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    Topic review

    Tormentic Acid

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    Submitted by: Marta Olech

    Definition

    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. 

    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].

    The entry is from 10.3390/molecules26133797

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