90]

3. Pharmacological Activity of TA

Tormentic acid was found to possess various biological activities, including anti-inflammatory [60], antidiabetic, hypoglycemic [4][71], hepato-, neuro-, cardio-protective [15][69][91], anticancer, cytotoxic, antiproliferative [30][79][92], anti-osteoarthritic [93], antinociceptive [89], antibacterial [23], antiviral [62], and insect antifeedant [32] activities. The molecule was investigated in both in vitro and in vivo assays. Table 2 summarizes available data on TA activities and mechanisms of its action.
Table 2. Pharmacological activity of tormentic acid.

Biological Activity

Model

Ref.

Anti-inflammatory (anti-osteoarthritic):

–decreasing the interleukin (IL)-1β-stimulated expression of MMP-3 and MMP-13;

–inhibition of the IL-1β-induced expression of iNOS and COX-2, and the production of PGE2 and NO; inhibition of IL-1β-induced NF-κB activation

In vitro

Human Articular Chondrocyte Culture

[94]

Anti-inflammatory:

–inhibition of nitric oxide (NO) and prostaglandin E 2 (PGE 2) production by inhibiting iNOS and COX-2 expression;

–inhibition of LPS-stimulated production of TNF-α and IL-1β;

–activation of LXRα (liver X receptor α) and inhibition of LPS-induced NF-κB activation

In vitro

BV2 microglial cells

[95]

Antioxidative and anti-inflammatory:

–decreasing reactive oxygen species (ROS) generation;

–inhibition of the expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase (NOX);

–decreasing the production of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-1β;

–preventing phosphorylation of nuclear factor-κB (NF-κB) subunit p65 and degradation of NF-κB inhibitor α (IκBα)

In vitro

Rat vascular smooth muscle cells (RVSMCs);

[96]

Anti-inflammatory:

–decreasing paw edema;

–increasing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in liver tissue;

–attenuating the level of thiobarbituric acid reactive substances (TBARS) in the edematous paw;

–decreasing the nitric oxide (NO) levels at the serum level and diminishing the serum tumor necrosis factor (TNF-α);

–decreasing the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)

Ex vivo and in vivo

RAW264.7 macrophages and λ-carrageenin-induced hind paw edema model in mice

[57]

Anti-inflammatory:

–reducing the production of NO, prostaglandin E2 (PGE2), and tumor necrosis factor-α (TNF-α) induced by LPS;

–suppressing the LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-α at the mRNA and protein levels;

–decreasing DNA binding of nuclear factor kappa B(NF-kB) and nuclear translocation of the p65 and p50 subunits of NF-kB;

–suppressing degradation and phosphorylation of inhibitor of kappa B-Alpha

In vitro

LPS stimulated RAW264.7 cells

[97]

Anti-inflammatory/antinociceptive (20–30 mg/kg)

In vivo

Writhing Assay;

Hot-Plate Test;

Carrageenan-Induced Edema in Sprague–Dawley Rats

[75]

Anti-inflammatory:

–inhibition of the production of interleukin-6 and interleukin-8;

–inhibition of TLR4 (Toll-like receptor 4) expression;

–inhibition of activation of nuclear factor kappa B (NF-κB);

–inhibition of activation of mitogen-activated protein kinases (MAPKs)

In vitro

LPS-stimulated human gingival fibroblasts (HGFs)

[98]

Anti-inflammatory:

–inhibition of LPS-induced NO production

In vitro

[52]

Anti-inflammatory:

–inhibitory effect on IFN-γ secretion

–inhibition of COX-1 and COX-2

–apoptosis-inducing effect

In vitro

LPS-stimulated Raw 264.7 macrophage

[34]

–Anti-inflammatory;

–Potent inhibitory effect on

Epstein-Barr virus early antigen (EBV-EA) activation;

–Antitumor-promoting activity (strong)

In vivo:

–TPA-induced ear edema inflammation in mice;

–two-stage carcinogenesis test of mouse tumor;

In vitro

EBV-EA activation experiment

[37]

–Cytotoxic activity against the HeLa cell line;

–Antidiabetic activity

–Inhibition of PTP1B (Protein tyrosine phosphate)

In vitro

[47]

Cytotoxic to sensitive and multidrug resistant leukemia cell lines;

Active toward a multidrug resistant (MDR) leukemia cell line overexpressing glycoprotein-P (P-gp)

In vitro

(anti-MDR activity in Lucena-1, a leukemia cell line that overexpresses P-gp and presents cross resistance to several unrelated cytotoxic drugs)

[13]

Cytotoxic

In vitro

HCT-8, A549, P-388, L-1210 tumor cell lines

[30]

–Cytotoxicity in human oral tumor cell lines: human salivary gland tumor and human oral squamous cell carcinoma

–Inhibition of the activation of Epstein–Barr virus early antigen (EBV-EA)

In vivo

EBV genome-carrying lymphoblastoid cells

In vitro

human oral squamous cell carcinoma (HSC-2), human salivary gland tumor (HSG)

[58]

Antidiabetic and antihyperlipidemic:

–Antihyperlipidemic: decreasing gene expressions of fatty acids, increasing the content of phosphorylated AMPK-α in liver and adipose tissue, inhibition of DGAT 1 expression, and decreasing the level of triglycerides in blood

–Antidiabetic: down-regulation of phosphenolpyruvate carboxykinase (PEPCK), improving insulin sensitization (at 1.0 g/kg), and decreasing the expression of the hepatic and adipose 11-β-hydroxysteroid dehydroxygenase (11β-HSD1) gene

In vivo

high-fat fed C57BL/6J mice

[4]

Hypoglycemic: decreasing the blood glucose level (at 10 mg/kg)

In vivo

normoglycemic Wistar rats

[71]

Hypoglycemic effect (at 30 mg/kg):

–decreasing glucose levels in normal rats;

–increasing fasting plasma insulin levels

Acute toxicity not observed (at 600 mg/kg, intraperitoneally)

In vivo

normoglycemic, hyperglycemic,

and streptozotocin-induced diabetic Wistar rats

[72]

Hypoglycemic effect:

–direct stimulation of insulin secretion by pancreatic islets of Langerhans

In vitro

pancreatic islets of Langerhans

isolated from fed Wistar rats

[99]

Antidiabetic:

–inhibition of alfa-glucosidase

In vitro

[70]

Antidiabetic and antihyperlipidemic activity:

–lowering blood glucose, triglycerides, free fatty acids, leptin levels;

–decreasing the area of adipocytes and ballooning degeneration of hepatocytes;

–reducing visceral fat mass, reducing hepatic triacylglycerol contents;

–enhancing skeletal muscular Akt phosphorylation and increasing insulin sensitivity;

–decreasing blood triglycerides by down-regulation of the hepatic sterol regulatory element binding protein-1c (SREBP-1c) and apolipoprotein C-III (apo C-III) and increasing the expression of peroxisome proliferator activated receptor (PPAR)-α

In vivo

C57BL/6J mice with induced type 2 diabetes and hyperlipidemia

[100]

Influencing the processes present in vasculoproliferative diseases (diseases related to vascular smooth muscle cell (VSMC) abnormal proliferation):

–increasing apoptosis of serum-deprived A7r5 cells and inhibiting A7r5 cell proliferation;

–rapid induction of significant modifications in the vascular smooth muscle cell (VSMC) phenotype;

–inhibition of VSMC proliferation and VSMC cell death

In vitro

Clonal rat embryonic VSMCs (A7r5) and human umbilical vein endothelial cells (HUVEC)

[90]

Anti-melanogenesis effect (melanin synthesis inhibitory activity with less cytotoxicity)

Antibacterial activity against Propionibacterium acnes

Promotion of skin collagen synthesis

In vitro

Mouse melanoma cell line B16;

Propionibacterium acnes (NBRC 107605)

[101]

Hepatoprotective (preventing fulminant hepatic failure):

–blocking the NF-κB signaling pathway for anti-inflammatory response (alleviating the pro-inflammatory cytokines, e.g., TNF-α and NO/iNOS by inhibiting nuclear factor-κB activity);

–inhibition of hepatic lipid peroxidation;

–decreasing serum aminotransferase and total bilirubin activities;

–attenuating hepatocellular apoptosis

In vivo

lipopolysaccharide/d-galactosamine-induced acute hepatic failure in male C57BL/6 mice

[69]

Hepatoprotective:

–inhibition of the production of pro-inflammatory factors such as: tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and IL-6;

–inhibition of inducible NO synthetase (iNOS) and cyclooxygenase-2 (COX-2);

–inhibition of nuclear factor –κB (NF-κB) activation;

–inhibition of the activation of mitogen-activated protein kinases (MAPKs);

–retention of enzymes (essential for the antioxidative properties of liver): superoxidase dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT)

In vivo

Acetaminophen-induced hepatotoxicity in male ICR mice

[102]

Protective effect against liver fibrosis:

–inhibition of the activation of hepatic stellate cells;

–reducing aspartate aminotransferase, alanine aminotransferase, and total bilirubin activity;

–inhibition of expression of collagen type I and III; alleviation of collagen-based extracellular matrix deposition;

–promoting cell apoptosis via blocking of the PI3K/Akt/mTOR and NF-κB signaling pathways

In vitro

Hepatic stellate cells (HSCs) stimulated with platelet-derived growth factor-BB

[103]

Cardioprotective

(protective effects on hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury)

In vitro

Neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation (H/R) insult

[15]

Anti-hypoxic

(protecting vascular endothelial cells against hypoxia-induced damage via the PI3K/AKT and ERK 1/2 signaling pathway)

In vitro

(EA.hy926 cells)

[104]

Antiproliferative:

–causing apoptosis and G0/G1 phase arrest in cancer cell lines;

–induction of cell cycle arrest via changing the cyclin D1 and cyclin-dependent kinase 4 mRNA expression levels;

–down-regulation of the NF-kappa-B cell survival pathway and the expression level of phosphorylated ERK (extracellular signal-regulated kinase)

In vitro

Cancer cell lines: human hepatoma cells HepG-2 and Bel-7402, lung cancer cell A549, breast cancer cell MCF-7

Normal LO2 cell line

[105]

Antiproliferative

In vitro

[79]

Anti-cancer (anti-hepatocellular carcinoma activity):

–decreasing cell viability, colony formation, and cell migration;

–induction of apoptosis;

–changing the levels of caspase-3 and poly ADP-ribose polymerase expression

In vitro

Hepatocellular carcinoma cells (HepG2, Bel-7405, Sk-hep-1)

[59]

Anti-cancer:

–induction of cell cycle arrest;

–enhancement of ROS production;

–targeting the mTOR/PI3K/AKT signaling pathway in cisplatin-resistant human cervical cancer cells

In vitro

Cisplatin-resistant human cervical cancer cells (HeLa cells)

[92]

Anti-osteoarthritic (inhibition of IL-1β-induced chondrocyte apoptosis by activation of the PI3K/Akt signaling pathway):

–inhibition of IL-1β induced cytotoxicity and apoptosis in chondrocytes;

–increasing B-cell lymphoma (Bcl)-2 expression;

–decreasing capsase-3 activity and Bax expression;

–increasing the expression of p-PI3K and p-Akt in IL-1β-induced chondrocytes

In vitro

IL-1β-treated human osteoarthritic chondrocytes

[93]

Antinociceptive (anti-allodynic)

In vivo

two models of chronic pain (neuropathic pain and inflammatory pain) in mice

[89]

Antibacterial

In vitro

[23]

Antibacterial and antibiofilm effect:

–inhibition of growth of P. aeruginosa;

–depolarization of bacterial P. aeruginosa membrane;

–inhibition of biofilm formation due to suppressed secretion of pyoverdine and suppressed secretion of protease and swarming motility of P. aeruginosa

In vivo

Mouse model of catheter infection for evaluation of antibiofilm activity and BALB/c mouse model for determination of in vivo toxicity

In vitro

P. aeruginosa cultures; murine macrophage cell line (RAW 264.7) for cytotoxicity assay

[88]

Antibacterial against S. aureus

Antifungal against C. albicans

In vitro

[64]

Antibacterial against S. aureus

In vitro

[73]

Bacteriostatic against S. aureus:

–inhibition of extracellular protease production resulting in inhibition of S. aureus growth

In vitro

[45]

Antivirus: inhibition of virus HIV-1 protease

In vitro

[62]

Insect antifeedant

In vivo

Spodoptera littoralis L6 larvae

[32]

Neuroprotective:

–protecting against neurotoxicity (preventing neuronal loss);

–blocking MPP+-induced apoptosis;

–inhibiting intracellular accumulation of reactive oxygen species (ROS);

–protecting from neuronal death through reversing the inhibition of the PI3-K/Akt/GSK3b pathway

In vitro

Parkinson’s disease cellular model: MPP+-induced neurotoxicity in human neuroblastoma SH-SY5Y cells

[106]

Neuroprotective:

–decreasing amyloid plaque deposition;

–reducing microglial activation and decreasing the secretion of pro-inflammatory factors;

–suppressing the production of pro-inflammatory markers and the nuclear translocation of nuclear factor-κB (NF-κB);

–reducing inhibited neurotoxicity and improving neuron survival

In vivo

Amyloid β precursor protein (APP)/presenilin 1 (PS1) transgenic mice

In vitro

BV2 microglia cells

[91]

4. Derivatives of Tormentic Acid

Although tormentic acid (TA) is found in a variety of plants in its “basic form”, it also occurs in the form of various derivatives. Some common structures are shown in Figure 1. TA and its derivatives are found in commonly known cultivated and consumed fruits or vegetables, e.g., strawberries [107], rose fruits [73], apples [65], and quince [51].
Figure 1. Structure of tormentic acid (1) and its common natural derivatives; 2—euscaphic acid; 3—3β-acetyl tormentic acid; 4—rosamultin; 5—23-hydroxytormentic acid; 6—3-O-trans-caffeoyltormentic acid; 7—3-O-cis-p-coumaroyltormentic acid.
The reported TA derivatives include:
  • euscaphic acid (EA)—a stereoisomer of tormentic acid [9][77][75][83][108][109][110];
  • 2-epi-tormentic acid (2β,3β,19α-trihydroxy-urs-12-en-28-oic acid) [9][111];
  • acetylated compounds, e.g., 3β-acetyl tormentic acid; 2α-acetyl tormentic acid [13][112][113][114]
  • hydroxylated derivatives, e.g., 23-hydroxytormentic acid [77]; 24-hydroxytormentic acid [43][115]; 11α-hydroxytormentic acid [25][107][109]; hydroxytormentic acid [25];
  • coumaroyl esters, e.g., 3-O-cis-p-coumaroyltormentic acid; 3-O-trans-p-coumaroyltormentic acid [6][19][116];
  • caffeoyl esters, e.g., 3-O-trans-caffeoyltormentic acid [6][52];
  • glucosides, e.g., tormentic acid 3β-O-β-d-quinovopyranoside; tormentic acid 3β-O-β-d-fucopyranoside; tormentic acid 3β-O-β-d-rhamnopyranoside; rosamultin (tormentic acid 28-O-glucoside) [77][75][107][117][118]; tormentic acid β-d-glucopyranosyl ester [66][119];
  • others, e.g., 6-methoxy-β-glucopyranosyl ester [109]; dihydrotormentic acid and methoxytormentic acid [107]; 3b-p-hydroxybenzoyloxytormentic acid [120]; (3R,19R)-methyl-3,19-dihydroxy-2-oxo-urs-12-en-28-carboxylate; (2R,19R)–methyl-2,19-dihydroxy-3-oxo-urs-12-en-28-carboxylate; (19R)-methyl-2,19-dihydroxyursa-3-oxo-1,12-dien-28-carboxylate; (2S,3R,19R)–methyl-2,3,19-trihydroxyurs-12-en-28-carboxylate; (2R,3R,19R)-2,3-bis(acetyloxy)-19-hydroxyurs-12-en-28-carboxylic acid; (2R,3R,19R)-2-acetyloxy-3,19-dihydroxyurs-12-en-28-carboxylic acid; (2R,3R,19R)-3-acetyloxy-2,19-dihydroxyurs-12-en-28-carboxylic acid; (3R,19R)–methyl-3-acetyloxy-19-hydroxy-2-oxo-urs-12-en-28-carboxylate; (2R,19R)-methyl-2-acetyloxy-19-hydroxy-3-oxo-urs-12-en-28-carboxylate; (2R,3R,19R)–methyl-2,3-bis(chloroacetyloxy)-19-hydroxy-urs-12-en-28-carboxylate; (2R,3R,19R)–methyl-2-chloroacetyloxy-3,19-dihydroxyurs-12-en-28-carboxylate; (2R,3R,19R)–methyl-3-chloroacetyloxy-2,19-dihydroxyurs-12-en-28-carboxylate [9].

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