Short Review revista.iq.unesp.br | Vol. 47 | n. 4 | 2022 | 17 Eclética Química Journal, vol. 47, n. 4, 2022, 17-26 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p17-26 Secondary metabolites and pharmacological potential of Thuja orientalis and T. occidentalis: A short review Maria Eduarda Tech1 , Cássia Gonçalves Magalhães1+ , Sidney Augusto Vieira Filho2 1. State University of Ponta Grossa, Department of Chemistry, Ponta Grossa, Brazil. 2. Federal University of Ouro Preto, Department of Pharmacy, Ouro Preto, Brazil. +Corresponding author: Cássia Gonçalves Magalhães, Phone: +55 4232203062, Email address: cgmagalhaes@uepg.br ARTICLE INFO Article history: Received: June 01, 2022 Accepted: October 10, 2022 Published: October 28, 2022 Keywords: 1. Cupressaceae 2. flavonoids 3. terpenes 4. antimicrobial potential 5. antioxidant activity Section Editors: Marcos Carlos de Mattos CONTENTS 1. Introduction 2. Methodology 3. Chemical composition 4. Pharmacological potential of T. orientalis and T. occidentalis 5. Concluding remarks Authors’ contribution Data availability statement Funding Acknowledgments References ABSTRACT: Species from Thuja genus (Cupressaceae) are found in Brazil, North America and Asia. In the traditional medicine, these plants are used in the treatment of cough, skin allergies, and asthma. In Brazil, Thuja species are also used in the ornamentation of urban areas. Different parts of these plants displayed insecticidal, antitumor, and antioxidant activities. The essential oil of the leaves from Thuja spp. are constituted by monoterpenes and sesquiterpenes. The main substances found in the extracts of these species are flavonoids, which display relevant biological activities. This brief review shows recent phytochemical studies involving T. orientalis and T. occidentalis, as well as 40 constituents isolated from these species. The existing pharmacological potential justifies the growing scientific interest in this genus. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p17-26 mailto:cgmagalhaes@uepg.br https://orcid.org/0000-0002-3429-3783 https://orcid.org/0000-0003-4168-3365 https://orcid.org/0000-0002-8171-8035 Short Review revista.iq.unesp.br 18 Eclética Química Journal, vol. 47, n. 4, 2022, 17-26 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p17-26 1. Introduction Scientific interest for plants is growing, mainly due to the accelerated loss of the biodiversity (Singh et al., 2021). The world market of phytotherapeutics has attracted a growing number of people who seek cheaper medicines with fewer side effects, when compared to synthetic pharmaceuticals (Silva et al., 2021). The diversified potential of natural products has been widely explored, and the resulting data are considered an important key for the development of new drugs (Atanasov et al., 2021). Additionally, the development of green semisynthesis of metal nanoparticles (Gour and Jain, 2019) and biosensors (Kumar and Arora, 2020) highlighting the variety of application of plants. Within the plant biodiversity, species of the Cupressaceae family stand out. Cupressaceae trees comprise important classes of organic compounds, especially terpenes and terpenoids, both of which have intense and often pleasant odors. These compounds are mainly present in heartwood, bark and leaves of Cupressaceae trees (Bhardwaj et al., 2021). The most known terpenoids found in conifers are sesquiterpenoids, diterpenes, and tropolones. Some sesquiterpenoids, e.g., bisabolanes, cubenanes, guaianes, ylanganes, himachalanes, longifolanes, longibornanes, longipinanes, cedranes, thujopsanes, are also present in the Pinaceae, Podocarpaceae (Pereira et al., 2020) and Taxodiaceae (Jiang et al., 2018) families. However, tropolone derivatives, such as nootkatin, chanootin, and hinokitiol, are particularly characteristic in Cupressaceae (Park et al., 2021; Yatoo et al., 2018). In this context, species from the Thuja genus (Cupressaceae family) represent a relevant object of study, considering its use in the traditional medicine for the treatment of scurvy and rheumatism. It is endemic in Asia and is cultivated in Northern Europe and Brazil as an ornamental shrub (Pradhan et al., 2021; Viezzer et al., 2018). Species of the genus Thuja, similar to various other conifers, are evergreen trees that grow from 3 to 60 meters tall, with stringy-textured reddish-brown bark. There are five species belonging to this genus of which T. orientalis and T. occidentalis L. are well characterized (Gupta and Sharma, 2021). These species are monoecious and large evergreen shrub or small to medium sized trees (Jain and Sharma, 2017). The main secondary metabolites associated to the therapeutic potential of Thuja spp. are flavonoids, terpenes, and coumarins (Bhardwaj et al., 2021; Gupta and Sharma, 2021). Thuja orientalis is a synonym of Platycladus orientalis (L.) Franco, an accepted name in the genus Platycladus (Cupressaceae family). All parts of T. orientalis, popularly known as tuia, are used for several objectives. Extracts from leaves have antipyretic, diuretic, and astringent properties, while the root bark extracts are used to treat skin burns. The leaves extract of T. orientalis also shows relevant antimicrobial activity (Burange et al., 2021). Extracts from stems are used against parasites of the skin, dysentery, and constipation. T. orientalis extracts can be also used for dermatological treatments, renal, and gastrointestinal disorders (Gupta and Sharma, 2021). Also, the significant occurrence of phenolic compounds in the polar extracts from this species is related to its antioxidant activity (Moawad and Amin, 2019). Thuja occidentalis L., commonly known as white cedar, is used in traditional medicine to treat bronchial catarrh, enuresis, psoriasis, uterine carcinomas, amenorrhea, and other diseases (Gupta and Sharma, 2021). The tincture from this species is used in the treatment of warts, papillomas, and condylomas related to human papilloma virus (Aguilar-Velázquez et al., 2018). T. occidentalis also present pharmacological properties, such as antioxidant, gastroprotective, antimicrobial, antitumor, antidiabetic, and anti- atherosclerotic activities (Gupta and Sharma, 2021; Stan et al., 2019). Due to the scientific importance of this species, the aim of this work was to provide a short review related to chemical constitution and biotechnological potential of T. orientalis and T. occidentalis reported in the last five years. 2. Methodology Data relating to T. orientalis and T. occidentalis were obtained through PubMed and Google Scholar published in the last five years. The following exclusion criteria were adopted: (i) article whose full text was not accessible in the database; (ii) publications that did not include the search phrases in the abstract or title; (iii) articles in other languages; and (iv) articles in which the phytochemicals used in the biological activity assays were not isolated from these species, but were acquired from industries. The chemical structures of compounds from these species were drawn using ChemDrawn 12.0 software. 3. Chemical composition Essential oils from T. orientalis and T. occidentalis leaves are mainly constituted by terpenes 1 to 21 (Fig. 1). The major compounds found in the oil from T. orientalis collected in India are α-pinene (1, 29.2%), δ-3-carene https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p17-26 Short Review revista.iq.unesp.br 19 Eclética Química Journal, vol. 47, n. 4, 2022, 17-26 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p17-26 (2, 20.1%), and the sesquiterpene alcohol α-cedrol (3, 9.8%) (Bhardwaj et al., 2021). A similar profile was reported for an oil sample of T. orientalis collected in Iran (Sanei-Dehkordi et al., 2018). Terpenes 1 to 3, and β-caryophyllene (4) are the major compounds found in essential oil from Chinese populations of T. orientalis (Bae et al., 2021). A comparison of the chemical composition of essential oils extracted from wild and planted T. orientalis leaves in Korea was carried out (Seo et al., 2019). The main compounds found in these essential oils were artemisiatriene (5, 17.7%), trans- isolimonene (6, 17.2%), terpinolene (7, 5.2%), and isopulegol (8, 4.8%). The main constituents of essential oil from T. orientalis cultivated in Tokat, Turkey, were d-limonene (9, 36.7%), β-phellandrene (10, 36.7%), and β-myrcene (11, 15.3%). The quantitative and qualitative characteristics of secondary metabolites variation observed in these essential oils occur due to the existence of different chemotypes of a same species (Seo et al., 2019) and mainly by the influence of environmental conditions (Li et al., 2022). https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p17-26 Short Review revista.iq.unesp.br 20 Eclética Química Journal, vol. 47, n. 4, 2022, 17-26 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p17-26 Figure 1. Chemical structure of compounds 1 to 21 found in T. orientalis and T. occidentalis essential oils. Gas chromatography coupled to mass spectrometry (GC-MS) analysis of the essential oil from leaves of T. orientalis cultivated in Egypt and Saudi Arabian showed a similar profile considering the major compounds (α-cedrol and β-caryophyllene). In contrast, limonene was present in the Saudi Arabian T. orientalis essential oil, while caryophyllene oxide and vellerdiol were found in the Egyptian sample (Elsharkawy et al., 2017). In general, the chemical constitution of essential oils is determined by GC-MS. However, the use of high- performance counter current chromatography, allowed to the isolation of α-cedrol (3) from essential oil of T. orientalis leaves (Rehman et al., 2022). The analysis of fruit oil from T. orientalis grown in Egypt revealed the occurrence of sesquiterpenes α- pinene (1, 11.3%), α-cedrol (3, 11.2%), β-myrcene (11, 9.6%), geranyl acetate (12, 9.0%) and β- caryophyllene (4, 8.9%) (Moawad and Amin, 2019). A comparison between the essential oil from Egyptian T. orientalis leaves with the one cultivated in Saudi Arabia was performed, being 3 and 4 the main terpenes found in the two oil samples. However, the third major compound, d-limonene (9), found in the Saudi sample, was absent in the Egyptian oil, probably due to influence from the severe environmental conditions of this country (Moawad and Amin, 2019). The main compounds found in the essential oil from T. occidentalis L. leaves, known as cedar oil, are α- thujone (13, 65%), isothujone (14, 8%), and fenchone (15, 8%) (Caruntu et al., 2020). Besides compound (13, 57%), the diterpenes hibaene (16, 7.3%) and rimuene (17, 5%) were detected in expressive amount in the essential oil from Chinese cultivar for this species (Bai et al., 2020). The constituents of the essential oil from leaves and cones of T. occidentalis collected in Tunisia was described (Bellili et al., 2018). Interestingly, the chemical profile of the essential oil of T. occidentalis leaves was similar to that of T. orientalis essential oil collected in India. A bioassay-guided fractionation of T. occidentalis extract carried out by Nakano et al. (2021) led to the isolation of the compounds (+)-7-oxo-13-epi-pimara- 14,15-dien-18-oic acid (18), (+)-isopimaric acid (19), isopicrodeoxypodophyllotoxin (20), and (−)- deoxypodorhizone (21) (Fig. 1). Phytochemical methods applied to study extracts of T. orientalis showed that it is a source of flavonoids and diterpenes, which are considered the majority compounds found in this species. From methanolic extract of T. orientalis fruits, the metabolites cupressuflavone (22), amentoflavone (23), robustaflavone (24), (+)-catechin (25), kaempferol-3- rhamnoside (afzelin) (26), quercitrin (27), 3- glucosylquercetin (isoquercitrin) (28), and myricitrin (29), quercetin (30), rutin (31), luteolin (32), and naringenin (33), (Fig. 2) were isolated (Bai et al., 2019; Chakraborty et al., 2018; Darwish et al., 2021). Quercitrin (27), isocupressic acid (34), trans- communic acid (35), isopimara-7,15-dien-3β-ol (36), abietatriene-3β-ol (36), and 15-isopimaren-3β,8β-diol (37) (Fig. 2) were isolated from methanolic extract of leaves and stems of T. orientalis (Bae et al., 2021). In this context, extracts from T. occidentalis also were considered a source of the flavonoids afzelin (26), quercitrin (27), isoquercitrin (28), and coumarins (Caruntu et al., 2020). The above data demonstrate the significant variety of secondary metabolites in T. orientalis and T. occidentalis species, and their potential to be applied mainly in pharmacological areas. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p17-26 Short Review revista.iq.unesp.br 21 Eclética Química Journal, vol. 47, n. 4, 2022, 17-26 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p17-26 Figure 2. Chemical structure of compounds 22 to 40 found in T. orientalis and T. occidentalis essential oils or extracts. Glu = D-glucosyl, Rham = L-rhamnosyl. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p17-26 Short Review revista.iq.unesp.br 22 Eclética Química Journal, vol. 47, n. 4, 2022, 17-26 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p17-26 4. Pharmacological potential of T. orientalis and T. occidentalis T. orientalis and T. occidentalis are used for the treatment of different diseases and symptoms, such as cough, asthma, cutaneous affections, bacterial dysentery, and premature blindness. Its leaves also show astringent, diuretic, antipyretic, and emmenagogue properties (Gupta and Sharma, 2021). The seeds of these two species have sedative effects and their barks are used to treat skin burns (Caruntu et al., 2020; Srivastava et al., 2022). There are a large number of research papers that support the traditional use of these plants, as is described in the sequence. The essential oil from T. orientalis exhibits antimicrobial activity. For instance, the inhibition of the growth of Salmonella mutans and S. typhimurium was attributed to three naturally occurring monocyclic tropolones: -thujaplicin (38), −thujaplicin (39) and −thujaplicin (40) (Fig. 2), which act as chelating agents in the bacterial wall cell (Jain and Sharma, 2017). The antimicrobial potential of T. orientalis and T. occidentalis has been reported. The antimicrobial property of T. occidentalis leaves extract obtained with methanol inhibited the growth of Bacillus cereus and Candida albicans (Caruntu et al., 2020). A synergism between Psidium guajava and T. orientalis leaves extracts was observed when they were evaluated against methicillin-resistant Staphylococcus aureus. This synergism was probably due to the combined inhibitory effect of phenolics present in the leaf extracts, i.e., quercetin and gallic acid and catechin (Chakraborty et al., 2018). Extracts from leaves and cones from T. orientalis grown in Tunisia were assayed against foodborne microorganisms, such as Listeria monocytogenes ATCC 7644, S. aureus ATCC 29213, Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 27853, S. typhimurium NCTC 6017, Aspergillus flavus (foodborne isolate), and Aspergillus niger CTM 10099. The highest antimicrobial activities by disk diffusion assay were observed for T. orientalis essential oil from leaves. The most potent antimicrobial activity was recorded against E. coli and S. typhimurium, highlighting the potential of this essential oil as a natural preservative against foodborne pathogens (Bellili et al., 2018). T. orientalis is appointed as a relevant alternative to improve the immunity, considering the infections caused by viruses, with emphasis on SARS-CoV-2 (Srivastava et al., 2022). Considering the cytotoxic activity of these two species of the Cupressaceae family, T. occidentalis extracts also showed antiproliferative and proapoptotic activity against the A549 lung cancer cell line, and T. orientalis was active against breast cancer and leukemia cells (Srivastava et al., 2022). Based on teratogenic assays, the T. orientalis extract revealed low therapeutic index (TI = 0.808) with and median lethal concentration (LC50 = 0.703 mg mL–1) after a period of 24 h that is within the desirable value (below 1) for drug administration (Breeta et al., 2018). The presence of phenolic compounds in Thuja spp. evidence their antioxidant potential. The mother tincture of T. orientalis showed higher inhibitory activity against the generation of the 1,1-diphenyl-2 picryl-hydrazyl (DPPH) radical, and effective oxygen radical absorbance capacity (Stan et al., 2019). The antioxidant activity of T. orientalis extracts obtained using solvents of different polarities was tested in erythrocytes from a healthy donor. The ethyl acetate extract showed the higher reduction of reactive oxidant species (Alamdari et al., 2018). The antidiabetic activity of hydroalcoholic extract from T. orientalis aerial parts, collected from three different regions of India, showed an expressive activity when compared to glibenclamide, used as positive control (Pradhan and Sarangdevot, 2020). This antidiabetic effect was attributed to the presence of flavonoids such as quercetin (27), rutin (31), luteolin (32), and naringenin (33), previously reported as potential antidiabetic drugs (Bai et al., 2019). The administration of methanolic extracts of T. occidentalis twigs in alloxan-induced rats significantly increased glucose homeostasis and alleviate kidney and liver functions. The twigs of this species could be a potential source of the new oral antidiabetic drug (Tyagi et al., 2019). To flavonoids 27, 31–33 was also attributed the potential phytotherapeutic of a mother tincture from a mixture of branches and leaves of T. occidentalis. This sample inhibited the inflammation of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (Stan et al., 2019). The efficacy of the gastroprotective effect induced by the methanolic extract of T. occidentalis was similar to that produced by omeprazole, a proton pump inhibitor that decreases the amount of acid produced in the stomach (Caruntu et al., 2020). The anti-inflammatory activity of the aqueous extract and of a polysaccharide rich fraction of T. occidentalis, both at 300 mg kg–1, did not induce gastric toxicity in experimental models of acute inflammation. The effect of these samples was attributed to mechanisms involving mediators such as histamine, serotonin, prostaglandin E2, and bradykinin, as well as reduction of the vascular permeability and neutrophil migration to the damaged site. In addition, both of the samples reduced https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p17-26 Short Review revista.iq.unesp.br 23 Eclética Química Journal, vol. 47, n. 4, 2022, 17-26 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p17-26 the production of proinflammatory cytokines (TNF- and IL-6), decreased immunostaining of COX-2 and iNOS, and inhibited oxidative stress (Silva et al., 2017). The successful anti-inflammatory property of T. occidentalis was also proved considering the decreasing of the gene expression of the inflammation markers (interleukin-6 and tumor necrosis factor-α) induced by the administration of f 2,4,6-trinitrobenzenesulfonic acid after the application of the mother tincture from this plant (Stan et al., 2019). The antioxidant potential of the essential oil from cones and leaves of T. occidentalis grown in Tunisia was assayed by DPPH free-radical scavenging activity method. All essential oils tested showed better antioxidant activity than trolox against DPPH radical scavenging. However, the essential oil from leaves exhibited the highest total antioxidant activity (Bellili et al., 2018). The cytotoxic effect of α-thujone, the major compound of T. occidentalis essential oil, was evaluated against glioblastoma multiforme (GBM) cells, with special emphasis on the mechanisms of its effect on cell viability and invasiveness (Nakano et al., 2021; Pudełek et al., 2019). An attenuating effect on the viability and proliferation of GBM cells was observed when α-thujone was administered at doses varying from 660 to 3.2 mmol L–1. This effect was correlated with the induction of apoptosis in GBM cells and with considerable inhibition of GBM cells motility. Mechanistic analyses demonstrated the induction of oxidative stress and autophagy in α-thujone-treated tumor cells. It was demonstrated that α-thujone exerts pro-apoptotic and anti-invasive effects on GBM cells, confirming the potential of this monoterpene for the treatment of glioblastoma multiforme. Other reports demonstrate the potential of T. occidentalis for the treatment of polycystic ovary syndrome (Ahmad and Safuan, 2019; Nakano et al., 2021; Parveen and Das, 2021) and inform that there is no contraindication in the administration of T. occidentalis mother tincture in the sycosis secondary to cancer treatments (Bagot, 2020). Besides the relevant biological potential of species from Thuja genus, T. orientalis extract is a very important bioresource for synthesis of metal nanoparticles with silver (Bandyopadhyay et al., 2017; Burange et al., 2021), gold (Dong et al., 2020) and copper (García-Hernández et al., 2021). The aqueous leaves extract of T. orientalis was also efficient in the green synthesis of silica nanoparticles (SiO2NPs) through magnetic stirrer method and using cold plasma. The biofilm inhibition of SiO2NPs were evaluated against S. aureus and E. coli. The SiO2NPs synthesized by cold plasma method showed the highest antimicrobial effect (Al-Azawi et al., 2019). The dried leaves of T. orientalis was evaluated as an adsorbent and showed an effective result in the remotion of Remazol Brilliant Blue R dye from aqueous solution (Arya et al., 2020). Other important application reported for T. orientalis seeds extract is related to its use as a green reductant of graphene oxide. The analysis through GC-MS confirmed that α-tocopherol present in T. orientalis seeds extract was most likely responsible for the reduction of graphene oxide to reduced graphene oxide (Kumar et al., 2021). Besides, the leaves extract of T. orientalis was capable of retard the oxidation of soybean biodiesel (Devi et al., 2019). The above data showed the versatile application of Thuja genus species and demonstrated the scientific potential of these plants. 5. Concluding remarks Forty constituents have been identified from T. orientalis or T. occidentalis. Due to its diversified chemical structures, important pharmacological properties are attributed to these species, a part of their application in different areas within an industry context. The effective biotechnological potential of these species stimulates the research of new applications for these plants, which can improve the economic value of this natural resource and its sustainable management. Authors’ contribution Conceptualization: Tech, M. E.; Magalhães, C. G. Data curation: Tech, M. E. Formal Analysis: Magalhães, C. G.; Vieira Filho, S. A. Funding acquisition: Not applicable. Investigation: Tech, M. E. Methodology: Tech, M. E. Project administration: Magalhães, C. G. Resources: Not applicable. Software: Not applicable. Supervision: Magalhães, C. G.; Vieira Filho, S. A. Validation: Not applicable. Visualization: Not applicable. Writing – original draft: Tech, M. E. Writing – review & editing: Magalhães, C. G.; Vieira Filho, S. A. Data availability statement Data sharing is not applicable. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.4.2022.p17-26 Short Review revista.iq.unesp.br 24 Eclética Química Journal, vol. 47, n. 4, 2022, 17-26 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.4.2022.p17-26 Funding Not applicable Acknowledgments PIBIC-UEPG. References Aguilar-Velázquez, G.; Espinosa, D.; Ordaz-Pichardo, C. Effects of Homeopathic Dilutions of Echinacea angustifolia and Thuja occidentalis on Cervical Cancer Cells. Homeopathy. 2018, 107 (S1), 55–78. https://doi.org/10.1055/s-0037-1608960 Ahmad, F.; Safuan, S. Assessing the Effectiveness of Plant Extracts in Polycystic Ovarian Syndrome: A Systematic Review. Mal. J. Med. Health Sci. 2019, 15 (2), 120–129. Alamdari, D. H.; Aghasizadeh-Sharbaf, M.; Mohadjerani, M.; Ferns, G. A.; Avan, A. 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