1J Contemp Med Sci | Vol. 4, No. 1, Winter 2018: 1–6 Review on Teucrium polium biological activities and medical characteristics against different pathologic situations Mozafar Khazaei,a Seyed Noureddin Nematollahi-Mahani,b Tahmineh Mokhtari,c Fatemeh Sheikhbahaeib aFertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. b Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran. cResearch Center of Nervous System Stem Cells, Department of Anatomy, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran. Correspondence to Fatemeh Sheikhbahaei (email: am23384@gmail.com). (Submitted: 08 September 2017 – Revised version received: 27 September 2017 – Accepted: 13 October 2017 – Published online: 26 March 2018) Objective Herbal medicines and the use of these drugs in treating and preventing of certain diseases in the world and Iran have increased dramatically. Teucrium polium, one of the plants that has been used in traditional medicine nearly 2,000 years ago belongs to Labiatae family and is used as a diuretic, tonic, antipyretic, anti-fungal, anti-spasmodic, anti-rheumatic, carminative and an antibacterial agent. Methods Information of this article has collected from the database of PubMed, ScienceDirect and Scopus. Results The effects of T. polium on the liver, kidney, stomach, brain has investigated and antidiabetic, antioxidant, antimicrobial, and anticancer effects of this agent, has introduced. Several studies revealed that T. polium has a hypoglycemic effect and can help to control blood sugar. In addition, due to the undeniable effects of this plant against cancer cells, it can be considered as a natural resource, for the treatment of cancer. Conclusion This review investigates multiple properties of T. polium. Keywords cytotoxicity, medicinal properties, Teucrium polium Introduction Treatment of various diseases using medicinal plants traced back to ancient times. Teucrium polium, the herb that has used in traditional medicine, almost 2,000 years ago, is found mainly in the Mediterranean region and different areas of Iran especially in semi-arid parts of the mountains and plains.1,2 This herbaceous plant, belonging to the Lamiaceae family and flowering time is between June and August.3 (Fig. 1). This plant includes 300 species around the world, and has identified in 12 species in Iran. Among them, T. polium, has been used in traditional medicine.4 This plant has diuretic, tonic, antipy- retic, anti-fungal, anti-spasmodic, anti-rheumatic, carmina- tive and antibacterial properties.5,6 Moreover, it has hypoglycemic effects and has been used in diabetic patients as a hypoglycemic agent. Daily consump- tion of this plant helps to maintain normal levels of blood sugar and can be appropriate for conventional medications to control blood sugar.7 In addition, T. polium has anti- inflammatory activity,8 as well as reduce high body weight and high blood pressure9 and has antioxidant and lipid- lowering properties. Numerous studies investigated the effects of T. polium against different pathological situations in different organs. So, in this review, we tried to demonstrate the different biological activates and medical properties of T. polium as a traditional plant. Particularly, we focused on the mechanisms underlying T. polium’s antioxidant, antibacterial and anti- cancer properties. Source and Chemical Compounds of T. polium pheochromocytoma Teucrium polium is perennial, herbaceous, with almost woody plants, to a height of 30 cm and has a white appearance and cotton. Flowers can be seen in white, yellow and white to yellow. This variability is seen not only in color, but also in flower stems that are branched or lying.10 T. polium distributes in rocky and sandy areas of Mediterranean, different parts of Europe, North of Africa and Southwest of Asia, including Iran (in various regions of North, West, South and Central arid mountains).2 Some compounds of T. polium have been intro- duced in different investigations including tannin, terpenoid, saponin, flavonoid, sterol, β-caryophyllene, diterpenoids, caryophyllene oxide, asparagine, ditryne and resinous sub- stances.11,12 Vokou and Bessiere13 reported that T. polium con- tain tannin, terpenoid, saponin, sterol, and flavonoid. It is used in the treatment of gastrointestinal diseases. Several compounds extracted from different parts of this plant have been structurally characterized: including Iridoid, flavonoid, eudesman and clerodane. The first returns to the years 1974–1979. In Egypt, α-pinene, menthofuran, monoterpenes (myrcene, ocimene, pulegone have presented as the main of T. polium components). β-Eudesmol has detected in T. polium in Tunisia.14 In the region of Saudi Arabia (subspecies not listed), monoterpenes (β-pinene, limonene, α-phellandrene, linalool, and terpinen-4) and terpenes (γ-cadinenes, cedrenol, guaiol) have detected.6 In Greece (subspecies not reported), T. polium contains ter- penes: α- and τ-cadinols and β-caryophyllene.13 It has been reported that this agent in Spain is rich of monoterpenes that often consisting of α- and β-pinenes, limonene, terpinen-4 and pinocarveol-18 (Table 1).15 Antioxidant Capacity of T. polium Therapeutic benefits of medicinal plants are often attributed to their antioxidant properties.16,17 Different researches in recent years demonstrated that T. polium has high antioxidant prop- erties. Many species of medicinal plants, especially those belonging to the mint family, such as sage, tucrium, penny- royal and thyme have strong antioxidant activity.18 Number of phenolic compounds with strong antioxidant activity in extracts of these plants have been identified.19 HPLC analysis ISSN 2413-0516 Review 2 J Contemp Med Sci | Vol. 4, No. 1, Winter 2018: 1–6 Review on Teucrium polium biological activities and medical characteristics Khazaei M et al. showed that the highest levels of flavonoid in T. polium species are in chamaedrys and T. polium. In vitro research showed that T. polium has the antioxidant activity and free radical scav- enging activity.19,20 In several research, the effect of T. polium on oxidation of various tissues have studied and the inhibitory effects of the plant extract against peroxidation, have proved. In this regard, the methanolic extract of T. polium protects red blood cells against lipid peroxidation induced by hydrogen peroxide.21 Kadifkova Panovska et al.20 reported that different factions of T. polium (diethyl ether, ethyl acetate and n-bu- tanol) have inhibitory effect against oxidation. Aqueous extracts prepared from leaves of T. polium, suppresses iron-in- duced lipid peroxide oxidation in rat liver as well as Trolox, i.e., analog of vitamin E. Anti-diabetes Effects of T. polium Some plants are used as hypoglycemic agents and their extracts have studied in the treatment of diabetic patients.22,23 Several animal studies were carried out to evaluate the effect of T. polium on blood glucose concentrations. In a study by Jemal et al. (2012), it was shown that intravenous injection of boiled T. polium caused a significant reduction in blood glucose in diabetic group, compared with a control group that received normal saline.7 Hydro-alcoholic extract of T. polium can reduce blood cholesterol and glucose and also improves insulin secretion in diabetic rats.24 Esmaeili et al. (2009) reported that flavonoid compounds of T. polium, increase insulin secretion from pancreatic beta cells (56%). This finding was related to flavonoid antioxidant effects of T. polium.25 Zal et al.26 demonstrated that T. polium decreased blood glu- cose in diabetic mice and it has been normal within 8 days. Other studies have shown that aqueous extract of T. polium reduces blood sugar in diabetes rat with single dose; it increases insulin secretion and thereby decreases blood glucose in dia- betic rats.27 But, the extracts of this plant did not have a signif- icant effect on blood sugar of rabbits.28 According to studies that evaluated the effect of T. polium on blood sugar levels, it seems that the plant extract may improve insulin function in an animal model. But according to the conflicting reports and deficit of human studies on the effects of this herb on blood sugar level, currently commenting on proven effects of T. polium as hypoglycemic agent is difficult and clinical research seems is necessary. Anti-cancer Effects of T. polium Cancer has remained a major cause of disability and mortality in worldwide.29 Despite recent advances in early detection and treatment of cancer, continues to be unstoppable, threatening health and quality of human life. Traditionally, herbal com- pounds have long been considered in the treatment of cancer and drugs such as doxorubicin and paclitaxel that are derived from plants are also used in the treatment of cancer. Despite the abundance of different plant species in the world, only 1–10% of plant species composition around the world, have been studied.30 In recent years, anti-cancer properties of T. polium have evaluated in several experiments and cytotoxic effects of total extracts and derivatives of this plant against cancer cells has been reported. Anti-cancer properties of this plant know more about to terpenoid and flavonoid com- pounds. For example, in a study, anti-cancer effect of metha- nolic extract of T. polium and vincristine, vinblastine and doxorubicin against cell lines is shown: Skmel -3 (melanoma), Saos-2 (osteosarcoma), SW480 (colon cancer), MCF-7 (breast cancer), KB (oral epidermal cell line), EL (bladder carcinoma) and A431 (epidermoid carcinoma). Administration of T. polium and anti-cancer drugs such as vincristine, vinblastine or doxorubicin can enhance the ability of chemotherapy drugs to cancer and also minimizes side effects.31 Flavonoids have been considered as the most potent inducer of apoptosis.32 Anti-cancer and cytotoxic effects of T. polium in different types of human cell lines is tested such as cervical cancer (HeLa), chronic myeloid (K562), colon cancer (Caco-2, HCT-116, LoVo, SW480), glioblastoma multiforme (REYF-1), hepato- blastoma (HepG2), carcinoma of the larynx (HEP-2), lung cancer (COR-l23), prostate cancer (DU145, PC3).33–36 Addi- tionally, the cytotoxic effects of ethanolic extract of T. polium in four cell lines were examined to evaluate the for- mation of colonies: A549 (adenocarcinoma of the lung), BT20 (cancer of the ducts of the breast), MCF7 (breast adeno- carcinoma) and PC12 (pheochromocytomaFV mice). As well, they compared cytotoxicity of T. polium with taxol, an anti-cancer agent. The results demonstrated that ethanolic extract of T. polium, inhibits growth of all cell lines effectively. Fig 1. Teucrium polium. Table 1. Isolated chemical compounds of T. polium in different studies Chemical compound Country Year Author (Reference) β-pinene, limonene, α-phellandrene, lin- alool, terpinen-4-ol, γ- and δ-cadinenes, cedrol, cedrenol, guaiol Saudi Arabia 1979 Hassan et al.(6) Tannin, terpenoid, saponin, sterol, and flavonoid Greece 1985 Vokou et al.(13) Myrcene, α-pinene, menthofuran, ocimene, pulegone Egypt 1974 Wassel et al.(14) α- and β-pinenes, sabinene, ter- pinen-4-ol and pinocarveol Spain 1993 Pérez-Alonso(14) Review Khazaei M et al. 3J Contemp Med Sci | Vol. 4, No. 1, Winter 2018: 1–6 Review on Teucrium polium biological activities and medical characteristics Table 2. T. polium biological activities and medical characteristics according to the different studies Authors Groups T. polium Twaij (1987) Rat Recovery of stomach ulcer Munir (1988) Rat A significant reduction in blood glucose concentration Lalibert and Villeneuve (1996) Human Lethargy, jaundice, elevated liver enzymes (using T. polium 6 months) Zal et al. (2001) Rat Glucose reduction within 8 days Zal et al. (2001) Rat Degenerative changes in liver lobules Rasekh (2001) Hyperlipidemic rat Lower cholesterol and triglycerides Afifi et al. (2005) Rabbit No significant effect on blood sugar Baluchnejadmojarad T et al. (2005) Rat Analgesic effect Shahraki et al. (2006) Rat Lower blood sugar levels of diabetic mice Shahraki et al. (2006) Rat Analgesic effect of visceral and somatic Panovska et al. (2007) Rat Repair and regeneration of liver Mehrabani et al. (2009) Rat Reducing gastric ulcer index by 90% Mousavi (2011) Rat Lower obesity parameters Ayoubi et al. (2013) Rat Lower glucose in diabetic mice Belmekki et al. (2013) In vitro The inhibitory effects on bacteria Tabatabaei et al. (2014) In vitro Antimicrobial effect against gram positive bacteria Mousavi et al. (2015) Rat Improving the devastating effects of diabetes on memory Nematollahi (2007) In vitro Inhibit the growth of cell lines: IC 50 : BT20:106 µg/ml IC 50 : MCF-7:140 µg/ml IC 50 : PC12:120 µg/ml IC 50 : A549:90 µg/ml Eskandary (2007) In vitro Reduce the formation of clonal cell lines REYF-1 Methanolic extract: IC 50 : 95 µg/ml Mahdinia (2012) In vitro Cytotoxicity on (U87) IC 50 : 64.47 µg/ml Rajabalian et al. (2008) In vitro Cytotoxicity on cell lines: IC 50 : Saos-2:109 µg/ml IC 50 : Skmel:3–83 µg/ml IC 50 : MCF-7:174 µg/ml IC 50 : SW480:139 µg/ml IC 50 : KB:174 µg/ml IC 50 : EJ:108 µg/ml IC 50 : A431:93 µg/ml Kundaković (2011) In vitro Cytotoxicity on cell lines: IC 50 : MDA-MB-361:130 µg/ml IC 50 : MDA-MB-453:367 µg/ml Menichin (2009) In vitro Cytotoxicity on cell lines: IC 50 : RAW264/7:29/4 µg/ml IC 50 : CACO-2:52/7 µg/ml IC 50 : 2C32:91 µg/ml IC 50 : 23COR-L:104 µg/ml Review 4 J Contemp Med Sci | Vol. 4, No. 1, Winter 2018: 1–6 Review on Teucrium polium biological activities and medical characteristics Khazaei M et al. Among the cell lines, A549 was more sensitive to PC12.37 Cyto- toxic and anti-tumor effects of the aqueous and methanolic extract of T. polium on human glioblastoma cell line (REYF-1) has been studied and proved that methanolic extract of T. polium decreases colony formation in a dose-dependent. The metha- nolic extract was more effective than aqueous extract, due to the better solubility of the active chemical components in methanol.34 It has been reported (2012) that terpenoids and antioxidants compounds derived from petroleum ether frac- tion of T. polium accelerate cytotoxic effects against U87.38 Antimicrobial Effects of T. polium Teucrium polium aqueous extract has anti-bacterial proper- ties, but anti-fungal effect has not been confirmed.39 The results demonstrated that T. polium extract significantly has antimicrobial activity in vitro, especially on the strains of gram-positive bacteria.40 Oil extracted from the T. polium with a minimum concentration of 3–5 μl/ml, has the inhibitory effect on Bacillus cereus bacteria, Enterococcus faecalis and Escherichia coli.41 Raei et al.42 confirmed the antibacterial activity of T. polium essential oil against urinary-isolated Kleb- siella pneumoniae. Motamedi et al.43 evaluated the antibacte- rial effects of T. polium on Staphylococcus aureus strains and they suggested that T. polium was an effective medicinal plant for treatment of infections caused by S. aureus. Sevindik et al.44 determined the antimicrobial activity and chemical composi- tion of T. polium essential oils provided from North Anatolian. They showed that this plant had an inhibition effect on resistant micro-organisms including methicillin-resistant Pseudomonas aeruginosa, S. aureus ATCC 6538, S. aureus (MRSA), E. coli Q157:H7 and B. cereus CCM 99.44 So, this nat- ural antibacterial source can be carried out to produce new drugs against different bacteria. Antinociceptive and Analgesic Effects of T. polium Oral administration of this plan is used as a visceral analgesic agent. In one study, use of T. polium extract, increased the time of tail reaction to painful stimulus in rats and it can be con- cluded that this plant extract may has a visceral analgesic in addition to somatic analgesic. Although the exact mechanism, needs further investigation. T. polium extract at a dose of 200 mg/kg for a period of 2 weeks, has been created a significant analgesic effect.69 Verdi et al.45 proved that aqueous extract of T. polium leaves induced antinociceptive effects through the central mechanisms in rat model of pain. Zendehdel et al.46 showed that the analgesic effect of T. polium mediated by opi- oidergic and histaminergic H1 and H2 receptors in mice model of visceral pain. Effects of T. polium on Nervous System Related Disorders Teucrium polium extract had positive effects on mice that were suffering from amnesia with scopolamine. It has been reported that T. polium extract can significantly reduce lipid peroxida- tion in the hippocampus and cerebral cortex. Different doses of this agent were able to prevent learning difficulties.47 In another study, results revealed T. polium (200 and 400 mg/kg), prevents the damaging effects of diabetes on memory, but a dose of 100 mg/kg T. polium does not has any positive effect on memory disorders.48 As well, Mousavi et al. (2015) investi- gated the beneficial effects of T. polium on diabetes-induced brain tissue oxidative damage and memory deficits in rats. Their findings of proved that T. polium protected the rat against the memory impairments induced diabetes by reducing the brain tissues oxidative damage in rats.47 Simonyan et al.49 demonstrated that hydroponic T. polium had protective effects on hippocampal neurodegeneration by modulating neurotransmitters activates and network plasticity in ovariect- omized rats. Effects of T. polium on Gastric Disorders Teucrium polium extract inhibits the movement of the stomach and in traditional medicine; it is used as an antispasmodic. In a study, rats were treated with indomethacin to induce gastric ulcer. T. polium reduced the scarring at a rate of 50% after a week, 80% after 2 weeks and 90% after 4 weeks. The mucosal healing, and the reduction of proliferation, mucosal hyper- plasia, migration of inflammatory cells were observed.50 This agent at a dose of 150 mg/kg promoted wound healing at the rate of 50% in mice that their stomach ulcers were induced by starvation. Whereas, oral consumption of the extract improves gastric ulcers at the rate of 85%.51 Vascular Effects of T. polium Teucrium polium decreases aortic smooth muscle contraction induced by KCl and phenylephrine. Endothelium can inhibit contraction of smooth muscle of vessels through the synthesis and secretion of substances such as nitric oxide (NO) and can induce the contraction through the synthesis and secretion of endothelin. The difference in the effect of the contraction induced by KCl and phenylephrine in the presence or without endothelium indicates that part of the effect, mediates by endothelium. It seems that factors secreted by the endothe- lium that effect vessels, are important due to relaxant proper- ties of this plant that effect through the endothelium, In addition to the smooth muscle. This effect mainly applies via the inhibition of calcium influx.52 Effects of T. polium on Renal Disorders Some herbs may lead to kidney damage and should be used with caution. In a study (2013), the effect of ethanolic extract of T. polium on rat kidney was evaluated. Treatment of mice with doses of 50, 100, 150, 200 mg/kg for 28 days, did not increase the kidney damage in-group receiving T. polium com- pared to the control group. However, 28 days after stopping the drug, kidney damage, emerged including degeneration, degra- dation and vacuolization compared to the control group.53 Effects of T. polium on Hepatic Disorders In recent years, extensive studies have been done to evaluate the effect of T. polium extract on the liver. In most of these studies, T. polium had been caused degenerative changes, necrosis, hepatic toxicity and general side effects. Zal et al.26 observed degenerative changes in hepatic lobuls in diabetic rats and it was concluded that although T. polium has hypoglycemic effect, but should be cautious about taking it. In another study, Mehdinia et al.54 Review Khazaei M et al. 5J Contemp Med Sci | Vol. 4, No. 1, Winter 2018: 1–6 Review on Teucrium polium biological activities and medical characteristics evaluated T. polium fractions of petroleum ether on the mice liver toxicity and their results presented that administration of the extract significantly decreased body weight and changes some liver enzymes. In humans, several cases about liver damage have been reported and in one case after eating T. polium, hepatitis cre- ated that need liver transplantation.55 In another report, following 5–6 months after taking T. polium, patients getting lethargy, jaun- dice with elevated liver enzymes and jaundice disappeared after 8 weeks of discontinuation.56 In five patients who were given T. polium, at least 1 month, liver biopsy showed acute hepatitis in these patients. Liver function tests, 10–30 days after use improved and liver function was normal after 2–6 months.57 In another report, 62 years old man, has used tea containing T. polium once daily, due to hypercholesterolemia and diabetes. Then after taking drug for 4 months, getting jaundice and liver biopsy revealed acute hepatitis and necrosis.58 Injection of T. polium in doses of 50–150 mg/kg for 10 days, significantly reduced serum choles- terol and triglyceride levels in rats with hyperlipidemia.12 A number of studies have also reported that T. polium consumption has cholestatic effects and causes hepatitis symptoms and reduc- tion of the nerve cells conduct.59,60 Hepatocyte necrosis, following T. polium, has reported in several studies, as well as elevated liver enzymes such as ALP, ALT, AST.52,61 Panovska et al. assessed protective activity of ethyl acetate extract of T. polium against carbon tetrachloride induced liver damage. In this study, injec- tion of T. polium extract induced liver regeneration for 7 days.62 Although, T. polium as the herbal medicine, can be useful agent, but according to the studies on the liver, it seems to have toxic effects on this tissue and its use in humans should be done with caution. Conclusion Due to the effect of different species of T. polium on cancer cell lines, this plant can be considered as a natural source of powerful anti-cancer drugs in the future. In addition, due to the important role of angiogenesis in tumor growth, it seems that it is necessary to study anti-angiogenesis effect of T. polium, as a confirmation of cancer prevention. 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Acta Pharm. 2007;57: 241–248. This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly. dx.doi.org/10.22317/jcms.03201801 Review