The therapeutic value of Myrtus communis L.: an updated review

Myrtus communis L. (Family: Myrtaceae) is naturally found in the western part of Asia, Southern Europe, and North Africa. It has been reportedly applied in pharmaceutical industry, traditional medicine, cosmetics, spices, and food. Pubmed, Google scholar, Web of Science, and Scopus were utilized to seek out relevant content concerning the therapeutic potential of M. communis. Subsequently, we conducted a review to identity noteworthy updates pertaining to M. communis. Myrtle berries, leaves, seeds, and essential oils are natural sources of several nutrients and bioactive compounds with marked health effects. The chemical analysis showed that M. communis contained oils, alkaloids, flavonoids, phenolics, coumarins, saponosides, tannins, quinines, and anthraquinones. A pharmacological investigation revealed that M. communis possessed anti-inflammatory, analgesic, antimicrobial, antiparasitic, antioxidant, antidiabetic, anticancer, antimutagenic, immunomodulatory, dermatological, cardiovascular, central nervous system, and gastrointestinal protective effects, among numerous other biological effects. This current review focused on the biochemical, pharmacological, therapeutic effects, and various biological activities of different parts of M. communis. It signifies that M. communis is a therapeutic plant with numerous applications in medicine and could be used as a drug isolate based on its safety and effectiveness.


Introduction
Myrtle (Myrtus communis L.) is an aromatic medicinal plant, typical of the coastal areas of the Mediterranean regions, such as North Africa or Southern Europe, but it is also present in South America, Australia, and in some areas of Himalaya (Alipour et al. 2014;Jabri et al. 2018;Sumbul et al. 2010, Gaber et al., 2021).It belongs to the Myrtaceae family, which includes about 3000 species, and grows spontaneously as an evergreen shrub or a small tree.The plant can reach a height of 2.5 m, with a full head deeply covered by branches and small leaves; flowers are starry, scented, and can be white or pink, whereas berry fruits are edible, small, with a round shape and many seeds inside, generally blue-black, even if some varieties have white-yellow fruits, and ripen in autumn, between October and February (Fig. 1).
Many plants that have therapeutic properties have recently been reviewed showcasing their biological and Extended author information available on the last page of the article pharmacological properties and expanding their prospect in the drug development pipeline against the management of various diseases (Batiha et al., 2023a, b;Teibo et al. 2021).
A comprehensive search was carried out on Pubmed, Google scholar, Web of Science, and Scopus to seek out relevant content concerning the therapeutic potential of M. communis.Subsequently, we conducted a review to identity noteworthy updates pertaining to M. communis which was used for the study.
This current review focused on the biochemical and pharmacological constituents and therapeutic effects of M. communis.

Description
It is a bushy, strong-scented evergreen, upright shrub, about 3 m high, that arches as the year goes by.The leaves are in threes, simple, and have the shape ovate-lanceolate (Fig. 1).The leaf length is 2.5-5 cm, its color is dark green, and other features include aromatic when crushed; the glossy nature; short petioles; veins that are pinnated and glabrous; the flowers that are white or pink; solitary, axillary; and could be rose-tinged.It has the shape of a bowl, with a length of 2 cm.The plant is also actinomorphic, bisexual, and epigynous with slender pedicels of length 2 cm; the calyx is turbinate calyx tube of four to five sepals; the corolla is four to five petalled; fruit is oblong-ellipsoid white and 1 cm long (Bouzabata 2013).The berry fruits are edible, small, with a round shape and many seeds inside, generally blue-black, even if some varieties have white-yellow fruits, and ripen in autumn, between October and February.Insects do pollination, and birds spread seeds in the environment (Alipour et al. 2014;Petretto et al. 2016).

M. communis berry
Myrtle berries are round fruits composed of a fleshy pericarp and a snail-shaped seed (Pezhmanmehr et al. 2010).Table 1 below shows the physicochemical properties of berries of M. communis.(Sumbul et al. 2012)

M. communis seed
Since myrtle fruit is rich in secondary metabolites, the seeds in particular have previously been reported to contain a larger number of phenolic compounds in comparison with other tissues in the pericarp (Wannes and Marzouk 2013;Taamalli, et al. 2014b, c, a;Andrea et al. 2019).Ellagic acid is released after hydrolysis of ellagitannins, and its presence in myrtle berries is well documented (Taamalli et al. 2014b, c, a;Taamalli et al. 2014b, c, a).Two main dimeric ellagitannins, eugeniflorin D2 (Al-Snafi 2013a, b) and oenothein B (Al-Snafi 2013a, b), with a specific macrocyclic structure were isolated from seed extracts and chemically characterized (Table 2).
The flavonoid contents and total phenol were abundant in the leaf extract (13.65 mg GAE/g dry weight as well as 250 mg GAE/g dry weight, respectively), and anthocyanin and tannin contents (176.50 ± 2.17 mg Cyd-3-glu /g dry weight and 220.81±1.21mg CE /g dry weight), respectively, were abundant in the extract of the pericarp (Bouzabata et al. 2015).
The total phenolics and flavonoids were assessed in aqueous extracts, ethyl acetate, chloroform, methanol of M. communis leaves.Elevated total phenolic and total flavonoid contents (435.37 mg gallic acid equivalents/g dried weight also 130.75 mg quercetin equivalent/g dried weight, respectively) were seen in the ethyl acetate extract (Hosseinzadeh et al. 2011).

Pharmacological effects
The pharmacological effects of M. communis are summarized in Fig. 2 and Table 5 below.

Anti-inflammatory
M. communis essential oil was assessed for anti-inflammatory property using lipopolysaccharide (LPS)-stimulated macrophages in vitro model; oils significantly inhibited the production of NO without altering the viability of the cell at 0.64 mg/ml concentrations (Cruciani et al. 2019).The aqueous extracts (0.03, 0.015, 0.005 g/kg) and ethanolic (0.05 g/ kg) possessed anti-inflammatory action against prolonged inflammation (Soomro et al. 2019).M. communis essential oil anti-inflammatory activity was assessed by mice with ear edema induced by croton oil and myeloperoxidase activity, and in rats' models, granuloma induced by cotton pellet and
The anti-inflammatory action of oenothein B isolated from M. communis seeds was assayed in vitro.It possessed anti-inflammatory properties.M. communis pulp and seed extracts were evaluated on human fibroblast for their effects against inflammation.The production of ROS was determined after H 2 O 2 treatment induced oxidative stress and expressions of gene of various proinflammatory cytokines and CYP3A4 and CYP27B1.The results revealed the synergic effect of Myrtus extracts with vitamin D to reduce inflammation, ROS production, thereby shielding cells from damages caused by oxidative stress, modulated CYP expression, and preventing chronic inflammation (Dragomanova et al. 2019).
M. communis leaf isolate oligomeric non-prenylated acylphloroglucinols (semi myrtucommulone and myrtucommulone A) directly inhibited 5-lipoxygenase and COX-1 in vivo, including in vitro, with IC 50 value around 1.8 to 29 microM, thereby significantly reducing eicosanoids biosynthesis.In polymorphonuclear leukocytes, calcium mobilization is prevented by the administration of myrtucommulone and semi myrtucommulone, which suppresses the concentration ROS and elastase formation, which is mediated through the signaling pathway of G protein of IC 50 values around 0.55 and 4.5 microM, respectively (Alem et al. 2008).
M. communis extract myrtucommuacetalone-1 (MCA-1) was assessed for anti-inflammation using hydrogen peroxide, superoxide, and macrophages nitric oxide assays.The translocation and phosphorylation transcription factor NF kappa B, iNOS activation regulator, was used to analyze the compound.MCA-1 action on the iNOS enzyme was also tested.In excited macrophages, MCA-1 caused the inhibition of hydrogen peroxide, superoxide, with 53% and 48% respectively, through nitric oxide an IC 50 of <1 µg/ml, showing solid binding pattern at the enzyme nitric oxide synthase active site.In addition, MCA-1 of 25 µg/ml stopped the expression of inducible nitric oxide synthase and eliminated the translocation and phosphorylation of transcription factor (NFκB) into the nucleus (Maxia et al. 2011).
M. communis extract acylphloroglucinol myrtucommulone effect on PGE2 synthase mPGES-1 and subsequent inhibition of prostaglandins as an intermediary of pain and inflammation was examined using the A549 cells stimulated by interleukin-1beta-prepared in a microsomal means for a precursor for mPGES-1, lipopolysaccharide-stimulated human whole blood, and intact cells A549 in a cell-free assay.Production of 6-oxo PGF 1α and 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid confirmed that the activity of COX-1 and COX-2 was inhibited in the cell-free and cellular tests.The conversion of PGE2 from PGH2 was done by cell-free mPGES-1-mediated (IC 50 = 1 micromole/l).Myrtucommulone concentration-dependently inhibited the production of PGE2, which decreased significantly in whole human blood and complete A549 cells at small micromolar concentrations.Activities of COX-2 in A549 cells and isolated human recombinant COX-2 were significantly inhibited, but COX-1 was inhibited slightly in cell-free and cells by the action of myrtucommulone (30 micromole/l) and (IC 50 > 15 micromole/l) respectively (Rossi et al. 2009).
Using a mouse model, inflammation was brought about by the intrapleural administration of carrageenan, while intraperitoneal of treatment myrtucommulone was given (0.5, 1.5, and 4.5 mg/kg).The result obtained showed the suppression of proinflammatory cellular response.The administration of 4.5 mg/kg myrtucommulone ip at half of an hour before and after the introduction of carrageenan causes the decrease in the amount of leukocyte in the blood, neutrophil infiltration seen through myeloperoxidase, lung injury, lung intercellular adhesion molecule-1 including P-selectin immunohistochemical localization, an equally pleural fluid reduction in the cytokine levels (TNF-α and IL-1β) of the lungs, leukotriene B4.In the pleural fluid, and their immunohistochemical localization in the lung, the leukotriene B4, but not prostaglandin E2, levels in the pleural exudates and lung peroxidation (thiobarbituric acidreactant substance) and nitrotyrosine and poly (ADP-ribose) immunostaining.Myrtucommulone reportedly suppressed eicosanoids biosynthesis by inhibiting cyclooxygenase-1 and 5-lipoxygenase in vitro, ROS, and elastase formation in activated polymorphonuclear leukocytes (Raoof et al. 2019).

Analgesic effects
M. communis aerial parts of both aqueous and ethanolic extracts were tested for antinociceptive activity by testing with a hot plate and writhing.Antinociception was shown by the aqueous and ethanolic extracts, with marked antinociception inhibited through naloxone.Antinociception was exhibited by extracts against the writhing induced by acetic acid.
The bicyclic monoterpenoid myrtenal, which was isolated from M. communis essential oil (5%), was tested for analgesic.Anti-nociceptive activity (30 mg/kg, bw, ip) was tried on two experimental pain models of male mice using a writhing test of acetic acid including the hot plate, after single administration in addition to repetitive administration.
The bicyclic monoterpenoid myrtenal showed significant antinociception (concerning thermal and peripheral pain).During severe administration, the writhing number of the abdomen significantly decreased in the 15 th and 20 th minutes (at P< 0.01 and P< 0.05) by 47.25% and 50.55% respectively.It reduced (P<0.001)treatment group number versus control group after continuous treatment, 40.4% on 7 th and 14 th day 43.1% when assessed with the controls (Koeberle et al. 2009).

Antimicrobial effects
M. communis seed isolate oenothein B was tested for its fungicidal effect on Candida in vitro, and its MIC anticandidal effect was <8-64 μg/ml (Barboni e al. 2010).
M. communis leaf ethanolic extract was examined for antibacterial effect (0, 15, 30, 45, 60 mg/ml) against Grampositive bacteria (Bacillus subtilis and Staphylococcus aureus and Gram-negative bacteria (Escherichia coli and Klebsiella pneumonia).The results revealed the potency of extracts against all the bacteria tested.Escherichia coli showed the highest sensitivity to the extract of M. communis.The extract was applied in the study of its action on biofilm formation.High sensitivity was seen when biofilm formation was assessed on all the bacterial strains with Escherichia coli and Bacillus subtilis being the most potent to M. communis extract (Sidkey 2006;Rasaie et al. 2017).An acylphloroglucinols (myrtucommulone-A) isolated from M. communis leaves exhibited great antibacterial activity versus Gram-positive bacteria, though inactive on the Gram negatives (Appendino et al. 2006).
The antimicrobial effect of M. communis extracts was studied against E. coli, E. coli ATCC 25922, P. mirabilis, S. typhi, Shigella flexneri, and K. pneumonia.All M. communis inoculates exhibited various degree of inhibition antimicrobial activity against all strains tested.The microbial extracts and strains showed inhibition zones values ranging from 21 to 25 mm.According to microbial strains and infusions.The values of MBC and MIC showed ranges from 12.5 to 25 mg dry leaves/ml and 12.5 to 50 mg dry leaves/ml against different isolates, respectively (Harassi et al. 2019).
M. communis alcoholic extract was assessed for its bactericidal effect against Listeria monocytogenes, Bacillus cereus (NCTC 7464 and ATCC 10876), and Staphylococcus aureus (ATCC 25923).At a concentration of 10 mg, M. communis demonstrated a growth inhibitory effect on the three examined bacteria.A maximum effect was observed on Staphylococcus aureus and a minimum effect against Bacillus cereus (Rahimvand et al. 2018) (Fani et al. 2014).
M. communis methanolic and aqueous extract antibacterial effect was examined against Prevotella intermedia, Porphyromonas gingivalis, and Actinobacillus actinomycetemcomitans.M. communis aqueous extract with a range 20 to 500 mg/ml and methanolic extract with a range 10-500 mg/ml possessed antibacterial effects against Prevotella intermedia, Porphyromonas gingivalis, and Actinobacillus actinomycetemcomitans.M. communis aqueous as well as methanolic extracts showed potency against microorganisms examined with a MIC of 10 mg/ml (Ben et al. 2014).
M. communis essential oil microbicidal effect was examined against Streptococcus mutans, Streptococcus sanguinis, and Streptococcus salivarius.According to the results, myrtle leaf essential oil possessed microbicidal activity against every strain of Streptococcus; however, S. mutants has the most of all the species (Cannas et al. 2013).
The M. communis essential oil antimicrobial activities (3.9-1000 µg/ml) were studied against some oral pathogens (30 strains of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Streptococcus mutans and 20 strains of Candida albicans and Streptococcus pyogenes) gotten out of pharyngitis, periodontal diseases, dental caries, and oral lesions related to artificial dentures.All the extracts had 8.1-41.25-mminhibition zones, with the sensitivity to oil at 125-1000 µg/ml.At 62.5 µg/ml, the strain sensitivity of C. albicans, S. mutans, and S. pyogenes was recorded, but only 70% and 66.6% of A. actinomycetemcomitans and P. gingivalis showed resistance to this concentration.At 31.25 µg/ml, the sensitivity of all the strains, S. mutans, and S. pyogenes was recorded.The oil at 7.8 and 15.6 µg/ml sensitivity of S. pyogenes strain was recorded.At 62.5 ± 0, 62.5 ± 0, 46.9 ± 16, 31.25 ± 0, 29.68 ± 4.8 µg/ml, the minimum inhibitory concentrations were recorded against the oil for these microorganisms: P. gingivalis, A. actinomycetemcomitans, C. albicans, S. mutans, and S. pyogenes, respectively (Aleksic et al. 2014).
Some microorganisms were able to access microbicidal activity of essential oils.The ranges for MIC and the zones of inhibition and of the bacteria strains are 0.078-2.5 mg/ml and 16-28 mm, respectively.Gram-negative bacteria showed lower oil activity of inhibition than the gram-positive ones.The oil inhibited several fungal strains significantly.The oil concentration at 312 μg/ml showed bactericidal action against Listeria monocytogenes after 5 min (Fadil et al. 2018).
Three essential oils of M. communis were examined for their action against Acinetobacter baumannii extracted from wound known to be multi-drug.Mytre oils exhibited excellent bactericidal effects, as shown by the result.The drug ciprofloxacin or polymyxin B, when combined with essential oil sun inhibition concentration, decreased the growth of bacterial interdependently (Masoudi et al. 2017).
A synergistic effect was noticed against the strain of Salmonella typhimurium by combining Thymus vulgaris and M. communis essential oils.The preparations include 45% of M. communis and 55% of Thymus vulgaris essential oil, which improved the sensitivity of Salmonella typhimurium (Cannas et al. 2014).
For bacterial vaginosis treatment, M. communis vaginal gel was used alongside with metronidazole gel for 7 days.It was discovered that the administration showed higher potency (P<0.05)compared to their use when not in combination.After 21 days, the patients that were treated with only metronidazole gel had bacterial vaginosis reoccurring, but others administered with a combination of M. communis in metronidazole gel did not show any relapse of the disease (Barac et al. 2018).
The essential oil of M. communis was examined for the formation of biofilm examined in three Candida species (Candida tropicalis, Candida albicans, and Candida parapsilosis).The results showed enhanced action against C. parapsilosis and C. albicans as compared to C. tropicalis.Therefore, anti-biofilm formation is one of its activities (Mehrabani et al. 2013).
The essential oil of M. communis was examined by isolating Malassezia sp.In pityriasis versicolor infection, fungicidal and inhibitory action was seen against Malassezia growth (Mahdi et al. 2006).
Its fungicidal action was examined using M. communis essential oil on various Aspergillus sp.(six isolates of Aspergillus flavus, Aspergillus parasiticus, and Aspergillus niger) and Candida albicans (one ATCC type strains and eight clinical isolates), which showed good inhibitory action against these strains.Also, the combination of amphotericin and essential oil showed an excellent synergistic effect (Penauelas et al. 2001).

Antiparasitic effect
At pH 4.65, M. communis extract killed Trichomonas vaginalis, but at pH 6.00, it was still alive (Chegeni et al. 2019).Both cell culture and cell-free medium were used in anti-Toxoplasma action on M. communis extracts in vitro against Toxoplasma gondii RH strain tachyzoites.The extract caused the inhibition of tachyzoites in cell-free medium.However, the cell culture of M. communis extract and EC 50 sensitivity were significantly decreased compared to pyrimethamine (Amiri et al. 2019).At 6.47, 7.62, and 11.64 mg/ml, the LC 50 was recorded at 30, 20, and 10 min, respectively (Tayoub et al. 2012).Apoptosis of protocolizes of hydatid cyst was seen when M. communis extract at (50 and 100 mg/ml) was administered through the increased action of caspases 3 and 9 (Amensour et al. 2009).
The essential of M. communis leaf extract possesses fumigant toxicity against Trogoderma granarium at different stages.At 24 and 48 h of exposure to 562.5 µl/l air, the larva showed 94% and 100% death, but the adult was very sensitive at little exposure.The LC 90 and LC 50 include 487 and 221 µl/l air after 48-h exposure, respectively (Dairi et al. 2014).
In vitro analysis of M. communis extract in water and ethanol (10, 5, 2.5, and 1.25 mg/ml) was conducted for the anti-Acanthamoeba effect of crude for (1-3 day) cysts of Acanthamoeba and on trophozoites.After administration, M. communis ethanolic extract showed 0% for trophozoites viability and 8.62% for cysts.
After 3 days, 0% trophozoites and 31.10%cysts were seen after administering M. communis aqueous extract at 10 mg/ ml (Shahnazi et al. 2017).M. communis methanolic and essential oil extracts had a leishmanialicidal effect on the amastigote and promastigote types of Leishmania tropica.The essential oil of M. communis brought about apoptosis to the J774 cells (P<0.05),amastigote and promastigote types of L. tropica in a manner that is dependent on dose.The amastigote as well as promastigote forms showed 11.6 and 40.8 μg/ml and 8.4 and 28.9 μg/ml as their IC 50 values after the essential oil and methanolic extract administration.The extract of methanol and essential oils was not cytotoxic to J774 cells.It was seen that M. communis essential oil was more cytotoxic than the methanolic extract (Rotsein et al. 1974).M. communis methanolic extract administered against hydatid cyst protoscoleces showed scolicidal effect at 50 and 100 mg/ml concentrations.

Antioxidant effect
The assays of reducing antioxidant power, and beta-carotene linoleic acid were used to examine action against oxidants, leaf total phenolic content, and M. communis berries.The ranges of the total phenol content include 9.0 mg and 35.6 mg GAE/g of myrtle extract.The berry extracts possess fewer total phenolic compounds, but the leaves have more total phenolic compounds.The aqueous, ethanol, methanol of both leaves and berry extract showed antioxidant activity, but these activities were higher in leaves.The order of these activities includes berry extract (methanol > ethanol > water) and leaf extract (methanol > water > ethanol), respectively (Tumen et al. 2012).The antioxidant activities of phenolic compounds extracted by conventional hydro distillation and microwave-assisted extraction were investigated using different models.The extracts produced by the two extraction techniques produced phenolic compound content that were alike.According to ABTS assay, the extract of myrtle was the highest scavenger compared to α-tocopherol and butylated hydroxyanisole.In ORAC assay, butylated hydroxytoluene was not as strong as both extracts, but the strongest were as myricitrin (myricetin 3-O-rhamnoside) and caffeic acid.The manufacture of conjugated diene andCu 2+ -induced LDL oxidation during the lag phase responded in a manner dependent on the dose, as myrtle extract and myricitrin inhibited them all.Micelles appearance and bilayer vesicles as seen in the dispersion phospholipid analysis of bile salts through cryo-electron microscopy in bile salts oxidation or 2,2′-azobis (2-amidinopropane) hydrochloride-induced phospholipid myricitrin exhibited a greater protective effect than myrtle extracts, despite the similar effects of caffeic acid with tocopherol and myrtle extract (Ines et al. 2012).M. communis leaf extract 5-O-di-galloylquinic acid (DGQA), when administered on K562 cell line, inhibited lipid peroxidation induced by H 2 O 2, pointing out its antioxidant activity.Also, 82.2% of malondialdehyde formed was inhibited by the pure sample, which equally inhibited H 2 O 2 -induced genotoxicity.DGQA increased DNA repair enzymes and antioxidant enzymes; it also prevented gene expression in H 2 O 2 stressed chronic myelogenous leukemia cell line (K562) (Wannes and Marzouk 2016).M. communis extracts showed high antioxidant activity due to derivatives of gallonyl and polyphenols present.
The unique oligomeric, nonprenylated acylphloroglucinols (semi myrtucommulone and myrtucommulone A) are M. communis leaf isolate with great antioxidant properties, protected linoleic acid action against free radical attack, FeCl 3 − and autoxidation inhibition, including EDTA-mediated oxidation.Although the two compounds lack pro-oxidant action, semi myrtucommulone is more potent than myrtucommulone A. It was seen more in hepatic cells homogenates for action against ferric-nitrilotriacetateinduced lipid peroxidation than in cytotoxicity cell cultures for TBH inhibition or oxidation of induced FeCl 3 .The overall effects confirmed that semi myrtucommulone was a novel dietary antioxidant lead (Demir et al. 2016).
The exceptional oligomeric non-prenylated acylphloroglucinols (myrtucommulone A and semi myrtucommulone) displayed great antioxidant properties in solvent-free and cholesterol thermal (140 °C) degradation.There was significant preservation of LDL from oxidative damage of induced Cu 2+ ions after 120 min of oxidation due to the semi myrtucommulone and myrtucommulone.In pre-treatment, oxidative products (7-ketocholesterol, 7-beta-hydroxycholesterol, and conjugated dienes fatty acids hydroperoxides) were inhibited, pointing out great protection because of reduced cholesterol and polyunsaturated fatty acids (Elfellah et al. 1984).
The antioxidant effect of the methanolic extract of the seeds and oil was assessed using 1,1-diphenyl-2-picrylhydrazyl radical scavenging, reducing power β-carotenelinoleic acid bleaching, and metal chelating activity assays.In all tests of myrtle seed methanolic extract, the methanolic extract of myrtle seed exhibited enhanced antioxidant action to the oil (Rosa et al. 2008).
The essential oil and methanolic extract of M. communis var.italica variety were examined for their antioxidant activity using assays like beta-carotene-linoleic acid bleaching, metal chelating activity, and reducing power assays.The methanolic extracts of various parts of myrtle in all the tests displayed more antioxidant action compared to the essential oils (Mimica-Dukic et al. 2010;Cottiglia et al. 2012).
Antioxidant activity was exhibited by the essential oil of Myrtle leaf extracted by solvent-free-microwave extraction and conventional hydro distillation; however, their antioxidant effects were significantly lesser than the quercetin and gallic acid extract.The essential oil of fresh myrtle leaf obtained by solvent-free-microwave extraction showed more antioxidant activity than the one found in conventional hydro distillation (Flaminia et al. 2004).

Antidiabetic effect
M. communis berry aqueous extract was assessed for its hepatoprotective and antidiabetic effects (oral administration for 14 days with 250, 500, or 1000 mg/kg) in diabetic rats induced with streptozotocin.The extract administration significantly reduced AST, ALT, ALP, and serum glucose levels in all the diabetic groups.For the antioxidant, level of activity of SOD and GSH significantly increased, while a reduction of MDA was noticed in the diabetic rats as compared to control (P<0.05).The antioxidant and hypoglycemic effect was seen at a dose of 1000 mg/kg (Baz et al. 2016).M. communis aqueous with an ethanolic extract of (2 g/kg) when intragastrically administered 30 min prior to the injection of streptozotocin eliminated the early hyperglycemia.M. communis extract given 24 h and 30 h prior to streptozotocin inhibited the development of hyperglycemia 48 h later.Hyperglycemia was reduced significantly after administering Myrtus extract 48 h after streptozotocin; this effect was seen after administration.In normal mice, the blood glucose level was unaltered upon Myrtus extract administration (Panjeshahin et al. 2016).
M. communis leaf aqueous extract was investigated for antidiabetic and antioxidant effects in diabetic rats induced with streptozotocin (STZ) and normal rats.MC leaf aqueous extract given at 150, 300, and 600 mg/kg significantly reduced ALT, AST, ALP in serum blood glucose and MDA levels, in STZ-induced diabetic rats when compared to controls groups (P<0.05)(Karimlar et al. 2019).
The leaf hydroalcoholic extract displayed a mild antidiabetic effect in streptozotocin induced diabetic rats.However, the ethanolic extract of leaves (2 g/kg) possessed superior hypoglycemic effect in the diabetic rats than the aqueous extract (P < 0.05) (Tas et al. 2018).The hypolipidemic and hypoglycemic effects of M. communis hydroalcoholic fruits extract were studied in diabetic rats induced with streptozotocin.M. communis hydroalcoholic fruits extract was supplemented with drinking water for 35 days.M. communis hydroalcoholic fruit extract group exhibited reduced lipid profile, serum glucose, and level of malondialdehyde in tissue but increased erythrocyte SOD, aryl esterase, total blood GSH-Px, insulin, and serum paraoxonase activities (Medhat et al. 2017).
M. communis possessed α-glucosidase inhibitory activity and protein tyrosine phosphatase 1B (PTP1B), with IC 50 values ranges from 34.3 to 88.5 μM and 8.9 to 69.4 μM, respectively.The results supported M. communis application as a bifunctional food for type-2-diabetes treatment or management (Taamalli et al. 2014b, c, a).

Cardiovascular effects
M. communis aqueous extract showed an adverse inotropic effect on isolated Guinea pig atria, which atropine administration did not reverse.The whole extract induced cardiac depressive concentration-dependent effect in rabbits under an anaesthesia (Ebrahimi et al. 2020).
The hypotensive effects of M. communis methanolic and ethyl acetate leaf extracts were assessed in rats under an aesthesia by using invasive blood pressure recording.Intravenous administration of methanol and ethyl acetate reduced the maximum mean arterial systolic and diastolic blood pressure by 32.49% and 20.6% at 12 mg/kg bw, respectively, in rats anesthetized (Hosseinzadeh et al. 2011).
Studies were done to assess the leaf extract of M. communis ability to mitigate endothelial dysfunction and atherosclerosis in ovariectomized rats to model post menopause.Parameters assessed were antioxidant, aortic oxidant, asymmetric dimethyl arginine, interleukin 1beta, lipid profile, plasma estrogen, von Willebrand factor, lipoxin A4, and erythrocyte membrane fatty acids.The inflammatory and oxidant parameters were significantly increased in ovariectomized rats, but the administration of M. communis extract (100 mg/kg bw) for about 60 days reduced the treated group values.The leaf extract of M. communis possessed protective effects against endothelial dysfunction and atherosclerosis in ovariectomized rats because of its high amount of antioxidant and anti-inflammatory compounds, including ω-3 fatty acids (Youness et al. 2016).

Hemostatic effect
The application of 5% extract to the cut tail in the bleeding model of rat-tail significantly reduced the time of bleeding (P< 0.001) as compared to normal saline group.The figures of PT and aPTT were elevated >120 s and >180 s by 5% extract, respectively.Likewise, serum proteins and protein precipitation were significantly reduced in the extract group of extract with 5% (Hajiaghaee et al. 2016).
Myrtle's ability to protect the neuron in rats was studied against neurotoxicity induced with lipopolysaccharides (LPS), malondialdehyde, tumor necrosis factor α, nitric oxide, interleukin1β, Willebrand factor (VWF), asymmetric dimethyl arginine (ADMA), estrogen, 5LOX, 15LOX, and lipoxin A4.The tissue and serum of challenged rat's brain were examined.The outcomes showed that investigated stress parameters significantly increased while estrogen level significantly decreased in rats intoxicated with LPS.Notable improvement was discovered in every studied biomarker (Shahmohammadi et al. 2012).
The central nervous effects of 80% M. communis leaf ethanolic extract (25-400 mg/kg, ip) were evaluated in mice and rats.Mice were subjected to grip strength, pentylenetetrazol-induced seizure, open field, and righting reflex assessments.Male rats were assessed for rapid eye movement (REM) as well as non-REM (NREM) sleep alterations.M. communis extract (50 -200 mg/kg) assessment was done for horizontal activity (ED 50 = 251 ± 55 mg/kg) and vertical activity (ED 50 = 40.2± 6.6 mg/kg), while treatment with 200 and 400 mg/kg mitigated significant muscle tone in a method that is dependent on the dose.An important hypnotic, but no anticonvulsant effect, was recorded on administration with the extract at 200 mg/kg (P< 0.01).The reduced REM time of sleeping was shown by the electroencephalography results, while the NREM and total sleep times were significantly elevated compared to the mice control group (Aykac et al. 2019).
The mouse model was examined for the sedative-hypnotic effect of the aqueous extract.In the myrtle aqueous extract 200 mg/kg, the locomotor activity was significantly reduced in open field test (P<0.01).The hypnotic effect of aqueous extract of myrtle showed significance and was recorded in righting loss reflex test induced with pentobarbital induced (P <0.05) (EL-Kholy et al 2018).The efficacy of M. communis treatment on the factors that play a vital role in Alzheimer's disease pathogenesis was compared with galantamine administration.The level of expression of muscarinic receptors M 1 , AchE, Ach activity, BDNF, GSH level, MPO, and MDA activity, and the gene expression of AchE were examined in rats induced with scopolamine.The results revealed that, M. communis administration in treatment significantly improved the reduction of latency in scopolamine-induced rats and object recognition time, elevating M 1 , BDNF, and Ach receptor levels of expression in the various regions of the brain.Furthermore, M. communis administration exhibited elevated AchE by improving GSH activity and decreasing MPO activity and MDA level (Naji et al. 2018).

Protective effects
M. communis extract (300mg/kg bw, daily for 49 days) was studied for its protective effect against acrylamide and monosodium glutamate-induced hepatotoxicity in male rats.The results verified that the administration of monosodium glutamate and acrylamide lead to a significant elevation in LDL-C, TC, TL, TG, GGT, ALT, AST, ALP, TB, and MDA.However, myrtle leaves extract caused noticeable decrease in TP, GSH, Alb, TAC, CAT, SOD, GSH-Px, and HDL-C (Sen et al. 2016).
M. communis extract ameliorative effect was assessed on the arsenic chloride (AsCl 3 ) toxicity-inducing tumor suppressor protein (P53) production in rats.The results showed that AsCl 3 induced negative effects on the levels of P53-based gene expression and possibly P53 gene protein activity, bringing about low expression of gene.However, M. communis improved the status by elevating P53-based gene expression levels if used alone or mixed with AsCl 3 (Samareh et al. 2018).
M. communis sp. was also examined for its antifibrotic and antioxidant effects against hepatic fibrosis and injury arising from biliary obstruction in rats.Direct bilirubin, plasma total bilirubin, alanine aminotransferase, aspartate aminotransferase, interleukin-1β levels, tumor necrosis factor-α were significantly elevated in the group with bile duct ligation, while these figures significantly declined in the bile duct ligation group administered with M. communis sp.Communis extract.Superoxide dismutase and glutathione were reduced significantly in the bile duct ligation group as compared to the groups in the control but increased significantly in extract-treated group.The levels of tissue luminol, myeloperoxidase activity, malondialdehyde, transforming growth factor-beta, lucigenin, and hydroxyproline increased dramatically in the bile duct ligation and were reduced in the group treated with the extract (Ozbeyli et al. 2020).
The therapeutic and protective effects of M. communis methanolic extracts (50 mg/kg/day, intraperitoneal ip, from days 0 to 13) and (50 mg/kg, ip, from 14 to 27 days), respectively, of the methanolic extract of M. communis were studied in rats against bleomycin-induced pulmonary fibrosis.Parenchymal inflammation and fibrotic changes, lipid peroxidation, and hydroxyproline content were significantly decreased in the myrtle extract-treated group, but catalase activity was greater.An enhancement in fibrosis and inflammation was seen in myrtle-treated group, particularly in the initial fibrosis phase (preventive regime) (Mahboubi et al. 2016).
M. communis ssp.leaf ethanol extract protective effect administration (for 14 days before induction) was studied against acute pancreatitis induced with cerulenin in rats.Pancreatic damage induced by cerulenin was related with elevated serum activity of amylase and lipase, the pancreatic activity, level of myeloperoxidase, malondialdehyde, interleukin-1β, and interleukin-6.Acute pancreatitis similarly manifested by a decline in the levels of anti-inflammatory interleukin-10 and glutathione in the pancreas.In the extract pretreatment group, before the induction of pancreatitis, the pancreatic injury detected through the histological analysis was significantly reduced, including a reversal in biochemical changes (Zohalinezhad et al. 2016).

Gastrointestinal effects
M. communis essential oil and its decoction reduced the average time of pain and lessened ulcers size in patients with slight recurring aphthous stomatitis, showing no antagonistic effects.All the patients were content with M. communis topical essential oil (5%); 81% of patients preferred M. communis topical decoctions (5%).The effectiveness of M. communis was linked to its antiseptic, anti-inflammatory, analgesic, and its wound healing effects (Jabri et al. 2016a, b, c).
The aqueous seed extract of myrtle berry's protective effects against induced esophageal reflux was studied in rats.The induced esophageal reflux caused noticeable histopathological and macroscopic variations in the esophagus.It also followed oxidative stress as measured by a rise in lipid peroxidation, a reduction of the sulfhydryl groups, and levels of glutathione, including the depletion of antioxidant enzyme activities.The extract nullified all biochemical, histopathological, and morphological changes.The induced esophageal reflux also amplified esophageal calcium, free iron levels, and hydrogen peroxide, while extract management protected compared to intracellular mediator's deregulation (Bouzabata 2013).
M. communis effects in gastroesophageal reflux disease were investigated in comparison with omeprazole through 42 days double-blind randomized controlled scientific trial.About 45 applicants were randomly given three groups: myrtle berries freeze-dried aqueous extract (1000 mg/day), omeprazole capsules (20 mg/day), and the third group received a combination of both treatments.The dyspeptic and reflux scores decreased significantly in all groups when compared with the respective standards.However, substantial changes existed in myrtle extract group (acid reflux and dysmotilitylike symptoms related scores) (Benchikh et al. 2016).
The anti-gastric ulcer effect of M. communis dried berry aqueous extract (105 and 175 mg/kg, orally) and methanolic extract (93 and 154 mg/kg, orally) was studied against rats induced with pyloric ligation, ethanol, and indomethacin.Aqueous extract administered orally (at both doses) caused the ulcer index in all prototypes of ulcers to decrease significantly.The aqueous extract (small dose) and methanolic extract (high dose) of M. communis demonstrated effects that were more significant than those of omeprazole in ulcer models induced with ethanol.Two doses of extracts lessened gastric juice volume and total acidity but elevated gastric wall mucus content and gastric pH in the ulcer's models.Histopathological studies of rat's gastric tissues administered with methanolic and aqueous extracts in ulcer induced with indomethacin exhibited a significant protective effect against ulcer at that dose level (Sumbul et al. 2012).
The effects of M. communis berry juice (5 and 10 ml/kg bw, orally) on gastric emptying and normal gastro-intestinal transit, including diarrhea induced by castor oil, oxidative stress in the small intestine, and entero-pooling tests, were studied in rats.The juice inhibited intestinal motility and gastric emptying in a dose-dependent manner.The juice administration equally caused a significant dose-dependent defense against diarrhea and intestinal fluid buildup.The status of oxidative stress in the intestine associated with intestinal hypersecretion induced with castor oil was attenuated via juice administration (Jabri et al. 2016a, b, c).

Antidiarrheal effects
In mice, model-treated M. communis essential oils were examined for their antidiarrheal and antisecretory activities.The M. communis oil [abundant in 1.8-cineole 26.5% and α-pinene 54.1%] reduced significantly the gastric emptying dose of 500 mg/kg and the intestinal transfer at the entire doses utilized (50, 250, and 500 mg/kg).The extract essential oil similarly possessed anti-diarrheal and anti-secretory action depending on the dose (Sisay et al. 2017).
The antidiarrheal effects of an aqueous extract of M. communis berry seeds were studied in diarrhea induced with castor oil in rats.The defense of the extract depended on the dose against intestinal fluid and diarrhea buildup.Hypersecretion of the intestine induced with castor oil was complemented by the intestinal status of oxidative stress; hydrogen peroxide in the intestine also increased, as did free iron and calcium levels; however, the group pre-treated with the extract showed alteration in all castor oil-induced intracellular mediators' turbulence.The results also showed that the extract has abundant total and condensed tannins and presents antibacterial action in a broad spectrum (Panahi et al. 2014).
The methanol extracts of 200 mg/kg (P< 0.05) and 400 mg/kg (P< 0.01), including the methanol and chloroform fractions of 400 mg/kg (P< 0.05), all significantly hindered the commencement of diarrhea.All doses of methanol extract, and both segments at 300 and 400 mg/ kg, expressively lessened the regularity and mass of fecal yields.Charcoal meal test output showed the methanol extract at all prescriptions (P< 0.001) as well as the two fractions of 300 mg/kg (P< 0.05) and 400 mg/kg produced a significant (P< 0.001) anti-motility effect.In the entero-pooling test, the methanolic extract at all verified prescriptions (P< 0.01), and the fractions at 300 mg/kg and 400 mg/kg (P< 0.05) produced a notable decrease in the capacity and mass of intestinal substances (Mahboubi et al. 2017).

Anti-hemorrhoid effects
The efficiency of topical cream from the essential oil M. communis in alleviating hemorrhoids symptoms compared to ointments that are anti-hemorrhoid (containing zinc oxide, lidocaine, hydrocortisone, and aluminum subacetate) was evaluated in a random double-blind doubledummy trial performed on 106 patients.All assessed indications (long-lasting pain, bleeding, pain during excretion, and irritation, anus itching, tenesmus, and heaviness) were considerably diminished by trial end (P<0.001).No remarkable difference was noticed in the level of improvement of evaluated symptoms concerning ointment of antihemorrhoid and M. communis (P>0.05)(Malekuti et al. 2019).
The therapeutic effect of the essential oil of M. communis on hemorrhoids management was clinically examined.The results pointed out that the essential oil of M. communis (cream or ointment) significantly ameliorated hemorrhage, excretion pain, perpetual pain, anal itching, anal irritation, and anal weightiness in types I and II hemorrhoids' patients.M. communis was dynamic in patients' treatment, not responding to organic product usages (antihemorrhoids cream) (Janbaz et al. 2013).
A triple-blind random controlled trial was done to regulate the anti-hemorrhoid effect of M. communis ointments (two times a day, every single 12 ± 2 h, through the rectum for 28 days) compared with anti-hemorrhoid ointment, taking the life quality and hemorrhoid into consideration (main outcomes) with contentment of the management and harmful effects (minor results) in females with grade I and II hemorrhoid.The colorectal assessment of a clinical therapeutics gauge (CORECTS) was utilized to measure the severity of hemorrhoid and the World Health Organization Life Quality Survey (WHOQOL-BREF) to decide the value of life.The harshness of hemorrhoid symptoms was reduced in both groups, showing no significant difference statistically between both groups (P>0.05).The anal itching mean was significantly lower 28-56 days after involvement in the M. communis cream group (P<0.05).No significant difference was seen between groups at 28-56 days after considering life quality (P>0.05).The participants given M. communis cream remained significant, showing satisfaction in the drug usage (Harassi et al. 2019).

Effects on smooth muscles
M. communis crude methanol extract triggered full contractions induced by K + (80 mM) that are also spontaneous in isolated rabbit jejunum.It induced right-side shift similar to response curves of calcium.M. communis crude methanol extract also caused relaxation on K + (80 mM)induced contractions in isolated rabbit tracheal arrangements and caused phenylephrine relaxation (1 μM) and K + (80 mM)-induced contractions in isolated rabbit aorta preparations, like verapamil, a standard calcium channel blocker (Ozturk and Duran 2018).

Anticancer and antimutagenic effects
The cytotoxicity of M. communis oils was investigated against MCF-7 and P815 cells.P815 cells showed less activity than MCF-7 cells, with IC 50 values of 4-6.25 µg/ ml against the essential oils.Cell toxicity is related to DNA fragmentation, an important apoptosis hallmark (Tretiakova et al. 2008).
The cytotoxic effect of water, ethanol, methanol, n-hexane, and ethyl acetate extracts of M. communis leaves was assessed in vitro against brine shrimp.All the extracts showed cell toxicity against brine shrimp (LC 50 < 1000).The extracts of n-hexane extracts and ethyl acetate showed additional cytotoxic activity compared to other extracts (Fani et al. 2014).The essential oil of M. communis antiproliferative effect was studied against cancer Vero cells and HCT 116.M. communis IC 50 values were examined at 25 μg/ml in HCT 116 and 15 μg/ml in Vero cells (Hayder et al. 2008).
Myrtucommulone strongly induced the death of cells of diverse cancer cell lines (EC 50 3-8 microM); apoptosis was visualized by stimulating cleavage of poly (ADP-ribose) polymerase (PARP) cleavage, caspase-3, -8, and -9, DNA fragmentation, and nucleosomes release into the cytosol.It was not cytotoxic against foreskin fibroblasts with EC 50 of cell death around 20-50 microM or non-transformed human peripheral blood mononuclear cells (PBMC).Furthermore, its apoptotic effects were facilitated by the intrinsic, not extrinsic death pathway.It triggered the reduction of mitochondrial membrane potential in MM6 cells, and mitochondria cytochrome c release is induced (Choudhary et al. 2013).
M. communis aqueous, chloroform, ethyl acetate, methanol, hexane, total flavonoids oligomer fraction, and essential oil significantly reduced the response to DNA damage caused by nifuroxazide and aflatoxin B1 in a system of bacterial assays (Escherichia coli PQ 37 with the SOS chromotest).The extracts of methanol and ethyl acetate displayed strong inhibition against DNA damage response caused by secondary genotoxic aflatoxin B1 (Ghadami et al. 2014).
M. communis oils antimutagenic properties were assessed against reactive mutagenesis induced by t-BOOH in Escherichia coli oxyR mutant IC 202, (a bacterial strain) unable to eliminate ROS.A decline in reactive mutagenesis occurred when myrtle oil was administered with the highest concentration at 13%.During the use of oxidative mutagen, the oil greatly reduced mutagenesis in a manner dependent on the concentration (at the highest concentration of 28%) (Cottiglia et al. 2012).

Immunomodulatory effect
Myrtucommuacetalone, myricetin, myrtucommulone M, myrtucommulone E isousnic acid, and growth regulator G3 factor are all M. communis isolates assessed for their ability to lessen the immune response through their effects on various immune system constituents.Compounds of myrtucommuacetalone and growth regulator G3 factor were significantly inhibited against nitric oxide (NO) production.Myrtucommuacetalone also revealed important antiproliferation (IC 50 < 0.5 μg/ml) against proliferation of T-cell.Significant inhibition was caused by myricetin (IC 50 = 1.6 μg/ml) on the blood phagocytes stimulated by zymosan in ROS generation.The compounds myrtucommuacetalone and myricetin were active against ROS generation stimulated by PMA (Ozcan et al. 2019).

Dermatological effects
M. communis can be applied topically in wart treatment.It displayed an additional rapid response compared to salicylic acid and very few side effects (Salehpour et al. 2016).
The protective effect of oral or topical M. communis management (100 mg/kg per day) either topically or orally for 2 days was investigated against rats induced with burn damage (in the burn group, dorsum was clean-shaven and kept in water bath with a temperature of about 90 °C).The burn injury in the skin was triggered by heat, causing a significant reduction in glutathione and nitric oxide levels and activities of catalase, superoxide dismutase, and tissue factor, followed by a significant increase in skin malondialdehyde levels.Myrtle management altered every biochemical index and also caused histopathological alterations as a result of heat trauma.The topical and oral administration of myrtle extract possessed an ameliorative role in the oxidative damage induced by the wound (Hayder et al. 2008).

Toxicity and side effects
The ethanolic and aqueous extracts of aerial parts of M. communis showed LD 50 values of 0.79 and 0.473 g/kg in mice separately (Soomro et al. 2019).
In Arabi sheep, blood parameters were assessed for the effect of M. communis leaf on them.The result showed significant reduction in the glucose, triglyceride, and blood urea of sheep when fed a diet containing 4% myrtle leaf compared with the control diet (D'Urso et al. 2017).
Recent studies that elaborated on various aspects of the therapeutic potential of M. communis include Dabbaghi et al. (2023) that states that myrtle's strong antioxidant concentration is one of its most important defensive qualities.Research have demonstrated that myrtle's antioxidant qualities can offer defense against dangerous compounds like pesticides, heavy metals, and other pollutants found in the environment.Furthermore, myrtle possesses antiinflammatory qualities that may lessen the harm brought on by prolonged exposure to pollutants.Myrtle's antiinflammatory and antibacterial qualities have also shown promise in treating gastrointestinal disorders like stomach ulcers.
In fact, product from M. communis is getting closer to the clinic as a randomized clinical trial was out to assess the therapeutic effects of M. communis on chromic skin lesions, and they measured the duration of sleep, number of nighttime awakenings, quality of life, and chronic skin problems and itching-related characteristics (such as the itching time, severity, distribution, frequency, and calculated itching score) in the two groups.Applying myrtle cream effectively reduced skin issues, such as itching and burning feeling, according to our data research.Furthermore, when compared to pre-treatment, myrtle significantly reduced skin lesion symptoms such as excoriation in the case group.Myrtle cream was found to have a notable positive impact on the patients' quality of life within the case group.More detailed information about the preventive effect of myrtle against skin complications caused by sulfur mustard is provided by this study.Additionally, myrtle significantly raised the veterans' quality of life who had been exposed to sulfur mustard (Iman et al. 2022).

Conclusion
M. communis is used at different places throughout the world as a traditional herbal remedy.It contained many bioactive ingredients and possessed a wide range of pharmacological effects like anti-inflammatory, analgesic, antimicrobial, antiparasitic, antioxidant, antidiabetic, cardiovascular, central nervous, protective, gastrointestinal, anticancer, antimutagenic, immunomodulatory, dermatological, and many other biological effects.According to the data on in vitro and in vivo studies, M. communis has the potential to be used in pharmaceutical development as a medicine for wound healing, treatment of gastrointestinal disorders, and cancer management, to name a few, because of its safety and effectiveness.

Fig. 2
Fig. 2 Schematic diagram for the pharmacological properties of M. communis

Table 1
Physicochemical properties of berries of M. communis

Table 2
Ellagic acid and ellagitannins in myrtle berry seeds (Franco et al. 2019)g/g dry weight and are mean ± standard deviation from three independent experiments(Franco et al. 2019)

Table 4
Detailed chemical constituents of M. communis