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Santalum Genus: phytochemical constituents, biological activities and health promoting-effects

113 Pages

Santalum Genus: phytochemical constituents, biological activities and health promoting-effects

Santalum Genus: phytochemical constituents, biological activities and health promoting-effects

Profile image of Sena TütüncüSena TütüncüProfile image of Zehra MertdinçZehra Mertdinç

Zeitschrift für Naturforschung C

Santalum genus belongs to the family of Santalaceae, widespread in India, Australia, Hawaii, Sri Lanka, and Indonesia, and valued as traditional medicine, rituals and modern bioactivities. Sandalwood is reported to possess a plethora of bioactive compounds such as essential oil and its components (α-santalol and β-santalol), phenolic compounds and fatty acids. These bioactives play important role in contributing towards biological activities and health-promoting effects in humans. Pre-clinical and clinical studies have shown the role of sandalwood extract as antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, neuroleptic, antihyperglycemic, antihyperlipidemic, and anticancer activities. Safety studies on sandalwood essential oil (EO) and its extracts have proven them as a safe ingredient to be utilized in health promotion. Phytoconstituents, bioactivities and traditional uses established sandalwood as one of the innovative materials for application in the pharma, f...

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Phytochemistry and Pharmacology of Santalum album L.: A Review

Y.C. Tripathi

Santalum album L. (Santalaceae) commonly known as Indian Sandalwood is one of the oldest and precious sources of natural fragrance with immense medicinal and commercial significance. S. album has been grown in India for the last 25 centuries and esteemed all over the world for its sweet, long-lasting and medicinally valued fragrant oil. Sandalwood and the essential oil derived from sandal heartwood have been used in various traditional systems of medicine, like Ayurveda, Siddha and Unani medicine in the treatment and prevention of wide range of ailments. The versatile therapeutic and healthcare importance of sandawood is attributed to the rich source of phytochemicals particularly sesquiterpeness. A thorough bibliographic investigation was carried out by analyzing worldwide accepted scientific database (Pub Med, SciFinder, Scopus, ACS and Web of Science), recognized books, Indexed as well as non indexed journals. Modern pharmacological studies have demonstrated a wide range of pharmacological activities ranging from antibacterial to anti-cancer. No significant toxicity has been indicated by sandalwood oil and its individual constituents; however, further study on chemical constituents and their mechanisms in exhibiting certain biological activities are needed to understand the full phytochemical profile and the complex pharmacological effects of this plant. The increased commercial exploitation of Sandalwood and low productivity of this endangered plant has raised the concern over its conservation and productivity enhancement through modern tools and techniques. The review discusses traditional uses, ethnopharmacology, phytochemistry and biological activities of sandalwood in order to divulge its medicinal and industrial worth and gaps requiring future research.

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Zeitschrift für Naturforschung C

Santalum Genus: phytochemical constituents, biological activities and health promoting-effects

2022 •

Daniela Calina

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International Journal of Ayurveda and Pharma Research

Sandalwood (Santalum Album): Ancient Tree with Significant Medicinal Benefits

2021 •

Dr.gitika Chaudhary

Santalum album L. is commonly known as East Indian sandalwood, Shrigandha, sandalwood and Chandana. The plant is considered as the oldest, precious and commercially significant herbal plant which is also used as timber in India. The plant is well known for its unique and distinctive fragrance. Also, this plant is considered sacred and its importance and usage are also mentioned in Vedas, Puranas, Buddhism, epics and scriptures. It is used in various religions like Hindu, Buddhism and Jainism culture for auspicious work. The heartwood of the plant is very expensive and is associated with great commercial value in the national and international market as it is enriched with fragranced essential oil. The aromatic essential oil of the plant is used in various perfumes, food products, cosmetics, aromatherapy and pharmaceutical industries. Traditionally, the plant is used in various medicinal systems such as Ayurveda, Unani and Siddha to cure diseases like jaundice, dysentery, gastric irr...

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Phytomedicine

Evaluation of in vivo anti-hyperglycemic and antioxidant potentials of α-santalol and sandalwood oil

2013 •

Biswapriya Misra

Sandalwood finds numerous mentions across diverse traditional medicinal systems in use worldwide. The objective of this study was to evaluate the in vivo anti-hyperglycemic and antioxidant potential of sandalwood oil and its major constituent α-santalol. The in vivo anti-hyperglycemic experiment was conducted in alloxan-induced diabetic male Swiss albino mice models. The in vivo antioxidant experiment was performed in d-galactose mediated oxidative stress induced male Swiss albino mice models. Intraperitoneal administration of α-santalol (100 mg/kg BW) and sandalwood oil (1 g/kg BW) for an week modulated parameters such as body weight, blood glucose, serum bilirubin, liver glycogen, and lipid peroxides contents to normoglycemic levels in the alloxan-induced diabetic mice. Similarly, intraperitoneal administration of α-santalol (100 mg/kg BW) and sandalwood oil (1 g/kg BW) for two weeks modulated parameters such as serum aminotransferases, alkaline phosphatase, bilirubin, superoxide dismutase, catalase, free sulfhydryl, protein carbonyl, nitric oxide, liver lipid peroxide contents, and antioxidant capacity in d-galactose mediated oxidative stress induced mice. Besides, it was observed that the beneficial effects of α-santalol were well complimented, differentially by other constituents present in sandalwood oil, thus indicating synergism in biological activity of this traditionally used bioresource.

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Letters in Applied Microbiology

Comparative Phytochemical Analysis and Antibacterial Efficacy Of In Vitro And In Vivo Extracts From East Indian Sandalwood Tree

2012 •

Biswapriya Misra

Sandalwood oil has been found in numerous therapeutic applications in traditional medicines such as Chinese traditional medicine and Ayurveda. However, there are no comparative accounts available in the literature that focused on in vitro and in vivo tree sample-derived extracts. Combined dichloromethane and methanol extracts were obtained from in vitro samples, that is, callus, somatic embryo and seedlings, and in vivo from leaves of non-oil-yielding young and oil-yielding matured trees. Phytochemical evaluation of the extracts reveals that the tree is rich in terpenoids, saponin, phenolics and tannins. The antibacterial properties of the five extracts were compared with sandalwood oil by screening against nine Gram-negative and five Gram-positive bacterial strains by disc diffusion, agar spot and TLC bioautography methods. Minimum inhibitory concentration (MIC) for sandalwood oil was determined to be in the range of 0·078–5 μg ml−1 for most of the test micro-organisms screened. Bioautography results indicated the presence of potential antimicrobial constituents in somatic embryo extracts and sandalwood oil. Among the extracts screened, the somatic embryo extracts showed the strongest antibacterial activity comparable only with sandalwood oil and matured tree leaves' extract. The findings presented here also suggest that apart from sandalwood oil, other parts of this tree across developmental stages are also enriched with antibacterial principles. Significance and Impact of Study This study constitutes the first systematic investigation on phytochemical composition and antimicrobial efficacy of sandalwood tree across in vitro and in vivo developmental stages screened against thirteen bacterial strains by four methods. Using a battery of antimicrobial assay techniques, it is possible to follow the differential bioactive metabolic richness of plant parts, to decipher, for example comparable efficacy of somatic embryo extracts and sandalwood oil.

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Analyzing The Therapeutic Effects Of Sandalwood Powder (Santalum Album) In Management Of Hypercholesterolemic Patients: An Experimental Trail

Analyzing The Therapeutic Effects Of Sandalwood Powder (Santalum Album) In Management Of Hypercholesterolemic Patients: An Experimental Trail

2023 •

Anwaar Iftikhar

Cardiovascular diseases (CVDs), which significantly increase mortality, disabilities, and medical costs globally, are at risk to health due to dyslipidemia. Components of Chinese medicine that can be used to cure illness and provide healthcare include medicinal and culinary plants because of the similarity between their roles as food and medicine. Primary prevention is critical in lowering the incidence of CVDs, breakthroughs in reducing dyslipidemia can significantly reduce morbidity and mortality associated with CVDs. Sandalwood oil and its extract are traditionally used to treat different conditions which include diabetes, cancer, dyslipidemia, and cardiovascular diseases. The current research was examined to evaluate the cardio-protective effects of sandalwood powder as primary prevention in treatment of hyperlipidemia. For this purpose, sandalwood powder was initially analyzed for chemical phytochemical analysis. Furthermore, to check its hypolipidemic effects Hyperlipidemic females were selected from age 30-50 years and divided into three equal groups in which Control group were not given any doses, While the experimental group G1 and G2 were given 2g and 4g doses respectively along their regular medication. Biochemical test of patients along with physical parameters like weight and height were also observed before the initiation and after the end of trial. The results showed that wood powder contains 0.44% moisture content,15.94% ash content, 0.00% crude fat, 04.05% crude fiber, 3.625% crude protein and NFE 75.90%. Sandalwood powders also contain a certain amount of antioxidant Total phenolic content (TPC) 315.33±11.51. Total flavonoids contents (TFC) 25.39±2.87. The patient's biochemical data revealed that the experimental groups G1 and G2 had considerably (P 0.001) lower serum lipid profiles before the study ended, whereas HDL levels had increased. Besides helping people lose weight and drink more water, sandalwood powder also has anti-hyperlipidemic properties.

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Int J PharmTech Res

Santalum album Linn: A review on morphology, phytochemistry and pharmacological aspects

2010 •

Rakesh Sindhu

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Molecules

A Comparison of the Composition of Selected Commercial Sandalwood Oils with the International Standard

2021 •

Wiktor Wesołowski

Sandalwood oils are highly desired but expensive, and hence many counterfeit oils are sold in high street shops. The study aimed to determine the content of oils sold under the name sandalwood oil and then compare their chromatographic profile and α- and β santalol content with the requirements of ISO 3518:2002. Gas chromatography with mass spectrometry analysis found that none of the six tested “sandalwood” oils met the ISO standard, especially in terms of α-santalol content. Only one sample was found to contain both α- and β-santalol, characteristic of Santalum album. In three samples, valerianol, elemol, eudesmol isomers, and caryophyllene dominated, indicating the presence of Amyris balsamifera oil. Another two oil samples were found to be synthetic mixtures: benzyl benzoate predominating in one, and synthetic alcohols, such as javanol, polysantol and ebanol, in the other. The product label only gave correct information in three cases: one sample containing Santalum album oil an...

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Zenodo (CERN European Organization for Nuclear Research)

Sandalwood Fruit Hot Water Extract as an Antioxidant

2022 •

Aloysius Marawali

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Phytotherapy Research

Suppression of Lipopolysaccharide-stimulated Cytokine/Chemokine Production in Skin Cells by Sandalwood Oils and Purified α-santalol and β-santalol

2013 •

Robert Bell

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<xref ref-type="aff" rid="j_znc-2022-0076_aff_018"/> <xref ref-type="aff" rid="j_znc-2022-0076_aff_017"/> <email xlink:href="mailto:marcello.iriti@unimi.it">marcello.iriti@unimi.it</email> </contrib> <contrib contrib-type="author" corresp="yes"> <name> <surname>Calina</surname> <given-names>Daniela</given-names> </name> <xref ref-type="aff" rid="j_znc-2022-0076_aff_019"/> <email xlink:href="mailto:calinadaniela@gmail.com">calinadaniela@gmail.com</email> </contrib> <aff id="j_znc-2022-0076_aff_001"> <institution content-type="dept">Facultad de Medicina</institution>, <institution content-type="university">Universidad del Azuay</institution>, <city>Cuenca</city>, <country country="EC">Ecuador</country> </aff> <aff id="j_znc-2022-0076_aff_002"> <institution content-type="dept">Facultad de Ciencias de la Salud</institution>, <institution content-type="university">Universidad Arturo Prat</institution>, <addr-line>Avda. Arturo Prat 2120, 1110939</addr-line>, <city>Iquique</city>, <country country="CL">Chile</country> </aff> <aff id="j_znc-2022-0076_aff_003"> <institution content-type="dept">Higher School of Medicine</institution>, <institution content-type="university">Al-Farabi Kazakh National University</institution>, <city>Almaty</city>, <country country="KZ">Kazakhstan</country> </aff> <aff id="j_znc-2022-0076_aff_004"> <institution content-type="dept">School of Pharmacy</institution>, <institution content-type="university">JSC “S. D. Asfendiyarov Kazakh National Medical University”</institution>, <city>Almaty</city>, <country country="KZ">Kazakhstan</country> </aff> <aff id="j_znc-2022-0076_aff_005"> <institution content-type="dept">Faculty of Chemical and Metallurgical Engineering, Department of Food Engineering</institution>, <institution content-type="university">Istanbul Technical University</institution>, <addr-line>34469 Maslak</addr-line>, <city>Istanbul</city>, <country country="TR">Turkey</country> </aff> <aff id="j_znc-2022-0076_aff_006"> <institution content-type="university">BIOACTIVE Research &amp; Innovation Food Manufacturing Industry Trade LTD Co.</institution>, <city>Maslak</city>, <addr-line>Istanbul 34469</addr-line>, <country country="TR">Turkey</country> </aff> <aff id="j_znc-2022-0076_aff_007"> <institution content-type="dept">Department of Forage Crop Production</institution>, <institution content-type="university">Institute of Soil Science and Plant Cultivation – State Research 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content-type="university">Fakir Chand College</institution>, <city>Diamond Harbour</city>, <state>West Bengal</state>, <addr-line>743331</addr-line>, <country country="IN">India</country> </aff> <aff id="j_znc-2022-0076_aff_011"> <institution>Medicine Standartization Department of Vitebsk State Medical University</institution>, <city>Vitebsk</city>, <country country="BY">Republic of Belarus</country> </aff> <aff id="j_znc-2022-0076_aff_012"> <institution content-type="dept">Department of Plant and Soil Sciences</institution>, <institution content-type="university">University of Pretoria</institution>, <state>Gauteng</state> <addr-line>0002</addr-line>, <city>Pretoria</city>, <country country="ZA">South Africa</country> </aff> <aff id="j_znc-2022-0076_aff_013"> <institution content-type="dept">Department of Nutrition and Dietetics, Faculty of Pharmacy</institution>, <institution content-type="university">Centre for Healthy Living, University of Concepción</institution>, <addr-line>4070386</addr-line> <city>Concepción</city>, <country country="CL">Chile</country> </aff> <aff id="j_znc-2022-0076_aff_014"> <institution content-type="university">Universidad de Concepción, Unidad de Desarrollo Tecnológico</institution>, <addr-line>UDT, 4070386</addr-line> <city>Concepción</city>, <country country="CL">Chile</country> </aff> <aff id="j_znc-2022-0076_aff_015"> <institution content-type="dept">Chemical and Biochemical Processing Division</institution>, <institution content-type="university">ICAR – Central Institute for Research on Cotton Technology</institution>, <addr-line>400019</addr-line> <city>Mumbai</city>, <country country="IN">India</country> </aff> <aff id="j_znc-2022-0076_aff_016"> <institution content-type="dept">Department of Biomedical, Surgical and Dental Sciences</institution>, <institution content-type="university">Università degli Studi di Milano</institution>, <addr-line>20133</addr-line> <city>Milano</city>, <country country="IT">Italy</country> </aff> <aff id="j_znc-2022-0076_aff_017"> <institution content-type="university">National Interuniversity Consortium of Materials Science and Technology (INSTM)</institution>, <addr-line>50121</addr-line> <city>Firenze</city>, <country country="IT">Italy</country> </aff> <aff id="j_znc-2022-0076_aff_018"> <institution content-type="dept">Department of Agricultural and Environmental Sciences</institution>, <institution content-type="university">Università degli Studi di Milano</institution>, <addr-line>20133</addr-line> <city>Milano</city>, <country country="IT">Italy</country> </aff> <aff id="j_znc-2022-0076_aff_019"> <institution content-type="dept">Department of Clinical Pharmacy</institution>, <institution content-type="university">University of Medicine and Pharmacy of Craiova</institution>, <addr-line>200349</addr-line> <city>Craiova</city>, <country country="RO">Romania</country> </aff> </contrib-group> <author-notes> <corresp id="cor1"> <bold>Corresponding author: Javad Sharifi-Rad</bold>, <institution content-type="dept">Facultad de Medicina</institution>, <institution content-type="university">Universidad del Azuay</institution>, <city>Cuenca</city>, <country country="EC">Ecuador</country>, E-mail: <email xlink:href="mailto:javad.sharifirad@gmail.com">javad.sharifirad@gmail.com</email>. <bold>Marcello Iriti</bold>, <institution content-type="dept">Department of Biomedical, Surgical and Dental Sciences</institution>, <institution content-type="university">Università degli Studi di Milano</institution>, <addr-line>20133</addr-line> <city>Milano</city>, <country country="IT">Italy</country>; and <institution content-type="university">National Interuniversity Consortium of Materials Science and Technology (INSTM)</institution>, <addr-line>50121</addr-line> <city>Firenze</city>, <country country="IT">Italy</country>, E-mail: <email xlink:href="mailto:marcello.iriti@unimi.it">marcello.iriti@unimi.it</email>. <bold>and Daniela Calina</bold>, <institution content-type="dept">Department of Clinical Pharmacy</institution>, <institution content-type="university">University of Medicine and Pharmacy of Craiova</institution>, <addr-line>200349</addr-line> <city>Craiova</city>, <country country="RO">Romania</country>, E-mail: <email xlink:href="mailto:calinadaniela@gmail.com">calinadaniela@gmail.com</email> </corresp> </author-notes> <pub-date pub-type="epub"> <day>07</day> <month>09</month> <year>2022</year> </pub-date> <volume content-type="ahead-of-print">0</volume> <issue>0</issue> <history> <date date-type="received"> <day>02</day> <month>04</month> <year>2022</year> </date> <date date-type="accepted"> <day>15</day> <month>07</month> <year>2022</year> </date> </history> <permissions> <copyright-statement>© 2022 the author(s), published by De Gruyter, Berlin/Boston</copyright-statement> <copyright-year>2022</copyright-year> <copyright-holder>the author(s), published by De Gruyter, Berlin/Boston GmbH, Berlin/Boston</copyright-holder> <license license-type="open-access" specific-use="rights-object-archive-dnb" xlink:href="http://creativecommons.org/licenses/by/4.0"> <license-p>This work is licensed under the Creative Commons Attribution 4.0 International License.</license-p> </license> </permissions> <related-article related-article-type="pdf" xlink:href="znc-2022-0076.pdf"/> <abstract> <title>Abstract</title> <p> <italic>Santalum</italic> genus belongs to the family of Santalaceae, widespread in India, Australia, Hawaii, Sri Lanka, and Indonesia, and valued as traditional medicine, rituals and modern bioactivities. Sandalwood is reported to possess a plethora of bioactive compounds such as essential oil and its components (α-santalol and β-santalol), phenolic compounds and fatty acids. These bioactives play important role in contributing towards biological activities and health-promoting effects in humans. Pre-clinical and clinical studies have shown the role of sandalwood extract as antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, neuroleptic, antihyperglycemic, antihyperlipidemic, and anticancer activities. Safety studies on sandalwood essential oil (EO) and its extracts have proven them as a safe ingredient to be utilized in health promotion. Phytoconstituents, bioactivities and traditional uses established sandalwood as one of the innovative materials for application in the pharma, food, and biomedical industry.</p> </abstract> <kwd-group> <title>Keywords</title> <kwd>bioactivities</kwd> <kwd>clinical studies</kwd> <kwd>essential oil</kwd> <kwd>phytochemistry</kwd> <kwd>safety</kwd> <kwd>sandalwood</kwd> </kwd-group> <counts> <fig-count count="004"/> <table-count count="002"/> <ref-count count="143"/> <page-count count="017"/> </counts> </article-meta> </front> <body> <sec id="j_znc-2022-0076_s_001"> <label>1</label> <title>Introduction</title> <p>The genus <italic>Santalum</italic> is a woody flowering plant that belongs to the family Santalaceae commonly known as sandalwood. The members of the genus are generally trees or shrubs. The plant is obligate hemiparasite attaching itself by haustoria to establish contact with the host and extracts xylem sap for nutrients and water [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_001">1</xref>]. The family Santalaceae comprises 29 genera with around 400 species out of which 18 well-recognized species are under the genus <italic>Santalum</italic> [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_001">1</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_002">2</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_003">3</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_004">4</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_005">5</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_006">6</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_007">7</xref>] (<xref ref-type="table" rid="j_znc-2022-0076_tab_001">Table 1</xref>).</p> <table-wrap id="j_znc-2022-0076_tab_001" position="float"> <label>Table 1:</label> <caption> <p>Section, recognized species, according to the International Union for Conservation of Nature (IUCN) category, common name and geographical distribution of <italic>Santalum</italic> species.</p> </caption> <table frame="hsides"> <colgroup> <col align="left"/> <col align="left"/> <col align="left"/> <col align="left"/> <col align="left"/> </colgroup> <thead> <tr> <th>Taxonomic group/Section</th> <th>Species and IUCN Red List Category</th> <th>Common name</th> <th>Geographical Occurrence</th> <th>Reference</th> </tr> </thead> <tbody> <tr> <td>Section <italic>Santalum</italic> skottsb.</td> <td> <italic>S. album</italic> L.</td> <td>Indian sandalwood</td> <td>Australia, Belgium, Cambodia, China, Germany, Great britain, Holand, India, Indonesia, Japan, Madagaskar, Malaysia, Norway, Spain, Srilanka, Switzerland, and the United States.</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_003">3</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_008">8</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_009">9</xref>]</td> </tr> <tr> <td rowspan="3">Section <italic>Solenantha</italic> Tuyama</td> <td> <italic>S. fernandezianum</italic> Phil.</td> <td>Freycinet sandalwood, or iliahi</td> <td>Hawaiian islands (O‘ahu, Moloka‘i)</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_010">10</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_011">11</xref>]</td> </tr> <tr> <td> <italic>S. haleakalae</italic> Hillebr.</td> <td>Haleakala sandalwood or iliahi</td> <td>Hawaiian islands (Maui)</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_011">11</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_012">12</xref>]</td> </tr> <tr> <td> <italic>S. pyrularium</italic> A. Gray</td> <td>Hawaiian sandalwood or iliahi</td> <td>Hawaiian islands (Kaua‘i)</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_003">3</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_005">5</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_013">13</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_014">14</xref>]</td> </tr> <tr> <td rowspan="2">Section <italic>Hawaiiensia</italic> skottsb.</td> <td> <italic>S. ellipticum</italic> Gaudich.</td> <td>Coastal sandalwood or ʻIliahialoʻe</td> <td>Hawaiian islands</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_003">3</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_011">11</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_012">12</xref>]</td> </tr> <tr> <td> <italic>S. paniculatum</italic> Hook. &amp; Arn.</td> <td>Hawai‘i</td> <td>Hawaiian islands</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_003">3</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_011">11</xref>]</td> </tr> <tr> <td>Section <italic>Polynesica</italic> skottsb.</td> <td> <italic>S. fernandezianum</italic> F.Phil.</td> <td>Chile sandalwood</td> <td>Juan fernandez islands</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_003">3</xref>]</td> </tr> <tr> <td>Genus <italic>Eucarya</italic> T.Mitch.</td> <td> <italic>S. acuminatum</italic> (R.Br.) A.DC.</td> <td>Desert Quandong, native Peach</td> <td>Australia</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_015">15</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_016">16</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_017">17</xref>]</td> </tr> </tbody> </table> </table-wrap> <p>Sandalwood is generally popular for its fragrant heartwood oil used by cosmetic industries for the production of perfume [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_013">13</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_018">18</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_019">19</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_020">20</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_021">21</xref>]. The high demand for sandalwood oil and timber has resulted in drastic over-harvesting; as a result, many taxa are now considered as rare, threatened or listed as endangered [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_022">22</xref>]. Moreover, one species <italic>Santalum fernandezianum</italic> Phil. from the Juan Fernandez Islands (South Pacific Ocean), has been reported extinct due to over-exploitation by human beings [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_023">23</xref>]. About 25 species belong to the genus <italic>Santalum</italic>, they are evergreen trees or shrubs characterized by a semi-parasitic lifestyle. They conduct photosynthesis; however, they take in water and inorganic nutrients by parasitizing on the roots of other plant species.</p> <p>Plants of the genus <italic>Santalum</italic> are characterized by the production of EOs with many biological properties due to the high content of bioactive substances such as lignans, glycosides, triterpenoids, and sesquiterpenoids (α/β-santalol - the compound found in the largest amount). These bioactive compounds include antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, neuroleptic, antihyperglycemic, antihyperlipidemic, and anticancer activities.</p> <p> <italic>Santalum</italic> genus has been known to possess many health benefits proved based on traditional uses and modern biological approaches through preclinical studies. Traditionally, <italic>Santalum</italic> genus has been used as an antipyretic, immune booster, antidiarrhea, and for treating cold and cough. Modern uses have shown their effect as antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, neuroleptic, antihyperglycemic, antihyperlipidemic, and anticancer activities. One of the most important parameters considered for the application of plant extracts in the biomedical field is its safety. The safety aspects of EO components have been studied by various researchers and it is concluded that extracts from <italic>Santalum</italic> genus are fairly safe to be used as health-promoting effects. The current review is the first of its kind that gives a snapshot of the <italic>Santalum</italic> genus concerning its traditional uses, bioactive components, bioactivities (<italic>in vitro</italic>, <italic>in vivo</italic> and clinical trials), and its safety aspects while using it as a health-promoting agent in humans.</p> </sec> <sec id="j_znc-2022-0076_s_002"> <label>2</label> <title>Review methodology</title> <p>Available information on the genus <italic>Santalum,</italic> its biological properties, and its potential mechanisms of action was collected by searching the following databases: PubMed/Medline, Web of Science and ScienceDirect. The following MeSH terms were used: “Santalum/growth &amp; development”, “Santalum/chemistry”, “Plant Oils/isolation &amp; purification”, “Animals”, “Apoptosis/drug effects”, “Carcinogenesis/drug effects”, “Cell Cycle Checkpoints/drug effects”, “Humans”, “Mice”, “Plant Extracts/chemistry”, “Plant Extracts/therapeutic use”, “Plant Oils/therapeutic use”, “Antioxidants/metabolism”.</p> <p>The study included research articles and reviews published in extenso, written in English language in scientific journals, book chapters and books with information about <italic>Santalum</italic> genum and sandalwood. Editorials/letters to publishers, case reports, conference abstracts, studies that included homeopathic preparations were excluded. The PlantList database was used to verify the taxonomy and provide information on the classification and distribution of <italic>Santalum</italic> subspecies [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_024">24</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_025">25</xref>].</p> </sec> <sec id="j_znc-2022-0076_s_003"> <label>3</label> <title>Botany</title> <p> <italic>Santalum</italic> is widely distributed to semi-arid areas from Indonesia in the West to Juan Fernandez Islands (Chile) in the East and from Hawaiian Archipelago in the North to New Zealand in the South [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_008">8</xref>] (<xref ref-type="fig" rid="j_znc-2022-0076_fig_001">Figure 1</xref>). The major production places of the plant are shown in <xref ref-type="table" rid="j_znc-2022-0076_tab_001">Table 1</xref>.</p> <fig id="j_znc-2022-0076_fig_001" position="float" fig-type="figure"> <label>Figure 1:</label> <caption> <p>Geographical distribution of <italic>Santalum</italic> genus.</p> </caption> <graphic xlink:href="graphic/j_znc-2022-0076_fig_001.jpg"/> </fig> <p>The well-recognized species are broadly grouped into four categories viz. Indian sandalwood (<italic>Santalum album</italic> L.), Australian sandalwood (<italic>Santalum acuminatum</italic> (R. Br.) A. DC.), Hawaiian sandalwood (<italic>Santalum ellipticum</italic> Gaudich<italic>., Santalum freycinetianum</italic> F. Phil.<italic>, Santalum haleakalae</italic> Hillebr<italic>., Santalum paniculatum</italic> Hook. &amp; Arn.<italic>,</italic> and <italic>Santalum pyrularium</italic> A. Gray), and Pacific Islands sandalwood (<italic>S. fernandezianum</italic> Phil.)<italic>.</italic> </p> <p>A taxonomic grouping in <italic>Santalum</italic> is purely based on morphological characters. It has been reported that Section <italic>Santalum</italic> is described as reddish corollas that are longer than wide and partly superior ovaries [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_012">12</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_026">26</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_027">27</xref>]. Based on smaller ovaries, longer perianth tubes and absence of hairs to the filament [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_028">28</xref>] separated the two Hawaiian members (<italic>S. freycinetianum</italic> and <italic>S. haleakalae</italic>) from the section <italic>Santalum</italic> into the endemic section <italic>Solenantha</italic>. The characteristic features of the section <italic>Hawaiiensia</italic> are explained as having white, brown, orange or green corollas that are as wide as long and inferior ovaries [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_012">12</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_026">26</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_027">27</xref>].</p> <p>Section <italic>Polynesica</italic> is similar in appearance to the section <italic>Hawaiiensia</italic> but with partly superior ovaries [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_026">26</xref>]. A molecular phylogenetic study reveals that the sectional classification of <italic>Santalum</italic> needs revision [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_003">3</xref>]. Skottsberg [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_026">26</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_029">29</xref>] suggested that sections <italic>Hawaiiensia</italic> and <italic>Polynesica</italic> were closely related based on morphological characters and section <italic>Polynesica</italic> was treated as a synonym of section <italic>Hawaiiensia</italic> by [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_030">30</xref>]. But molecular phylogenetic analysis indicates that sections <italic>Hawaiiensia</italic> and <italic>Polynesica</italic> are not close to one another rather related to other taxa of section <italic>Santalum</italic> and should not be united taxonomically [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_003">3</xref>]. Revisionary studies based on molecular data considered six species of <italic>Santalum</italic> in Hawaii, whereas previously there were only four recognized species [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_005">5</xref>]. Hawaiian species are considered to be a result of two colonization processes which comprises four species within red-flowered section <italic>Solenantha</italic> (i.e., <italic>S. freycinetianum</italic>, <italic>S. haleakalae</italic>, and <italic>S. pyrularium</italic>); and two species within white-flowered section <italic>Hawaiiensia</italic> (i.e., <italic>S. ellipticum</italic>, and <italic>S. paniculatum</italic>) [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_014">14</xref>].</p> <p>General features of the genus <italic>Santalum</italic> are evergreen trees or shrubs; leaves opposite rarely alternate, sometimes in whorls, glabrous or sometimes glaucous, ovate, obovate or lanceolate, coriaceous [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_031">31</xref>]. Flowers cymose panicle, axillary or in the terminal, tetra or pentamerous, hermaphrodite; bracts small. Perianth-tube campanulate to conical or ovoid, adnate to the base of the ovary; stamens 4-5, dorsifixed, filament slender, short, anthers ovate; 4-lobed; style long, stigma 2-4 lobed; ovary inferior or partly inferior; ovules 2-3. Flowers produce sweet to a week or no fragrance. Fruit globose to sub-globose drupe, annulate on the top by the deciduous perianth; seed subglobose; albumen copious. Morphological differences of some important species are summarized in <xref ref-type="table" rid="j_znc-2022-0076_tab_002">Table 2</xref>.</p> <table-wrap id="j_znc-2022-0076_tab_002" position="float"> <label>Table 2:</label> <caption> <p>Contrasting morphological characters of important <italic>Santalum</italic> species.</p> </caption> <table frame="hsides"> <colgroup> <col align="left"/> <col align="left"/> <col align="left"/> <col align="left"/> <col align="left"/> <col align="left"/> <col align="left"/> </colgroup> <thead> <tr> <th>Category</th> <th>Species</th> <th>Size</th> <th>Leaves</th> <th>Flower</th> <th>Fruit</th> <th>Reference</th> </tr> </thead> <tbody> <tr> <td>Indian sandalwood</td> <td> <italic>S. album</italic> L.</td> <td>Small to the medium-size tree with slender drooping branches</td> <td>Opposite, lanceolate to ovate; acute to obtuse at base, entire; apex acute to acuminate; pale green to lush green</td> <td>Initially, straw yellow coloured and gradually turn to deep purplish or brown</td> <td>Green to purplish–black; succulent</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_008">8</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_009">9</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_031">31</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_032">32</xref>]</td> </tr> <tr> <td>Australian sandalwood</td> <td> <italic>S. acuminatum</italic> (R. Br.) A. DC.</td> <td>A shrubby small tree</td> <td>Opposite, more or less lanceolate; pale green to olive-green; acute apex</td> <td>Small, creamy white or greenish-white</td> <td>Globose, green turning to orange–red to bright, glossy red; persistent tepal scar</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_015">15</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_016">16</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_033">33</xref>]</td> </tr> <tr> <td rowspan="5">Hawaiian sandalwood</td> <td> <italic>S. ellipticum</italic> Gaudich.</td> <td>Shrub to small tree</td> <td>Elliptic to orbicular, ovate, or obovate; leathery to succulent; glaucous; dull, greyish green</td> <td>Greenish in bud but tinged with brown, orange, or salmon after opening; produce a sweet fragrance; flower as long as wide</td> <td>Purple to black drupes, with a distinctive apical receptacular ring</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_011">11</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_034">34</xref>]</td> </tr> <tr> <td> <italic>S. paniculatum</italic> Hook. &amp; Arn.</td> <td>Shrub or tree</td> <td>Ovate, obovate or elliptic; upper surfaces glossy and lower surface dull; yellowish orange to bluish or olive green.</td> <td>Greenish in bud but tinged with brown, orange, or salmon after opening; produce a sweet fragrance; flowers as long as wide</td> <td>Purple to black with a distinctive apical receptacular ring.</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_011">11</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_034">34</xref>]</td> </tr> <tr> <td> <italic>S. freycinetianum</italic> F. Phil.</td> <td>Shrub to tree</td> <td>Narrowly elliptic, oblong, to narrowly ovate; acute to rounded apex; bit glaucous; green</td> <td>Light pink turning deep pink with maturity (rarely with white interiors); produce a weak fragrance; flowers longer than wide</td> <td>Reddish–purple to almost black with a distinctive sub-apical receptacular ring</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_005">5</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_010">10</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_011">11</xref>]</td> </tr> <tr> <td> <italic>S. haleakalae</italic> Hillebr.</td> <td>Small tree</td> <td>Ovate, obovate, or orbicular; stiff to coriaceous surfaces; olive green</td> <td>Deep pink to red throughout, or with white to pink interiors; produce a weak fragrance; flowers longer than wide</td> <td>Black or purplish–black with a distinctive sub-apical receptacular ring.</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_005">5</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_011">11</xref>]</td> </tr> <tr> <td> <italic>S. pyrularium</italic> A. Gray</td> <td>Small tree or shrubby tree</td> <td>Opposite; elliptic, ovate, to oblong; glaucous abaxially not much paler on abaxial surface; acute to obtuse apices; medium to dark green</td> <td>Cream to purple throughout, greenish with the purple interior, or greenish-white turning red with age</td> <td>Red, elliptic, with subapical ring</td> <td>[<xref ref-type="bibr" rid="j_znc-2022-0076_ref_005">5</xref>]</td> </tr> </tbody> </table> </table-wrap> </sec> <sec id="j_znc-2022-0076_s_004"> <label>4</label> <title>Traditional uses</title> <p>The close-grained heartwood of <italic>Santalum</italic> is used for ornamental and carving work. <italic>Santalum</italic> fruits are edible and the seeds contain fatty oil which is suitable for the manufacture of paint. Incense sticks are made of powdered heartwood and are used in houses and temples. In addition, powered heartwood is ground into a paste and used as a cosmetic [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_035">35</xref>]. <italic>Santalum</italic> genus is mentioned in Indian mythology, folklore, scripture, and the oldest literature (for example, Vinaya Pitaka (400–300 BC) and Milinda Pahna (200 BC)) and also in the epic Ramayana and Mahabharata. The ancient Egyptians used <italic>Santalum</italic> plants oil for embalming the dead and in the ritual burning to venerate the gods. In certain communities among the Hindus it is traditional to put a piece of sandalwood in the funeral pyre. A beige-coloured paste obtained from sandalwood is put in on the forehead and other body parts, especially by devotees of God Krishna (Vaishnavites) and for ritual bathing of Hindu gods [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_036">36</xref>]. In Zoroastrian temples, <italic>Santalum</italic> burns in sacred lights to soothe the problems of all mankind. It is used by Jews, Buddhists, Hindus, as well as almost all other belief systems for its huge variety in attributes [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_035">35</xref>].</p> </sec> <sec id="j_znc-2022-0076_s_005"> <label>5</label> <title>Bioactive composition</title> <sec id="j_znc-2022-0076_s_005_s_001"> <label>5.1</label> <title>Essential oil, terpenes, and derivatives</title> <p>After 30 years of growth with a natural condition, oil is collected from the heartwood of sandalwood. The yield of the oil depends on the age of the tree; an old mature tree gives an oil yield between 2.5–6%; the colour of the heartwood, individual tree understudy, location within the tree, and the environment of growth of the tree. Sandalwood oil consists of main terpenoids: mono- and sesquiterpenes and their oxygenated derivatives (mostly the alcohols, ketones, and aldehydes) and also some fatty acids, and phenylpropanoids chemical compounds [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_037">37</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_038">38</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_039">39</xref>] (<xref ref-type="fig" rid="j_znc-2022-0076_fig_002">Figure 2</xref>).</p> <fig id="j_znc-2022-0076_fig_002" position="float" fig-type="figure"> <label>Figure 2:</label> <caption> <p>Illustrative scheme with the most important bioactive constituents of <italic>Santalum</italic> essential oil and their pharmacological properties.</p> </caption> <graphic xlink:href="graphic/j_znc-2022-0076_fig_002.jpg"/> </fig> <p>The bark extract of <italic>S. album</italic> contains mainly santalol (90%) [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_040">40</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_041">41</xref>], exo-norbicycloekasantalal, β-santalic, teresantalic, nortricycloekasantalic, bicycloekasantalic, di-hydro-β-santalic acids, urs-12-en-3b-il-palmitate, β -sitosterol, (+)epi- β-santalol, (-) β-santalol, (-)trans-β-santalol, α-santalol (52%), β-santalol (23%), epi-β-santalene, cis-lanceol, cis-nuciferol, β-, epi-β-teresantalic acid, β-, epi-β-norekasantalic acid, β-, epi-β-ekasantalic acid, α-santalic acid, 11-keto-dihydro- α -santalic acid, bisabolenols A, B, C, D and E, tricycloekasan-talol, α- and β-santalenes, trans- α -bergamotene, α-curcumone, nuciferol. The bark extract of <italic>S. album</italic> includes l-allohydroxiproline, betulinic acid, β-sitosterol, and fatty acids. The bark extract of <italic>S. album</italic> contains betulinic acid (0.05%), β -sitosterol, glucose, fructose, and sucrose [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_038">38</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_040">40</xref>]. Although including a low amount of trans-β-santalol, cis-lanceol hydrocarbons, α-santalene, β-santalene, α-bergamotene, epi-β-santalene, as α-curcumene, β-curcumene, γ-curcumene, β-bisabolene and α-bisabolol; cis-α-santalol (53%), cis-β-santalol (23%), α-trans-bergamotol, epi-cis-β-santalol sesquiterpene alcohols are the major components of the sandalwood oil [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_042">42</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_043">43</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_044">44</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_045">45</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_046">46</xref>].</p> <sec id="j_znc-2022-0076_s_105_s_001_s_001"> <label>5.1.1</label> <title>Extraction of the <italic>Santalum</italic> Oil</title> <p>EO is one of the important components of an important component of sandalwood and its isolation from sandalwood depends on the methods of extraction. The EO of the sandalwood is widely used in the fragrance industry due to having a strong aroma and has various biological activities such as: anticancer, antiviral, antidiarrheal, cytotoxic activities, among others [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_047">47</xref>]. The different extraction methods can be applied to the <italic>Santalum</italic> during oil extraction. Therefore, the composition and amount of the fragrance and volatile compounds found in oil may vary dependent on the extraction methods. The conventional steam distillation and hydrodistillation methods are performed under high temperatures (around 100 °C) which can often result in loss of volatile compounds and changes in the odour [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_048">48</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_049">49</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_050">50</xref>]. Maceration or Soxhlet type solvent extraction are other techniques that have some the drawbacks such as large volume of solvent usage, exposure to hazardous and flammable liquid organic solvents, and environmental issues [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_051">51</xref>]. Therefore, the use of some solvent-free “green methods” during the extraction of EO has gained prominence in recent years. Microwave-assisted extraction, subcritical CO<sub>2</sub> (SC–CO<sub>2</sub>) extraction and some other combined novel technologies, such as microwave-assisted hydrodistillation method, are preferred due to having higher selectivity and extraction yield, need for less time for analysis and not posing environmental and safety concerns [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_052">52</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_053">53</xref>].</p> <p>Kusuma and Mahfud [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_052">52</xref>] objected to looking into the effects of the newly employed microwave air-hydrodistillation method for extraction of EOs and comparison with classical microwave hydrodistillation method. Results of this research showed that additional airflow to the microwave hydrodistillation can help obtain the sandalwood oil in higher yield directly proportional with air flow rate. The compound composition of microwave air-hydro distilled sandalwood oil is larger than another method concerning identification 43 compounds whereas 37 compounds are recorded in microwave hydrodistillation. Microwave air-hydrodistillation provides better aroma/fragrance quality than microwave hydrodistillation extracts [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_052">52</xref>].</p> <p>Nautiyal [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_054">54</xref>] mentioned that extraction yield and quality affect the trade of sandalwood oil. It was also highlighted that heartwood preparation and the extraction method have an influence on α- and β-santalol levels in the obtained oil. In the study, eight different extraction methods which are SC–CO<sub>2</sub>, ethyl alcohol, benzene, diethyl ether, toluene, steam distillation, hydrodistillation, and alkaline-hydro distillation are examined. The highest yield is obtained from SC–CO<sub>2</sub> extraction, 3.83 grams per liter (g/L). In the analysis of extracted sandalwood oil for α- and β-santalol levels were examined through gas chromatography (GC). The most efficient extraction methods are SC–CO<sub>2</sub>, ethyl alcohol, and steam distillation; they include nearly 84% total α- and β- santalol. Hydrodistillation is the least efficient in terms of having α:β- santalol ratio, 3:1, whereas SC–CO<sub>2</sub>, ethyl alcohol, and steam distillation had 1.9:1. Furthermore, Nautiyal [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_054">54</xref>] stated that organoleptic characteristics are affected by the levels of α- and β-santalol, besides other compounds. Pleasant sandalwood oil extracts are found via SC–CO<sub>2</sub> extraction, hydro, alkaline-hydro, and steam distillation. Furthermore, Nautiyal [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_055">55</xref>] extracted sandalwood (<italic>S. album</italic>) oil via SC–CO<sub>2</sub> at 200 bar and 28 °C under two conditions, and the fractionation of the extract was analyzed continuously. Extractions by steam distillation, hydro distillation, Soxhlet extraction were conducted for comparison. The results showed that SC–CO<sub>2</sub> extraction is much more effective in terms of the physical properties of oil than commercial sandalwood oil [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_055">55</xref>].</p> <p>Over the last 25 years, about 65,000 chemical structures of the terpenoids and over 7,000 sesquiterpenes (C15) have been reported in previous studies [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_056">56</xref>]. The EO of the <italic>S. album</italic> tree is composed of the mixture of sesquiterpenes i.e., α-santalol, β-santalol, epi-β-santalol, α-trans-bergamotol, α-bisabolol, lanceol, sesquisabinene hydrate, and farnesol [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_057">57</xref>]. According to the literature research, α-santalol and β-santalol (<xref ref-type="fig" rid="j_znc-2022-0076_fig_003">Figure 3</xref>) which are the main sesquiterpene alcohol compounds found in sandalwood oil are known to indicate biological activities against the skin and prostate cancer and malaria [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_058">58</xref>]. In the same context, GC analysis of <italic>S. album</italic> oil shows that Z-α-santalol and Z- β-santalol are found with proportions 41–55% and 16–24%, respectively according to the standard [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_052">52</xref>]; identified some of the sesquiterpenes and monoterpenols, such as α-santalol, β-santalol, α-bergamotol, and cis-lanceol.</p> <fig id="j_znc-2022-0076_fig_003" position="float" fig-type="figure"> <label>Figure 3:</label> <caption> <p>Structure of α-santalol and β-santalol.</p> </caption> <graphic xlink:href="graphic/j_znc-2022-0076_fig_003.jpg"/> </fig> <p>According to this chromatographic analysis, santalol levels below these specifications can be related to extraction from undeveloped heartwood, adulteration with synthetic or semi-synthetic substitutes, or substitution with EOs from other species [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_042">42</xref>].</p> <p>Mohankumar et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_059">59</xref>] conducted a study on the heartwood of <italic>S. album</italic> EO concerning antioxidant and stress modulatory efficacy. The traditional steam distillation method is preferred for <italic>S. album</italic> oil extraction and the oil chemical profile identified by the GC–MS technique. <italic>Santalum album</italic> oil has at least 19 main components, accounting for 96.81% of the total content. The main compounds of <italic>S. album</italic> oil followed the order as α-santalol with 41.77% &gt; β-santalol with 18.02% &gt; (Z)-α-trans-bergamotol (8.50%) &gt; (Z)-lanceol (6.57%) &gt; epi-β-santalol (5.78%), cis-nuciferol (3.21%) &gt; docosahexaenoic acid (2.54%) &gt; β-trans-santalol (2.24%) &gt; β-costol (1.41%) &gt; β-santalene (1.24%) &gt; (Z)-β-curcumen-12-ol (1.02%). Besides all components, the pleasant odour of <italic>S. album</italic> oil was contributed by α- and β-santalol.</p> <p>Subasinghe et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_060">60</xref>] investigate the Indian sandalwood (<italic>S. album</italic>) EO content and composition in Sri Lanka. Two naturally grown trees heartwoods are studied for comparing the oil properties. The maceration method is applied overnight with deionized water. One of the three the oil yield was measured at 15 cm below ground and found with the highest yield of EO whereas other trees showed a yield varying from 1.46 to 3.35 % w/w.</p> <p>Another study examines the phytochemical analysis and antibacterial efficiency of extracts of <italic>S. album</italic> in preclinical studies<italic>. In vitro</italic> extracts contain callus, somatic embryo, and seedlings; non-oil-yielding young and oil-yielding matured trees are included <italic>in vivo</italic> part. Combined dichloromethane and methanol are used for the 18 h maceration method. Seedlings have the highest amount of sesquiterpenoids with 51.4 mg/g, and the old tree has the least (8.07 mg/g). Monoterpenoids compound content range changes between 3.1 and 4.5 mg/g, except young tree leave extract that has the highest content with 9.5 mg/L [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_061">61</xref>].</p> <p>The volatile oil from <italic>S. album</italic> wood and of <italic>Boswellia sacra</italic> Flueck, (syn. <italic>Boswellia carteri</italic> Birdw.) the resin obtained by SC–CO<sub>2</sub> extraction and the effects of extraction conditions on the composition is analyzed in the study of [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_037">37</xref>]. In general, oxygenated sesquiterpenes dominate the composition of the oil with a 90% ratio and hydrocarbon sesquiterpenes follow these compounds around 5%. According to the results, the best operative conditions is obtained working at 120 bar and 45 °C with the 0.658 g/mL density of CO<sub>2</sub> in the extraction vessels for both matrices.</p> <p>Another research was conducted on EO composition from roots of <italic>S. album</italic> [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_062">62</xref>]. Samples were kept in ethyl ether at 48 h for extracting the oil from the root bark. <italic>Santalum album</italic> root heartwood had 10.3% in fresh weight oil yield. Fifty-three different chemical compounds are detected by GC-MS; moreover, β-santalol and α- santalol were included in the ethanolic extract at the highest level with 19.6 and 16%.</p> <p>In the study of Jones et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_063">63</xref>]; the yield of the oil from 22 <italic>S. album</italic> trees was evaluated with the use of core sampling at two different heights (30 cm and 100 cm ground level). The results showed that the total concentration of sesquiterpene hydrocarbons is found in a slightly higher proportion in samples. On the other hand, the ratio of α-santalol and β-santalol is lower generally at 100 cm above ground level.</p> <p>In recent years, procurement of sandalwood resources and their biologically active compounds such as EO or terpenoids have been decreased due to the devastating of the natural stocks and habitats. Therefore, some of the strategies like the heterologous expression, plant cell cultures and plant cell bioreactors have gained prominence to promote the synthesis of sandalwood terpenoids [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_047">47</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_064">64</xref>].</p> </sec> </sec> <sec id="j_znc-2022-0076_s_005_s_002"> <label>5.2</label> <title>Fatty acids</title> <p>The identification of fatty acid in the oil is generally performed using gas chromatography/mass spectrometry (GC-MS) [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_065">65</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_066">66</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_067">67</xref>]. Zhang et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_068">68</xref>] examined the 60 compounds from the pericarp-derived volatile oil of <italic>S. album</italic> with different extraction methods. Colourless EOs are obtained in 2.6 and 5% yield by hydrolyzation and n-hexane extraction and analyzed by GC and GC-MS. Fatty acids, especially palmitic and oleic acids, dominated the total extracted oil with 40–70% depending on the extraction method. <italic>Santalum album</italic> berries proximate analysis, and <italic>in vitro</italic> activities of these compounds have been done by Sri Harsha et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_069">69</xref>]. Soxhlet method with hexane is used for taking off the oil. The oil that contains a higher amount of oleic acid (45.4%) and palmitic acid (32.5%) is measured 1.5 g/100 g fresh weight. Berries have a very low amount of α-tocopherol when compared to other berry tocopherol content.</p> </sec> <sec id="j_znc-2022-0076_s_005_s_003"> <label>5.3</label> <title>Phenolics and saponins</title> <p> <italic>Santalum album</italic> berries phenolic content is found 310 mg gallic acid equivalents (GAE)/100 g fresh weight in methanolic extract of berries. Acidified methanolic extract of <italic>S. album</italic> berries anthocyanin level is measured 0.21% in fresh weight, and the anthocyanin is confirmed as cyanidin 3-glucoside [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_069">69</xref>]. Various extract of <italic>S. album</italic> has antioxidant activity and a significant role in fighting against free radicals. Kaur et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_070">70</xref>] reported that the methanolic extract of this strain indicates higher phenolic fractions than other extracts. Besides, cyanidin-3-glucoside is one of the anthocyanin pigments that show antioxidant properties and nutritional potential in <italic>S. album.</italic> </p> <p>Like <italic>S. album</italic> callus, somatic embryo, and seedlings (<italic>in vitro</italic>); non-oil-yielding young and oil-yielding matured trees (<italic>in vivo</italic>) phenolic results, a similar result is shown in saponin content, <italic>in viv</italic>o extracts with 31.6 and 43.6 mg/g show higher saponin content than <italic>in vitro</italic> extract (9.4 and 17.1 mg/g) [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_061">61</xref>]. Phytoconstituents and antioxidant activity were analyzed <italic>in vitro</italic> grown callus cultures of <italic>S. album.</italic> The yield of the extract for a dichloromethane–methanol (1:1) solvent mixture was found as 4.3%. The results uncover the abundance of phenolic extracts (18.2 µg). Other major phytoconstituents are found in the extract as terpenoids (16.4 µg/mg), saponins (9.4 µg/mg) and flavan-3-ols (7.0 µg/mg) [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_071">71</xref>].</p> <p>Chintamani and Dikshit [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_072">72</xref>] investigated the antioxidant potential and secondary metabolite of the fruit pulp and the kernels of the <italic>S. album.</italic> As a result of the GC-MS analysis, phenols that have been found in the free form are detected in the acetonitrile extract of fruit kernel and sterol derivatives such as cholest-4-en-3 one compound is recorded mostly in the dichloromethane extract of fruit pulp and. Besides, pyrazine amide and acetamide-2-cyano were obtained as a major constituent of the kernel with the extraction in the methanol and acetonitrile, respectively.</p> </sec> <sec id="j_znc-2022-0076_s_005_s_004"> <label>5.4</label> <title>Phytosterols</title> <p>β-Sitosterol is found in the <italic>S. album</italic> combined hexane and isopropanol solvent extract (85.35 mg/100 g oil) and <italic>S. album</italic> supercritical CO₂ extract (88.9 mg/100 g oil) at the highest level. Stigmasterol and δ-5-avenasterol amounts are quite higher than other types of chemical compounds [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_073">73</xref>].</p> </sec> </sec> <sec id="j_znc-2022-0076_s_006"> <label>6</label> <title>Pharmacological activities</title> <sec id="j_znc-2022-0076_s_006_s_001"> <label>6.1</label> <title>Anticancer activity</title> <p>Cancer is a population of cell cells with uncontrolled growth and multiplication [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_074">74</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_075">75</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_076">76</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_077">77</xref>]. Natural bioactive compounds help us with anti-inflammatory qualities to fight infections like bacterial, fungal and viral, but also with antioxidant properties with cancer [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_078">78</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_079">79</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_080">80</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_081">81</xref>]. Cytotoxicity is one of the biological activities that characterize sandalwood oil. Mishra et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_082">82</xref>] in their study showed that new cyclic octapeptide cyclosaplin was cytotoxic against MDA-MB-231 that are human breast cancer cells. Its anticancer activity is based on inducing apoptosis in cells but also on suppression of viability of the cells (<xref ref-type="fig" rid="j_znc-2022-0076_fig_004">Figure 4</xref>). Different scientists from the world found that compounds from sandalwood have anticancer activities in many types of skin cancer and leukaemia cells [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_082">82</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_083">83</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_084">84</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_085">85</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_086">86</xref>]. Matsuo and Mimaki [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_083">83</xref>] found new neolignan and known lignans in sandalwood and this study, they showed that new neolignan was cytotoxic towards HL-60 cells, which are human promyelocytic leukaemia cells. In different work, Matsuo et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_084">84</xref>] showed that cis-β-santalol and -β-santaldiol were cytotoxic against HL-60 human promyelocytic leukaemia cells by inducing apoptosis in them. According to Santha and Dwivedi [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_085">85</xref>]; α-santalol from sandalwood oil from <italic>Santalum album</italic> have anticancer properties, because it can induce apoptosis, have an anti-angiogenic effect and also antioxidant activity on various types of cancer cells.</p> </sec> <sec id="j_znc-2022-0076_s_006_s_002"> <label>6.2</label> <title>Antibacterial, antifungal and antiviral activities</title> <p>Antibacterial activities are another one that was found among compounds of sandalwood oil due to the content of α/β-santalol and were active against <italic>Salmonella typhimurium</italic> and <italic>Staphylococcus aureus</italic> which are bacteria that cause well known and still threatening diseases throughout the whole world [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_039">39</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_061">61</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_087">87</xref>]. Epi-β-santalene was found to effective against <italic>S. typhimurium</italic> [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_088">88</xref>] (<xref ref-type="fig" rid="j_znc-2022-0076_fig_004">Figure 4</xref>).</p> <fig id="j_znc-2022-0076_fig_004" position="float" fig-type="figure"> <label>Figure 4:</label> <caption> <p>Illustrative scheme with the most representative pharmacological properties of <italic>Santalum</italic> genus and the correlation with bioactive compounds. Symbols: ↑ increase, ↓ decrease.</p> </caption> <graphic xlink:href="graphic/j_znc-2022-0076_fig_004.jpg"/> </fig> <p>In seeds of <italic>Santalum album</italic> there is a compound known as santalbic acid, which has antibacterial properties against gram-positive bacteria and antifungal effect on many types of pathogenic fungi [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_089">89</xref>]. Ochi et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_090">90</xref>] found that crude organic fractions and sesquiterpenoids from sandalwood oil have antimicrobial activity against <italic>Helicobacter pylori</italic> which caused peptic ulcers and also can be the cause of gastric cancer. Vadnere et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_091">91</xref>] purposed to conduct phytochemical analysis and antimicrobial screening of <italic>S. album</italic> seeds petroleum ether and ethanol extracts. <italic>In vitro</italic> antimicrobial activity of both extracts was analyzed using a disk diffusion method for <italic>Bacillus subtilis, S. aureus, Pseudomonas aeruginosa, Escherichia coli</italic> and <italic>C. albicans.</italic> The outcome of the investigations highlights the potential high efficacy of petroleum ether extract related to santalbic acid, which can function as an antimicrobial agent [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_091">91</xref>].</p> <p>Different research showed that derivatives from <italic>S. album</italic> possess significant antifungal properties against species as <italic>Microsporum canis</italic>, <italic>Trichophyton mentagrophytes,</italic> and <italic>Trichophyton rubrum</italic> which is due to the inhibitory effect on mitosis [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_039">39</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_087">87</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_092">92</xref>]. Powers et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_093">93</xref>] in their studies have shown that the most active, of the 60 EOs obtained from commercial sources against <italic>Aspergillus niger, Candida albicans</italic>, and <italic>Cryptococcus neoformans</italic>, both in terms of antifungal and cytotoxic activity, were the sandalwood species (<italic>S. album, S. paniculatum</italic>), rich in santalols.</p> <p>Gupta and Chaphalkar [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_094">94</xref>] found that aqueous root extract of <italic>S. album</italic> has anti-inflammatory and antiviral activities because it inhibits proliferation, production of monocytes marker – CD14 and also inhibition of nitric oxide in their study on immunopharmalogical activities of it against hepatitis B virus surface antigen – HbsAg, and New Castle disease virus. Antiviral properties were also reported by other scientists in the study of <italic>Herpes simplex</italic> viruses type 1 and 2 [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_095">95</xref>]. The authors showed that antiviral activity is dose-dependent and didn’t exist due to virucidal activity but rather because of the effect on the replication. Sandalwood oil has been also shown to be used against warts, skin blemishes, and other viral-induced tumours on the skin [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_096">96</xref>].</p> </sec> <sec id="j_znc-2022-0076_s_006_s_003"> <label>6.3</label> <title>Antioxidant</title> <p>Antioxidants are a group of compounds that protect the body from the chemical process called oxidation [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_097">97</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_098">98</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_099">99</xref>]. This process produces free radicals that attack cell membranes, and for this reason natural antioxidants are important for human health [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_100">100</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_101">101</xref>]. Antioxidant efficacy is also a known property of sandalwood oil and methanolic extracts from the heartwood of <italic>S. album</italic> [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_102">102</xref>] but Misra and Dey [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_071">71</xref>] found it <italic>in vitro</italic> in callus extract of Sandalwood tree and their study showed that it is comparable. Also, antioxidative properties were found in anthocyanins pigment cyanidin-3-glucoside [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_069">69</xref>].</p> </sec> <sec id="j_znc-2022-0076_s_006_s_004"> <label>6.4</label> <title>Other pharmacological activities</title> <p>Diabetes is a disease that is widespread along with all the world and sandalwood oil is also found effective in managing the complications of this disease [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_103">103</xref>]. Kulkarni et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_104">104</xref>] found that it has antihyperglycemic and antihyperlipidemic activities in their studies with diabetic rats, because of the antihyperlipidemic properties it can also help with protecting the liver and also with cardiovascular diseases. Sandalwood extract was reported to inhibit the cardiac tissue damage via reduction of lipid peroxidation damage on the doxorubicin induced cardiotoxicity rat model and significant protective effect against induced myocardial infarction in albino rats in a dose-dependent manner [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_105">105</xref>].</p> <p>Sedative activities are known as properties of derivatives from sandalwood [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_106">106</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_107">107</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_108">108</xref>]. Sandalwood oil is reported to produce a relaxing effect on the nerves and is used for headaches, insomnia and nervous tensions. Studies carried out by [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_109">109</xref>] observed that inhalation of sandalwood oil decreased the motility of mice to an extent of 40–78%. Also showed in their studies that a mild sedative effect occurred in female Swiss albino mice after inhaling sandalwood oil.</p> <p>Okugawa et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_107">107</xref>] showed an antipsychotic effect <italic>in vitro</italic> and <italic>in vivo</italic> on mice. In addition, α-santalol is a strong inhibitor of both tyrosinase and cholinesterase <italic>in vivo</italic>, and hence there is a great potential of the EO for use in the treatment of Alzheimer’s disease [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_039">39</xref>].</p> <p>The potential pharmacological property of <italic>S. album</italic> oil in infective skin conditions have been examined during a few clinical against a wide range of skin conditions. The therapeutic potential of <italic>S. album</italic> oil in dermatology is attributed to its antioxidant, anti-inflammatory and antimicrobial properties. Furthermore, <italic>S. album</italic> oil inhibits the hyper-proliferation of keratinocytes, which is problematic in eczema and psoriasis [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_110">110</xref>]. Dulal et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_111">111</xref>] reported that sandalwood oil restores and rejuvenates ageing and wrinkled skin. Sandalwood oil has anti-inflammatory activity as well as emollient used in skincare.</p> <p>All these pharmacological activities show the value of genus <italic>Santalum</italic> (<xref ref-type="fig" rid="j_znc-2022-0076_fig_004">Figure 4</xref>). Sandalwood or sandalwood oil can be used in medicine, cosmetology, and aromatherapy. These innovative materials can solve major issues or diseases such as diabetes, cardiovascular problems, infections of different types, cancer, and also help assist to maintain healthy and beautiful skin and a calm mind.</p> </sec> </sec> <sec id="j_znc-2022-0076_s_007"> <label>7</label> <title>Health-promoting effects: clinical studies</title> <p>Among all the <italic>Santalum</italic> species, the results of several preclinical studies on <italic>S. album</italic> revealed the vast variety of pharmaceutical properties of this valuable medicinal plant [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_061">61</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_091">91</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_094">94</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_112">112</xref>]. Although there are promising <italic>in vitro</italic> and <italic>in vivo</italic> research results on <italic>S. album</italic> oil that shows the high potential capacity of <italic>S. album</italic> oil to treat skin cancer, to date there are limited human studies. Although the available information on sandalwood oil toxicity is limited, it is considered safe due its long history of oral use without any reported adverse effects.</p> <p>Regarding skin safety, <italic>S. album</italic> oil has a good safety profile in terms of patch testing for contact dermatitis in both irritation and allergy. According to Burdock and Carabin [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_043">43</xref>]; undiluted <italic>S. album</italic> oil and 10% <italic>S. album</italic> oil are non-irritant. In five dermatology reports, some allergic reactions have been reported. Number of 12 out of 3,542 patients (0.34%) were sensitive to a 2% dilution of <italic>S. album</italic> oil, and in three reports, 69 of 5,595 patients (1.2%) exhibited sensitivity to a 10% dilution [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_113">113</xref>]. In a subsequent multicenter European study, 3 fragrance markers (FMs) (fragrance mix I, fragrance mix II, and Myroxylon pereirae) have been tested on consecutive patients to determine the frequency of positive patch-test reactions to EOs tested in the baseline. The result revealed that 656 of 48,956 dermatitis patients (1.38%) revealed positive reactions to 10% <italic>S. album</italic> oil [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_114">114</xref>].</p> <p>Skin inflammation and irritation, known as radiodermatitis, are common side effects in radiation therapy for cancer patients [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_115">115</xref>]. Radio dermatitis is associated with oxidative stress and an increase in cytokines, including interleukin (IL)-1β, IL-6, and IL-8 [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_116">116</xref>]. In a study conducted by [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_117">117</xref>]; the effectiveness of a turmeric and sandalwood oil containing proprietary cream [Vicco<sup>®</sup> turmeric cream (VTC); Vicco Laboratories, Parel, India] on radiodermatitis in patients with head and neck cancer undergoing radiotherapy have been assessed. In this nine-week open-label clinical study, the degree of radiodermatitis of 46 cancer patients experiencing radiotherapy, significantly inhibited (24 patients) compared to baby oil (22 patients) applying Vicco<sup>®</sup> cream containing 16% turmeric extract and 0.5% <italic>S. album</italic> oil [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_117">117</xref>]. In a similar study, the same product (Vicco<sup>®</sup>) exhibited significantly delayed and moderated on 40 breast cancer patients (20 in each group) radiodermatitis in the sandalwood/turmeric group compared to the control group [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_118">118</xref>].</p> <p>Based on four clinical trial projects on photoallergy testing, nine of 621 patients (1.45%) tested demonstrated positive effect to <italic>S. album</italic> oil at 2% [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_119">119</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_120">120</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_121">121</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_122">122</xref>]. It should be noted that photoallergy to EOs is very rare, and its clinical application was generally not established.</p> <p>The potential clinical anti-inflammatory action of sandalwood oil was tested in a clinical trial performed in 50 patients with mild to moderate facial acne for 8 weeks. This pilot study of a topical regimen treatment (foaming cleanser, serum, spot treatment, and mask) containing 0.5% salicylic acid and up to 2% <italic>S. album</italic> oil was conducted in teenage and adult subjects with mild to moderate facial acne [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_123">123</xref>]. For the eight-week treatment period, treatment was well tolerated by nearly all patients (42 of 47 participants (89.4%). Patients experienced an improvement when compared with baseline with notable reductions in lesion counts in patients with more severe or inflamed lesions, using the Global Aesthetic Improvement Scale (GAIS). There is no report of limitation of use of this regimen due to no adverse events [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_123">123</xref>].</p> <p>According to the literature, it is assumed that <italic>S. album</italic> oil might have therapeutic benefits to psoriasis patients due to its anti-inflammatory, antiproliferative properties via inducing autophagy and cell death in proliferating keratinocytes [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_124">124</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_125">125</xref>], [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_126">126</xref>]. A Phase 2 clinical trial results in patients with mild to moderate psoriasis illustrated that the topically applied 10% <italic>S. album</italic> oil serum administered twice a day for 28 days was well tolerated and alleviates mild to moderate psoriasis symptoms [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_127">127</xref>].</p> <p>In a pilot study, undiluted <italic>S. album</italic> oil to common warts twice daily for 12 weeks has been applied to ten candidates with the age range from six to adult. The results showed that 10 of the 12 (80%) participants had complete resolution of all treated warts over their hands, feet, legs, or face, with the other two subjects experiencing moderate improvement. There was no report of skin irritation, redness, pain or other adverse symptoms [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_128">128</xref>].</p> </sec> <sec id="j_znc-2022-0076_s_008"> <label>8</label> <title>Safety, adverse effects and therapeutic limitations</title> <p>Due to the chemical composition of the sandalwood, its EO is most popularly used in folk medicine, cosmetics, pharmacy, as well as the food industry. The list of internal and external health problems, in which the oils of <italic>Santalum</italic> plants are used, contains inter alia general weakness, headache and stomach ache, common colds, bronchitis, skin diseases such as infectious sores, ulcers, acne, and rashes, heart ailments, fever, infection of the urinary tract, and inflammation of the mouth [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_129">129</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_130">130</xref>].</p> <p>Just as the positive effect of EOs depend on their chemical composition, their safety and side effects result from the main phytochemicals and as well as the synergistic action of compounds that are present in lower concentrations. The main components present in the sandalwood EOs, that should be taken into the consideration regarding the safety are α-santalol, β-santalol, β-santalene, Z-α-trans-bergamotol [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_043">43</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_131">131</xref>].</p> <p>In the food industry, natural flavouring substances may be safely used in the products, meeting some criteria: must be used in the appropriate forms, in the minimum quantity required to produce their intended physical or technical effect, and following all the principles of the good manufacturing practice. Following this, the Food and Drug Administration (FDA) recommendation, a wide range of EO (clove, oregano, thyme, nutmeg, basil, mustard, and cinnamon) and components (linalool, thymol, eugenol, carvone, cinnamaldehyde, vanillin, carvacrol, citral) are classified as generally recognized as safe (GRAS) and have been accepted in the application in food products [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_132">132</xref>].</p> <p>According to the FDA, <italic>S. album</italic> is an accepted natural flavouring substance and can be used in the food industry in any kind of product, without restrictions.</p> <p>Although some limitations with the dosage of the <italic>S. album</italic> EOs are recommended. According to the data of Flavor and Extract Manufacturers Association (FEMA) published in the article of Burdock and Carabin [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_043">43</xref>] the maximum doses of sandalwood oil in alcoholic beverages should not exceed 0.77 ppm; in non-alcoholic beverages 1.96 ppm, hard candy 89.98 ppm, while in the case of baked products the maximum level is 9.72 ppm. Even though it is difficult to determine how much sandalwood EO is consumed with food by humans, National Academy of Sciences (NAS) data are estimated to 0.0074 mg/day or 0.000123 mg/kg/day sandalwood oil for 60 kg individual.</p> <p>On the other hand, FEMA reported that these values are 0.0058 mg/day and 0.0001 mg/kg/day, while the mean consumption of foods containing the usual amount- PADI (Possible Average Daily Intake) - is estimated to 0.97 mg/person/day or 0.016 mg/kg/day of sandalwood oil [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_043">43</xref>]. In general, the information on the safety and adverse effects of the genus <italic>Santalum</italic> is extremely limited.</p> <p>Even though the EOs are generally considered as safe, toxicological studies showed that some of them may be harmful to human health. Studies have been shown that different chemicals of EOs (menthol, carvone, limonene, citral, cinnamaldehyde, benzaldehyde, as well as methyl anthranilate, geranyl acetate, furfural, and eugneol) taken at high levels showed no carcinogenic effects [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_133">133</xref>]. Although low concentrations of EOs are usually devoid of mutagenicity and carcinogenicity, some single components or crude EOs may act as carcinogens. For example, estrogen-dependent malignancy can be induced by <italic>Salvia sclarea</italic> L. EOs, while estragole from <italic>Artemisia dracunculus</italic> L. shows carcinogenic potential in rodents. Following, psoralen (bergamia EOs) is photosensitive compound that may induce DNA adduct formation and skin cancer, while methyleugenol (<italic>Laurus nobilis</italic> L.) and D-limonene (citrus EOs) is being known as carcinogenic in rodents [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_134">134</xref>].</p> <p>The lethal dose (LD<sub>50</sub>) of the sandalwood EOs was evaluated for rats (5.58 g/kg body weight) and rabbits (&gt;5 g/kg BW, body weight). The LD<sub>50</sub> was also estimated for the major constituent of the EOs, α-santalol and the values for rats were 3.8 g/kg BW, and for rabbits &gt;5 g/kg BW. 3 mL/kg of α-bisabolol showed a reduction in fetal numbers in rats and rabbits, while 1 mL/kg showed no teratogenic effects [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_113">113</xref>].</p> <p>Interestingly, studies on the effects of the inhaled sandalwood oil have shown that female Swiss exposed to the oil for 1 h shown 40% decreased motility, and in the blood of these animals, α- and β-santalols were present [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_043">43</xref>, <xref ref-type="bibr" rid="j_znc-2022-0076_ref_135">135</xref>]. Some studies with animal models suggest that sandalwood EO can irritate rabbit skin, but it seems that this oil has no such effect on human skin [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_113">113</xref>]. The results of studies showed that sandalwood EO is characterized by low sensitization potential. In the work of Paulsen and Andersen [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_136">136</xref>] of 318 patients responded that 10% of sandalwood EOs gave a positive effect.</p> <p>At the same time, 2% concentration did not cause any negative effects on any of the respondents [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_136">136</xref>]. A total of 1.4% of all tested dentists and dental nurses responded to sandalwood oil in the case of the paper published by Kiec-swierczyńska and Krecisz [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_137">137</xref>]. A total of 0.9% of patients (total of 1606 patients) responded to 10% sandalwood oil, at the same time 0.4% of patients responded to 2% concentration [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_138">138</xref>].</p> <p>In the study with 641 patients with eczema, sandalwood oil had no response by any of the tested patients [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_139">139</xref>], while in the case of 422 patients with suspected contact allergy, 2.4% gave the positive response to sandalwood, and 3.1% to cinnamic alcohol [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_140">140</xref>]. Similar percentage results were obtained in the studies on the photoallergies’ caused by sandalwood oil. 2.2% (3 of 138 patients) were positive to sandalwood oil reaction in the study conducted by Fotiades et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_119">119</xref>] while 2 of 1050 probable photodermatitis patients (0.19%) in the study of Pigatto et al. [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_141">141</xref>].</p> <p>In general sandalwood, EOs are recognized as nontoxic in the matter of phototoxicity, but the suggested maximum dose of the <italic>S. album</italic> EO is 2% [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_113">113</xref>]. The results of the study with 4266 Japanese people with cosmetic dermatitis showed that 57 (1.34%) was positive to 2% α-santalol. This suggests that the concentration of the sandalwood EOs should be lower for people of Japanese origin [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_113">113</xref>]. In general, the use of sandalwood oil in eczema, psoriasis, radiation dermatitis, and antifungal is reported in the literature, and the EOs is well tolerated with acceptable safety [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_142">142</xref>]. What is more, the major constituent of <italic>S. album</italic> EOs, α-santalol is being recognized as a chemopreventive effect with nontoxic side effects against normal cells [<xref ref-type="bibr" rid="j_znc-2022-0076_ref_143">143</xref>].</p> </sec> <sec id="j_znc-2022-0076_s_009"> <label>9</label> <title>Conclusions and future perspectives</title> <p>The review highlighted the bioactive compounds present in the sandalwood and bioactivities of its extract proven by the <italic>in vivo</italic>, <italic>in vitro</italic> and clinical trials. The EO components such as α-santalol and β-santalol are considered important for evaluating the commercial value of the sandalwood. These components are responsible for most of the biological activities along with the soothing aroma of <italic>Santalum</italic> species. Traditional uses of the EO from sandalwood have been proven to be beneficial in treating somatic and other disorders such as common cold, fever, lung infection, and many types of inflammations. Antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, neuroleptic, antihyperglycemic, antihyperlipidemic, and anticancer activities of <italic>Santalum</italic> extracts have been recently proved through clinical trials. Recent scientific studies have not shown any adverse effect of consumption of sandalwood EO in <italic>in vivo</italic> trials. Hence, extracts from sandalwood are presently used in cosmetic products and as a flavouring agent in food items. More detailed studies are needed to decipher the exact molecular mechanism of the sandalwood extracts in improving human health. These molecular studies will also assist in delineating the more precise use of sandalwood extracts for human consumption. Exhaustive clinical studies are also needed to further promote the use of sandalwood ingredients in food and pharma application. Pharmaceutical formulation of the sandalwood extracts is another area that needs the attention of the scientific community to further improve the use of <italic>Santalum</italic> species in health promotion.</p> </sec> </body> <back> <ack id="j_znc-2022-0076_ack_001"> <title>Acknowledgements</title> <p>MM wants to thank ANID CENTROS BASALES ACE210012.</p> </ack> <fn-group> <fn id="j_znc-2022-0076_fn_001" fn-type="con"> <p> <bold>Author contributions:</bold> All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas that is, revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and confirming to be accountable for all aspects of the work.</p> </fn> <fn id="j_znc-2022-0076_fn_002" fn-type="financial-disclosure"> <p> <bold>Research funding:</bold> None declared.</p> </fn> <fn id="j_znc-2022-0076_fn_003" fn-type="other"> <p> <bold>Competing interest:</bold> The author declares no conflict of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.</p> </fn> <fn id="j_znc-2022-0076_fn_004" fn-type="other"> <p> <bold>Data availability:</bold> All supporting data for this manuscript are included in the figures and available from the corresponding authors on reasonable request.</p> </fn> </fn-group> <ref-list id="j_znc-2022-0076_reflist_001"> <title>References</title> <ref id="j_znc-2022-0076_ref_001"> <label>1.</label> <mixed-citation>Subasinghe, U. 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