Pistacia lentiscus L. (PlL) is a wild-growing shrub rich in terpenoids and polyphenols, the oil and extracts of which have been widely used against inflammation and infections, and as wound healing agents.
Group | Species |
---|---|
Lenticella | Pistacia mexicana HBK |
Pistacia texana Swingle | |
Eu lentiscus | Pistacia lentiscus L. (mastic tree) |
Pistacia saporte Burbar | |
Pistacia weinmannifolia Poisson | |
Butmela | Pistacia atlantica Desf. |
Eu terebintus | Pistacia chinensis Bge. |
Pistacia khinjuk Stocks | |
Pistacia palaestina Bois. | |
Pistacia terebinthus L. | |
Pistacia vera L. |
Geographical Area | Ailment/Uses | Ref. |
---|---|---|
Sardinia, Italy | Oral cavity inflammation and infection, tooth ache, osteoarthritis, bronchitis, cough sedative, antipyretic, allergies, asthma, ulcerations, gastrointestinal disorders, wound healing and haemostatic | [19,25,26,27,28,29,30,31] |
Southern regions of Italy (Calabria and Campania) | Inflammation of the mouth, tooth ache, mycosis, herpes and refreshing feet | [27,32] |
Central regions of Italy (Abruzzi, Marche and Tuscany), Spain | Hypertension and cardiac diseases | [27,33] |
Spain | Analgesic, teeth strengthening, hypertension and cardiac diseases | [33,34] |
Tunisia | Antipyretic, astringent, eczema, paralysis, antimicrobial, throat infections, asthma, hypertension, cardiac diseases, paralysis, diuretic properties, renal stones, jaundice, antiatherogenic effect, antihepatotoxic and gastrointestinal diseases | [27,35] |
Algeria | Stomach ache, dyspepsia, peptic ulcer, diarrhea and rheumatism | [36] |
Morocco and North Africa |
Hypertension, cardiac diseases and diabetes | [37] |
Libya | Immuno-stimulant and antimicrobial | [23] |
Jordan | Ameliorate jaundice | [38,39] |
Israel | Heartburn and soothes stomach | [40] |
Iran | Gum tissue strengthened, breath deodorizer, brain and liver tonic and gastrointestinal ailments | [41,42] |
Turkey | Throat infections, asthma, eczema, stomach ache, renal stones, paralysis, diarrhea, jaundice, anti-inflammatory, antimicrobial, antipyretic, stimulant and astringent | [43] |
Table 3. Chemical profiles of Pistacia lentiscus
Plant Material | Origin | Main Components of Essential Oils or Plant Extracts | Test Assays | Ref. |
---|---|---|---|---|
Essential oils from | ||||
Leaves | Spain | β-myrcene (19%), α-terpineol + terpinen-4-ol (15%), α-pinene (11%) | GC-MS | [53] |
Unripe fruit | β-myrcene (54%), α-pinene (22%), | GC-MS | ||
Ripe fruit | β-myrcene (19%), α-pinene (11%), δ-3-carene | GC-MS | ||
Leaves | Egypt | δ-3-carene (65%), sesquiterpene alcohols (4%) | GC-MS | [52] |
Leaves | Greece | Myrcene (20.6%), germacrene D (13.3%), E-caryophyllene (8.3%), α-cadinol (7.3%), t5-cadinene (7.0%) | GC-MS | [62] |
Leaves | Turkey | Terpinen-4-ol (29.9%), α-terpineol, (11.6%), limonene (10.6%), (Z)-3-Hex-1-enyl benzoate (6.7%), α-pinene (4.2%), β-caryophyllene (3.2%) | GC-MS | [63] |
Leaves | Morocco | Myrcene (39.2%), limonene (10.3%), β-gurjunene (7.8), germacrene (4.3%), α-pinene (2.9%), muurolene (2.9%) | GC-FID; GC-MS | [54] |
Leaves | Tunisia | α-pinene (16.8%), 4-terpinenol (11.9%), β-phellandrene (8.9%), sabinene (5.7%9, γ-terpinene (5.5%) and β-pinene (4.3%) | GC–MS | [55] |
Aerial parts | Algeria (Algiers) | Longifolene (12.8%), γ-cadinene (6.2%), trans-β-terpineol (5%), α-acorneol (4.6%), γ-muurolene (4.2%), β-pinene (3.7%) | GC, GC-MS | [64] |
Algeria (Tizi-Ouzou) |
Longifolene (16.4%), trans-β-terpineol (15.6%), terpinen-4-ol (7%), γ-muurolene (5.7%), β-pinene (3.3%), α-pinene (2.8%) | GC, GC-MS | ||
Algeria (Oran) | α-pinene (19%), trans-β-terpineol (13.1%), sabinene (12.6%), β-pinene, (6.5%), (E)-β-ocimene (5.5%), longifolene (5.2%) | GC, GC-MS | ||
Leaves | Sardinia (Italy) | α-pinene (14.8–22.6%), terpinen-4-ol (14.2–28.3%), β-myrcene (1.0–18.3%), p-cymene (14.8–16.2%), sabinene (2.5–8.1%), limonene (0.9–3.8%) | GC-MS | [19] |
Leaves | Greece | α-pinene (9.4–24.9%), terpinen-4-ol (6.8–10.6%), p-cymene (0.5–7.5%), limonene (9.0–17.8%), γ-terpinene (3.1–3.6%) | GC-MS | [51] |
Leaves | Sardinia (Italy) | α-pinene, α-thujene, camphene, sabinene, β-pinene, myrcene, α-phellandrene, α-terpinene, para-cymene, β-phellandrene, trans-ocemene, γ-terpene, terpinolene, 2-nonanone, linalool, isopentyl isovalerate, terpin-4-ol, α-terpiniol and others. | GC-MS | [29] |
Leaves | Algeria | β-caryophyllene (54–198 μg g−1 dw), δ-cadinene (15–186 μg g−1 dw), cubebol (15–117 μg g−1 dw), β-bisabolene (22.1- 105 μg g−1 dw), α-pinene (1.9–105 μg g−1 dw), γ-muurolene (29.7–67.3 μg g−1 dw) | GC-MS | [65] |
Leaves | Sardinia (Italy) | Germacrene D (19.9%), β-caryophyllene (6.6%), α-pinene (6.3%), myrcene (3.9%), β-phellandrene (3.7%), α-humulene (2.4%) | GC-MS | [12] |
Leaves | Eastern Morocco | Taforalt and Saidia areas: limonene, α-pinene, α-terpineol and β-caryophyllene;Laayoune and Jerada areas: myrcene and β-caryophyllene. |
GC-MS | [66] |
Fresh leaves | Greece | δ-germacrene (24.78%), myrcene (19.5%), α-cadinol (9.53%), γ-cadinene (5.59%), trans-caryophyllene (5.03%), limonene (4.84%) | GC-MS | [67] |
Dried leaves | δ-cadinene (17.04%), α-amorphene (10.32%), δ-germacrene (9.01%), trans-caryophyllene (6.32%), α-cubebene (5.55%), naphthalene (4.13%) | GC-MS | ||
Ripe fruits | Tunisia | Phenolic composition of seed oil (concentrations not shown) | GC-MS | [68] |
Leaves | Tunisia | Germacrene D (11.9%), pinene (9.9%), limonene (8.5%), δ-cadinene (8.5%), β-caryophyllene (8.2%), terpinen 4-ol (5.1%) | GC-FID, GC-MS | [69] |
Fruits | Tunisia | α-pinene (13.35%), α-phellandrene (10.12%), β-phellandrene (10.45%), sabinene (7.01%), germacrene-D (6.86%), β-caryophyllene (4.58%) | GC-MS | [70] |
Leaves | Tuscany (Italy) | α-pinene (24.6–9.2%), 1–4 terpineol (14.9–7.1%), β-phellandrene (11.4–4.7%), β-pinene (8.6–1.2%), β-mircene (9.2–0.7%), α-terpineol (8.4–4.9%) | GC-MS | [71] |
Leaves and twigs | Sardinia (Italy) | Terpinen-4-ol (25.2%), α-phellandrene (11.9%), β-phellandrene (10.2%), γ-terpinene (10.1%), α-pinene (7.6%) | GC-FID, GC-MS | [72] |
Fruits | Tunisia | 4-{3-[(2hydroxybenzoyl) amino] anilino}4-oxobut-2-enoic acid (28.96%), β-myrcene (11.47%), 3-pentadecylphenol (8.51%), p-tolyl ester (8.36%), amino formic acid (7.51%) | GC–MS | [73] |
Male flowers | Tunisia | β-caryophyllene (12.8%), germacrene-D (9.6%), elemol (8.9%), α-terpineol (7.8%), γ-cadinene (7.1%), bornyl acetate (6.2%) | GC-MS | [74] |
Female flowers | α-limonene (28.7%), germacrene-D (23.7%), elemol (6.7%), β-caryophyllene (6.6%), α-pinene (6.0%), bornyl acetate (3.7%) | GC-MS | ||
Leaves of male plants at flowering | α-limonene (18.8%), germacrene-D (13.1%), β-caryophyllene (8.8%), δ-cadinene (8.7%), γ-cadinene (6.2%), α-pinene (4.8%) | GC-MS | ||
Leaves of female plants at flowering | Germacrene-D (20.7%), δ-cadinene (15.6%), β-caryophyllene (12.1%), γ-cadinene (6.6%), δ-cadinol (6.1%), α-limonene (5%) | GC-MS | ||
Ripe fruits | β-myrcene (75.6%), α-pinene (12.6%), α-limonene (3.2%), α-terpineol (1.4%), camphene (0.8%) | GC-MS | ||
Leaves | Morocco | Myrcene (33.5%), α-pinene (19.2%), limonene (6.6%), α-phellandrene (4.6%), γ-terpineol (3.7%), α-terpineol (3.6%) | GC-MS | B [75] |
Leaves | Sardinia (Italy) | α-pinene (16.9%), terpinen-4-ol (16.5%), sabinene (7.8%), α-phellandrene (7.4%), γ-terpinene (6.3%), β-pinene (4.3%) | GC-MS | [49] |
Plant extracts/solvent used | ||||
Leaves/ethyl acetate and methanol | Italy | 3,5-O-digalloyl quinic acid (26.8 ± 0.15 mg/g DW), 3,4,5-O-trigalloyl quinic acid (10.3 ± 2.45 mg/g DW), 5-O- galloyl quinic acid (9.6 ± 2.45 mg/g DW), myricetin 3-O-rhamnoside (6.8 ± 1.04 mg/g DW), myricetin 3-O-rutinoside (4.5 ± 0.18 mg/g DW), myricetin glucuronide (3.9 ± 0.65 mg/g DW) | HPLC-DAD, HPLC-MS, NMR | [60] |
Berries/methanol | Apulia (Italy) | Cyanidin 3-O-glucoside (71%), delphinidin 3-O-glucoside, cyanidin 3- O arabinoside (28–31%) | HPLC-DAD-MS | [76] |
Fruits during maturation/petroleum ether | Tunisia | Oils, fatty acids and sterols | GC-MS | [35] |
Leaves/methanol | Algeria | 46 compounds (most abundant flavonoids, phenolic acids and their derivatives) | HPLC-ESI-QTOF | [61] |
Leaves/methanol | Italy | 46 secondary metabolites | LC-ESI-MS/MS | [77] |
Fruits/methanol-water | Tunisia | Total phenolic acids 436.4–2762.7 mg/kg; total flavones 75.3–1222.9 mg/kg; total flavonols 24.2–377.4 mg/kg; total secoiridoids 12.6–366.8 mg/kg; total phenols 538.0–4260.6 mg/kg | HPLC-DAD/MSD | [78] |
Leaves/ethanol | Italy | Tannin derivatives (70.5%), myricetin derivatives (22%), quercetin derivatives (7.2%) | HPLC-DAD | [79] |
Leaves/methanol | Egypt | α-pinene (38.1%), 3,5-O-digalloyl quinic acid (13.5%), D-limonene (11.9%), α-phellandrene (10.1%), β-pinene (9.5%), γ muurolene (8.0%), luteolin-3-O-rutinoside (7.8%), quercetin 3-O-di-hexose O-pentose (7.6%), 3,4,5-O-trigalloyl quinic acid (6.1%), quercetin 3-O-glucuronide (4.6%), epicatechin 3-gallate (4.5%), camphene (3.8%) | UHPLC-ESI-MS, GC-MS | [80] |
Among the compounds in PlL extracts there were discovered to be relevant antioxidant agents, which may attest not only to the activity of PlL in preventing diabetic complications, cholesterol absorption and lipid metabolism [81,82], but also the remarkable capacity of PlL in managing intestinal inflammatory diseases as reported in the ethnopharmacological survey (Table 2). In fact, recent studies validated the capacity of polyphenols in managing the microbial and metabolomic patterns in the body [83–86]. Particularly, at the intestinal tract, these compounds can stimulate the multiplication of beneficial microorganisms and prevent the adhesion or directly disrupt the membrane ions flux of pathogens [87,88].
6. Anti-Inflammatory and Antioxidative Activities
As mentioned above, the anti-inflammatory effect of PlL is of high relevance in ethnopharmacology. The presence of important anti-inflammatory terpenes in the com
position of PlL EO can explain its efficacy. It is well-demonstrated that terpenes are capable of inhibiting several inflammatory molecules, e.g., IL-1β, IL-6, TNFα and COX- 2 [6,7,10], thus disrupting the amplification of inflammatory mechanisms. Meanwhile, the anti-inflammatory properties of PlL extracts can be related to the richness of polyphe- nols, the interplay of which in the inflammatory cascade is mainly demonstrated toward macrophages by inhibiting multiple key regulators of the inflammatory response [89]. Additionally, polyphenols reduce the release of arachidonic acid, prostaglandins and leukotrienes directly related to the inhibition of COX and LOX [90]. Other considerations regard several flavonoids in polyphenols, which can directly modulate the expression of pro-inflammatory cytokines and chemokines [91]. The ability of these natural compounds to modify the expression of several pro-inflammatory genes in addition to their antioxi- dant characteristics, such as reactive oxygen species (ROS) scavenging, contributes to the regulation of inflammatory signaling [92,93].
To clarify scientifically the anti-inflammatory character of PlL EO and extracts, they have undergone investigations by in vitro and in animal model studies with the intent to elucidate any selective interaction toward proteins and enzymes participating in the inflammatory pathway (Table 4).
Table 4. Antioxidant and anti-inflammatory activity of Pistacia Lentiscus
Exp. Setting |
Origin Model |
Plant Material |
Model |
Exp. Protocol |
Results |
Ref. |
Antioxidant activity |
Sardinia, Italy |
Leaves oil |
Cells free |
DPPH as Trolox equivalent antioxidant capacity (TEAC) |
Great seasonal variability inhibition |
[19] |
Algeria |
Leaves extract |
Cells free |
FRAP |
↑ High |
[86] |
|
|
|
H2O2 scavenging activity |
↓ Low |
|
||
Algeria |
Leaves extract |
Cells free |
Ferric reducing antioxidant power (FRAP) |
↑ High and dose dependent |
[94] |
|
|
|
|
DPPH |
↑↑ Very high |
|
|
|
|
|
H2O2 scavenging activity |
↑↑ Very high |
|
|
|
|
|
Linoleic acid peroxidation inhibition |
↑↑↑ Outstanding |
|
|
Zakynthos (Greece) |
Leaves extract |
Cells free |
DPPH |
↑↑ Very high |
[51] |
|
|
Ferric reducing antioxidant power (FRAP) |
↑ High |
|
|||
Sardinia, Italy |
Leaves extract |
Cells free |
DPPH as Trolox equivalents |
↑↑ High |
[95] |
|
|
ABTS as Trolox equivalents |
↑↑ High |
|
|||
Algeria |
Leaves extract |
Cells free |
DPPH (%) |
↑ High |
[35] |
|
|
|
Ferric reducing antioxidant power (FRAP) |
↑ High |
|
||
|
|
β-carotene bleaching method (%) |
↑↑ Very high |
|
||
Morocco |
Fruits oil, leaves oil |
Cells free |
DPPH |
Fruits oil: ↑↑ high Leaves oil: ↑ high |
[75] |
|
|
|
FRAP |
Fruits oil: ↑↑ high Leaves oil: ↑ high |
|
||
|
|
ABTS |
Fruits oil: ↑↑ high Leaves oil: ↑ high |
|
||
Campania (Italy) |
Leaves extract |
Cell lines |
Lipid peroxidation |
↑↑ Very high |
[15] |
|
Intracellular ROS |
↑↑ Very high |
|
||||
Oxidized glutathione |
↑↑ Very high |
|
||||
Sardinia, Italy |
Leaves oil |
Animals |
DHA |
↑↑ High protection |
[12] |
|
Algeria |
Fruits extract, leaves extract |
Cells free and cell lines |
Intracellular ROS in THP-1 monocytic cells |
Fruits extract: dose-dependent protection |
[96] |
|
|
|
ORAC as μmol Trolox Equivalents |
Fruits extract: ↑ High; Leaves extract: ↑↑ Very high |
|
||
Sardinia, Italy |
Leaves oil |
Cells free and cell lines, human fibroblasts |
H2O2 scavenging activity |
↓ Low |
[49] |
|
|
|
ECC |
↓ Low |
|
||
Anti-inflammatory activity |
Sardinia, Italy |
Leaves oil |
Animals |
COX-2 |
↑↑ High inhibition |
[12] |
Sardinia, Italy |
Leaves oil |
Animals |
TNF-α |
↓↓ High decrease |
[29] |
|
|
IL-6 |
↓↓↓ High decrease |
|
|||
Algeria |
Fruits extract, leaves extract |
Cells free and cell lines |
IL-1β inhibition by ATP stimulated THP-1 |
Fruit extract: no reduction; Leaves extract: ↑↑ high |
[96] |
|
|
|
IL-1β inhibition by H2O2stimulated THP-1 |
Fruit extract: ↓ low; Leaves extract: dose-dependent |
|
||
Sardinia, Italy |
Leaves oil |
Cells free and cell lines, Human fibroblasts |
COX-1 |
Inhibition |
[49] |
|
COX-2 |
↑ high inhibition |
|
||||
LOX |
no inhibition |
|
6.1. Inhibitory Activity against Proinflammatory Cytokines and against Arachidonic Acid Cascade
Remila and co-workers [96] examined the anti-inflammatory activity of leaves and fruits extracts by measuring the secretion of IL-1β by macrophages exposed to adenosin triphosphate (ATP) or H2O2. The authors found PlL leaves extract significantly reduced the production of IL-1β from ATP- or H2O2-activated cells. The inhibitory capacity of the leaves extract was higher in comparison to that of the fruits and of quercetin and gallic acid (tested as isolated fractions of the polyphenol mixture). The data was explained by the higher content of the total phenols and flavonoids in the leaves compared to the fruits and by the synergy between the pharmacological biomolecules of PlL extract. Similar considerations and a dose-dependent anti-inflammatory effect of the leaves extract was reported in other studies, which further strengthened the capacity of flavonoids and tannins [97].
Comparable anti-inflammatory values were reported in regard to PlL EO using the carrageenan-induced paw edema and cotton pellet-induced granuloma in a rat model [29]. Particularly, it was evidenced that when applied topically, PlL EO from leaves significantly inhibited the development of granuloma and the serum level of TNF-α and IL-6 in re- ply to the irritants. The result was mainly related to the activity of α-pinene, β-pinene, α- phellandrene and sabinene, which were highly represented in the chemistry of the hydrodistilled oil.
Only one study has investigated the inhibitory activity of the whole PlL EO. It was ob- tained from the leaves of plants growing in Sardinia and tested against COXs and LOX [49]. The IC50 values were 10.3 ± 4.4 μg/mL and 6.1 ± 2.5 μg/mL PlL EO for COX-1 and COX-2, respectively, with higher inhibitory activity toward COX-2 in comparison to that produced towards COX-1. Additionally, COX-2 inhibition by the EO was similar to that recorded using ibuprofen as a positive control. The activity of the oil against LOX did not reach the IC50 value, as PlL EO lowered LOX activity by 30% compared to the control. Despite the low LOX inhibition, the study strengthens the oil as a potential dual inhibitory com- pound, which was intensively researched in pharmacology to antagonize a great number of inflammatory processes where these enzymes sustain and amplify the disease [68,78]. The data obtained in that investigation were addressed to the mixture of terpenoids com- prising the oil, with particular regard to α-pinene and terpinen-4-ol (33.38%), enriched by the non-cannabinoid terpenoid limonene (3.4%), β-myrcene (0.9%), (Z)-caryophyllene (1.4%) and (E)-β-caryophyllene (0.1%). The mixture allowed the classification of the oil as pharmacologically active [50].
6.2. Inhibiting Activity against ROS Molecules
The protective effect of PlL EO and extracts against ROS has been deeply documented in the literature (Table 5). From a scientific point of view, this capacity can be related to the terpenes and polyphenols of the EO and of the extracts, respectively [10,59]. As the accumulation of ROS directly affects the healthy tissue systems, including cellular lipids, nucleic acids and proteins [98], the capacity of the EO and the extracts was studied directly using cell lines and intracellular ROS evaluation assays, or by chemical methods, particularly using the 2,20-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) and the 1,1-diphenyl-2- picrylhydrazyl (DPPH) chemical assays, and more recently using electron chemical devices.
As it is shown in Table 4, the anti-ROS ability has been mainly investigated in PlL extracts. Scientifically, this ability has been addressed to the richness in polyphenols the extracts possess, which not only inhibits the production of ROS by the direct involvement of specific molecules [99], but also can modulate the Keap1-Nrf2/ARE pathway [100]. This is a powerful oxidation-reduction defense system, where polyphenols act to degrade specifically the Keap1 protein and regulate the Nrf2-related pathway [59,101].
Remila and co-workers [96] proved the high antioxidant capacity of PlL leaves extract using the oxygen radical absorbance capacity in macrophages, melanoma and mammary mouse cell lines. Furthermore, due to the activation of apoptosis mechanisms, the extracts significantly inhibited the growth of melanoma cells. The data was related to the richness in phenolics, flavonoids and tannins in the extracts. Similar conclusions were obtained by Atmani [94], who examined hexane and chloroform aqueous extracts of PlL leaves containing highly concentrated flavonoids. In relation to the peak of hydroxyl groups, the aqueous formulations strongly inhibited lipid peroxidation. The mechanism was explained by the scavenging of peroxyl radicals by the extracts. Radicals play a role in the development of cardiovascular disease and cancer. In this regard, the scavenger activity of gallic acid and galloylquinic derivatives, isolated from PlL leaves, is particularly attractive. Notably, a progressive increase in the anti-radical activity associated with the number of galloyl groups in quinic acid was found [102]. Furthermore, all the tested metabolites strongly reduced the oxidation of low-density lipoproteins, thus strengthening the protection of PlL against the lipid peroxidation.
In addition to having a preventive capacity, a potential ability to halt or reverse oxidative stress-related diseases has been attributed to PlL. In fact, the ability to fight aggressive tumors, i.e., neuro-blastoma [19], and other important tumor cell lines has been proved by in vitro studies [103,104].
Animal testing further explored the anti-ROS efficacy of PlL derivates. Ben Khedir and co-workers [70] determined the scavenger and anti-inflammatory activity of the fruits oil using the carrageenan-induced paw edema in a rat model. In that study, PlL oil demon- strated significantly better anti-inflammatory activity with edema inhibition, in comparison to those produced by the control NADPH. Moreover, PlL oil was able to increase the ex- pression of superoxide dismutase, catalase and glutathione peroxidase, which are released as a response to the oxidative stress in the inflamed tissue. The effects were interpreted as a consequence of the content of humulene, caryophyllene and polyunsaturated fatty acid in the oil. Humulene and caryophyllene have been shown to inhibit the nuclear factor kappa B (NF-kB) pathway, responsible for the transcription of several proinflammatory cytokines, i.e., TNF-α, IL-1β, IL-6 and iNOS and COX-2 enzymes [105]. The polyunsaturated fatty acid in the oil might have partially replaced the arachidonic acid in the inflamed cell membranes [57], consequently lowering COX-2 production, the local inflammation and ROS generation.
Other in vivo studies demonstrated that an administration of PlL oil before the in- duction of the Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BC-CAO/R) was able to prevent the oxidative stress challenge in the nervous tissue due to the ischemic insult [12,106]. In the cerebral tissue, PlL oil restored the membrane phospholipid DHA and decreased the activity of the COX-2 enzyme. Additionally, PlL oil increased the concentration of the anti-inflammatory endocannabinoid congeners palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) [12]. The outcomes were related to the high presence of the phytocannabinoid (E)-β-caryophyllene, which worked synergistically with the other compounds in the oil, expanding the levels of cannabinoid receptor type 2 (CB2) and PPAR-alpha receptors. Further studies attest to the role of β-caryophyllene as CB2 agonists, demonstrating its capacity to antagonize the release of cytokines from LPS-stimulated monocytes (TNF-α and IL-1 β) [7].
7. Potential Cytotoxicity
Starting from Paracelsus’ statement “the right dose differentiates a poison to a rem- edy”, investigations have been conducted with the intent to validate pharmaceutically PlL derivatives. For this reason, many studies have been conducted, in particular using in vitro and cell lines models testing different doses of PlL oil and extracts (Table 4). As a measure of risk versus benefit, many of them also applied enzymes testing, looking for the capacity of the EO and extracts to interact with the proteins and their involvement in inflammation and oxidative stress. In fact, it is well-known that the in vitro and cell lines systems are largely recommended to elucidate the safety of herbal products and propose the natural agents as nutraceuticals or xenobiotics [110]. Although such models lack the complexity of animals, and the compounds in testing should not exert in vivo the same effects as reported in isolated cell tissues [111], they have a significant role in predicting of risks and toxicology.
As a result of this work, it can be stated that not any published laboratory study reported cytotoxic effects which could be connected to PlL oil or extracts. Conversely, the experiments demonstrated direct or indirect biocompatibility of PlL derivatives to humans and non-human animals.
Notably, a wide range of biocompatibility was documented in oral cells. It was remarked specifically in oral human fibroblast cell lines using the EO from leaves and the MTT reduction assay [49]. That fact was further validated in the periodontal liga- ment fibroblasts, the gingival fibroblasts, the gingival keratinocytes and dysplastic oral keratinocytes applying the WST-1 metabolic activity assay [49].
The absence of side effects to oral cells is strengthened concerning the polyphenol extracts. In detail, the fruits extract showed high biocompatibility and a selecting index (SI) of cytotoxicity equal to > 256 toward the human gingival cells, at the same time demonstrating a strong response against periodontal bacteria [112].
8. Antimicrobial Activity
Several studies reported the antimicrobial activity of PlL oils and extracts, trying to clarify scientifically their popular use in infectious diseases.
Commonly studied pathogens comprise bacteria known for antibiotic resistance (Staphylococcus aureus incl. methicillin-resistant strains (MRSA), Escherichia coli and Pseu- domonas aeruginosa), and other bacteria associated with the oral diseases, as well as yeasts, with particular regard to Candida albicans (Table 5a,b).
Table 5. (a) Antibacterial activity of Pistacia lentiscus L. determined by agar diffusion test (ADD) or minimal inhibitory concentration (MIC). (b) Antifungal activity of Pistacia lentiscus L. determined by agar diffusion test (ADD) or minimal inhibitory concentration (MIC).
(a) |
|
||||
Origin |
Plant Material |
Bacteria |
Origin of Strain |
Antimicrobial Activity |
Ref. |
Sicily (Italy) |
Aerial parts ethanol extract, aerialparts water extracts |
Staphylococcus aureus |
ATCC 29213 |
Yes |
[107] |
|
|
Escherichia coli |
ATCC 35218 |
Yes |
|
Tunisia |
Leaves essential oil |
S. aureus |
ATCC 25923 |
Yes |
[55] |
|
|
Enterococcus faecalis |
ATCC 29212 |
Yes |
|
|
|
Salmonella enteritidis |
ATCC 13076 |
Yes |
|
|
|
Salmonella typhimurium |
NRRLB 4420 |
Yes |
|
|
|
E. coli |
ATCC 25922 |
Yes |
|
|
|
Pseudomonas aeruginosa |
ATCC 27853 |
Yes |
|
Algeria |
Leaves ethanol extract |
S. aureus |
ATCC 601 |
Yes |
[86] |
|
|
Listeria monocytogenes |
ATCC 19111 |
Yes |
|
|
Klebsiella pneumoniae |
5215773 |
Yes |
|
|
|
P. aeruginosa |
22212004 |
Yes |
|
|
|
S. typhi |
4404540 |
Yes |
|
|
|
Proteus mirabilis |
0536040 |
Yes |
|
|
|
E. coli |
5044172 |
Yes |
|
|
|
Enterobacter cloacae |
1305573 |
Yes |
|
|
|
|
444 |
Yes |
|
|
Eastern Morocco |
Aerial parts from different areas of Morocco essential oils |
S. aureus |
Not given |
Yes |
[66] |
|
|
Streptococcus spp. |
Not given |
Yes |
|
E. coli |
Not given |
Yes |
|
||
K. pneumoniae |
Not given |
Yes |
|
||
Pseudomonas spp. |
Not given |
Yes |
|
||
Salmonella spp. |
Not given |
Yes |
|
||
Tunisia |
Fruits essential oil, phenolic extract |
S. aureus |
Not given |
Yes |
[68] |
|
|
Bacillus subtilis |
Not given |
Yes |
|
|
L. monocytogens |
Not given |
Yes |
|
|
|
E. coli |
Not given |
Yes |
|
|
|
P. aeruginosa |
Not given |
Yes |
|
|
|
Aeromonas hydrophila |
Not given |
Yes |
|
|
|
Salmonellatyphimurium |
Not given |
Yes |
|
|
Algeria |
Aerial part methanol extract |
S. aureus |
Not given |
Yes |
[36] |
|
|
E. coli |
Not given |
Yes |
|
|
P. aeruginosa |
Not given |
Yes |
|
|
Algeria |
Leaves and stems methanol extract, leaves and stems aqueous extracts |
S. aureus
E. coli |
Not given
Not given |
No
No |
[44] |
Sardinia (Italy) |
Fruits essential oil |
Bacillus clausii |
Probiotic |
No |
[58] |
|
|
Staphylococcus hominis |
Clinical |
No |
|
S. aureus |
ATCC 6538 |
No |
|
||
Streptococcus pyogenes |
Clinical |
No |
|
||
Streptococcus agalactiae |
Clinical |
Yes |
|
||
Streptococcus salivarius |
Probiotic (n = 2) |
No |
|
||
Streptococcus mitis |
Clinical |
No |
|
||
Streptococcus mutans |
Collection |
No |
|
||
Streptococcus intermedius |
Collection |
Yes |
|
||
Sardinia (Italy) |
Fruit methanol extract, leaves methanol extract, |
S. aureus |
ATCC 25293 |
Yes |
[108] |
|
|
Staphylococcusepidermidis |
ATCC 12,228 |
Yes |
|
|
E. coli |
ATCC 25,922 |
In part |
|
|
|
K. pneumoniae |
ATCC 9591 |
In part |
|
|
Sardinia (Italy) |
Leaves essential oil |
Streptococcus gordonii |
ATCC 10,558 |
Yes |
[49] |
|
|
Actinomyces naeslundii |
ATCC 12104 |
Yes |
|
|
|
Fusobacterium nucleatum |
ATCC 25586 |
Yes |
|
|
|
Porphyromonas gingivalis |
ATCC 33277 |
Yes |
|
|
|
P. gingivalis |
Clinical (n = 2) |
Yes |
|
|
|
Tannerella forsythia |
ATCC 43300 |
Yes |
|
|
|
T. forsythia |
Clinical (n = 2) |
Yes |
|
(b) |
|
Origin |
Plant Material |
Fungi |
Origin of Strain |
Antifungal Activity |
Ref. |
Sicily (Italy) |
Aerial parts ethanol extract, aerial parts water extracts Leaves ethyl acetate and methanol extract |
Candida albicans
Candida parapsilosis
Candida glabrata
Cryptococcus neoformans |
Clinical (n = 18) Clinical (n = 9) Clinical (n = 11) Clinical (n = 5) |
Yes
Yes
Yes
Yes |
[107] |
Tuscany (Italy) |
Leaves ethyl acetate and methanol extract |
C. albicans |
Clinical |
No |
[109] |
|
C. glabrata |
Clinical |
No |
|
|
|
C. parapsilosis |
Clinical |
No |
|
|
|
C. tropicalis |
Clinical |
No |
|
|
|
C. zeylanoides |
Clinical |
No |
|
|
Algeria |
Leaves ethanol extract |
C. albicans |
444 |
Yes |
[86] |
Tunisia |
Fruits essential oil, phenolic extract |
Aspergillus flavus |
Not given |
No |
[68] |
|
Aspergillus niger |
Not given |
No |
|
|
|
C. albicans |
Not given |
In part |
|
|
Sardinia (Italy) |
Fruits essential oil |
C. albicans |
Clinical |
No |
[58] |
C. glabrata |
Clinical |
No |
|
||
C. krusei |
Clinical |
No |
|
||
Sardinia (Italy) |
Leaves essential oil |
C. albicans |
Laboratory |
Yes |
[49] |
|
|
C. albicans |
Clinical (n = 2) |
Yes |
|
|
|
C. glabrata |
Laboratory |
Yes |
|
|
|
C. glabrata |
Clinical (n = 2) |
Yes |
|
Different antimicrobial activity was reported in the studies testing PlL EO and ex- tracts. A high capacity against both bacteria and yeasts was demonstrated in regard to the leaves EO from plants growing in different regions [16,57,67]. Whereas the fruits EO from Tunisia [68] and Sardinia [58] were found to have a limited effect against bacteria and yeasts, the ethanol and water extracts of leaves from plants growing in Sicily inhibited the growth of S. aureus, E. coli and yeasts [107]. Additionally, the leaves ethanol or methanol extracts showed activity against several Gram-positive and Gram-negative bacteria [38,87,113].
However, leaves and stems methanolic or water extracts prepared in Algeria were inactive against S. aureus and E. coli [44], and leaves alcoholic extracts from Tuscany did not act against yeasts [109].
The research started from the fact that terpenoids in EO exert a wide-spectrum of antibacterial, antifungal and even anti-viral activity, and have been demonstrated to inhibit the growth of drug-resistant microbial strains, which are difficult to be treated even by con- ventional antibiotics [113]. Although α-pinene together with the monoterpenes terpinene and myrcene are among the most represented fractions in the Mediterranean oils showing antimicrobial capacity (Table 5), it is of general interest if higher activity could be related to specific PlL chemotypes [114]. In this context, as reported regarding the anti-inflammatory capacity, synergy between the chemical fractions of terpenes is proposed to explain PlL EO antimicrobial activities. Synergy was recently claimed to explain the inhibitory ac- tivity of the EO against Porphyromonas gingivalis, Tannerella forsythia and Fusobacterium nucleatum [49]. The result was related to the pharmacological interplay of the terpenes characterizing the oil chemotype from North Sardinia, which was α-pinene-terpinen-4- ol, further augmented by the non-cannabinoid terpenoids limonene and β-myrcene, the sesquiterpenes (Z)-caryophyllene and (E)- β- caryophyllene. Similarly, the antimicrobial efficacy of extracts can be attributed to the richness of polyphenols [25,38,46,69,70,76,111], in particular in regard to the concentrations of tannins, flavonoids, and lignin-carbohydrate complexes in the polyphenols mixture [11]. This is also the case with the ethanol extract of fruits, which showed the highest inhibition potential against P. gingivalis in comparison to 20 other extracts of pharmaceutical plants [112]. Furthermore, the potency of the fruits extract were higher than that of the leaves and woody parts, with MIC values against P. gingivalis of 8 μg/mL.
Recently, Mandrone and co-workers [108] related the antimicrobial activity of aqueous MeOH extracts of fruits and leaves to the concentration of phenolic components. That research further attested to the fact that phenols are active against multi-resistant bacteria, among them MRSA and carbapenemase-producing Klebsiella pneumoniae.
Concerning Candida spp., the activity of PlL derivates is reportedly controversial (Table 5). Low or no susceptibility of the yeasts to the leaves extract, or to the fruits oil, was found. Despite this, PlL leaves EO from Sardinia had low MIC values against C. glabrata and C. albicans [49]. The results were explained as a consequence of the recurrence of pharmacological concentrations of six terpenes, which were above 0.05% in the fingerprint. Additionally, the EO documented the ability to inhibit COX-2 and LOX, which are very important proteins for the development of Candida virulence [115].
Furthermore, a high inhibition of C. albicans was reported when using PlL extracts. The activity of water or ethanol extracts has been attributed to the flavonoid contents. Notably, the phenolic compound tannic acid was reported as more active against the yeast than the antifungals nystatin and amphotericin [68,75].
9. Summary and Conclusions
In this review, we summarized the existing knowledge about PlL phytochemistry and some of its biological activities, mainly focusing on its anti-inflammatory and antimicrobial capacity.
The chemistry shows that PlL EO is composed of up to 64 molecules, while 46 con- stituents have been identified in the extracts. Further minor fractions were determined in the reports analyzing both the EO and the extracts even if they could not be quan- tified. The more recurrent chemical components in the EO from plants growing in the Mediterranean area are represented by α-pinene, terpinenes, caryophyllene, limonene and myrcene. Important properties in antagonizing immune-mediated and autoimmu- nity, neuro-inflammatory, neurological and neurodegenerative diseases, in addition to infections and cancer have been addressed to these molecules. However, the biological character of PlL cannot be entirely focused on one of the main concentrated molecules. The abilities should be attributed to the whole mixture of the terpenes working in synergy,
or in addition independently by their concentration in the agent. It is remarkable to note that concentrations of non-cannabinoid terpenoids equal to or above 0.05% increase the pharmacological potency of PlL oil.
Regarding the extracts, the high polyphenol content is attractive for prevention, and for therapy of chronic illness and infections. The richness in polyphenols suggests the use of the extracts as nutraceuticals in human health. Among the compounds, flavonol glycosides, i.e., myricetin and quercetin glycosides, could indicate a possible role of PlL in preventing diabetic complications and managing intestinal inflammatory response. Meanwhile, the concentration of bioactive flavanones should put forward the extracts to manage cholesterol absorption, glucose and lipid metabolism. Furthermore, the quinic acid, lignans and anthocyanins content is attractive in view of the high antioxidant capacity, in particular when water-extracted from PlL.
Nevertheless, although useful information has been provided in in vitro and animal model studies, clinical trials are necessary to fully understand the capacity and limitations of PlL EO and extracts in humans.
Regarding the anti-inflammatory capacity, PlL EO and extracts are able to inhibit the proinflammatory cytokines IL-1β, IL-6 and TNF-α. Additionally, the capacity to anatgonize the arachidonic acid cascade was highlighted in previous studies. In particular, the antagonism towards the COX-2 enzyme emerged in the research, and then the ability to antagonize the first phase of the active inflammation by inhibiting prostaglandins. Furthermore, the potential LOX inhibitory capability could propose the EO as a COX-2- LOX dual inhibitory natural compound, which might be promising against inflammation and tissue damage.
Among the non-cannabinoid terpenoid fractions, (E)-β-caryophyllene has been sug- gested to possess an important role in the anti-inflammatory activity of the oil. Interestingly, the molecule has a strong affinity to CB2, where it inhibits the release of cytokines from LPS- stimulated monocytes, such as TNF-α and IL-1 β expression. Furthermore, studies in ani- mals have proved the relevance of (E)-β-caryophyllene in preventing ischemic/reperfusion oxidative injury when the oil was administered as a dietary assumption. In this context, studies strengthened the adjuvant capacity of α-pinene merged with caryophyllene, in PlL oils by the high anti-inflammatory properties. Conversely, when merged with the non-cannabinoid myrcene, caryophyllene contributed to inhibit nitric oxide production and IL-1β-induced iNOS mRNA, NF-kB and other catabolic and inflammatory mediators of importance in rheumatoid arthritis. Regarding the limonene fraction of the EO, it should be relevant in the oxidative stress-related diseases by inhibiting pro-inflammatory mediators, leukocyte migration and the vascular permeability.
The high antioxidant property of the extracts is remarkable in the literature. This fact has been explained by the richness of polyphenols, including tannins and flavonoids, and sterols showing high protection against free radical damage. Animal testing further supports the in vitro anti-ROS potency of PlL extracts, with a higher effect in comparison to NADPHs. Notably, the aqueous formulations show great capacity in inhibiting lipid per- oxidation. The mechanism is interpreted as scavenging of peroxyl radicals, which suggests PlL to be preventive in cardiovascular disease and cancer. Furthermore, the antioxidant properties of polyphenols in PlL extracts should be beneficial in therapy and prevention of gastrointestinal diseases, where oxidative stress has been shown to damage the barrier protection, leading to intestinal pathologies. In this matter, the proved capacity of polyphe- nols to manage the microbial and metabolomic patterns in the body might represent an additional advantage. These facts should validate scientifically the popular use of PlL extracts to resolve infections and persistent inflammation at the intestinal tract, proposing the materials as natural agents in prevention and therapy of gastro-intestinal diseases.
In regard to the antimicrobial activity, the capacity of the oil and extracts against periodontal bacteria has been largely documented. These evidences can prove scientifically the popular use of PlL in the relief of gingival bleeding and tooth ache. The ability against periodontal bacteria, further ameliorated by the anti-inflammatory potency, is attractive
with regards to a possible use of the EO to antagonize gingivitis, as a primary strategy to prevent periodontitis and as a secondary preventive strategy to prevent recurrent peri- odontitis after periodontal surgery. The possibility to formulate PlL derivates as potential oral health care products or therapeutics in periodontal disease is further strengthened by the largely documented biocompatibility and antioxidant capacity.
Other important considerations concern the activity of PlL against Candida infections. PlL inhibits the growth of C. albicans and C. glabrata with low MICs. In addition, the prevention of arachidonic acid oxidation by COX-2 and LOX antagonism by PlL oil should be of interest for inhibiting the development of Candida biofilm and disseminations. Subse- quently, PlL could act directly against the yeast and indirectly against its virulence, with no oral cytotoxicity.
Taken together, all the above argumentations propose PlL as a nutraceutical, and also as a therapeutic agent against a wide range of diseases based on inflammation and infections. Further research may include the activity of PlL not only on planktonic mi- croorganisms but also on biofilms. It should verify the best and most efficient preparation method of PlL plant material related to its activity.
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This entry is adapted from the peer-reviewed paper 10.3390/antibiotics10040425