Review of the Chemical Composition, Pharmacological Effects, Pharmacokinetics, and Quality Control of Boswellia carterii

Objective This review aimed to systematically summarize studies that investigated the bioactivities of compounds and extracts from Boswellia. Methods A literature review on the pharmacological properties and phytochemicals of B. carterii was performed. The information was retrieved from secondary databases such as PubMed, Chemical Abstracts Services (SciFinder), Google Scholar, and ScienceDirect. Results The various Boswellia extracts and compounds demonstrated pharmacological properties, such as anti-inflammatory, antitumour, and antioxidant activities. B. carterii exhibited a positive effect on the treatment and prevention of many ageing diseases, such as diabetes, cancer, cardiovascular disease, and neurodegenerative diseases. Conclusion Here, we highlight the pharmacological properties and phytochemicals of B. carterii and propose further evidence-based research on plant-derived remedies and compounds.


Introduction
Frankincense resin comes from the tree of the genus Boswellia (family Burseraceae). Boswellia resins are recorded in texts with their traditional medical practices in an ancient civilization such as ancient China, Persia, and India. It was subsequently included in Chinese Pharmacopoeia Volume I. B. carterii was firstly used as a traditional Chinese medicine for treating urticaria. Modern pharmacological studies confirmed that B. carterii could be not only anti-inflammation, antioxidation, antiviral, antimalarial, and antitumour, but also protect liver and nerve. 3-O-Acetyl-11keto-β-boswellic acid, 3α-acetoxy-8,24-dienetirucallic acid, and 3α-acetoxy-7,24-dienetirucallic acid are related to its anti-inflammatory effect. Incensole acetate plays an important role in its neuroprotective effect.
According to previous comments and reports [1][2][3][4], volatile oils and terpenes are the main components of B. carterii. However, although many chemical components have been isolated and identified from B. carterii, the toxicology and pharmacokinetic studies of Boswellia long-term use are lacking. Some review articles on B. carterii have been published, mainly concerning its chemical composition and pharmacological activity [1,[5][6][7][8][9]. In this review, we strictly analyze the current state of knowledge of phytochemistry, quality control, pharmacological effects, and pharmacokinetics. It is hoped that this review will fill the knowledge gap, complement the published review on its chemical composition and pharmacological activity, and provide support and perspectives on future research and clinical application of B. carterii.

Phytochemistry.
e chemical structure of B. carterii is primarily composed of terpenoids. A total of 304 compounds were identified, including 148 triterpenes, 94 diterpenes, and 62 compounds classified as volatile oils. All identified compounds are listed and numbered in Table 1.

Volatile Oil.
Volatile oil, also known as an essential oil, is a general term for a class of oily compounds with aromatic odors. It can volatilize at average temperature and can be distilled with water vapor. Volatile oil from B. carterii primarily contains monoterpenes, sesquiterpenes, and ester compounds. It is worth mentioning that the classification here does not contain volatile diterpenoids and triterpenes, and we have described them in the corresponding classification (Scheme 1).

Diterpenoid.
Diterpenoid refers to a group of compounds whose molecular skeleton contains four isoprene units and 20 carbon atoms.

Triterpenoid.
e triterpenoid is a terpenoid composed of 30 carbon atoms. According to the "Isoprene Rule," most triterpenes consist of the condensation of 6 isoprene units (30 carbons). It can be divided into tetracyclic triterpenoids and pentacyclic triterpenoids. Fifty-seven tetracyclic triterpenes and ninety-one pentacyclic triterpenes were identified from B. carterii.

Quality Control
It is vital that quality control is for the safety and effectiveness of traditional Chinese medicine (TCM). Many rapid, sensitive, and stable technologies have been applied for quality analysis of B. carterii. A thin-layer chromatography method is developed to differentiate and identify three crucial Boswellia species [11]. A total of twenty compounds, which contained two tricyclic diterpenes, twelve triterpenes, and six volatile oil, were detected by GC, GC/MS, SPME, TRSDMC [47], TLC, and HPLC. We summarized the information in Table 2.

Pharmacology
B. carterii has acted as an ethnodrug for a long history because of its pharmacological effects. Boswellia contains Evidence-Based Complementary and Alternative Medicine biologically active compounds that exhibit pharmacological activities (Table 3).

Antioxidant Effects.
Research on the antioxidative effects of B. carterii has focused on the compounds 3-O-acetyl-9, 11-dehydro-β-mastic acid [28] and alcohol extracts [56]. e antioxidative effects were observed by inhibiting 5lipoxygenase [28], scavenging oxygen free radicals [78], and inhibiting a significant increase in the lipid peroxidation marker malondialdehyde (MDA) [56]. Besides, the extracts from B. carterii showed antioxidant effects using the DPPHand ABTS-free radical scavenging methods [79].  Interestingly, the methanol fraction of the mastic-containing complex showed anti-inflammatory and antioxidant effects and promoted angiogenesis and epithelial regeneration in mice that had epithelial damage [79]. Oxidative damage is one of the causes of human ageing, and the antioxidant effect of frankincense helps to slow down this process.
Clinically, the combination of B. carterii, betaine, and inositol could reduce breast density, relieve pain in benign breast masses, reduce anxiety, and reduce masses in menopausal women [83][84][85]. Besides, B. carterii prolonged the survival of patients with lung cancer [86], reduced fatigue, enhanced vitality, and reduced insulin use in patients with pancreatic cancer [87]. B. carterii also exhibited a beneficial effect for patients with bilateral lung and metastatic bladder cancers [88].

Antiviral Effects.
e n-hexane-soluble mixture, MeOH extract, EtOAc-soluble mixture, n-BuOH-soluble mixture, water extract, and H 2 O-soluble mixture of B. carterii showed an antiviral effect by inhibiting the hepatitis C virus protease [67] and the Epstein-Barr virus early antigen [21].

Antimicrobial
Effects. An antimicrobial effect of B. carterii for bacteria (Gram-positive and Gram-negative) and fungi was associated with its essential oils and its smoke [68,69,89,90].

Neuroprotective Effects.
A neuroprotective effect has been associated with B. carterii extracts that demonstrated antidepressant properties, resistance to inflammation caused by cerebral ischemia, promotion of neurodevelopment, and resistance to Alzheimer's disease [81]. Research in this area has focused on incensole acetate and gum resin from Boswellia. e TPRV3 pathway was associated with the antidepressant effect of B. carterii [52,70]. e ability of B. carterii to promote nerve development may be related to its ability to increase CaMKII mRNA expression [71]. Incensole acetate reduced NF-κB activity, and GFAP expression in the brain [53] showed an antidepressant effect in acute and chronic treatment cases [91] and reduced the inflammatory response of nerve tissues via the NF-κB pathway [52]. Also, triterpene acids showed cytotoxicity in neuroblastoma [21].

Kidney Protective Effects.
Prophylactic treatments using B. carterii showed benefits in anti-acute and anti-chronic renal failure cases. Oral administration of B. carterii induced a reduction in serum creatinine, serum urea, blood urea nitrogen, and C-reactive protein activity [72].  e compounds and fractions of B. carterii promoted the transformation of peripheral blood lymphocytes, regulated the expression of lymphokines in mouse spleen cells, dose-dependently inhibited the expression of 1 cytokines, and dose-dependently promoted the expression of 2 cytokines [37]. Furthermore, acetyl-11-keto-β-boswellic acid, by preventing IL-1R-related kinase 1 phosphorylation and subsequently inhibiting STAT3 phosphorylation, affected the IL-1β signalling, thereby inhibiting 17 cell differentiation [73]. Moreover, it is interesting that the purified compounds showed carrier-dependent immunomodulation in vitro and that the purified compounds are less active than the total compounds [12].

Other
Effects. B. carterii compounds showed an effect on the lung cell structure of rats [74], affected the development of Callosobruchus species by increasing oxidative stress [47], and reduced the level of oxidation to promote cardiovascular protection [56].

Side Effects.
e side effects refer to the pharmacological effects of a drug beyond its therapeutic purpose following the application of a therapeutic amount of the drug. Understanding drug side effects is required to formulate a clinical medication plan and to avoid health risks. e side effects of B. carterii are primarily related to smokeinduced reproductive toxicity. Histopathological sections and ultrastructure of the testis and epididymis showed adverse effects on sperm development. Sperm counts, viability, and speed decreased in varying degrees, and the proportion of abnormal sperm increased. Fructose levels in epididymal fluid and prostate fluid were reduced, and also, a luteinizing hormone, testosterone, and follicle-stimulating hormone levels in plasma and protein were reduced [75,92]. Other studies have shown that sialic acid and carnitine in cauda epididymal plasma are reduced [76].

Discussion
e resins of B. carterii have been used for the treatment of inflammation-related diseases, such as traumatic injury and inflammatory pain in China for a long time. Recently, the traditional medicine had become a hot research topic, while more positive effects and other potential medical values have been found. In this study, we listed the isolated components of Boswellia resin by category according to previous research and summarized their pharmacological effect on a different model. e different components of Boswellia resin have found a series of beneficial effects on many diseases when applied in laboratory research, and some have been approved for clinical use. We hope more research about quality control, and the novel component can be conducted in the future.
Incensole acetate (IA) IA has shown potent TRPV3 agonists, which caused anti-anxiety-like and anti-depression-like behavioural effects, with changes in c-Fos activation in the brain [70] Anterior cerebral artery ligation-induced cerebral ischemic injury in C57BL/6 mice and TRPV 3-deficient mice Incensole acetate (IA) 0-50 mg/kg IA dose-dependently reduced the cerebral infarction area and the contents of TNF-α, IL-1β, and TGF-β in the brain of the model mice, the activity of NF-κB, and the expression of GFAP in the brain. e behavioural assessment found that IA dose-dependently reduced nerve damage. Interestingly, IA showed only partial neuroprotective effects in TRPV3-deficient mice [52] Evidence-Based Complementary and Alternative Medicine 31 IA (50 mg/kg) alleviated inflammation and neurodegeneration in the hippocampus by inhibiting the mRNA level of TNF-α and IL-1β after closed head injury. Incensole acetate induced a mild hypothermic effect, but it did not affect tissue oedema formation [52] HEK293 cells, female Sabra mice, wildtype C57BL/6, and TRPV3(KO) female mice Incensole acetate (IA) IA (50 mg/kg) regulated the expression of c-Fos in mice brain areas, including that related to anxiety and depression. IA (500 μM) activated TRPV3 channels as determined by calcium imaging. IA activated a TRPV3 current in HEK293 cells and relieved depression and anxiety in wild-type but not in TRPV3 KO mice [70] e mice fed by breast milk which was generated from the Boswellia-fed mice B. carterii Pregnancy or lactation mother mice receiving B. carterii injection upregulated CaMKII mRNA in the hippocampus of offspring, but no significant change in hippocampal CaMKIV mRNA expression [71] Kidney protective effects Oral adenine-induced chronic renal failure model in adult male albino rats ischemia-reperfusion injury-induced acute renal failure model in adult male albino rats

Conclusion
is article reviewed the research performed on the components of B. carterii in terms of quality control, phytochemistry, pharmacological effects (including side effects), and pharmacokinetics. We highlighted studies showing that frankincense exhibits anti-inflammatory, antitumour, and antioxidant activities, including some important organprotective effects on the heart, liver, and kidney. We also found that B. carterii exhibits a good effect on the treatment and prevention of geriatric diseases. e review also presented studies showing that pure compounds could exhibit 3-O-Acetyl-9,11-dehydro-β-boswellic acid 3-O-Acetyl-11-hydroxy-β-boswellic acid 3-O-Acetyl-11-keto-β-boswellic acid 11-Keto-β-boswellic acid Four compounds presented an inhibitory effect on Jack bean urease with IC50 of 6. 27, 9.21, 16.34, and 85.23 μmol/L, respectively. e inhibitory force may be because of the formation of appropriate hydrogen bonds and the hydrophobic interaction between 3-O-acetyl-9,11dehydro-β-boswellic acid and the urease active site [43] Callosobruchus chinensis (C. chinensis) and C. maculatus B. carterii essential oil (BEO) e essential oil showed toxicity to C. chinensis with LC50 and LC90 of 0.066 and 0.096 μL/mL, respectively. It expressed the same effect in C. maculatus with LC50 and LC90 of 0.050 and 0.075 μL/mL. BEO showed a concentration-dependent inhibitory effect on its spawning, growth, and development behaviour. It was found that the essential oil induced an increase in the levels of ROS, SOD, and CAT in pests. It also decreased the level of GSH and GSH/GSSG [47] Wistar male albino rats Alcohol extract of olibanum At a concentration of 1,000 μg/kg, the alcohol extract of olibanum, advertising dose-dependence NOscavenging action, resulted in a marked increase in the serum levels of LDH, AST, and CK-MB, as well as MDA [56] Side effects Male albino rat Boswellic smoke Histopathological sections and ultrastructure of the testis showed adverse effects on sperm development. Sperm analysis revealed that sperm counts, viability, and speed decreased in varying degrees, and the proportion of abnormal sperm increased [75] Wistar male albino rat Boswellic smoke e smoke resulted that fructose levels in epididymal fluid and prostate fluid were decreased. e histopathological sections and morphological analysis of the epididymis showed an adverse effect on sperm development [75] Wistar male albino rat Boswellic smoke e smoke caused a decrease in follicle-stimulating hormone, luteinizing hormone, testosterone and protein, sialic acid, and carnitine. Also, the smoke resulted in a decrease in sperm count, reduced vitality, and reduced speed. e testicular ultrastructure showed adverse changes to sperm [76] lower immunomodulatory activities than the crude extract, with some progress being made in identifying the mechanisms involved. However, we found that some studies did not investigate relevant toxicology and pharmacokinetic aspects. Furthermore, the studies did not provide an in-depth evaluation of the bioactivity of the extracts and the isolated compounds, or in vivo experiments that might indicate therapeutic relevance. Based on the above research and deficiencies, clinicians should remain cautious when using this plant as a therapeutic drug until further research demonstrates the safety, quality, and efficacy of B. carterii. As such, extensive pharmacological and chemical experiments, including human metabolism studies, require future investigations.

Data Availability
A literature review on the pharmacological properties and phytochemicals of B. carterii was performed. e information was retrieved from secondary databases such as PubMed, Chemical Abstracts Services (SciFinder), Google Scholar, and ScienceDirect.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
KH conceptualized the idea. KH conducted the literature survey and edited the manuscript. YRC provided input during preparation and edited the manuscript. Xiaoyan Xu submitted the manuscript. KYL and Xiaoyan Xu provided input during preparation and edited the manuscript. FHZ and MHL provided guide and technical support. Kai Huang and Yanrong Chen contributed equally to this work.