Bioactive compounds, pharmacological actions and pharmacokinetics of Cupressus sempervirens

The roles of plants and its products in all forms of life cannot be overemphasized. The medicinal products from plant are phytochemicals, drugs, food supplements, beauty products, etc. In ethnomedicine, leaves, fruits, stem, bark, root and fluids from plants are used in the cure, management and prevention of several diseases. Cupressus sempervirens, sometimes called Italian or Mediterranean cypress, is found in subtropical Asia, North America and eastern Mediterranean region. Pharmacological investigations of Cupressus sempervirens showed biological properties such as aromatherapeutic, antiseptic, astringent, balsamic or anti-inflammatory, astringent, antiperspirant, diuretic and antispasmodic. Chemical analysis of Cupressus sempervirens gives phytochemicals like monoterpenes, diterpenes, flavonoid glycosides and bioflavonoids. The current review highlights interactions, conventional uses and biological actions of Cupressus sempervirens plant and plant products.


Introduction
In the last two decades, the need to research medicinal plants has expanded enormously around the world. In 1978, World Health Organization emphasized the importance of scientific research into herbal medicine. Herbs are generally valued for their virtues as food as well as medicine (Oliver 1960, Balogun et al. 2016. From the evidence gathered, medicinal plants are source of compounds which are free radical scavengers and antioxidants that may mitigate oxidative stress-induced pathologies and toxicities (Rossato et al. 1999;Famurewa et al. 2018). Parts of plants produce various secondary metabolites added as formulations in pharmaceutical drugs. Plants have the ability to synthesize a wide variety of chemical compounds that * Gaber El-Saber Batiha gaberbatiha@gmail.com
This cypress oil was extracted by using the hydrodistillation method, using a clevenger apparatus. Cupressus sempervirens leaves were collected from Hit city in Al-Anbar province-Iraq (Hamid et al. 2021). The influences of three important parameters on the process of oil Anti-acetylcholinesterase effect Khan et al. 2014) extraction, water which is used as a solvent to the solid ratio (5:1 and 14:1 (ml solvent/g plant)), temperature (30 to 100 °C) and processing time, were examined to obtain the best processing conditions to achieve the maximum yield of the essential oil. Therefore, the best conditions, which were obtained from a study, were at 4 h as a reaction time, the temperature of about 100 °C and solvent to solid ratios of 10:1 ml solvent/g plant (Hamid et al. 2021). The volumetric mass transfer coefficient at ratios 10:1 and 14:1 solvent to solid ratio were 0.017 and 0.007 min respectively. Thus, it took less time to extract the Cupressus sempervirens oil by using the 10:1 compared to using 14:1 solvent to solid ratio. The composition compounds of extracted C. sempervirens L. essential oil were analyzed and identified by gas chromatography mass spectrometry (GC-MS) (Hamid et al. 2021).
Comparison between the main compounds of C. sempervirens L. leaves essential oil in different countries (origins) (Hamid et al. 2021).

Traditional use
The drug was used orally for coughs, colds and bronchitis.
(Al-Snafi 2018). A decoction of Cupressus sempervirens leaves and cones was used in a sitz bath three times a day for 1 week for hemorrhoids. The cones and leaves were used orally for internal illnesses. Externally, cypress extract was combined to give formulations (ointments and suppositories) and was used in the treatment of hemorrhoids, venous circulation disorders and varicose veins.
The essential oil was utilized as an antispasmodic for persistent coughs and antiseptic (Rawat et al. 2010). Cypress has also been used as diuretic to increase kidney's and venous circulation, improve bladder tone and treat urinary incontinence and enuresis (Mahmood et al. 2013). The parts of the plant utilized for medicinal purposes were the cones and leaves (Rawat et al. 2010) (Fig. 2).

Antifungal effects and antibacterial
The assessment of ethanol's antibacterial action, extracts of ethyl acetic acid and methanol from the aerial parts of Cupressus sempervirens against different plants including Klebsiella pneumonia (MTCC618), Staphylococcus aureus (ATCC6538), Bacillus subtilis (ATCC6633), Escherichia coli (ATCC15224), Pseudomonas aeruginosa (ATCC6643) and Salmonella typhimurium (ATCC13048). These extracts' concentration was utilized (1, 2, 3, 5, 7.5, 10, 12.5 and 15 mg/ml). All Cupressus sempervirens extract administered showed a dose-dependent inhibition of bacterial development against all microbes examined (Boukhris et al. 2012) which were six bacterial strains Proteus vulgaris, Bacillus subtilis, Salmonella typhi (Gram-negative), Staphylococcus aureus (Gram-positive), Escherichia coli, Pseudomonas aeruginosa and parasitic species of Aspergillus niger and Candida albicans. Cupressus sempervirens was used to assess the bactericidal and antifungal action of Cupressus sempervirens chloroform and water extracts' high intensity against Gram positive microbes (inhibition zone of 9-12 mm and 9-14 mm and chloroform and water extracts respectively) and reduced action against Gram negative microorganisms (zone of inhibition 1-6 mm and 1-5 mm water extract and chloroform extract). In any case, the water extract did not show much potency against growths; however, the chloroform extract displayed slight action against Candida albicans (3 mm) (Hassanzadeh Khayyat et al. 2005 Therefore, the MIC/MCC proportion affirmed antibacterial and anti-fungi essential oil action. In spite of the fact that the antimicrobial action of Cupressus sempervirens essential oils was evident against Gram-positive compared to Gramnegative bacteria (Toroglu, 2007). The inhibition zones are 2 and 4 µl/circle of Cupressus sempervirens essential oil against the microorganisms examined ( separately): Staphylococcus aureus 7 and 8; Micrococcus luteus 10 and 13; Mycobacterium simegmatis 10 and 11; Bacillus megaterium 7 and 9; Enterococcus faecalis 7 and 9; Streptococcus faecalis 7 and 9; Saccharomyces cerevisiae 9 and 10; Bacillus brevis 7 and 8; Pseudomonas pyocyaneus 9 and 11; Aeoromonas hydrophila 7 and 10; Yersinia enterolitica 8 and 9; and Klyveromyces fragilis 15 and 17 mm (Amri et al. 2013

Antiviral effect
Earlier investigations have been steered to assess the influence on herpes infections (HSV-1) that are treated with Cupressus sempervirens ethanolic extracts of Cupressus sempervirens var. cereiformis and C. sempervirens var. horizontalis. Herpes infection (HSV-1) contamination was performed on HeLa cell monolayers to assess the antiviral property of plant extract under a light magnifying lens utilizing the hematoxylin and eosin technique. Test outcomes were estimated against acyclovir, a positive control. As indicated by the outcomes, antiviral properties against the HSV-1 infection were seen in the three plants. The strongest extract was that of C. sempervirens. Of the different parts tried, the organic product extract was appeared to have the highest anti-HSV action (92). The in vitro assessment done indicated that a small amount of proanthocyanidin polymer (MW 1500-2000 Daltons) was extracted from Cupressus sempervirens L. (Amouroux et al. 1998).

Antioxidant effect
The methanol and chloroform extracts from Cupressus sempervirens leaf were examined to ascertain antioxidant action utilizing the DPPH assay. Methanol extract action (50 μg/ml) against radicals was 65% unlike the chloroform extract (50 μg/ml) which is 6% (Asgary et al. 2013 test. Cupressus sempervirens essential oil was examined for its antioxidant property by estimating the scavenging effect of the radical on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and utilizing 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonate) (ABTS) paper. The test result showed elevated antioxidant activities (2.14 mM and 7.7 μg/ml and Trolox for the ABTS and DPPH tests, separately) matched with BHT (Toroglu 2007). After extraction of the essential oils, assessment of the antioxidant and antagonistic effect to glycation action of Cupressus sempervirens var. horizontalis branch and fruit oils was done. Cupressus sempervirens var. horizontalis twigs and other product were accessed for essential oils isolation by the use of steam refining technique. A gas chromatography-mass spectrometry technique was utilized to assess the quantity of essential oils. While trying to assess the antioxidant effects of oils at various fixations (180, 220 and 260 μg/ml), the peroxyl radical-interceded red platelet hemolysis (RBC) and linoleic acid peroxidation test and test were utilized. To conclude, linoleic acid peroxidation was lessened by the oil; after 4 h the greatest point was reached for the two twigs (53.4, 35.6 and 39.5%) and also for organic products (59.8, 58.6 and 47.5%) at 260, 220 and 180 μg/ml of oil individually. (Ali et al. 2012). The antioxidant properties of Cupressus sempervirens leaves hydroethanolic extract were evaluated in vitro, and comparison was made with ascorbic acid and also the hepatoprotective activity in vivo in a paracetamol-induced hepatotoxicity rat model. From the in vitro study, the extract was shown to contain high volume of phenolic compounds including flavonoids; this can be linked to the antioxidant potential in various rat models.
The study was done in vivo for 4 weeks; pretreatments with silymarin (100 mg/kg/day, po) or extract (250 mg/kg/day, po) or) show the safety index in normal rats and hepatoprotective action against toxicity of paracetamol (4 g/kg bw, po) (Loizzo et al. 2008).

Anticancer effect
Various compounds from plants have been shown to have anti-cancer properties either on cell line model or rat model with great anti-proliferative potential (Teibo et al. 2021a, b).
With the assistance of the sulforhodamine B examined, the essential oil of Cupressus sempervirens sp. Pyramidalis, the antiproliferative action of was inspected in nephridial adenocarcinoma cells and C32 amelanotic melanoma cells. The leaf oil of Cupressus sempervirens ssp. Pyramidalis showed the maximum cytotoxic action with an IC50 estimation of 104.90 microg/ml against C32 (Verma et al. 2014). The proliferation of BPH stromal cells in humans was inhibited by the Cupressus sempervirens (CS) ethanolic extract of the fruits of the soil activity given in its part rich in diterpene, solvent in chloroform. Eight essential diterpenes were gotten indicating mild to strong action with the strongest diterpene (labda-8 (17), 12,14-trien-19-oic acid) showed an IC50 of 37.5 μM (with antiproliferative action against BPH stroma cells in humans). There was a significant inhibition of Stat-3 enactment (phosphorylation) in BPH stromal cells and inhibited androgen-delicate KLK3/PSA transamination in LNCaP cells TMPRSS2 qualities. The CS fraction in acid12, 14-trien-19-oico, labda-8 (17), inhibited rat model prostatic hyperplasia thereby causing TUNEL marking in stromal cells with lower articulations of bcl portion-2/bax, IGF-I, TGF-ß and PCNA (Donya and Ibrahim 2012). A strong cytotoxic activity of taxodione disengaged from Cupressus sempervirens cones (natural products) was monitored. Utilizing the trial rat model, paracetamol was utilized to induce liver toxicity in rats, Cupressus sempervirens hydroethanolic extract were used to find out the hepatoprotective and anticancer activities of while using silymarin as reference agent. A 4-week study from previous researches has used silymarin (50 mg/kg/day, po) or hydroethanolic extract (250 mg/kg/ day, po) or) showing hepatoprotective activities compared to one toxic dose of paracetamol (4 g/kg bw) and a good profile in normal rats (Demetzos et al. 2003).

Hypolipidemic effect
Research on the lipid profile of the cone extract effect of Cupressus sempervirens (CSE) in Wistar rats was done with hypolipidemic effect. The extract orally administered caused a huge reduction in total serum cholesterol, which remain significant for a period of 6 weeks. After the beginning of treatment (p < 0.001), the animals were presented with lower cholesterol levels at (p < 0.05); there was a substantial decrease in serum fatty oils, contrasting 0 weeks and 6-24 weeks. It was seen that between the animals treated with CSE and the control there were no significant difference in fatty substance levels and HDL cholesterol level throughout the experiment (Ali et al. 2010).

Protective effect
Biochemical assays like total serum protein, creatinine, albumin, urea, LDH tests and histopathological assessments were performed to assess the curative effect against CCl 4 hepatotoxicity utilizing Cupressus sempervirens extract.
In female Wistar rat, one intraperitoneal administration of 10% CCl 4 was done in olive oil (1 ml/kg body weight) (positive control), another group got CCl 4 and were treated with Cupressus sempervirens extract thrice each week for 6 weeks and a group got CCl 4 for about 6 weeks and were allowed to recover by themselves. After the experiment, all animals were sacrificed after which biochemical and histological parameters were assayed. There was a clear difference across all the groups. The rats treated with CCl 4 and left for 6 weeks to recover on their own exhibited mild enhancements in the parameters studied. Administration of plant extract improved the altered biochemical parameters to a large extent. The histopathological evaluation of the liver and kidney of the group treated with Cupressus sempervirens was closely related to that of control groups (Koriem 2009). Four-week pretreatment with silymarin (50 mg/kg/day, po) or hydroethanolic extricate (250 mg/kg/ day, po) showed good profile in normal rats; also, it indicated hepatoprotective action against the paracetamol toxicity (4 g/kg bw, po) as shown by a rapid decrease in DNA fragmentation and significant reduction in the level of chromosomal distortions in bone marrow cells (Koriem 2009). The assessment of Cupressus sempervirens flavonoids protective action (quercetin and rutin) against the toxicological effect of lead acetate on the liver was studied. Thirty male albino rats were distributed into five groups (six rats for each group). The control is group I; Group II got lead acetate of 0.5 mg/g in their feed for 60 days. Group III got 8 mg/100 g body weight of Cupressus sempervirens (lyophilized from methanol extract of seeds) 14 days before the administration of lead acetate. Group IV were given 0.3 mg/100 g of body weight of the flavonoid quercetin every day for 14 days before the administration of lead acetate; Group V were given flavonoid daily 0, 1 mg/100 g of body weight for 14 days before lead acetate. Lead acetate was found to cause elevated serum and tissue ALT, ALP, AST and tissue MDA, bilirubin, tissue and plasma NO, regardless of significant elevated serum cholesterol, fatty substances, LDL and HDL. Though, lead caused a significant reduction in all out serum and tissue protein, albumin/globulin proportion albumin, globulin, SOD and GPx in blood and tissue compared with the benchmark group. Treatment with methanolic extract of Cupressus sempervirens, quercetin and rutin for 14 days before lead acetate did not allow increase in parameters. In like manner, treatment with methanolic extract of Cupressus sempervirens and its flavonoids can increase the defensive activity against the poisonous effect of lead acetate (Aazza et al. 2011).

Anti-acetylcholinesterase effect
Assessment of inhibitory action of extracts of ethyl acetate, dichloromethane, acetone and methanol from Cupressus sempervirens var. horizontalis (CSH) and var. pyramidalis (CSP) cones and leaves was performed to counter acetylcholinesterase (AChE), tyrosinase (TYRO) and butyrylcholinesterase (BuChE). The extracts demonstrated mild to adequate cholinesterase inhibition at 200 µg/ml. The CSP cone dichloromethane extricate demonstrated the maximum inhibition (36.10 ± 1.45%) against AChE, while the greatest inhibition (40.01 ± 0.77%) against BuChE was done by the CSH leaf acetone extract (Fleming 2000). The Cupressus sempervirens essential oil was investigated as anti-acetylcholinesterase. It demonstrated that the inhibitory group of essential oil (IC50) was 0.2837 ± 0.0115 mg/ml (Khan et al. 2014).

Osteogenic effect
The validated model for osteogenic effect was assessed; this includes the alkaline phosphatase, and mineralization assay, osteogenic genes expression, osteoblast transcription factor and bone morphogenetic protein 2, in primary cultures of the calvarium extracted from newborn mice using four diterpenoids (sugiol, 15-acetoxy imbricatolic acid, transcommunic acid and imbricatolic acid). Among the four studied, it was observed that the dose of 1.0 mg/kg bw of sugiol showed osteoprotective effects significantly, but at the same dose there was not uterine estrogenicity. Additionally, there was an improvement of biomechanical properties, as demonstrated by increase energy, power and rigidity in the femoral bones in the group treated with sugiol compared to the Ovx animals that were untreated (Ulusal et al. 2006).

Anticoagulant and effect on the viability of isochemically challenged folds
Cone water extract pretreated with cypress prolonged the blend of endothelial-determined nitric oxide (eNO) in rats from endothelial cellular function in isolated aortic rings assessed in vitro. Also, it had anticoagulant properties.
Because of these effects, their effect on the endurance of arbitrary augmentations of ischemic pivotal folds was analyzed. The previously treated group was treated for 7 days with 30% cypress cone water extract before a fold rise, another 3 days a short time later. The ischemic objective was a 6 × 7 cm islet epigastric supply route flap dependent on the inferior epigastric pedicle at the right. At the time of the conclusion of the research, hemodynamic factors, mean arterial pressure including the pulse rate were evaluated. Flap endurance and perfusion rates were assessed using laser Doppler flowmetry and microangiography. The aortic isometric pressure separated from the control and pretreated groups was extracted to mirror the vascular feedback. Dose-response connections to acetylcholine were resolved and placed side by side with the control group. Hemodynamic factors did not show any difference. In the group pretreated, micro angiograms caused prolonged angiogenesis, slender thickness and expanded folds' perfusion (blood perfusion parts) in the proximal and distal parts (p < 0.05). The endotheliumderived nitric oxide-associated maximal unwinding (Emax) and EC50 approved for acetylcholine were notably higher in the pretreated group compared with the control. From the information, it was proposed isochemically tested rats pretreated with cypress water extracts build the suitability ).

Wound healing effect
The healing and mitigating effects of wounds were assessed from essential oils got from Cupressus cones. The linear incision and circular excision wound models were used to evaluate wound healing in vivo using hydroxyproline content assessment, then histopathological research. The regenerative potential was evaluated with Madecassol balm as control or standard. Likewise, the anti-inflammatory effect of oil was checked using acetic acid-induced capillary permeability test. Cupressus sempervirens var. horizontalis and Cupressus sempervirens var. pyramidalis essential oils did not bring about serious healing (Graziani et al. 1997).

Amentoflavone
In assessment done on the pharmacokinetic, administration of amentoflavone to rats was intraperitoneally (ip, 10 mg/ kg, intravenously (iv, 10 mg/kg) and orally (po, 300 mg/ kg)). From the outcome, it was discovered that 90.7% of the total amentoflavone circulated as metabolite that are conjugated after oral administration. The infusion ip and iv in the plasma of rats 70.2% ± 5.18% and 73.2% ± 6.29% became metabolites from amentoflavone administered altogether.
Moreover, the compound bioavailability declined in the ip infusion (77.4% ± 28.0%) than oral intake 0.04% ± 0.01% (Liao et al. 2015). The pharmacokinetics of amentoflavone alone or along with different constituent have been studied in hyperlipidemic and normal rats' models (Liao et al. 2015). Bioflavonoid administered orally has amentoflavone T1/2 and Tmax as 2.06 h ± 0.13 h, 1.13 h ± 0.44 h in normal rats and 1.91 h ± 0.32 h, 0.96 h ± 0.10 h in model rats, respectively. A renowned Chinese drug is Shixiao San that contains amentoflavone (Zhou et al. 2013 Recently, pharmacokinetic investigations of extracts and bioactive combinations from TCM and characteristic medication have become research patterns. Amentoflavone was not special in anyway, as a delegate bioflavonoid with a few pharmacological capabilities. The study done on the pharmacokinetics, showed that rats got amentoflavone intraperitoneally (ip, 10 mg/kg), intravenous (iv, 10 mg/kg) and orally (po, 300 mg/kg). Therefore, it was discovered that 90.7% of the total amentoflavone turned into metabolites after oral administration. The iv and ip infusion was seen in rats' plasma in the placebo; 73.2% _6.29% and 70.2% _ 5.18% of the all amentoflavone were available as formed metabolites (Liao et al. 2015).

Monoterpenes
From research by Cheng et al. (2016) the paeoniflorin bioavailability in a single 'four-site' rat intestinal perfusion model and refined Caco-2 cells was seen orally. The retention was slower than the aglycone (paeoniflorigenin) in cultured cells. It was seen that some factor pointing out the poor bioavailability of paeoniflorin was because of helpless saturation, efflux mediated by P-gp and hydrolysis through glucosidase. At the point of Paonia lactiflora (Chishao) crude extraction from roots as the major component (85.5%) was given to human subjects intravenously and through multiple infusion; the half-lives were − 1.2-1.3 h for paeoniflorin. Following the exposure to major organs (Cheng et al. 2016) the bioavailability of paeoniflorin has been seen to be lower in rabbits (7.24%) and rats (3.24%) after oral administration (Martey et al. 2013). Monoterpene agicones like thymol and carvacrol have moderate retention in circulation system after oral administration (Austgulen et al. 1987). Unchanged glucuronide and sulfate forms have been found, too. As Dong et al. showed that cavacrol, uridine-diphosphate glucuronyl transferase is a substrate, that can repress the catalyst (Dong et al. 2012).
In research conducted to assess the possible anticancer properties, limonene was given to women with recently analyzed operable malignancy in the tissue of the breast, arriving at a high tissue focus (mean 41.3 μg/g of tissue) while its essential urging dynamic metabolite was accounted for peric acid (Miller et al. 2010). Past studies done by Li et al. (2012) have demonstrated the concentration of limonene in fat tissue (TA) (Li et al. 2012). Possible digestion and/or discharge of swertiamarin is liver and kidney from oral administration in rats confirming fast and wide movement in tissues with the greatest amount (Cheng et al. 2014). It was seen that for genopiside, the administration of these combinations as crude plant extract could be desirable for bioavailability over pure compounds (Delea et al. 2003). The function of AMPK in the control of glucose digestion is an objective for DM to which much consideration has been given to lately. Medications that enact AMPK increase phosphorylation of insulin receptor 1 (IRS1) substrate. Phosphorylation of Ser 789 was equal to or greater than the actuation course of phosphoinositide 3 kinase/protein kinase B (PI3K/PKB) signaling (Meng et al. 2015). The notable antidiabetic drug metformin also acts by initiating the AMPK pathway in various target organs (Gaidhu et al. 2009). The anti-obesity effect can be accomplished by actuating AMPK in adipocytes which represses lipogenesis while advancing energy loss (Kim et al. 2016). Even though, a few studies have shown the shocking awareness of glucose activation by AMPK and lipid digestion is essentially identified with the degree of more facts that is expected to set up a reasonable bioavailability and/or pharmacokinetic profile of monoterpene.
Therefore, these combinations can be assimilated/made bioavailable for bioactivity in different organs since they show antidiabetic effects when orally administered in moderate and mild dosages. More studies are needed on the formulations and optimization because of their extreme nonpolar properties, implying their ability to permeate the cell membrane, with its low polarity.

Toxicity and side effects
After the right administration of the therapeutic dosages, no observable changes were detected. Report by Al-Snafi (2016) indicated that kidney disease can happen with consumption of higher doses. Various researches have demonstrated that Cupressus sempervirens pollen was major found in the air during spring winter.

Cypress essential oil toxicity
In an investigation by Fayed (2015), cypress essential oil was checked if it can be used as anticancer and antioxidant agents. In a 90-day treatment of mice with essential oil of C.
sempervirens, a few changes were seen in their biochemical parameters, without watching death of the mice during the treatment. In the mice serum albumin, glucose, globulin, fatty oils, uric acid and total protein did not change, while creatinine and total cholesterol diminished essentially (p £ 0.05), but urea increased (p £ 0.05) compared with the normal control group (Fayed 2015). Serum enzyme experiments done on C. sempervirens essential oil showed that the oil caused a critical increase in the transaminase amount (ALT and AST), but the control estimation of ALT (17.12 IU L-1) and AST (25.90 IU L-1), a huge increase in the degrees of 24.05 IU L-1 and 33, 73 IU L-1 of the separate compounds were seen in the essential oil. Besides, a huge elevation in serum LDH action was discovered in mice orally given the essential oil. The serum activity of important phosphatase was not significantly different (p £ 0.05) when compared to the control after the oil administration. Actually, all the properties acquired in these groups were within the normal range (Mitruka and Rawnsley 1977). The renal and hepatic tissues serum proteins valuable parameters show a decrease. In this research, no alteration was recorded in the amount of globulin, albumin creatinine, urea and total protein (nitrogenous waste product of metabolism) (Fayed 2015).
The function of renal tissues is obtained by screening for creatinine and urea. Since they remain overseen principally through filtration in the glomerulus with practically zero renal guideline or transformation throughout renal capacity deterioration (Kamal 2014). The massive increase in the concentration of urea in the serum is a pointer to dysfunction of the kidney (Yakubu et al. 2003). The cypress-treated group showed a critical decline in content of creatinine not causing any essential oil toxicity to kidney and muscle (Fayed 2015). Subsequently, the effect of the essential oil of cypress kidney damage investigated recommends toxicity. Serum levels of AST and ALT increase at whenever there is damage to the hepatic cell.
Whenever there is elevation in the enzyme's activities, there is also serious damage to the liver (Eteng et al. 2009). An elevated serum action of these enzymes in the current research shows that the liver may be affected by the essential oil from cypress. The cell membrane permeability could be affected and penetrable. The circulatory system becomes infused with these enzymes leading to their increase in the serum LDH activity is available in every body cell and is discovered distinctly in the cell cytoplasm. Activities of isozyme are noticed in the erythrocytes, lymph hubs, platelets, leukocytes, kidney, heart, myocardium, lung, liver, skeletal muscle and spleen (Drent et al. 1996). The level of protein in different tissues are seriously elevated compared to serum. In this manner, the levels in the tissue are roughly multiple times greater than the serum, and spillage of the enzymes from damaged tissue mass can elevate LDH level in the serum largely (McMurray 1986). This investigation has demonstrated that cypress oil toxicity is mild. The Cupressus sempervirens leaf essential oil is toxic, and it is accounted here for the first time (Fayed 2015).

Conclusion
From the previous studies, we could infer that Cupressus sempervirens extracts has various biological and pharmacological effects. Recent pharmacological discoveries have shown the effects of the extracts in different points of view; these include anti-inflammatory, antioxidant, antidiabetic, antiviral, anti-malignancy and also their effect on cardiovascular and central nervous system. Conversely, these bioactivities originate from animal studies in vivo and in vitro studies though still inconsequential. It is interesting that in vitro bioactivity cannot fully elucidate the biologic effect in vivo, while the animal's model is essential for pharmacological researches before clinical use. The bioactivities in vitro need to be explored by doing comprehensive research in future studies. Presently, the study done on the pharmacokinetics has recommended that the amentoflavone digestion was fast, and the bioavailability of bioflavonoid after indigestion orally is low in rats. Animal model experiments are few but available. We propose that the bioavailability can be improved by introducing synthetic compounds, modifying them structurally or adding specific drug that meets needs, which might be a focal point of the amentoflavones studies. Nevertheless, since there are some pharmacokinetic contrasts among normal and model animals of the evaluation of Cupressus sempervirens. Overall, the various bio and pharmacological activity of Cupressus sempervirens is owned to its rich phytochemicals which can be worked on for drug development in the future.